Hematologic Malignancies

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

A version of this article first appeared on Medscape.com.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

A version of this article first appeared on Medscape.com.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

A version of this article first appeared on Medscape.com.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Paraneoplastic syndrome is a rare disorder involving manifestations of immune dysregulation triggered by malignancy. The immune system develops antibodies to the malignancy, which can cause cross reactivation with various tissues in the body, resulting in an autoimmune response. Paraneoplastic cerebellar degeneration (PCD) is a rare condition caused by immune-mediated damage to the Purkinje cells of the cerebellar tract. Symptoms may include gait instability, double vision, decreased fine motor skills, and ataxia, with progression to brainstem-associated symptoms, such as nystagmus, dysarthria, and dysphagia. Early detection and treatment of the underlying malignancy is critical to halt the progression of autoimmune-mediated destruction. We present a case of a young adult female patient with PCD caused by Purkinje cell cytoplasmic–Tr (PCA-Tr) antibody with Hodgkin lymphoma.

Case Presentation

A 20-year-old previously healthy active-duty female patient presented to the emergency department with acute worsening of chronic intermittent, recurrent episodes of lightheadedness and vertigo. Symptoms persisted for 9 months until acutely worsening over the 2 weeks prior to presentation. She reported left eye double vision but did not report seeing spots, photophobia, tinnitus, or headache. She felt off-balance, leaning on nearby objects to remain standing. Symptoms primarily occurred during ambulation; however, occasionally they happened at rest. Episodes lasted up to several minutes and occurred up to 15 times a day. The patient reported no fever, night sweats, unexplained weight loss, muscle aches, weakness, numbness or tingling, loss of bowel or bladder function, or rash. She had no recent illnesses, changes to medications, or recent travel. Oral intake to include food and water was adequate and unchanged. The patient had a remote history of mild concussions without loss of consciousness while playing sports 4 years previously. She reported no recent trauma. Nine months before, she received treatment for benign paroxysmal positional vertigo (BPPV) with the Epley maneuver with full resolution of symptoms lasting several days. She reported no prescription or over-the-counter medications, herbal remedies, or supplements. She reported no other medical or surgical history and no pertinent social or family history.

Physical examination revealed a nontoxic-appearing female patient with intermittent conversational dysarthria, saccadic pursuits, horizontal nystagmus with lateral gaze, and vertical nystagmus with vertical gaze. The patient exhibited dysdiadochokinesia, or impaired ability to perform rapid alternating hand movements with repetition. Finger-to-nose testing was impaired and heel-to-shin motion remained intact. A Romberg test was positive, and the patient had tandem gait instability. Strength testing, sensation, reflexes, and cranial nerves were otherwise intact. Initial laboratory testing was unremarkable except for mild normocytic anemia. Her infectious workup, including testing for venereal disease, HIV, COVID-19, and Coccidioidies was negative. Heavy metals analysis and urine drug screen were negative. Ophthalmology was consulted and workup revealed small amplitude downbeat nystagmus in primary gaze, sustained gaze evoked lateral beating jerk nystagmus with rebound nystagmus R>L gaze, but there was no evidence of afferent package defect and optic nerve function remained intact. Magnetic resonance imaging of the brain demonstrated cerebellar vermis hypoplasia with prominence of the superior cerebellar folia. Due to concerns for autoimmune encephalitis, a lumbar puncture was performed. Antibody testing revealed PCA-Tr antibodies, which is commonly associated with Hodgkin lymphoma, prompting further evaluation for malignancy.

Computed tomography (CT) of the chest with contrast demonstrated multiple mediastinal masses with a conglomeration of lymph nodes along the right paratracheal region. Further evaluation was performed with a positron emission tomography (PET)–CT, revealing a large conglomeration of hypermetabolic pretracheal, mediastinal, and right supraclavicular lymph that were suggestive of lymphoma. Mediastinoscopy with excisional lymph node biopsy was performed with immunohistochemical staining confirming diagnosis of a nodular sclerosing variant of Hodgkin lymphoma. The patient was treated with IV immunoglobulin at 0.4g/kg daily for 5 days. A central venous catheter was placed into the patient’s right internal jugular vein and a chemotherapy regimen of doxorubicin 46 mg, vinblastine 11 mg, bleomycin 19 units, and dacarbazine 700 mg was initiated. The patient’s symptoms improved with resolution of dysarthria; however, her visual impairment and gait instability persisted. Repeat PET-CT imaging 2 months later revealed interval improvement with decreased intensity and extent of the hypermetabolic lymph nodes and no new hypermetabolic foci.

Discussion

PCA-Tr antibodies affect the delta/notchlike epidermal growth factor–related receptor, expressed on the dendrites of cerebellar Purkinje cells.¹ These fibers are the only output neurons of the cerebellar cortex and are critical to the coordination of motor movements, accounting for the ataxia experienced by patients with this subtype of PCD.² The link between Hodgkin lymphoma and PCA-Tr antibodies has been established; however, most reports involve men with a median age of 61 years with lymphoma-associated symptoms (such as lymphadenopathy) or systemic symptoms (fever, night sweats, or weight loss) preceding neurologic manifestations in 80% of cases.³

Our patient was a young, previously healthy adult female who initially presented with vertigo, a common concern with frequently benign origins. Although there was temporary resolution of symptoms after Epley maneuvers, symptoms recurred and progressed over several months to include brainstem manifestations of nystagmus, diplopia, and dysarthria. Previous reports indicate that after remission of the Hodgkin lymphoma, PCA-Tr antibodies disappear and symptoms can improve or resolve.^4,5 Treatment has just begun for our patient and although there has been initial clinical improvement, given the chronicity of symptoms, it is unclear if complete resolution will be achieved.

Conclusions

PCD can result in debilitating neurologic dysfunction and may be associated with malignancy such as Hodgkin lymphoma. This case offers unique insight due to the patient’s demographics and presentation, which involved brainstem pathology typically associated with late-onset disease and preceded by constitutional symptoms. Clinical suspicion of this rare disorder should be considered in all ages, especially if symptoms are progressive or neurologic manifestations arise, as early detection and treatment of the underlying malignancy are paramount to the prevention of significant disability.

Pancytopenia is a condition in which all 3 hematologic cell lines are lower than expected in the blood, often representing either an increase in cellular destruction or decrease in bone marrow production. Destruction often occurs in the setting of autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis) or splenic sequestration, often affecting erythrocytes and platelets more than leukocytes. Decreased production represents central etiologies, which are often due to nutritional deficiencies, infections, drug toxicities, or malabsorption.¹ Pancytopenia secondary to vitamin B₁₂ deficiency is rare, accounting for about 5% of the hematologic manifestations of symptomatic vitamin B₁₂ deficient patients.²

Pernicious anemia, named for a once lethal disease, is a form of vitamin B₁₂ (cobalamin) deficiency that results from an autoimmune (type II hypersensitivity) reaction to gastric parietal cells or intrinsic factor. Antibodies bind to gastric parietal cells and reduce gastric acid production, leading to atrophic gastritis, or they bind intrinsic factor and block the binding and absorption of vitamin B₁₂ in the gastrointestinal tract. While first described in the 1820s, it was not until a century later when scientists were studying hematopoiesis in response to the heavy casualty burden from battlefield exsanguination in World War I that dogs fed raw liver were noted to have significantly better blood regeneration response than those fed cooked liver. This discovery led physicians Minot and Murphy to use raw liver to treat pernicious anemia and found that jaundice improved, reticulocyte counts increased, and hemoglobin (Hb) concentration improved, resulting in the duo becoming the first American recipients of the Nobel Prize in physiology or medicine.³ It was ultimately determined in 1948 by chemists Folkers and Todd that the active ingredient in raw liver responsible for this phenomenon was vitamin B₁₂.⁴

Case Presentation

A 24-year-old active-duty female patient presented in late December 2020 to a theater hospital in Djibouti after a witnessed syncopal episode. She had a history of Hashimoto thyroiditis and was taking levothyroxine sodium 75 mcg daily. The patient reported gluten intolerance, which was never formally evaluated. The syncopal episode lasted a few seconds and was not associated with any prodromal or postictal symptoms. No seizure activity was observed, and she had no history of syncopal episodes. She reported that she had been feeling ill 24 to 48 hours prior, with nausea, fatigue, decreased oral intake, decreased urine output, and 2 episodes of nonbilious, nonbloody emesis.

When the patient arrived, she was tachycardic with heart rate in the 130s beats per minute (baseline, 100-110 beats per minute), febrile (103 °F), and had systolic blood pressure (SBP) in the low 100s (baseline, SBP 120s-130s). An electrocardiogram and chest radiographs were unremarkable. Her complete blood count (CBC) could not be processed due to Hb and platelet levels too low to detect on assay (Table 2). Lactate dehydrogenase (LDH) was elevated at > 1000 U/L with mild elevation in liver enzymes (aspartate aminotransferase, 98 U/L; alanine aminotransferase, 51 U/L) and prolonged partial thromboplastin time 70 seconds. She did not report any increased bleeding or bruising. The peripheral blood smear demonstrated pancytopenia, without any schistocytes, and she was started on broad-spectrum antibiotics for presumed sepsis from urinary source and possible TTP.

The patient received 5 units of packed red blood cells, transfusion of platelets, and 2 doses of vitamin B₁₂ in Djibouti with clinical improvement and resolution of orthostasis, hypotension, tachycardia, and fever. Her final posttransfusion CBC showed a Hb level of 11.2 g/dL, white blood cell (WBC) count of 1.7 K/µL, and platelet count of 23 K/µL (Table 3). Two days later her Hb level was 9.0 g/dL, WBC count 1.8 K/µL, and platelet count was 12 K/µL. She was evacuated via air to Landstuhl Regional Medical Center (LRMC) in Germany within 48 hours of presentation, given limited testing capabilities and persistent anemia and thrombocytopenia, refractory to transfusion, concerning for aplastic anemia or acute leukemia.

On arrival at LRMC, she was transfused 1 unit of platelets and given 3 doses of intramuscular vitamin B₁₂ for undetectable levels (< 50 pg/mL) at presentation. An extensive infectious workup was obtained, which did not reveal any viral, bacterial, or parasitic causes. The patient also had a bone marrow biopsy performed at a civilian site, which revealed hypocellular bone marrow. She was transferred to Walter Reed National Military Medical Center (WRNMMC) for further workup and evaluation, given the infectious workup, which was negative. Concern for hematologic malignancy remained. At the time of her arrival, the laboratory values had drastically improved with vitamin supplementation. The patient’s absolute reticulocyte count indicated adequate bone marrow response and because of her improvement, a repeat bone marrow biopsy was not performed.

Intrinsic factor antibodies were elevated (34.5 AU/mL; reference range, 0.0-1.1), which confirmed that this patient’s underlying etiology was secondary to pernicious anemia. The patient continued to improve and repeat vitamin B₁₂ and folate levels revealed that she was responding to therapy. At discharge, intramuscular vitamin B₁₂ injections were planned to continue monthly, indefinitely per guidelines. Oral supplementation is typically avoided due to poor absorption.

Of note, during her inpatient admission at WRNMMC, further evaluation of reported gluten intolerance was performed, which revealed a negative celiac disease panel (IgG/IgA tissue transglutaminase antibodies). On discharge, she was to establish care with gastroenterology for further evaluation, likely including endoscopic evaluation, at her next duty station. She was able to resume full travel and duty functions on discharge from WRNMMC.

