Hematologic Malignancies

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Newer targeted drugs for chronic lymphocytic leukemia also appear to have a beneficial impact on underlying autoimmune cytopenias (AICs), results of a large retrospective study suggest.

Many autoimmune cytopenias improved or resolved during treatment with ibrutinib, idelalisib, or venetoclax, according to authors of the study, which appears in the journal Blood.

Treatment-emergent autoimmune cytopenias were seen in a “negligible portion” of patients overall, according to the report. The prevalence was about 1% each for patients treated with ibrutinib or idelalisib, though seen more frequently (at 7%) among patients who received venetoclax.

Nevertheless, treatment-emergent autoimmune cytopenias were “easily manageable” without interventions such as steroids and rituximab, and without need to interrupt the targeted treatment for chronic lymphocytic leukemia (CLL), according to the authors, led by Candida Vitale, MD, PhD, of the department of molecular biotechnology and health sciences at the University of Torino in Italy.

“Ibrutinib, idelalisib, and venetoclax have a beneficial impact on CLL-related preexisting AICs, achieving in most patients, in parallel with the consolidated antitumor efficacy, an effective control of the autoimmune phenomena,” Dr. Vitale and coauthors wrote in their report.
 

Study results

The retrospective study included 815 patients, of whom 572 were treated with ibrutinib, 143 with idelalisib plus rituximab, and 100 with venetoclax. Nine percent of ibrutinib-treated patients and 12% of venetoclax-treated patients also received an anti-CD20 monoclonal antibody, rituximab or obinutuzumab.

One hundred and four patients (13%) had preexisting autoimmune cytopenias, though the majority were resolved or controlled at the time targeted therapy was started.

Of patients with autoimmune cytopenias that were unresolved at the beginning of targeted therapy, 80% improved or resolved after starting targeted treatment, authors reported.

Most patients who developed autoimmune cytopenias on treatment had high-risk features such as unmutated IGHV, del(17)p, or TP53 mutation, according to the report.

Those treatment-emergent autoimmune cytopenias were seen in 1% of the ibrutinib group, 0.9% of the idelalisib group, and 7% of the venetoclax group. Out of 12 total treatment-emergent autoimmune cytopenias, all but 2 were resolved or controlled with dose reductions or temporary suspensions and use of steroids or rituximab, the report shows.

The higher incidence of autoimmune cytopenias in the venetoclax group held steady even when considering just the patients who had relapsed/refractory disease or had at least two prior lines of therapy, suggesting a “more meaningful” incidence, compared to what was observed for ibrutinib and idelalisib, the investigators said.

“However, the risk of autoimmune cytopenia episodes should not limit the use of venetoclax, considering the strong efficacy of this drug in treating patients with CLL, including those with high-risk features, and the possibility of effectively managing autoimmune complications, mostly without treatment interruption,” they concluded in their report.
 

Implications for patients with CLL

Findings of this study indicate that targeted therapies are effective for managing both CLL and autoimmune cytopenias, according to Carol Moreno, MD, PhD, of Hospital Sant Pau in Barcelona.

Moreover, the targeted therapies do not appear to change the overall prevalence of autoimmune cytopenias, compared to untreated patients, Dr. Moreno said in a commentary on the findings also published in Blood.

“These results are consistent with the concept that targeted therapies are not associated with a higher risk of autoimmune cytopenias, and that, if present, can be managed with immunosuppressive agents,” she wrote.
 

Autoimmune cytopenias and CLL

Autoimmune cytopenias are a relatively common complication of CLL, occurring in 5%-9% of CLL patients, Dr. Vitale and coauthors said in their report. The most common presentations include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).

Evidence from earlier studies suggests that treatment for CLL may trigger autoimmune cytopenias. Results of retrospective studies in the 1990s linked single-agent fludarabine to increased risk of AIHA, Dr. Moreno said in the commentary.

However, subsequent studies showed that fludarabine plus cyclophosphamide (FC) and fludarabine, cyclophosphamide, and rituximab (FCR) were associated with low proportions of AIHA.