Discussion

We highlight a complex case of pancytopenia secondary to pernicious anemia in a deployed service member. With limited resources downrange, the workup of pancytopenia can be resource intensive, expensive, and time sensitive, which can have detrimental impacts on medical readiness. Additionally, undiagnosed coagulopathies can have lethal consequences in a deployed service member where bleeding risk may be elevated depending on the mission. The differential for pancytopenia is vast, and given its relative rarity in pernicious anemia, the HCP must use key components of the history and laboratory results to narrow the differential (eAppendix).¹⁰

Pernicious anemia commonly presents as an isolated anemia. In a study looking at the hematologic manifestations of 201 cohort patients with well-documented vitamin B₁₂ deficiency, 5% had symptomatic pancytopenia and 1.5% had a hemolytic anemia.² The majority (> 67%) of hematologic abnormalities were correctable with cobalamin replacement.² In our case, the solider presented with symptomatic anemia, manifesting as syncope, and was found to have transfusion-resistant pancytopenia.She had a hemolytic anemia with an LDH > 1000 U/L, haptoglobin < 3 mg/dL, and mild transaminitis with hyperbilirubinemia (1.8 mg/dL). No schistocytes were observed on peripheral smear, suggesting intramedullary hemolysis, which is believed to be due to the destruction of megaloblastic cells by macrophages in bone marrow.¹¹ A French study found high LDH levels and low reticulocyte counts to be strongly suggestive of vitamin B₁₂ deficiency and helpful in differentiating pernicious anemia from TTP, given that bone marrow response to anemia in TTP is preserved.⁸

While vitamin B₁₂ deficiency is not often associated with hemolytic anemia, multiple cases have been reported in the literature.⁶ Screening for vitamin B₁₂ deficiency may have shortened this patient’s clinical course and limited the need for air evacuation to a stateside quaternary medical center. However, testing for cobalamin levels in overseas deployed environments is difficult, timely, and costly. New technologies, such as optical sensors, can detect vitamin B₁₂ levels in the blood in < 1 minute and offer portable, low-cost options that may be useful in the deployed military setting.¹²

Diet plays a key role in this case, since the patient had a reported history of gluten intolerance, although it was never documented or evaluated prior to this presentation. Prior to deployment, the patient ate mostly rice, potatoes, and vegetables. While deployed in an austere environment, food options were limited. These conditions forced her to intermittently consume gluten products, which led to gastrointestinal issues, exacerbating her nutritional deficiencies. In the 2 months before her first syncopal episode, she reported worsening fatigue that impacted her ability to exercise. Vitamin B₁₂ stores often take years to deplete, suggesting that she had a chronic nutritional deficiency before deployment. Another possibility was that she developed an autoimmune gastritis that acutely worsened in the setting of poor nutritional intake. Her history of Hashimoto thyroiditis is also important, as up to one-third of patients with autoimmune thyroid disease have been associated with pernicious anemia (range, 3%-32%) with certain shared human leukocyte antigen alleles implicated in autoimmune gastritis.^13,14

Conclusions

This rare case of pernicious anemia presenting as pancytopenia illustrates the challenge in working up pancytopenia, especially in austere military environments with limited testing capabilities. Screening for chronic dietary and nutritional deficiency is important in a service member, raising the question of what role predeployment screening may have and what dietary accommodations may be available during overseas deployments, which can potentially dampen inflammation of the gastrointestinal tract, especially for those with preexisting autoimmune gastrointestinal conditions. Also, newer technology allows portable, low-cost testing of cobalamin and may aid in its diagnosis. In patients who are anemic with low vitamin B₁₂, HCPs can begin vitamin B₁₂ supplementation while continuing the workup (eg, antibody testing, endoscopy). If the patient responds appropriately, further workup becomes less urgent, therefore, decreasing resource use and increasing military readiness. When hemolysis is present, a low reticulocyte count can be beneficial to help differentiate this condition from TTP, a life-threatening condition that must also be ruled out or treated. Pernicious anemia should be on the differential in any patients with autoimmune conditions presenting with cytopenias, especially in those with a history of autoimmune thyroid disorders.

Pancytopenia is a condition in which all 3 hematologic cell lines are lower than expected in the blood, often representing either an increase in cellular destruction or decrease in bone marrow production. Destruction often occurs in the setting of autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis) or splenic sequestration, often affecting erythrocytes and platelets more than leukocytes. Decreased production represents central etiologies, which are often due to nutritional deficiencies, infections, drug toxicities, or malabsorption.¹ Pancytopenia secondary to vitamin B₁₂ deficiency is rare, accounting for about 5% of the hematologic manifestations of symptomatic vitamin B₁₂ deficient patients.²

Pernicious anemia, named for a once lethal disease, is a form of vitamin B₁₂ (cobalamin) deficiency that results from an autoimmune (type II hypersensitivity) reaction to gastric parietal cells or intrinsic factor. Antibodies bind to gastric parietal cells and reduce gastric acid production, leading to atrophic gastritis, or they bind intrinsic factor and block the binding and absorption of vitamin B₁₂ in the gastrointestinal tract. While first described in the 1820s, it was not until a century later when scientists were studying hematopoiesis in response to the heavy casualty burden from battlefield exsanguination in World War I that dogs fed raw liver were noted to have significantly better blood regeneration response than those fed cooked liver. This discovery led physicians Minot and Murphy to use raw liver to treat pernicious anemia and found that jaundice improved, reticulocyte counts increased, and hemoglobin (Hb) concentration improved, resulting in the duo becoming the first American recipients of the Nobel Prize in physiology or medicine.³ It was ultimately determined in 1948 by chemists Folkers and Todd that the active ingredient in raw liver responsible for this phenomenon was vitamin B₁₂.⁴

Case Presentation

A 24-year-old active-duty female patient presented in late December 2020 to a theater hospital in Djibouti after a witnessed syncopal episode. She had a history of Hashimoto thyroiditis and was taking levothyroxine sodium 75 mcg daily. The patient reported gluten intolerance, which was never formally evaluated. The syncopal episode lasted a few seconds and was not associated with any prodromal or postictal symptoms. No seizure activity was observed, and she had no history of syncopal episodes. She reported that she had been feeling ill 24 to 48 hours prior, with nausea, fatigue, decreased oral intake, decreased urine output, and 2 episodes of nonbilious, nonbloody emesis.

When the patient arrived, she was tachycardic with heart rate in the 130s beats per minute (baseline, 100-110 beats per minute), febrile (103 °F), and had systolic blood pressure (SBP) in the low 100s (baseline, SBP 120s-130s). An electrocardiogram and chest radiographs were unremarkable. Her complete blood count (CBC) could not be processed due to Hb and platelet levels too low to detect on assay (Table 2). Lactate dehydrogenase (LDH) was elevated at > 1000 U/L with mild elevation in liver enzymes (aspartate aminotransferase, 98 U/L; alanine aminotransferase, 51 U/L) and prolonged partial thromboplastin time 70 seconds. She did not report any increased bleeding or bruising. The peripheral blood smear demonstrated pancytopenia, without any schistocytes, and she was started on broad-spectrum antibiotics for presumed sepsis from urinary source and possible TTP.

The patient received 5 units of packed red blood cells, transfusion of platelets, and 2 doses of vitamin B₁₂ in Djibouti with clinical improvement and resolution of orthostasis, hypotension, tachycardia, and fever. Her final posttransfusion CBC showed a Hb level of 11.2 g/dL, white blood cell (WBC) count of 1.7 K/µL, and platelet count of 23 K/µL (Table 3). Two days later her Hb level was 9.0 g/dL, WBC count 1.8 K/µL, and platelet count was 12 K/µL. She was evacuated via air to Landstuhl Regional Medical Center (LRMC) in Germany within 48 hours of presentation, given limited testing capabilities and persistent anemia and thrombocytopenia, refractory to transfusion, concerning for aplastic anemia or acute leukemia.

On arrival at LRMC, she was transfused 1 unit of platelets and given 3 doses of intramuscular vitamin B₁₂ for undetectable levels (< 50 pg/mL) at presentation. An extensive infectious workup was obtained, which did not reveal any viral, bacterial, or parasitic causes. The patient also had a bone marrow biopsy performed at a civilian site, which revealed hypocellular bone marrow. She was transferred to Walter Reed National Military Medical Center (WRNMMC) for further workup and evaluation, given the infectious workup, which was negative. Concern for hematologic malignancy remained. At the time of her arrival, the laboratory values had drastically improved with vitamin supplementation. The patient’s absolute reticulocyte count indicated adequate bone marrow response and because of her improvement, a repeat bone marrow biopsy was not performed.

Intrinsic factor antibodies were elevated (34.5 AU/mL; reference range, 0.0-1.1), which confirmed that this patient’s underlying etiology was secondary to pernicious anemia. The patient continued to improve and repeat vitamin B₁₂ and folate levels revealed that she was responding to therapy. At discharge, intramuscular vitamin B₁₂ injections were planned to continue monthly, indefinitely per guidelines. Oral supplementation is typically avoided due to poor absorption.

Of note, during her inpatient admission at WRNMMC, further evaluation of reported gluten intolerance was performed, which revealed a negative celiac disease panel (IgG/IgA tissue transglutaminase antibodies). On discharge, she was to establish care with gastroenterology for further evaluation, likely including endoscopic evaluation, at her next duty station. She was able to resume full travel and duty functions on discharge from WRNMMC.

Discussion

We highlight a complex case of pancytopenia secondary to pernicious anemia in a deployed service member. With limited resources downrange, the workup of pancytopenia can be resource intensive, expensive, and time sensitive, which can have detrimental impacts on medical readiness. Additionally, undiagnosed coagulopathies can have lethal consequences in a deployed service member where bleeding risk may be elevated depending on the mission. The differential for pancytopenia is vast, and given its relative rarity in pernicious anemia, the HCP must use key components of the history and laboratory results to narrow the differential (eAppendix).¹⁰

Pernicious anemia commonly presents as an isolated anemia. In a study looking at the hematologic manifestations of 201 cohort patients with well-documented vitamin B₁₂ deficiency, 5% had symptomatic pancytopenia and 1.5% had a hemolytic anemia.² The majority (> 67%) of hematologic abnormalities were correctable with cobalamin replacement.² In our case, the solider presented with symptomatic anemia, manifesting as syncope, and was found to have transfusion-resistant pancytopenia.She had a hemolytic anemia with an LDH > 1000 U/L, haptoglobin < 3 mg/dL, and mild transaminitis with hyperbilirubinemia (1.8 mg/dL). No schistocytes were observed on peripheral smear, suggesting intramedullary hemolysis, which is believed to be due to the destruction of megaloblastic cells by macrophages in bone marrow.¹¹ A French study found high LDH levels and low reticulocyte counts to be strongly suggestive of vitamin B₁₂ deficiency and helpful in differentiating pernicious anemia from TTP, given that bone marrow response to anemia in TTP is preserved.⁸

While vitamin B₁₂ deficiency is not often associated with hemolytic anemia, multiple cases have been reported in the literature.⁶ Screening for vitamin B₁₂ deficiency may have shortened this patient’s clinical course and limited the need for air evacuation to a stateside quaternary medical center. However, testing for cobalamin levels in overseas deployed environments is difficult, timely, and costly. New technologies, such as optical sensors, can detect vitamin B₁₂ levels in the blood in < 1 minute and offer portable, low-cost options that may be useful in the deployed military setting.¹²

Diet plays a key role in this case, since the patient had a reported history of gluten intolerance, although it was never documented or evaluated prior to this presentation. Prior to deployment, the patient ate mostly rice, potatoes, and vegetables. While deployed in an austere environment, food options were limited. These conditions forced her to intermittently consume gluten products, which led to gastrointestinal issues, exacerbating her nutritional deficiencies. In the 2 months before her first syncopal episode, she reported worsening fatigue that impacted her ability to exercise. Vitamin B₁₂ stores often take years to deplete, suggesting that she had a chronic nutritional deficiency before deployment. Another possibility was that she developed an autoimmune gastritis that acutely worsened in the setting of poor nutritional intake. Her history of Hashimoto thyroiditis is also important, as up to one-third of patients with autoimmune thyroid disease have been associated with pernicious anemia (range, 3%-32%) with certain shared human leukocyte antigen alleles implicated in autoimmune gastritis.^13,14

Conclusions

This rare case of pernicious anemia presenting as pancytopenia illustrates the challenge in working up pancytopenia, especially in austere military environments with limited testing capabilities. Screening for chronic dietary and nutritional deficiency is important in a service member, raising the question of what role predeployment screening may have and what dietary accommodations may be available during overseas deployments, which can potentially dampen inflammation of the gastrointestinal tract, especially for those with preexisting autoimmune gastrointestinal conditions. Also, newer technology allows portable, low-cost testing of cobalamin and may aid in its diagnosis. In patients who are anemic with low vitamin B₁₂, HCPs can begin vitamin B₁₂ supplementation while continuing the workup (eg, antibody testing, endoscopy). If the patient responds appropriately, further workup becomes less urgent, therefore, decreasing resource use and increasing military readiness. When hemolysis is present, a low reticulocyte count can be beneficial to help differentiate this condition from TTP, a life-threatening condition that must also be ruled out or treated. Pernicious anemia should be on the differential in any patients with autoimmune conditions presenting with cytopenias, especially in those with a history of autoimmune thyroid disorders.

Pancytopenia is a condition in which all 3 hematologic cell lines are lower than expected in the blood, often representing either an increase in cellular destruction or decrease in bone marrow production. Destruction often occurs in the setting of autoimmune conditions (eg, systemic lupus erythematosus, rheumatoid arthritis) or splenic sequestration, often affecting erythrocytes and platelets more than leukocytes. Decreased production represents central etiologies, which are often due to nutritional deficiencies, infections, drug toxicities, or malabsorption.¹ Pancytopenia secondary to vitamin B₁₂ deficiency is rare, accounting for about 5% of the hematologic manifestations of symptomatic vitamin B₁₂ deficient patients.²

Pernicious anemia, named for a once lethal disease, is a form of vitamin B₁₂ (cobalamin) deficiency that results from an autoimmune (type II hypersensitivity) reaction to gastric parietal cells or intrinsic factor. Antibodies bind to gastric parietal cells and reduce gastric acid production, leading to atrophic gastritis, or they bind intrinsic factor and block the binding and absorption of vitamin B₁₂ in the gastrointestinal tract. While first described in the 1820s, it was not until a century later when scientists were studying hematopoiesis in response to the heavy casualty burden from battlefield exsanguination in World War I that dogs fed raw liver were noted to have significantly better blood regeneration response than those fed cooked liver. This discovery led physicians Minot and Murphy to use raw liver to treat pernicious anemia and found that jaundice improved, reticulocyte counts increased, and hemoglobin (Hb) concentration improved, resulting in the duo becoming the first American recipients of the Nobel Prize in physiology or medicine.³ It was ultimately determined in 1948 by chemists Folkers and Todd that the active ingredient in raw liver responsible for this phenomenon was vitamin B₁₂.⁴

Case Presentation

A 24-year-old active-duty female patient presented in late December 2020 to a theater hospital in Djibouti after a witnessed syncopal episode. She had a history of Hashimoto thyroiditis and was taking levothyroxine sodium 75 mcg daily. The patient reported gluten intolerance, which was never formally evaluated. The syncopal episode lasted a few seconds and was not associated with any prodromal or postictal symptoms. No seizure activity was observed, and she had no history of syncopal episodes. She reported that she had been feeling ill 24 to 48 hours prior, with nausea, fatigue, decreased oral intake, decreased urine output, and 2 episodes of nonbilious, nonbloody emesis.

When the patient arrived, she was tachycardic with heart rate in the 130s beats per minute (baseline, 100-110 beats per minute), febrile (103 °F), and had systolic blood pressure (SBP) in the low 100s (baseline, SBP 120s-130s). An electrocardiogram and chest radiographs were unremarkable. Her complete blood count (CBC) could not be processed due to Hb and platelet levels too low to detect on assay (Table 2). Lactate dehydrogenase (LDH) was elevated at > 1000 U/L with mild elevation in liver enzymes (aspartate aminotransferase, 98 U/L; alanine aminotransferase, 51 U/L) and prolonged partial thromboplastin time 70 seconds. She did not report any increased bleeding or bruising. The peripheral blood smear demonstrated pancytopenia, without any schistocytes, and she was started on broad-spectrum antibiotics for presumed sepsis from urinary source and possible TTP.

The patient received 5 units of packed red blood cells, transfusion of platelets, and 2 doses of vitamin B₁₂ in Djibouti with clinical improvement and resolution of orthostasis, hypotension, tachycardia, and fever. Her final posttransfusion CBC showed a Hb level of 11.2 g/dL, white blood cell (WBC) count of 1.7 K/µL, and platelet count of 23 K/µL (Table 3). Two days later her Hb level was 9.0 g/dL, WBC count 1.8 K/µL, and platelet count was 12 K/µL. She was evacuated via air to Landstuhl Regional Medical Center (LRMC) in Germany within 48 hours of presentation, given limited testing capabilities and persistent anemia and thrombocytopenia, refractory to transfusion, concerning for aplastic anemia or acute leukemia.

On arrival at LRMC, she was transfused 1 unit of platelets and given 3 doses of intramuscular vitamin B₁₂ for undetectable levels (< 50 pg/mL) at presentation. An extensive infectious workup was obtained, which did not reveal any viral, bacterial, or parasitic causes. The patient also had a bone marrow biopsy performed at a civilian site, which revealed hypocellular bone marrow. She was transferred to Walter Reed National Military Medical Center (WRNMMC) for further workup and evaluation, given the infectious workup, which was negative. Concern for hematologic malignancy remained. At the time of her arrival, the laboratory values had drastically improved with vitamin supplementation. The patient’s absolute reticulocyte count indicated adequate bone marrow response and because of her improvement, a repeat bone marrow biopsy was not performed.

Intrinsic factor antibodies were elevated (34.5 AU/mL; reference range, 0.0-1.1), which confirmed that this patient’s underlying etiology was secondary to pernicious anemia. The patient continued to improve and repeat vitamin B₁₂ and folate levels revealed that she was responding to therapy. At discharge, intramuscular vitamin B₁₂ injections were planned to continue monthly, indefinitely per guidelines. Oral supplementation is typically avoided due to poor absorption.

Of note, during her inpatient admission at WRNMMC, further evaluation of reported gluten intolerance was performed, which revealed a negative celiac disease panel (IgG/IgA tissue transglutaminase antibodies). On discharge, she was to establish care with gastroenterology for further evaluation, likely including endoscopic evaluation, at her next duty station. She was able to resume full travel and duty functions on discharge from WRNMMC.

Discussion

We highlight a complex case of pancytopenia secondary to pernicious anemia in a deployed service member. With limited resources downrange, the workup of pancytopenia can be resource intensive, expensive, and time sensitive, which can have detrimental impacts on medical readiness. Additionally, undiagnosed coagulopathies can have lethal consequences in a deployed service member where bleeding risk may be elevated depending on the mission. The differential for pancytopenia is vast, and given its relative rarity in pernicious anemia, the HCP must use key components of the history and laboratory results to narrow the differential (eAppendix).¹⁰

Pernicious anemia commonly presents as an isolated anemia. In a study looking at the hematologic manifestations of 201 cohort patients with well-documented vitamin B₁₂ deficiency, 5% had symptomatic pancytopenia and 1.5% had a hemolytic anemia.² The majority (> 67%) of hematologic abnormalities were correctable with cobalamin replacement.² In our case, the solider presented with symptomatic anemia, manifesting as syncope, and was found to have transfusion-resistant pancytopenia.She had a hemolytic anemia with an LDH > 1000 U/L, haptoglobin < 3 mg/dL, and mild transaminitis with hyperbilirubinemia (1.8 mg/dL). No schistocytes were observed on peripheral smear, suggesting intramedullary hemolysis, which is believed to be due to the destruction of megaloblastic cells by macrophages in bone marrow.¹¹ A French study found high LDH levels and low reticulocyte counts to be strongly suggestive of vitamin B₁₂ deficiency and helpful in differentiating pernicious anemia from TTP, given that bone marrow response to anemia in TTP is preserved.⁸

While vitamin B₁₂ deficiency is not often associated with hemolytic anemia, multiple cases have been reported in the literature.⁶ Screening for vitamin B₁₂ deficiency may have shortened this patient’s clinical course and limited the need for air evacuation to a stateside quaternary medical center. However, testing for cobalamin levels in overseas deployed environments is difficult, timely, and costly. New technologies, such as optical sensors, can detect vitamin B₁₂ levels in the blood in < 1 minute and offer portable, low-cost options that may be useful in the deployed military setting.¹²

Diet plays a key role in this case, since the patient had a reported history of gluten intolerance, although it was never documented or evaluated prior to this presentation. Prior to deployment, the patient ate mostly rice, potatoes, and vegetables. While deployed in an austere environment, food options were limited. These conditions forced her to intermittently consume gluten products, which led to gastrointestinal issues, exacerbating her nutritional deficiencies. In the 2 months before her first syncopal episode, she reported worsening fatigue that impacted her ability to exercise. Vitamin B₁₂ stores often take years to deplete, suggesting that she had a chronic nutritional deficiency before deployment. Another possibility was that she developed an autoimmune gastritis that acutely worsened in the setting of poor nutritional intake. Her history of Hashimoto thyroiditis is also important, as up to one-third of patients with autoimmune thyroid disease have been associated with pernicious anemia (range, 3%-32%) with certain shared human leukocyte antigen alleles implicated in autoimmune gastritis.^13,14

Conclusions

This rare case of pernicious anemia presenting as pancytopenia illustrates the challenge in working up pancytopenia, especially in austere military environments with limited testing capabilities. Screening for chronic dietary and nutritional deficiency is important in a service member, raising the question of what role predeployment screening may have and what dietary accommodations may be available during overseas deployments, which can potentially dampen inflammation of the gastrointestinal tract, especially for those with preexisting autoimmune gastrointestinal conditions. Also, newer technology allows portable, low-cost testing of cobalamin and may aid in its diagnosis. In patients who are anemic with low vitamin B₁₂, HCPs can begin vitamin B₁₂ supplementation while continuing the workup (eg, antibody testing, endoscopy). If the patient responds appropriately, further workup becomes less urgent, therefore, decreasing resource use and increasing military readiness. When hemolysis is present, a low reticulocyte count can be beneficial to help differentiate this condition from TTP, a life-threatening condition that must also be ruled out or treated. Pernicious anemia should be on the differential in any patients with autoimmune conditions presenting with cytopenias, especially in those with a history of autoimmune thyroid disorders.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

As a class of drugs, proteasome inhibitors are known to rarely cause drug-induced thrombotic microangiopathy (DITMA). In particular, carfilzomib is a second-generation, irreversible proteasome inhibitor approved for the treatment of relapsed, refractory multiple myeloma (MM) in combination with other therapeutic agents.¹ Although generally well tolerated, carfilzomib has been associated with serious adverse events such as cardiovascular toxicity and DITMA.^2-4 Thrombotic microangiopathy (TMA) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and end-organ damage.⁵ Its occurrence secondary to carfilzomib has been reported only rarely in clinical trials of MM, and the most effective management of the disorder as well as the concurrent risk factors that contribute to its development remain incompletely understood.^6,7 As a result, given both the expanding use of carfilzomib in practice and the morbidity of TMA, descriptions of carfilzomib-induced TMA from the real-world setting continue to provide important contributions to our understanding of the disorder.

At our US Department of Veterans Affairs (VA) medical center, 2 patients developed severe carfilzomib-induced TMA within days of one another. The presentation of simultaneous cases was highly unexpected and offered the unique opportunity to compare clinical features in real time. Here, we describe our 2 cases in detail, review their presentations and management in the context of the prior literature, and discuss potential insights gained into the disease.

Case Presentation

Case 1

A 78-year-old male patient was diagnosed with monoclonal gammopathy of undetermined significance in 2012 that progressed to Revised International Staging System stage II IgG-κ MM in 2016 due to worsening anemia with a hemoglobin level < 10 g/dL (Table 1). He was treated initially with 8 cycles of first-line bortezomib, lenalidomide, and dexamethasone, to which he achieved a partial response with > 50% reduction in serum M-protein. He then received 3 cycles of maintenance bortezomib until relapse, at which time he was switched to second-line therapy consisting of carfilzomib 20 mg/m² on days 1 and 2 and 56 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 56 mg/m² on days 1, 2, 8, 9, 15, and 16 for subsequent cycles plus dexamethasone 20 mg twice weekly every 28 days.

After the patient received cycle 3, day 1 of carfilzomib, he developed subjective fevers, chills, and diarrhea. He missed his day 2 infusion and instead presented to the VA emergency department, where his vital signs were stable and laboratory tests were notable for the following levels: leukocytosis of20.3 K/µL (91.7% neutrophils), hemoglobin 12.4 g/dL (prior 13.5 g/dL), platelet count 171 K/µL, and creatinine 1.39 mg/dL (prior 1.13 g/dL). A chest X-ray demonstrated diffuse bilateral opacities concerning for edema vs infection, and he was started empirically on vancomycin, piperacillin-tazobactam, and azithromycin. His outpatient medications, which included acyclovir, aspirin, finasteride, oxybutynin, ranitidine, omega-3 fatty acids, fish oil, vitamin D, and senna, were continued as indicated.

On hospital day 2, the patient’s platelet count dropped to 81 K/µL and creatinine level rose to 1.78 mg/dL. He developed dark urine (urinalysis [UA] 3+ blood, 6-11 red blood cells per high power field [RBC/HPF]) and had laboratory tests suggestive of hemolysis, including lactic dehydrogenase (LDH) > 1,200 IU/L (reference range, 60-250 IU/L), haptoglobin < 30 mg/dL (reference range, 44-215 mg/dL), total bilirubin 3.2 mg/dL (reference range, 0.2-1.3 mg/dL; indirect bilirubin, 2.6 mg/dL), and a peripheral blood smear demonstrating moderate microangiopathy (Figure 1).

Case 2

A 59-year-old male patient, diagnosed in 2013 with ISS stage I IgG-κ MM after presenting with compression fractures, completed 8 cycles of cyclophosphamide, bortezomib, and dexamethasone before undergoing autologous hematopoietic stem cell transplantation with complete response (Table 1). He subsequently received single-agent maintenance bortezomib until relapse nearly 2 years later, at which time he started second-line carfilzomib 20 mg/m² on days 1 and 2 and 27 mg/m² on days 8, 9, 15, and 16 for cycle 1, followed by 27 mg/m² on days 8, 9, 15, and 16 for cycles 2 to 8, lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg weekly every 28 days. Serum free light chain levels normalized after 9 cycles, and he subsequently began maintenance carfilzomib 70 mg/m² on days 1 and 15 plus lenalidomide 10 mg on days 1 to 21 every 28 days.