“Taken together, these results convincingly suggest that rather than treatment, it is the lack of response to it that conveys a higher risk of AIC,” Dr. Moreno wrote.
 

Management considerations

There are currently no clinical practice guidelines that advise on how to manage patients who develop AICs during targeted treatment for CLL, Dr. Vitale and colleagues said in their report.

However, this new study data may help inform management of patients with CLL and an autoimmune cytopenia, Dr. Moreno said in the commentary.

If the patient doesn’t immediately require CLL treatment, patients can be managed according to existing guidelines for AIHA and ITP, she said. “Nonresponding patients should be given CLL therapy,” she added.

For CLL patients who do require therapy and have a preexisting or treatment-emergent AIC, a “CLL-oriented” treatment approach could be considered, according to Dr. Moreno.

“A reasonable approach consists of a short course (2 to 4 weeks) of corticosteroids followed by effective CLL therapy (i.e., FCR, bendamustine plus rituximab or ibrutinib), depending on the clinical situation,” she added.

Dr. Vitale reported receiving consultancy fees from Janssen outside the submitted work. Dr. Moreno declared no competing financial interests related to her commentary.

Newer targeted drugs for chronic lymphocytic leukemia also appear to have a beneficial impact on underlying autoimmune cytopenias (AICs), results of a large retrospective study suggest.

Many autoimmune cytopenias improved or resolved during treatment with ibrutinib, idelalisib, or venetoclax, according to authors of the study, which appears in the journal Blood.

Treatment-emergent autoimmune cytopenias were seen in a “negligible portion” of patients overall, according to the report. The prevalence was about 1% each for patients treated with ibrutinib or idelalisib, though seen more frequently (at 7%) among patients who received venetoclax.

Nevertheless, treatment-emergent autoimmune cytopenias were “easily manageable” without interventions such as steroids and rituximab, and without need to interrupt the targeted treatment for chronic lymphocytic leukemia (CLL), according to the authors, led by Candida Vitale, MD, PhD, of the department of molecular biotechnology and health sciences at the University of Torino in Italy.

“Ibrutinib, idelalisib, and venetoclax have a beneficial impact on CLL-related preexisting AICs, achieving in most patients, in parallel with the consolidated antitumor efficacy, an effective control of the autoimmune phenomena,” Dr. Vitale and coauthors wrote in their report.
 

Study results

The retrospective study included 815 patients, of whom 572 were treated with ibrutinib, 143 with idelalisib plus rituximab, and 100 with venetoclax. Nine percent of ibrutinib-treated patients and 12% of venetoclax-treated patients also received an anti-CD20 monoclonal antibody, rituximab or obinutuzumab.

One hundred and four patients (13%) had preexisting autoimmune cytopenias, though the majority were resolved or controlled at the time targeted therapy was started.

Of patients with autoimmune cytopenias that were unresolved at the beginning of targeted therapy, 80% improved or resolved after starting targeted treatment, authors reported.

Most patients who developed autoimmune cytopenias on treatment had high-risk features such as unmutated IGHV, del(17)p, or TP53 mutation, according to the report.

Those treatment-emergent autoimmune cytopenias were seen in 1% of the ibrutinib group, 0.9% of the idelalisib group, and 7% of the venetoclax group. Out of 12 total treatment-emergent autoimmune cytopenias, all but 2 were resolved or controlled with dose reductions or temporary suspensions and use of steroids or rituximab, the report shows.

The higher incidence of autoimmune cytopenias in the venetoclax group held steady even when considering just the patients who had relapsed/refractory disease or had at least two prior lines of therapy, suggesting a “more meaningful” incidence, compared to what was observed for ibrutinib and idelalisib, the investigators said.

“However, the risk of autoimmune cytopenia episodes should not limit the use of venetoclax, considering the strong efficacy of this drug in treating patients with CLL, including those with high-risk features, and the possibility of effectively managing autoimmune complications, mostly without treatment interruption,” they concluded in their report.
 

Implications for patients with CLL

Findings of this study indicate that targeted therapies are effective for managing both CLL and autoimmune cytopenias, according to Carol Moreno, MD, PhD, of Hospital Sant Pau in Barcelona.