On the morning before admission, the patient received C6D17 of maintenance carfilzomib, which had been delayed from day 15 because of the holiday. Later that evening, he developed nausea, vomiting, and fever of 101.3 °F. He presented to the VA emergency department and was tachycardic (108 beats per minute) and hypotensive (86/55 mm Hg). Laboratory tests were notable for hemoglobin level 9.9 g/dL (prior 11.6 g/dL), platelet count 270 K/µL, and creatinine level 1.86 mg/dL (prior 1.12 mg/dL). A respiratory viral panel was positive for influenza A, and antimicrobial agents were eventually broadened to piperacillin-tazobactam, azithromycin, and oseltamivir. His outpatient medications, which included acyclovir, zoledronic acid, sulfamethoxazole/trimethoprim, aspirin, amlodipine, atorvastatin, omeprazole, zolpidem, calcium, vitamin D, loratadine, ascorbic acid, and prochlorperazine, were continued as indicated.

On hospital day 2, the patient’s platelet count declined from 211 to 57 K/µL. He developed tea-colored urine (UA 2+ blood, 0-2 RBC/HPF) and had laboratory tests suggestive of hemolysis, including LDH 910 IU/L (reference range, 60-250 IU/L), total bilirubin 3.3 mg/dL (reference range, 0.2-1.3 mg/dL; no direct or indirect available), and a peripheral blood smear demonstrating moderate microangiopathy. Although haptoglobin level was normal at this time (206 mg/dL; reference range, 44-215 mg/dL), it decreased to 42 mg/dL by the following day. Additional workup included a negative direct Coombs and a DIC panel showing elevated fibrinogen (596 mg/dL; reference range, 200-400 mg/dL) and mildly elevated INR (1.16). Blood cultures remained negative, and a 22-pathogen GI PCR panel identified no viral or bacterial pathogens, including E coli O157:H7. C3 (114 mg/dL; reference range, 90-180 mg/dL) and C4 (40 mg/dL; reference range, 16-47 mg/dL) complement levels were both normal.

Based on these findings, empiric treatment was started with plasma exchange and pulse-dosed steroids. The patient received 3 cycles of plasma exchange until the results of the ADAMTS13 activity ruled out TTP (63% enzyme activity). Over the next 6 days, his platelet count reached a nadir of 6 K/µL and creatinine level peaked at 10.36 mg/dL, necessitating the initiation of hemodialysis. Given severe renal insufficiency, a diagnosis of atypical HUS was again considered, and eculizumab 900 mg was administered on days 9 and 16 with stabilization of renal function. By the time of discharge on day 17, the patient’s creatinine level had decreased to 4.17 mg/dL and platelet count was 164 K/µL. Creatinine level normalized to 1.02 mg/dL by day 72.

Outpatient genetic testing through the BloodCenter of Wisconsin Diagnostic Laboratories was negative for gene mutations associated with atypical HUS. Approximately 1 month after discharge, the patient resumed maintenance lenalidomide alone without reinitiation of proteasome inhibitor therapy.

Discussion

In this case series, we describe the uncommon drug-related adverse event of TMA occurring in 2 patients with MM after receiving carfilzomib. Although the incidence of TMA disorders is low, reaching up to 2.8% in patients receiving carfilzomib plus cyclophosphamide and dexamethasone in the phase 2 CARDAMON trial, our experience suggests that a high index of suspicion for carfilzomib-induced TMA is warranted in the real-world setting.⁸ TMA syndromes, including TTP, HUS, and DITMA, are characterized by microvascular endothelial injury and thrombosis leading to thrombocytopenia and microangiopathic hemolytic anemia.^5,9 Several drug culprits of DITMA are recognized, including quinine, gemcitabine, tacrolimus, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib).^10-12 In a real-world series of patients receiving proteasome inhibitor therapy, either carfilzomib (n=8) or bortezomib (n=3), common clinical features of DITMA included thrombocytopenia, microangiopathic hemolytic anemia, gastrointestinal symptoms, and renal insufficiency with or without a need for hemodialysis.² Although DITMA has been described primarily as an early event, its occurrence after 12 months of proteasome inhibitor therapy has also been reported, both in this series and elsewhere, thereby suggesting an ongoing risk for DITMA throughout the duration of carfilzomib treatment.^2,13

The diagnosis of DITMA can be challenging given its nonspecific symptoms that overlap with other TMA syndromes. Previous studies have proposed that for a drug to be associated with DITMA, there should be: (1) evidence of clinical and/or pathologic findings of TMA; (2) exclusion of alternative causes of TMA; (3) no other new drug exposures other than the suspected culprit medication; and (4) a lack of recurrence of TMA in absence of the drug.¹⁰ In the case of patients with MM, other causes of TMA have also been described, including the underlying plasma cell disorder itself and stem cell transplantation.¹⁴ In the 2 cases we have described, these alternative causes were considered unlikely given that only 1 patient underwent transplantation remotely and neither had a previous history of TMA secondary to their disease. With respect to other TMA syndromes, ADAMTS13 levels > 10% and negative stool studies for E coli O157:H7 suggested against TTP or typical HUS, respectively. No other drug culprits were identified, and the close timing between the receipt of carfilzomib and symptom onset supported a causal relationship.

Because specific therapies are lacking, management of DITMA has traditionally included drug discontinuation and supportive care for end-organ injury.⁵ The terminal complement inhibitor, eculizumab, improves hematologic abnormalities and renal function in patients with atypical HUS but its use for treating patients with DITMA is not standard.¹⁵ Therefore, the decision to administer eculizumab to our 2 patients was driven by their severe renal insufficiency without improvement after plasma exchange, which suggested a phenotype similar to atypical HUS. After administration of eculizumab, renal function stabilized and then gradually improved over weeks to months, a time course similar to that described in cases of patients with DITMA secondary to other anticancer therapies treated with eculizumab.¹⁶ Although these results suggest a potential role for eculizumab in proteasome inhibitor–induced TMA, distinguishing the benefit of eculizumab over drug discontinuation alone remains challenging, and well-designed prospective investigations are needed.

Conclusions

DITMA is a known risk of proteasome inhibitors and is listed as a safety warning in the prescribing information for bortezomib, carfilzomib, and ixazomib.¹² Given the overall rarity of this adverse event, the simultaneous presentation of our 2 cases was unexpected and underscores the need for heightened awareness in clinical practice. In addition, while no underlying complement mutations were identified, eculizumab was used in both cases to successfully stabilize renal function. Further research investigating the efficacy of eculizumab and the role of complement activation in proteasome inhibitor–induced TMA will be valuable.

Acknowledgments

The authors would like to thank the patients whose histories are reported in this manuscript as well as the physicians and staff who provided care during the hospitalizations and beyond. We also thank Oscar Silva, MD, PhD, for his assistance in reviewing and formatting the peripheral blood smear images.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

CHICAGO – New results from a trial in patients with newly diagnosed multiple myeloma (MM) offer some answers to questions about which treatment route to choose.

The trial, known as DETERMINATION, found that newly diagnosed patients treated with a triplet of drugs had longer progression-free survival (PFS) if they received an autologous stem cell transplant (ASCT) soon after the drug therapy than if they simply had their stem cells collected for a possible future transplant.

Patients who received the triplet of lenalidomide, bortezomib, and dexamethasone (RVD) plus ASCT had a median PFS of 67.5 months, compared with 46.2 months for those who received RVD but did not have a transplant soon after.

However, patients were just as likely to be alive more than 6 years after treatment regardless of whether or not they underwent an immediate stem cell transplant.

In addition, treatment-related adverse events of grade 3 or above were higher in the group that received the transplant immediately after the triplet therapy.  

The results were presented during a plenary session at the American Society of Clinical Oncology annual meeting and simultaneously published in the New England Journal of Medicine.

“Our findings confirm the PFS benefit of transplantation as first-line treatment for patients with myeloma and confirms stem cell transplant as a standard of care with certain triplet therapy,” said lead author Paul G. Richardson, MD, professor of medicine, Harvard Medical School, and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana Farber Cancer Institute, Boston.

Another finding from the trial was that the use of maintenance lenalidomide in both groups continuously until progression conferred substantial clinical benefit.

“We can also say that the use of lenalidomide maintenance therapy is also a standard of care,” he added.
 

Study details

In this trial, Dr. Richardson and colleagues randomly assigned 873 patients newly diagnosed with multiple myeloma to the RVD-alone group (n = 357) or the transplantation group (n = 365). All patients had received one cycle of RVD prior to randomization and then received two additional RVD cycles plus stem-cell mobilization followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Lenalidomide was administered to all patients until disease progression, unacceptable side effects, or both.

At a median follow-up of 76.0 months, the risk of disease progression or death was 53% higher among patients who received RVD alone versus the transplantation group (hazard ratio [HR], 1.53; P < .001). The median duration of PFS among patients with a high-risk cytogenetic profile was 55.5 vs. 17.1 months, favoring the transplantation group.

The percentage of patients who were alive without progression at 5 years was 58.4% vs 41.6%, respectively (HR, 1.66) and median duration of response was 56.4 vs 38.9 months, also favoring transplantation (HR, 1.45).

The estimated 5-year overall survival was similar between groups: 80.7% for transplantation and 79.2% for RVD alone (HR for death, 1.10; P > .99). For patients with a high-risk cytogenetic profile, 5-year survival was 63.4% versus 54.3%, respectively.

“This tells us that for patients who had kept transplant in reserve, they had the same overall survival as those who had had a transplant right away, despite there being such impressive initial disease control for the patients in whom transplant was used early,” Dr. Richardson said in a press release from his institution.

Patients who did not undergo immediate transplant received treatment when their disease progressed with newer and active therapies, such as monoclonal antibodies and/or next-generation novel agents, he noted. Only 28% of patients used the reserve option of a transplant.

“It demonstrates the extent to which patients now have options and that we have new data to guide them in balancing the pluses and minuses of each approach,” he added.

When looking at safety, the authors noted that the most common treatment-related adverse events of grade 3 or higher occurred in 279 patients (78.2%) in the RVD-alone group and 344 patients (94.2%) in the transplantation group. Of those patients, 60.5% and 89.9%, respectively, reported hematologic events of grade 3 or higher (P < .001). The 5-year cumulative incidence of invasive second primary cancers was similar in both cohorts (RVD-alone group, 4.9%; transplantation group, 6.5%).

However, while the risk of secondary cancers was similar between groups, Dr. Richardson noted that there was a higher incidence of acute myeloid leukemia and myelodysplastic syndromes in the transplant cohort.

“There was also a significant drop in quality of life across transplant procedures, but the good news is that it was recoverable rapidly,” he said. “What is also really important is that we have prospective, multicenter, national comparative data on toxicity. That’s very important for providing patients with a choice as they move forward with their treatment plan.”

He noted that treatment continues to evolve. “This study was designed in 2009, begun in 2010, and now there is mature data in 2022,” Dr. Richardson said. “This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies and novel next-generation therapies. The results from these studies are extremely exciting.

“Now more than ever, treatment for multiple myeloma can be adapted for each patient,” Dr. Richardson said. “Our study provides important information about the benefits of transplant in the era of highly effective novel therapies and continuous maintenance, as well as the potential risks, to help patients and their physicians decide what approach may be best for them. This is particularly relevant as we have now further improved the induction treatment for younger patients with newly diagnosed myeloma using quadruplet regimens incorporating monoclonal antibodies, such as RVD combined with daratumumab.”
 

Lack of difference in overall survival

These new results further support an already established role of autologous hematopoietic stem cell transplantation in the management of patients with multiple myeloma, said Samer Al-Homsi, MD, clinical professor of medicine and director of the blood and marrow transplant program at Perlmutter Cancer Center, NYU Langone, New York, who was approached for comment.

“The treatment regimen is applicable to patients who are determined by an expert in transplantation to be fit to receive autologous hematopoietic transplantation,” he added. “Although this study, like many others, establishes hematopoietic stem cell transplantation as part of the standard of care in multiple myeloma, only a fraction of patients are actually offered this important modality of treatment for a variety of reasons, including provider bias,” he noted. “In fact, although improvement in supportive care has enhanced the safety of the procedure, many patients are denied this therapy.” 

Dr. Al-Homsi noted that the lack of difference in overall survival might be due to the fact that some patients (28%) in the RVD-alone group did end up undergoing transplantation at the time of progression. “Also, longer follow-up might reveal a difference in overall survival,” he said.