Moreover, the targeted therapies do not appear to change the overall prevalence of autoimmune cytopenias, compared to untreated patients, Dr. Moreno said in a commentary on the findings also published in Blood.

“These results are consistent with the concept that targeted therapies are not associated with a higher risk of autoimmune cytopenias, and that, if present, can be managed with immunosuppressive agents,” she wrote.
 

Autoimmune cytopenias and CLL

Autoimmune cytopenias are a relatively common complication of CLL, occurring in 5%-9% of CLL patients, Dr. Vitale and coauthors said in their report. The most common presentations include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).

Evidence from earlier studies suggests that treatment for CLL may trigger autoimmune cytopenias. Results of retrospective studies in the 1990s linked single-agent fludarabine to increased risk of AIHA, Dr. Moreno said in the commentary.

However, subsequent studies showed that fludarabine plus cyclophosphamide (FC) and fludarabine, cyclophosphamide, and rituximab (FCR) were associated with low proportions of AIHA.

“Taken together, these results convincingly suggest that rather than treatment, it is the lack of response to it that conveys a higher risk of AIC,” Dr. Moreno wrote.
 

Management considerations

There are currently no clinical practice guidelines that advise on how to manage patients who develop AICs during targeted treatment for CLL, Dr. Vitale and colleagues said in their report.

However, this new study data may help inform management of patients with CLL and an autoimmune cytopenia, Dr. Moreno said in the commentary.

If the patient doesn’t immediately require CLL treatment, patients can be managed according to existing guidelines for AIHA and ITP, she said. “Nonresponding patients should be given CLL therapy,” she added.

For CLL patients who do require therapy and have a preexisting or treatment-emergent AIC, a “CLL-oriented” treatment approach could be considered, according to Dr. Moreno.

“A reasonable approach consists of a short course (2 to 4 weeks) of corticosteroids followed by effective CLL therapy (i.e., FCR, bendamustine plus rituximab or ibrutinib), depending on the clinical situation,” she added.

Dr. Vitale reported receiving consultancy fees from Janssen outside the submitted work. Dr. Moreno declared no competing financial interests related to her commentary.

Newer targeted drugs for chronic lymphocytic leukemia also appear to have a beneficial impact on underlying autoimmune cytopenias (AICs), results of a large retrospective study suggest.

Many autoimmune cytopenias improved or resolved during treatment with ibrutinib, idelalisib, or venetoclax, according to authors of the study, which appears in the journal Blood.

Treatment-emergent autoimmune cytopenias were seen in a “negligible portion” of patients overall, according to the report. The prevalence was about 1% each for patients treated with ibrutinib or idelalisib, though seen more frequently (at 7%) among patients who received venetoclax.

Nevertheless, treatment-emergent autoimmune cytopenias were “easily manageable” without interventions such as steroids and rituximab, and without need to interrupt the targeted treatment for chronic lymphocytic leukemia (CLL), according to the authors, led by Candida Vitale, MD, PhD, of the department of molecular biotechnology and health sciences at the University of Torino in Italy.

“Ibrutinib, idelalisib, and venetoclax have a beneficial impact on CLL-related preexisting AICs, achieving in most patients, in parallel with the consolidated antitumor efficacy, an effective control of the autoimmune phenomena,” Dr. Vitale and coauthors wrote in their report.
 

Study results

The retrospective study included 815 patients, of whom 572 were treated with ibrutinib, 143 with idelalisib plus rituximab, and 100 with venetoclax. Nine percent of ibrutinib-treated patients and 12% of venetoclax-treated patients also received an anti-CD20 monoclonal antibody, rituximab or obinutuzumab.

One hundred and four patients (13%) had preexisting autoimmune cytopenias, though the majority were resolved or controlled at the time targeted therapy was started.

Of patients with autoimmune cytopenias that were unresolved at the beginning of targeted therapy, 80% improved or resolved after starting targeted treatment, authors reported.