The toxicities are manageable, and the incidence of secondary malignancies was not significantly different between cohorts. “However,” he emphasized, “lenalidomide has been associated in other studies with increased incidence of secondary malignancies and it must be noted that this study used extended administration of lenalidomide until progression.” 

Support for this study was provided by grants to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute, the National Cancer Institute, R. J. Corman Multiple Myeloma Foundation, Celgene/Bristol Myers Squibb, and Millennium/Takeda Pharmaceutical. Dr. Richardson has reported relationships with Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm Therapeutics, Oncopeptides, Sanofi, Secura Bio, Takeda, and Bristol Myers Squibb. Dr. Al-Homsi has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

In patients with B-cell deficiencies, CoVac-1, a SARS-CoV-2 vaccine currently in clinical trials in Germany, induced T-cell immune responses in a large proportion of patients, according to study results presented at the annual meeting of the American Association for Cancer Research.

The phase 1/2 trial included 54 patients with a B-cell deficiency (mean age, 63 years; 28% female): 4 had congenital B-cell deficiency and 50 had a blood cancer (lymphocytic leukemia or lymphoma). T-cell immune responses were observed in 86% of patients 28 days after vaccination with a single CoVac-1 dose. The potency of CoVac-1–induced T-cell responses exceeded those seen typically with B cell–deficient patient responses after mRNA vaccine treatment and were comparable with those seen among nonimmunocompromised COVID-19 patients.

In the majority of individuals, currently approved SARS-CoV-2 vaccines induce a robust immune response, however, their efficacy, has been shown to be decreased among individuals who are immunocompromised. Patients treated for hematologic cancers, in particular, receive treatment regimens that damage healthy immune cells, particularly B cells, said Juliane Walz, MD, the study’s senior author and professor of medicine at University Hospital Tübingen (Germany).

“In the clinic, we see many cancer patients who do not mount sufficient humoral immune responses after vaccination with available SARS-CoV-2 vaccines,” Dr. Walz said. “These patients are at a high risk for a severe course of COVID-19.”

B-cell deficiency, she stated, can be compensated for by enhancing T-cell responses against SARS-CoV-2, which can then combat infections in the absence of neutralizing antibodies.

In a prior study of CoVac-1 among 36 adults without immune deficiency, the vaccine elicited T-cell responses that were still robust 3 months post vaccination, and that included responses against omicron and other key SARS-CoV-2 variants.

While mRNA-based or adenoviral vector-based vaccines are limited to the spike protein and are thus prone to loss of activity because of viral mutations, CoVac-1–induced T-cell immunity is far more intense and broader, Dr. Walz said.

CoVac-1 is a peptide vaccine that is injected directly rather than being encoded via mRNA and targets different viral components. It would not be given, however, to healthy, immunocompetent adults because it is important for them to have both B-cell antibody and T-cell response.

The patients with B-cell deficiency recruited for the study were given a single dose of CoVac-1 and assessed for safety and immunogenicity until day 56. Prior vaccinations with an approved SARS-CoV-2 vaccine had failed to elicit a humoral response in 87% of the subjects.

“Our vaccine does not induce antibody responses,” Dr. Walz said. “However, it could be used to induce broad T-cell responses as a complementary or additive vaccine for elderly adults. In the elderly, antibody responses decline very, very fast after vaccination.”

Dr. Walz said that CoVac-1 could find application in various syndromes associated with congenital B-cell deficiencies, in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, or diseases treated with rituximab or other B cell–depleting therapies (for example, ofatumumab, blinatumomab, or chimeric antigen receptor T cells), and in transplant patients.

A phase 3 study of CoVac-1 versus placebo is under discussion and would require about 300-500 subjects, Dr. Walz said.

“CoVac-1 is designed to induce broad and long-lasting SARS-CoV-2 T-cell immunity, even in individuals who have impaired ability to mount sufficient immunity from a currently approved vaccine, and thus protect these high-risk patients from a severe course of COVID-19,” Dr. Walz said.

“Having an option for these patients is just critical – so this is significant work,” said Ana Maria Lopez, MD, MPH, of the Sidney Kimmel Cancer Center–Jefferson Health, Philadelphia.

Limitations of this study included the small sample size with low racial and ethnic diversity, Dr. Walz stated.

Funding was provided by the Ministry of Science, Research and the Arts of the state of Baden-Württemberg; the Federal Ministry of Research and Education in Germany; the German Research Foundation under Germany’s Excellence Strategy; and the Clinical Cooperation Unit Translational Immunology at University Hospital Tübingen. Dr. Walz holds the CoVac-1 patent.

In patients with B-cell deficiencies, CoVac-1, a SARS-CoV-2 vaccine currently in clinical trials in Germany, induced T-cell immune responses in a large proportion of patients, according to study results presented at the annual meeting of the American Association for Cancer Research.

The phase 1/2 trial included 54 patients with a B-cell deficiency (mean age, 63 years; 28% female): 4 had congenital B-cell deficiency and 50 had a blood cancer (lymphocytic leukemia or lymphoma). T-cell immune responses were observed in 86% of patients 28 days after vaccination with a single CoVac-1 dose. The potency of CoVac-1–induced T-cell responses exceeded those seen typically with B cell–deficient patient responses after mRNA vaccine treatment and were comparable with those seen among nonimmunocompromised COVID-19 patients.

In the majority of individuals, currently approved SARS-CoV-2 vaccines induce a robust immune response, however, their efficacy, has been shown to be decreased among individuals who are immunocompromised. Patients treated for hematologic cancers, in particular, receive treatment regimens that damage healthy immune cells, particularly B cells, said Juliane Walz, MD, the study’s senior author and professor of medicine at University Hospital Tübingen (Germany).

“In the clinic, we see many cancer patients who do not mount sufficient humoral immune responses after vaccination with available SARS-CoV-2 vaccines,” Dr. Walz said. “These patients are at a high risk for a severe course of COVID-19.”

B-cell deficiency, she stated, can be compensated for by enhancing T-cell responses against SARS-CoV-2, which can then combat infections in the absence of neutralizing antibodies.

In a prior study of CoVac-1 among 36 adults without immune deficiency, the vaccine elicited T-cell responses that were still robust 3 months post vaccination, and that included responses against omicron and other key SARS-CoV-2 variants.

While mRNA-based or adenoviral vector-based vaccines are limited to the spike protein and are thus prone to loss of activity because of viral mutations, CoVac-1–induced T-cell immunity is far more intense and broader, Dr. Walz said.

CoVac-1 is a peptide vaccine that is injected directly rather than being encoded via mRNA and targets different viral components. It would not be given, however, to healthy, immunocompetent adults because it is important for them to have both B-cell antibody and T-cell response.

The patients with B-cell deficiency recruited for the study were given a single dose of CoVac-1 and assessed for safety and immunogenicity until day 56. Prior vaccinations with an approved SARS-CoV-2 vaccine had failed to elicit a humoral response in 87% of the subjects.

“Our vaccine does not induce antibody responses,” Dr. Walz said. “However, it could be used to induce broad T-cell responses as a complementary or additive vaccine for elderly adults. In the elderly, antibody responses decline very, very fast after vaccination.”

Dr. Walz said that CoVac-1 could find application in various syndromes associated with congenital B-cell deficiencies, in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, or diseases treated with rituximab or other B cell–depleting therapies (for example, ofatumumab, blinatumomab, or chimeric antigen receptor T cells), and in transplant patients.

A phase 3 study of CoVac-1 versus placebo is under discussion and would require about 300-500 subjects, Dr. Walz said.

“CoVac-1 is designed to induce broad and long-lasting SARS-CoV-2 T-cell immunity, even in individuals who have impaired ability to mount sufficient immunity from a currently approved vaccine, and thus protect these high-risk patients from a severe course of COVID-19,” Dr. Walz said.

“Having an option for these patients is just critical – so this is significant work,” said Ana Maria Lopez, MD, MPH, of the Sidney Kimmel Cancer Center–Jefferson Health, Philadelphia.

Limitations of this study included the small sample size with low racial and ethnic diversity, Dr. Walz stated.

Funding was provided by the Ministry of Science, Research and the Arts of the state of Baden-Württemberg; the Federal Ministry of Research and Education in Germany; the German Research Foundation under Germany’s Excellence Strategy; and the Clinical Cooperation Unit Translational Immunology at University Hospital Tübingen. Dr. Walz holds the CoVac-1 patent.

In patients with B-cell deficiencies, CoVac-1, a SARS-CoV-2 vaccine currently in clinical trials in Germany, induced T-cell immune responses in a large proportion of patients, according to study results presented at the annual meeting of the American Association for Cancer Research.

The phase 1/2 trial included 54 patients with a B-cell deficiency (mean age, 63 years; 28% female): 4 had congenital B-cell deficiency and 50 had a blood cancer (lymphocytic leukemia or lymphoma). T-cell immune responses were observed in 86% of patients 28 days after vaccination with a single CoVac-1 dose. The potency of CoVac-1–induced T-cell responses exceeded those seen typically with B cell–deficient patient responses after mRNA vaccine treatment and were comparable with those seen among nonimmunocompromised COVID-19 patients.

In the majority of individuals, currently approved SARS-CoV-2 vaccines induce a robust immune response, however, their efficacy, has been shown to be decreased among individuals who are immunocompromised. Patients treated for hematologic cancers, in particular, receive treatment regimens that damage healthy immune cells, particularly B cells, said Juliane Walz, MD, the study’s senior author and professor of medicine at University Hospital Tübingen (Germany).

“In the clinic, we see many cancer patients who do not mount sufficient humoral immune responses after vaccination with available SARS-CoV-2 vaccines,” Dr. Walz said. “These patients are at a high risk for a severe course of COVID-19.”

B-cell deficiency, she stated, can be compensated for by enhancing T-cell responses against SARS-CoV-2, which can then combat infections in the absence of neutralizing antibodies.

In a prior study of CoVac-1 among 36 adults without immune deficiency, the vaccine elicited T-cell responses that were still robust 3 months post vaccination, and that included responses against omicron and other key SARS-CoV-2 variants.

While mRNA-based or adenoviral vector-based vaccines are limited to the spike protein and are thus prone to loss of activity because of viral mutations, CoVac-1–induced T-cell immunity is far more intense and broader, Dr. Walz said.

CoVac-1 is a peptide vaccine that is injected directly rather than being encoded via mRNA and targets different viral components. It would not be given, however, to healthy, immunocompetent adults because it is important for them to have both B-cell antibody and T-cell response.

The patients with B-cell deficiency recruited for the study were given a single dose of CoVac-1 and assessed for safety and immunogenicity until day 56. Prior vaccinations with an approved SARS-CoV-2 vaccine had failed to elicit a humoral response in 87% of the subjects.

“Our vaccine does not induce antibody responses,” Dr. Walz said. “However, it could be used to induce broad T-cell responses as a complementary or additive vaccine for elderly adults. In the elderly, antibody responses decline very, very fast after vaccination.”

Dr. Walz said that CoVac-1 could find application in various syndromes associated with congenital B-cell deficiencies, in autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, or diseases treated with rituximab or other B cell–depleting therapies (for example, ofatumumab, blinatumomab, or chimeric antigen receptor T cells), and in transplant patients.

A phase 3 study of CoVac-1 versus placebo is under discussion and would require about 300-500 subjects, Dr. Walz said.

“CoVac-1 is designed to induce broad and long-lasting SARS-CoV-2 T-cell immunity, even in individuals who have impaired ability to mount sufficient immunity from a currently approved vaccine, and thus protect these high-risk patients from a severe course of COVID-19,” Dr. Walz said.

“Having an option for these patients is just critical – so this is significant work,” said Ana Maria Lopez, MD, MPH, of the Sidney Kimmel Cancer Center–Jefferson Health, Philadelphia.

Limitations of this study included the small sample size with low racial and ethnic diversity, Dr. Walz stated.

Funding was provided by the Ministry of Science, Research and the Arts of the state of Baden-Württemberg; the Federal Ministry of Research and Education in Germany; the German Research Foundation under Germany’s Excellence Strategy; and the Clinical Cooperation Unit Translational Immunology at University Hospital Tübingen. Dr. Walz holds the CoVac-1 patent.

Valproic acid (VPA) and its derivative, divalproex (DVP) are prescribed for a variety of indications, commonly for seizure control in patients with epilepsy, mood stabilization in patients with bipolar disorder, and migraine prophylaxis. Gastrointestinal distress and sedation are among the most reported adverse effects (AEs) with DVP therapy.¹ Although serious hepatic and hematologic AEs are rare, monitoring is still recommended. DVP can cause various hematologic dyscrasias, the most common being thrombocytopenia.^1,2 Neutropenia and leukopenia have been reported in isolated cases, most occurring in pediatric patients or patients with epilepsy.^3-14

Several case reports of DVP-related neutropenia (absolute neutrophil count [ANC] < 1.50 10³/mcL) and leukopenia (white blood cell count [WBC] < 4.0 10³/mcL) were reviewed during our literature search, some caused by DVP monotherapy; others were thought to be related to concomitant use of DVP and another drug.^15-25 Quetiapine was the antipsychotic most commonly implicated in causing hematologic abnormalities when combined with DVP. We report a case of neutropenia and leukopenia that presented after a cross taper from quetiapine to DVP for the treatment of borderline personality disorder (BPD).