Most patients who developed autoimmune cytopenias on treatment had high-risk features such as unmutated IGHV, del(17)p, or TP53 mutation, according to the report.

Those treatment-emergent autoimmune cytopenias were seen in 1% of the ibrutinib group, 0.9% of the idelalisib group, and 7% of the venetoclax group. Out of 12 total treatment-emergent autoimmune cytopenias, all but 2 were resolved or controlled with dose reductions or temporary suspensions and use of steroids or rituximab, the report shows.

The higher incidence of autoimmune cytopenias in the venetoclax group held steady even when considering just the patients who had relapsed/refractory disease or had at least two prior lines of therapy, suggesting a “more meaningful” incidence, compared to what was observed for ibrutinib and idelalisib, the investigators said.

“However, the risk of autoimmune cytopenia episodes should not limit the use of venetoclax, considering the strong efficacy of this drug in treating patients with CLL, including those with high-risk features, and the possibility of effectively managing autoimmune complications, mostly without treatment interruption,” they concluded in their report.
 

Implications for patients with CLL

Findings of this study indicate that targeted therapies are effective for managing both CLL and autoimmune cytopenias, according to Carol Moreno, MD, PhD, of Hospital Sant Pau in Barcelona.

Moreover, the targeted therapies do not appear to change the overall prevalence of autoimmune cytopenias, compared to untreated patients, Dr. Moreno said in a commentary on the findings also published in Blood.

“These results are consistent with the concept that targeted therapies are not associated with a higher risk of autoimmune cytopenias, and that, if present, can be managed with immunosuppressive agents,” she wrote.
 

Autoimmune cytopenias and CLL

Autoimmune cytopenias are a relatively common complication of CLL, occurring in 5%-9% of CLL patients, Dr. Vitale and coauthors said in their report. The most common presentations include autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP).

Evidence from earlier studies suggests that treatment for CLL may trigger autoimmune cytopenias. Results of retrospective studies in the 1990s linked single-agent fludarabine to increased risk of AIHA, Dr. Moreno said in the commentary.

However, subsequent studies showed that fludarabine plus cyclophosphamide (FC) and fludarabine, cyclophosphamide, and rituximab (FCR) were associated with low proportions of AIHA.

“Taken together, these results convincingly suggest that rather than treatment, it is the lack of response to it that conveys a higher risk of AIC,” Dr. Moreno wrote.
 

Management considerations

There are currently no clinical practice guidelines that advise on how to manage patients who develop AICs during targeted treatment for CLL, Dr. Vitale and colleagues said in their report.

However, this new study data may help inform management of patients with CLL and an autoimmune cytopenia, Dr. Moreno said in the commentary.

If the patient doesn’t immediately require CLL treatment, patients can be managed according to existing guidelines for AIHA and ITP, she said. “Nonresponding patients should be given CLL therapy,” she added.

For CLL patients who do require therapy and have a preexisting or treatment-emergent AIC, a “CLL-oriented” treatment approach could be considered, according to Dr. Moreno.

“A reasonable approach consists of a short course (2 to 4 weeks) of corticosteroids followed by effective CLL therapy (i.e., FCR, bendamustine plus rituximab or ibrutinib), depending on the clinical situation,” she added.

Dr. Vitale reported receiving consultancy fees from Janssen outside the submitted work. Dr. Moreno declared no competing financial interests related to her commentary.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

Patients with relapsed or refractory B-cell non-Hodgkin lymphomas who are not candidates for hematopoietic stem cell transplant have a generally poor prognosis and few treatment options, but an experimental combination of the antibody-drug conjugate naratuximab with rituximab showed promising efficacy and acceptable safety in these patients in a phase 2 trial.

Among patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) the combination was associated with a 44.7% overall response rate, including 31.6% complete responses, and two-thirds of patients had responses lasting more than 12 months, reported Moshe Yair Levy, MD, from Texas Oncology–Baylor Charles A Sammons Cancer Center in Dallas.

“This is, in my viewpoint, very exciting therapy,” he said in a question-and-answer session following his presentation of the data in a late-breaking abstract session during the European Hematology Association annual congress. (Abstract LB1903).