Although no medications have been approved by the US Food and Drug Administration (FDA) for the treatment of BPD, mood stabilizers, including DVP, have literature to support their use for the treatment of affective dysregulation and impulsive behavioral dyscontrol.^26-28 A therapeutic range for DVP in the treatment of BPD has not been defined; therefore, for this case report, the generally accepted range of 50 to 100 µg/mL will be considered therapeutic.¹

Case Presentation

A 34-year-old male patient presented to the mental health clinic pharmacist reporting that his current psychotropic medication regimen was not effective. His medical history included posttraumatic stress disorder (PTSD), opioid use disorder, alcohol use disorder, stimulant use disorder, cannabis use, BPD, hypertension, hyperlipidemia, prediabetes, gastroesophageal reflex disease, and a pulmonary nodule. On initial presentation, the patient was prescribed buprenorphine 24 mg/naloxone 6 mg, quetiapine 400 mg, duloxetine 120 mg, and prazosin 15 mg per day. At the time of pharmacy consultation, last reported alcohol or nonprescribed opioid use was about 6 months prior, and methamphetamine use about 1 month prior, with ongoing cannabis use. The patient had a history of participating in cognitive processing therapy, dialectical behavior therapy (DBT), and residential treatment for both PTSD and substance use. Additionally, he was actively participating in contingency management for stimulant use disorder and self-management and recovery training group.

The patient reported ongoing mood lability, hypervigilance, and oversedation with current psychotropic regimen. The prescriber of his medication for opioid use disorder also reported the patient experienced labile mood, impulsive behavior, and anger outbursts. In the setting of intolerability due to oversedation with quetiapine, cardiometabolic risk, and lack of clear indication for use, the patient and health care practitioner (HCP) agreed to taper quetiapine and initiate a trial of DVP for affective dysregulation and impulsive-behavioral dyscontrol. To prevent cholinergic rebound and insomnia with abrupt discontinuation of quetiapine, DVP and quetiapine were cross tapered. The following cross taper was prescribed: quetiapine 300 mg and DVP 500 mg per day for week 1; quetiapine 200 mg and DVP 500 mg per day for week 2; quetiapine 100 mg and DVP 1000 mg per day for week 3; quetiapine 50 mg and DVP 1000 mg per day for week 4; followed by DVP 1000 mg per day and discontinuation of quetiapine.

During a 4-week follow-up appointment, the patient reported appropriate completion of cross taper but stopped taking the DVP 3 days prior to the appointment due to self-reported lack of efficacy. For this reason, serum VPA level was not obtained. After discussion with his HCP, the patient restarted DVP 1000 mg per day without retitration with plans to get laboratory tests in 1 week. The next week, laboratory tests were notable for VPA level 28.74 (reference range, 50-100) µg/mL, low WBC 3.51 (reference range, 4.00-10.00) 10³/mcL, platelets 169 (reference range, 150-420) 10³/mcL, and low ANC 1.00 (reference range, 1.50-7.40) 10³/mcL (Table). This raised clinical concern as the patient had no history of documented neutropenia or leukopenia, with most recent complete blood count (CBC) prior to DVP initiation 3 months earlier while prescribed quetiapine.

Discussion

Our case report describes isolated neutropenia and leukopenia that developed after a cross taper from quetiapine to DVP. Hematologic abnormalities resolved after discontinuation of DVP, suggesting a likely correlation. DVP has a well-established, dose-related prevalence of thrombocytopenia occurring in up to 27% of patients.¹ Fewer case reports exist on neutropenia and leukopenia. DVP-induced neutropenia is thought to be a result of direct bone marrow suppression, whereas the more commonly occurring blood dyscrasia, thrombocytopenia, is thought to be caused by an antibody-mediated destruction of platelets.⁶

Management of DVP-induced thrombocytopenia is often dependent on the severity of the reaction. In mild-to-moderate cases, intervention may not be necessary as thrombocytopenia has been shown to resolve without adjustment to DVP therapy.¹ In more severe or symptomatic cases, dose reduction or discontinuation of the offending agent is recommended, typically resulting in resolution shortly following pharmacologic intervention.

Guidance on the management of other drug-induced hematologic abnormalities, such as neutropenia and leukopenia are not as well established. A 2019 systematic review of idiosyncratic drug-induced neutropenia suggested that continuing the offending drug with strict monitoring could be considered in cases of mild neutropenia. In cases of moderate neutropenia, the author suggests temporary cessation of the drug and reinstatement once neutrophil count normalizes and definitive cessation of the drug in severe cases.³⁰

In our case, continuing the offending agent with close monitoring was considered, similar to the well-established management of clozapine-induced neutropenia. However, due to the concern that the ANC was bordering moderate neutropenia in the absence of a therapeutic VPA level as well as a significant reduction in platelets, although not meeting criteria for thrombocytopenia, the decision was made to err on the side of caution and discontinue the most likely offending agent.

It is important to highlight that DVP was replacing quetiapine in the form of a cross taper. Quetiapine is structurally similar to clozapine. While clozapine has strict monitoring requirements related to neutropenia, blood dyscrasias with quetiapine therapy are rare. Quetiapine-induced hematologic abnormalities may be due to direct toxicity or to an immune-mediated mechanism, leading to bone marrow suppression.²⁰ Case reports documenting blood dyscrasias with the combination of DVP and quetiapine were identified during literature review.^15-19 Despite these case reports, we believe DVP was the primary offending agent in our case as the patient’s last dose of quetiapine was 2 weeks before obtaining the abnormal CBC. There was no history of blood dyscrasias with quetiapine monotherapy; however, the effect of the combination of DVP and quetiapine is unknown as no CBC was obtained during the cross-taper period.

Although there are no FDA-approved medications for the treatment of BPD, mood stabilizers, including DVP, have some research to support their use for the treatment of affective dysregulation and impulsive-behavioral dyscontrol.^26-28 In our case, DVP was selected due to the evidence for use in BPD and ability to assess adherence with therapeutic monitoring. Although polypharmacy is a concern in patients with BPD, in our case we believed that the patient’s ongoing mood lability and impulsive behaviors warranted pharmacologic intervention. Additionally, DVP provided an advantage in its ability to quickly titrate to therapeutic dose when compared with lamotrigine and a lower risk of cognitive AEs when compared with topiramate.

Conclusions

To our knowledge, this case report demonstrates the first published case of neutropenia and leukopenia related to DVP therapy for the treatment of BPD. Routine CBC monitoring is recommended with DVP therapy, and our case highlights the importance of evaluating for not only thrombocytopenia, but also other blood dyscrasias during the titration phase even in the absence of a therapeutic VPA level. Further studies are warranted to determine incidence of DVP-related neutropenia and leukopenia and to evaluate the safety of continuing DVP in cases of mild-to-moderate neutropenia with close monitoring.

Valproic acid (VPA) and its derivative, divalproex (DVP) are prescribed for a variety of indications, commonly for seizure control in patients with epilepsy, mood stabilization in patients with bipolar disorder, and migraine prophylaxis. Gastrointestinal distress and sedation are among the most reported adverse effects (AEs) with DVP therapy.¹ Although serious hepatic and hematologic AEs are rare, monitoring is still recommended. DVP can cause various hematologic dyscrasias, the most common being thrombocytopenia.^1,2 Neutropenia and leukopenia have been reported in isolated cases, most occurring in pediatric patients or patients with epilepsy.^3-14

Several case reports of DVP-related neutropenia (absolute neutrophil count [ANC] < 1.50 10³/mcL) and leukopenia (white blood cell count [WBC] < 4.0 10³/mcL) were reviewed during our literature search, some caused by DVP monotherapy; others were thought to be related to concomitant use of DVP and another drug.^15-25 Quetiapine was the antipsychotic most commonly implicated in causing hematologic abnormalities when combined with DVP. We report a case of neutropenia and leukopenia that presented after a cross taper from quetiapine to DVP for the treatment of borderline personality disorder (BPD).

Although no medications have been approved by the US Food and Drug Administration (FDA) for the treatment of BPD, mood stabilizers, including DVP, have literature to support their use for the treatment of affective dysregulation and impulsive behavioral dyscontrol.^26-28 A therapeutic range for DVP in the treatment of BPD has not been defined; therefore, for this case report, the generally accepted range of 50 to 100 µg/mL will be considered therapeutic.¹

Case Presentation

A 34-year-old male patient presented to the mental health clinic pharmacist reporting that his current psychotropic medication regimen was not effective. His medical history included posttraumatic stress disorder (PTSD), opioid use disorder, alcohol use disorder, stimulant use disorder, cannabis use, BPD, hypertension, hyperlipidemia, prediabetes, gastroesophageal reflex disease, and a pulmonary nodule. On initial presentation, the patient was prescribed buprenorphine 24 mg/naloxone 6 mg, quetiapine 400 mg, duloxetine 120 mg, and prazosin 15 mg per day. At the time of pharmacy consultation, last reported alcohol or nonprescribed opioid use was about 6 months prior, and methamphetamine use about 1 month prior, with ongoing cannabis use. The patient had a history of participating in cognitive processing therapy, dialectical behavior therapy (DBT), and residential treatment for both PTSD and substance use. Additionally, he was actively participating in contingency management for stimulant use disorder and self-management and recovery training group.

The patient reported ongoing mood lability, hypervigilance, and oversedation with current psychotropic regimen. The prescriber of his medication for opioid use disorder also reported the patient experienced labile mood, impulsive behavior, and anger outbursts. In the setting of intolerability due to oversedation with quetiapine, cardiometabolic risk, and lack of clear indication for use, the patient and health care practitioner (HCP) agreed to taper quetiapine and initiate a trial of DVP for affective dysregulation and impulsive-behavioral dyscontrol. To prevent cholinergic rebound and insomnia with abrupt discontinuation of quetiapine, DVP and quetiapine were cross tapered. The following cross taper was prescribed: quetiapine 300 mg and DVP 500 mg per day for week 1; quetiapine 200 mg and DVP 500 mg per day for week 2; quetiapine 100 mg and DVP 1000 mg per day for week 3; quetiapine 50 mg and DVP 1000 mg per day for week 4; followed by DVP 1000 mg per day and discontinuation of quetiapine.

During a 4-week follow-up appointment, the patient reported appropriate completion of cross taper but stopped taking the DVP 3 days prior to the appointment due to self-reported lack of efficacy. For this reason, serum VPA level was not obtained. After discussion with his HCP, the patient restarted DVP 1000 mg per day without retitration with plans to get laboratory tests in 1 week. The next week, laboratory tests were notable for VPA level 28.74 (reference range, 50-100) µg/mL, low WBC 3.51 (reference range, 4.00-10.00) 10³/mcL, platelets 169 (reference range, 150-420) 10³/mcL, and low ANC 1.00 (reference range, 1.50-7.40) 10³/mcL (Table). This raised clinical concern as the patient had no history of documented neutropenia or leukopenia, with most recent complete blood count (CBC) prior to DVP initiation 3 months earlier while prescribed quetiapine.

Discussion

Our case report describes isolated neutropenia and leukopenia that developed after a cross taper from quetiapine to DVP. Hematologic abnormalities resolved after discontinuation of DVP, suggesting a likely correlation. DVP has a well-established, dose-related prevalence of thrombocytopenia occurring in up to 27% of patients.¹ Fewer case reports exist on neutropenia and leukopenia. DVP-induced neutropenia is thought to be a result of direct bone marrow suppression, whereas the more commonly occurring blood dyscrasia, thrombocytopenia, is thought to be caused by an antibody-mediated destruction of platelets.⁶

Management of DVP-induced thrombocytopenia is often dependent on the severity of the reaction. In mild-to-moderate cases, intervention may not be necessary as thrombocytopenia has been shown to resolve without adjustment to DVP therapy.¹ In more severe or symptomatic cases, dose reduction or discontinuation of the offending agent is recommended, typically resulting in resolution shortly following pharmacologic intervention.

Guidance on the management of other drug-induced hematologic abnormalities, such as neutropenia and leukopenia are not as well established. A 2019 systematic review of idiosyncratic drug-induced neutropenia suggested that continuing the offending drug with strict monitoring could be considered in cases of mild neutropenia. In cases of moderate neutropenia, the author suggests temporary cessation of the drug and reinstatement once neutrophil count normalizes and definitive cessation of the drug in severe cases.³⁰

In our case, continuing the offending agent with close monitoring was considered, similar to the well-established management of clozapine-induced neutropenia. However, due to the concern that the ANC was bordering moderate neutropenia in the absence of a therapeutic VPA level as well as a significant reduction in platelets, although not meeting criteria for thrombocytopenia, the decision was made to err on the side of caution and discontinue the most likely offending agent.

It is important to highlight that DVP was replacing quetiapine in the form of a cross taper. Quetiapine is structurally similar to clozapine. While clozapine has strict monitoring requirements related to neutropenia, blood dyscrasias with quetiapine therapy are rare. Quetiapine-induced hematologic abnormalities may be due to direct toxicity or to an immune-mediated mechanism, leading to bone marrow suppression.²⁰ Case reports documenting blood dyscrasias with the combination of DVP and quetiapine were identified during literature review.^15-19 Despite these case reports, we believe DVP was the primary offending agent in our case as the patient’s last dose of quetiapine was 2 weeks before obtaining the abnormal CBC. There was no history of blood dyscrasias with quetiapine monotherapy; however, the effect of the combination of DVP and quetiapine is unknown as no CBC was obtained during the cross-taper period.

Although there are no FDA-approved medications for the treatment of BPD, mood stabilizers, including DVP, have some research to support their use for the treatment of affective dysregulation and impulsive-behavioral dyscontrol.^26-28 In our case, DVP was selected due to the evidence for use in BPD and ability to assess adherence with therapeutic monitoring. Although polypharmacy is a concern in patients with BPD, in our case we believed that the patient’s ongoing mood lability and impulsive behaviors warranted pharmacologic intervention. Additionally, DVP provided an advantage in its ability to quickly titrate to therapeutic dose when compared with lamotrigine and a lower risk of cognitive AEs when compared with topiramate.

Conclusions

To our knowledge, this case report demonstrates the first published case of neutropenia and leukopenia related to DVP therapy for the treatment of BPD. Routine CBC monitoring is recommended with DVP therapy, and our case highlights the importance of evaluating for not only thrombocytopenia, but also other blood dyscrasias during the titration phase even in the absence of a therapeutic VPA level. Further studies are warranted to determine incidence of DVP-related neutropenia and leukopenia and to evaluate the safety of continuing DVP in cases of mild-to-moderate neutropenia with close monitoring.

Valproic acid (VPA) and its derivative, divalproex (DVP) are prescribed for a variety of indications, commonly for seizure control in patients with epilepsy, mood stabilization in patients with bipolar disorder, and migraine prophylaxis. Gastrointestinal distress and sedation are among the most reported adverse effects (AEs) with DVP therapy.¹ Although serious hepatic and hematologic AEs are rare, monitoring is still recommended. DVP can cause various hematologic dyscrasias, the most common being thrombocytopenia.^1,2 Neutropenia and leukopenia have been reported in isolated cases, most occurring in pediatric patients or patients with epilepsy.^3-14

Several case reports of DVP-related neutropenia (absolute neutrophil count [ANC] < 1.50 10³/mcL) and leukopenia (white blood cell count [WBC] < 4.0 10³/mcL) were reviewed during our literature search, some caused by DVP monotherapy; others were thought to be related to concomitant use of DVP and another drug.^15-25 Quetiapine was the antipsychotic most commonly implicated in causing hematologic abnormalities when combined with DVP. We report a case of neutropenia and leukopenia that presented after a cross taper from quetiapine to DVP for the treatment of borderline personality disorder (BPD).

Although no medications have been approved by the US Food and Drug Administration (FDA) for the treatment of BPD, mood stabilizers, including DVP, have literature to support their use for the treatment of affective dysregulation and impulsive behavioral dyscontrol.^26-28 A therapeutic range for DVP in the treatment of BPD has not been defined; therefore, for this case report, the generally accepted range of 50 to 100 µg/mL will be considered therapeutic.¹

Case Presentation

A 34-year-old male patient presented to the mental health clinic pharmacist reporting that his current psychotropic medication regimen was not effective. His medical history included posttraumatic stress disorder (PTSD), opioid use disorder, alcohol use disorder, stimulant use disorder, cannabis use, BPD, hypertension, hyperlipidemia, prediabetes, gastroesophageal reflex disease, and a pulmonary nodule. On initial presentation, the patient was prescribed buprenorphine 24 mg/naloxone 6 mg, quetiapine 400 mg, duloxetine 120 mg, and prazosin 15 mg per day. At the time of pharmacy consultation, last reported alcohol or nonprescribed opioid use was about 6 months prior, and methamphetamine use about 1 month prior, with ongoing cannabis use. The patient had a history of participating in cognitive processing therapy, dialectical behavior therapy (DBT), and residential treatment for both PTSD and substance use. Additionally, he was actively participating in contingency management for stimulant use disorder and self-management and recovery training group.

The patient reported ongoing mood lability, hypervigilance, and oversedation with current psychotropic regimen. The prescriber of his medication for opioid use disorder also reported the patient experienced labile mood, impulsive behavior, and anger outbursts. In the setting of intolerability due to oversedation with quetiapine, cardiometabolic risk, and lack of clear indication for use, the patient and health care practitioner (HCP) agreed to taper quetiapine and initiate a trial of DVP for affective dysregulation and impulsive-behavioral dyscontrol. To prevent cholinergic rebound and insomnia with abrupt discontinuation of quetiapine, DVP and quetiapine were cross tapered. The following cross taper was prescribed: quetiapine 300 mg and DVP 500 mg per day for week 1; quetiapine 200 mg and DVP 500 mg per day for week 2; quetiapine 100 mg and DVP 1000 mg per day for week 3; quetiapine 50 mg and DVP 1000 mg per day for week 4; followed by DVP 1000 mg per day and discontinuation of quetiapine.

During a 4-week follow-up appointment, the patient reported appropriate completion of cross taper but stopped taking the DVP 3 days prior to the appointment due to self-reported lack of efficacy. For this reason, serum VPA level was not obtained. After discussion with his HCP, the patient restarted DVP 1000 mg per day without retitration with plans to get laboratory tests in 1 week. The next week, laboratory tests were notable for VPA level 28.74 (reference range, 50-100) µg/mL, low WBC 3.51 (reference range, 4.00-10.00) 10³/mcL, platelets 169 (reference range, 150-420) 10³/mcL, and low ANC 1.00 (reference range, 1.50-7.40) 10³/mcL (Table). This raised clinical concern as the patient had no history of documented neutropenia or leukopenia, with most recent complete blood count (CBC) prior to DVP initiation 3 months earlier while prescribed quetiapine.

Discussion

Our case report describes isolated neutropenia and leukopenia that developed after a cross taper from quetiapine to DVP. Hematologic abnormalities resolved after discontinuation of DVP, suggesting a likely correlation. DVP has a well-established, dose-related prevalence of thrombocytopenia occurring in up to 27% of patients.¹ Fewer case reports exist on neutropenia and leukopenia. DVP-induced neutropenia is thought to be a result of direct bone marrow suppression, whereas the more commonly occurring blood dyscrasia, thrombocytopenia, is thought to be caused by an antibody-mediated destruction of platelets.⁶

Management of DVP-induced thrombocytopenia is often dependent on the severity of the reaction. In mild-to-moderate cases, intervention may not be necessary as thrombocytopenia has been shown to resolve without adjustment to DVP therapy.¹ In more severe or symptomatic cases, dose reduction or discontinuation of the offending agent is recommended, typically resulting in resolution shortly following pharmacologic intervention.

Guidance on the management of other drug-induced hematologic abnormalities, such as neutropenia and leukopenia are not as well established. A 2019 systematic review of idiosyncratic drug-induced neutropenia suggested that continuing the offending drug with strict monitoring could be considered in cases of mild neutropenia. In cases of moderate neutropenia, the author suggests temporary cessation of the drug and reinstatement once neutrophil count normalizes and definitive cessation of the drug in severe cases.³⁰

In our case, continuing the offending agent with close monitoring was considered, similar to the well-established management of clozapine-induced neutropenia. However, due to the concern that the ANC was bordering moderate neutropenia in the absence of a therapeutic VPA level as well as a significant reduction in platelets, although not meeting criteria for thrombocytopenia, the decision was made to err on the side of caution and discontinue the most likely offending agent.

It is important to highlight that DVP was replacing quetiapine in the form of a cross taper. Quetiapine is structurally similar to clozapine. While clozapine has strict monitoring requirements related to neutropenia, blood dyscrasias with quetiapine therapy are rare. Quetiapine-induced hematologic abnormalities may be due to direct toxicity or to an immune-mediated mechanism, leading to bone marrow suppression.²⁰ Case reports documenting blood dyscrasias with the combination of DVP and quetiapine were identified during literature review.^15-19 Despite these case reports, we believe DVP was the primary offending agent in our case as the patient’s last dose of quetiapine was 2 weeks before obtaining the abnormal CBC. There was no history of blood dyscrasias with quetiapine monotherapy; however, the effect of the combination of DVP and quetiapine is unknown as no CBC was obtained during the cross-taper period.

Although there are no FDA-approved medications for the treatment of BPD, mood stabilizers, including DVP, have some research to support their use for the treatment of affective dysregulation and impulsive-behavioral dyscontrol.^26-28 In our case, DVP was selected due to the evidence for use in BPD and ability to assess adherence with therapeutic monitoring. Although polypharmacy is a concern in patients with BPD, in our case we believed that the patient’s ongoing mood lability and impulsive behaviors warranted pharmacologic intervention. Additionally, DVP provided an advantage in its ability to quickly titrate to therapeutic dose when compared with lamotrigine and a lower risk of cognitive AEs when compared with topiramate.

Conclusions

To our knowledge, this case report demonstrates the first published case of neutropenia and leukopenia related to DVP therapy for the treatment of BPD. Routine CBC monitoring is recommended with DVP therapy, and our case highlights the importance of evaluating for not only thrombocytopenia, but also other blood dyscrasias during the titration phase even in the absence of a therapeutic VPA level. Further studies are warranted to determine incidence of DVP-related neutropenia and leukopenia and to evaluate the safety of continuing DVP in cases of mild-to-moderate neutropenia with close monitoring.

The preclinical phase of chronic lymphocytic leukemia (CLL) may be exist longer than previously thought, even in adverse-prognostic cases, as suggested by a sequencing analysis of blood samples obtained up to 22 years prior to CLL diagnosis.

Previous analyses showed that monoclonal B-cell lymphocytosis (MBL), a CLL precursor state, has been detected up to 6 years before CLL diagnosis, the investigators explained, noting that “[a]nother prognostically relevant immunogenetic feature of CLL concerns the stereotype of the B-cell receptor immunoglobulins (BcR IG).”

“Indeed, distinct stereotyped subsets can be defined by the expression of shared sequence motifs and are associated with particular presentation and outcomes,” P. Martijn Kolijn, PhD, a researcher in the department of immunology at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues wrote in a brief report published online in Blood. In an effort to “gain insight into the composition of the BcR IG repertoire during the early stages of CLL,” the investigators utilized next-generation sequencing to analyze 124 blood samples taken from healthy individuals up to 22 years before they received a diagnosis of CLL or small lymphocytic leukemia (SLL). An additional 118 matched control samples were also analyzed.

Study subjects were participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

“First, unsurprisingly, we observed a significant difference in the frequency of the dominant clonotype in CLL patients versus controls with a median frequency of 54.9%, compared to only 0.38% in controls,” they wrote.

Among 28 patients whose lymphocyte counts were measured at baseline, 10 showed evidence of lymphocytosis up to 8 years before CLL diagnosis.

This suggests undiagnosed instances of high-count MBL (cases with a cell count above 0.5x 109 cells/L, which can progress to CLL) or asymptomatic CLL, they explained.

“In contrast, next-generation sequencing results showed detectable skewing of the IGH gene repertoire in 21/28 patients up to 15 years before CLL diagnosis, often in the absence of elevated lymphocyte counts,” they wrote. “Remarkably, some patients with CLL requiring treatment and clinical transformation to an aggressive B-cell lymphoma displayed considerable skewing in the IGH gene repertoire even 16 years before CLL diagnosis.”

Patients with a prediagnostic IGHV-unmutated dominant clonotype had significantly shorter overall survival after CLL diagnosis than did those with an IGHV-mutated clonotype, they noted.

“Furthermore, at early timepoints (>10 years before diagnosis), patients with a high dominant clonotype frequency were more likely to be IGHV mutated, whereas closer to diagnosis this tendency was lost, indicating that the prediagnostic phase may be even longer than 16 years for [mutated] CLL patients,” they added.

The investigators also found that:

• Twenty-five patients carried stereotyped BcR IG up to 17 years prior to CLL diagnosis, and of these, 10 clonotypes were assigned to minor subsets and 15 to major CLL subsets. Among the latter, 14 of the 15 belonged to high-risk subsets, and most of those showed a trend for faster disease evolution.
• High frequency of the dominant clonotype was evident in samples obtained less than 6 years before diagnosis, whereas high-risk stereotyped clonotypes found longer before diagnosis (as early as 16 years) tended to have a lower dominant clonotype frequency (<20% of IGH gene repertoire)
• The stereotyped BcR IG matched the clonotype at diagnosis for both patients with diagnostic material.
• No stereotyped subsets were identified among the dominant clonotypes of the healthy controls.

“To our knowledge, the dynamics of the emergence of biclonality in an MBL patient and subsequent progression to CLL have never been captured in such a convincing manner,” they noted.

The findings “extend current knowledge on the evolution of the IGH repertoire prior to CLL diagnosis, highlighting that even high-risk CLL subtypes may display a prolonged indolent preclinical stage,” they added, speculating that “somatic genetic aberrations, (auto)stimulation, epigenetic and/or microenvironmental influences are required for the transformation into overt CLL.”

The investigators also noted that since the observed skewing in the IGH gene repertoire often occurs prior to B-cell lymphocytosis, they consider the findings “a novel extension to the characterization of MBL.”

“Further studies may prove invaluable in the clinical distinction between ‘progressing’ MBL versus ‘stable’ MBL. Notwithstanding the above, we emphasize that early detection is only warranted if it provides clear benefits to patient care,” they concluded.

In a related commentary, Gerald Marti, MD, PhD, of the National Heart, Lung, and Blood Institute, emphasized that the findings “represent the earliest detection of a clonotypic precursor cell for CLL.” .

They also raise new questions and point to new directions for research, Dr. Marti noted.

“Where do we go from here? CLL has a long evolutionary history in which early branching may start as an oligoclonal process (antigen stimulation) and include driver mutations,” he wrote. “A long-term analysis of the B-cell repertoire in familial CLL might shed light on this process. Further clarification of the mechanisms of age-related immune senescence is also of interest.”

The study authors and Dr. Marti reported having no competing financial interests.

The preclinical phase of chronic lymphocytic leukemia (CLL) may be exist longer than previously thought, even in adverse-prognostic cases, as suggested by a sequencing analysis of blood samples obtained up to 22 years prior to CLL diagnosis.

Previous analyses showed that monoclonal B-cell lymphocytosis (MBL), a CLL precursor state, has been detected up to 6 years before CLL diagnosis, the investigators explained, noting that “[a]nother prognostically relevant immunogenetic feature of CLL concerns the stereotype of the B-cell receptor immunoglobulins (BcR IG).”

“Indeed, distinct stereotyped subsets can be defined by the expression of shared sequence motifs and are associated with particular presentation and outcomes,” P. Martijn Kolijn, PhD, a researcher in the department of immunology at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues wrote in a brief report published online in Blood. In an effort to “gain insight into the composition of the BcR IG repertoire during the early stages of CLL,” the investigators utilized next-generation sequencing to analyze 124 blood samples taken from healthy individuals up to 22 years before they received a diagnosis of CLL or small lymphocytic leukemia (SLL). An additional 118 matched control samples were also analyzed.

Study subjects were participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

“First, unsurprisingly, we observed a significant difference in the frequency of the dominant clonotype in CLL patients versus controls with a median frequency of 54.9%, compared to only 0.38% in controls,” they wrote.

Among 28 patients whose lymphocyte counts were measured at baseline, 10 showed evidence of lymphocytosis up to 8 years before CLL diagnosis.

This suggests undiagnosed instances of high-count MBL (cases with a cell count above 0.5x 109 cells/L, which can progress to CLL) or asymptomatic CLL, they explained.

“In contrast, next-generation sequencing results showed detectable skewing of the IGH gene repertoire in 21/28 patients up to 15 years before CLL diagnosis, often in the absence of elevated lymphocyte counts,” they wrote. “Remarkably, some patients with CLL requiring treatment and clinical transformation to an aggressive B-cell lymphoma displayed considerable skewing in the IGH gene repertoire even 16 years before CLL diagnosis.”

Patients with a prediagnostic IGHV-unmutated dominant clonotype had significantly shorter overall survival after CLL diagnosis than did those with an IGHV-mutated clonotype, they noted.

“Furthermore, at early timepoints (>10 years before diagnosis), patients with a high dominant clonotype frequency were more likely to be IGHV mutated, whereas closer to diagnosis this tendency was lost, indicating that the prediagnostic phase may be even longer than 16 years for [mutated] CLL patients,” they added.

The investigators also found that:

• Twenty-five patients carried stereotyped BcR IG up to 17 years prior to CLL diagnosis, and of these, 10 clonotypes were assigned to minor subsets and 15 to major CLL subsets. Among the latter, 14 of the 15 belonged to high-risk subsets, and most of those showed a trend for faster disease evolution.
• High frequency of the dominant clonotype was evident in samples obtained less than 6 years before diagnosis, whereas high-risk stereotyped clonotypes found longer before diagnosis (as early as 16 years) tended to have a lower dominant clonotype frequency (<20% of IGH gene repertoire)
• The stereotyped BcR IG matched the clonotype at diagnosis for both patients with diagnostic material.
• No stereotyped subsets were identified among the dominant clonotypes of the healthy controls.

“To our knowledge, the dynamics of the emergence of biclonality in an MBL patient and subsequent progression to CLL have never been captured in such a convincing manner,” they noted.

The findings “extend current knowledge on the evolution of the IGH repertoire prior to CLL diagnosis, highlighting that even high-risk CLL subtypes may display a prolonged indolent preclinical stage,” they added, speculating that “somatic genetic aberrations, (auto)stimulation, epigenetic and/or microenvironmental influences are required for the transformation into overt CLL.”

The investigators also noted that since the observed skewing in the IGH gene repertoire often occurs prior to B-cell lymphocytosis, they consider the findings “a novel extension to the characterization of MBL.”

“Further studies may prove invaluable in the clinical distinction between ‘progressing’ MBL versus ‘stable’ MBL. Notwithstanding the above, we emphasize that early detection is only warranted if it provides clear benefits to patient care,” they concluded.

In a related commentary, Gerald Marti, MD, PhD, of the National Heart, Lung, and Blood Institute, emphasized that the findings “represent the earliest detection of a clonotypic precursor cell for CLL.” .

They also raise new questions and point to new directions for research, Dr. Marti noted.

“Where do we go from here? CLL has a long evolutionary history in which early branching may start as an oligoclonal process (antigen stimulation) and include driver mutations,” he wrote. “A long-term analysis of the B-cell repertoire in familial CLL might shed light on this process. Further clarification of the mechanisms of age-related immune senescence is also of interest.”

The study authors and Dr. Marti reported having no competing financial interests.

The preclinical phase of chronic lymphocytic leukemia (CLL) may be exist longer than previously thought, even in adverse-prognostic cases, as suggested by a sequencing analysis of blood samples obtained up to 22 years prior to CLL diagnosis.

Previous analyses showed that monoclonal B-cell lymphocytosis (MBL), a CLL precursor state, has been detected up to 6 years before CLL diagnosis, the investigators explained, noting that “[a]nother prognostically relevant immunogenetic feature of CLL concerns the stereotype of the B-cell receptor immunoglobulins (BcR IG).”

“Indeed, distinct stereotyped subsets can be defined by the expression of shared sequence motifs and are associated with particular presentation and outcomes,” P. Martijn Kolijn, PhD, a researcher in the department of immunology at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues wrote in a brief report published online in Blood. In an effort to “gain insight into the composition of the BcR IG repertoire during the early stages of CLL,” the investigators utilized next-generation sequencing to analyze 124 blood samples taken from healthy individuals up to 22 years before they received a diagnosis of CLL or small lymphocytic leukemia (SLL). An additional 118 matched control samples were also analyzed.

Study subjects were participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

“First, unsurprisingly, we observed a significant difference in the frequency of the dominant clonotype in CLL patients versus controls with a median frequency of 54.9%, compared to only 0.38% in controls,” they wrote.

Among 28 patients whose lymphocyte counts were measured at baseline, 10 showed evidence of lymphocytosis up to 8 years before CLL diagnosis.

This suggests undiagnosed instances of high-count MBL (cases with a cell count above 0.5x 109 cells/L, which can progress to CLL) or asymptomatic CLL, they explained.

“In contrast, next-generation sequencing results showed detectable skewing of the IGH gene repertoire in 21/28 patients up to 15 years before CLL diagnosis, often in the absence of elevated lymphocyte counts,” they wrote. “Remarkably, some patients with CLL requiring treatment and clinical transformation to an aggressive B-cell lymphoma displayed considerable skewing in the IGH gene repertoire even 16 years before CLL diagnosis.”

Patients with a prediagnostic IGHV-unmutated dominant clonotype had significantly shorter overall survival after CLL diagnosis than did those with an IGHV-mutated clonotype, they noted.

“Furthermore, at early timepoints (>10 years before diagnosis), patients with a high dominant clonotype frequency were more likely to be IGHV mutated, whereas closer to diagnosis this tendency was lost, indicating that the prediagnostic phase may be even longer than 16 years for [mutated] CLL patients,” they added.

The investigators also found that:

• Twenty-five patients carried stereotyped BcR IG up to 17 years prior to CLL diagnosis, and of these, 10 clonotypes were assigned to minor subsets and 15 to major CLL subsets. Among the latter, 14 of the 15 belonged to high-risk subsets, and most of those showed a trend for faster disease evolution.
• High frequency of the dominant clonotype was evident in samples obtained less than 6 years before diagnosis, whereas high-risk stereotyped clonotypes found longer before diagnosis (as early as 16 years) tended to have a lower dominant clonotype frequency (<20% of IGH gene repertoire)
• The stereotyped BcR IG matched the clonotype at diagnosis for both patients with diagnostic material.
• No stereotyped subsets were identified among the dominant clonotypes of the healthy controls.

“To our knowledge, the dynamics of the emergence of biclonality in an MBL patient and subsequent progression to CLL have never been captured in such a convincing manner,” they noted.

The findings “extend current knowledge on the evolution of the IGH repertoire prior to CLL diagnosis, highlighting that even high-risk CLL subtypes may display a prolonged indolent preclinical stage,” they added, speculating that “somatic genetic aberrations, (auto)stimulation, epigenetic and/or microenvironmental influences are required for the transformation into overt CLL.”

The investigators also noted that since the observed skewing in the IGH gene repertoire often occurs prior to B-cell lymphocytosis, they consider the findings “a novel extension to the characterization of MBL.”

“Further studies may prove invaluable in the clinical distinction between ‘progressing’ MBL versus ‘stable’ MBL. Notwithstanding the above, we emphasize that early detection is only warranted if it provides clear benefits to patient care,” they concluded.

In a related commentary, Gerald Marti, MD, PhD, of the National Heart, Lung, and Blood Institute, emphasized that the findings “represent the earliest detection of a clonotypic precursor cell for CLL.” .

They also raise new questions and point to new directions for research, Dr. Marti noted.

“Where do we go from here? CLL has a long evolutionary history in which early branching may start as an oligoclonal process (antigen stimulation) and include driver mutations,” he wrote. “A long-term analysis of the B-cell repertoire in familial CLL might shed light on this process. Further clarification of the mechanisms of age-related immune senescence is also of interest.”

The study authors and Dr. Marti reported having no competing financial interests.

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

 

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

 

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Federal Practitioner, in collaboration with the Association of VA Hematology/Oncology (AVAHO), present the 2022 edition of Cancer Data Trends (click to view the digital edition). This special issue provides updates on some of the top cancers and related concerns affecting veterans through original infographics and visual storytelling.

 

In this issue:

• Exposure-Related Cancers
• Cancer in Women
• Genitourinary Cancers
• Gastrointestinal Cancers
• Telehealth in Oncology
•  Precision Oncology
•  Palliative and Hospice Care
•  Alcohol and Cancer
•  Lung Cancer
•  Oropharyngeal Cancer
• Hematologic Cancers

Federal Practitioner and AVAHO would like to thank the following experts for their contributions to this issue:

Anita Aggarwal, DO, PhD; Sara Ahmed, PhD; Katherine Faricy-Anderson, MD; Apar Kishor Ganti, MD, MS; Solomon A Graf, MD; Kate Hendricks Thomas, PhD; Michael Kelley, MD; Mark Klein, MD, Gina McWhirter, MSN, MBA, RN; Bruce Montgomery, MD; Vida Almario Passero, MD, MBA; Thomas D Rodgers, MD; Vlad C Sandulache, MD, PhD; David H Wang, MD, PhD.

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).