Naratuximab emtansine is an investigational antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody against CD37, a surface marker on B lymphocytes that is highly expressed in non-Hodgkin lymphoma (NHL), conjugated to a cytotoxic derivative of maitansine.

CD37 is also an internalizable cell-surface antigen, making it an attractive candidate for an ADC approach.

In a phase 1 trial, naratuximab monotherapy showed a good safety profile and a 22% overall response rate, Dr. Levy noted.

“What they found is that, if you coadminister this ADC with rituximab, you’re actually going to get more internalization of the CD37 monoclonal, therefore more payload delivered to your target cells,” he said.

He reported results of a multicenter, adaptive phase 2 study of the combination in patients with DLBCL and other relapsed/refractory NHL.
 

DLBCL and others

The trial was divided into two parts, with the first consisting of a safety run-in phase with expansion in patients with confirmed diagnoses of relapsed/refractory NHL, including DLBCL, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma.

Patients with double- or triple-hit disease (with translocations in MYC plus either BCL2 and/or BCL6), bulky disease, or transformed lymphoma were eligible.

The second part consisted of two cohorts of patients with DLBCL treated with naratuximab and rituximab either weekly or every 3 weeks.

All patients in the study had received one to six prior lines of therapy, and had Eastern Cooperative Oncology Group performance status of 0-2. Patients with CNS lymphomas or prior anti-CD37 targeting therapy were excluded.

The safety population included 50 patients with DLBCL assigned to therapy every 3 weeks, 30 assigned to weekly therapy, and 20 patients with other NHL.
 

DLBCL efficacy

A total of 76 patients with DLBCL were evaluable for efficacy.

The ORR was 44% for patients in both the weekly and every 3 week cohorts, with 31.6% having complete responses.

Among 61 patients with nonbulky disease (longest diameter 7.5 cm or less), the ORR was 50.8%, and among 28 patients who had three or more prior lines of therapy the ORR was 46.4%, with 32.1% having a complete response.

Among responders followed for a median of 15 months, the median duration of response was not reached, and 66% had responses lasting beyond 12 months.

In the weekly dosing DLBCL cohort, 53.3% of patients discontinued treatment of both study drugs because of disease progression, as did 58% of those in the every 3 week cohort, and 30% of patients with other lymphomas. Only eight patients discontinued the combination because of treatment-emergent adverse events. Six patients had treatment-emergent adverse events leading to naratuximab dose reduction.

The most common grade 3 or 4 adverse events were neutropenia, leukopenia, lymphopenia and thrombocytopenias. Dr. Levy commented that the use of granulocyte colony-stimulating factor, which was not mandatory in the study, would likely have lowered the incidence of cytopenias.

There were 10 deaths during the study, 2 of which were considered to be treatment related, occurring in 1 patient each in the DLBCL dosing cohorts; 1 of the patients died from pneumonitis, and the other from left ventricular heart failure.

Other patients deaths were attributed to non–treatment-related cardiac arrest, acute renal failure, exacerbation of chronic heart failure, respiratory failure, multiorgan failure, lung infection, or colon adenocarcinoma.
 

Q 3 weeks suffices

In the question-and-answer session following the presentation, Kenny Lei, MD, from the Chinese University of Hong Kong asked Dr. Levy what the half-life of naratuximab is, and what was the investigator’s rationale for testing a weekly dosing schedule.

“I think the reason they checked the two different regimens, the Q week and the Q 3-week group, is that they noted that [naratuximab] was cleared relatively quickly, and they wanted to see whether or not, by giving Q weekly, when you get a continuous CD37 site occupancy if they would have a better outcome. But as you saw, in the groups there was really no clinically relevant difference in outcome,” Dr. Levy said.

Andrew Davies, MD, PhD, from the University of Southampton (England), asked whether the neutropenia seen in the study was related to myeloid expression of the target of from the off-target deconjugated payload.

“I don’t know that I necessarily have the answer to that,” Dr. Levy replied. “Remember there is the CD20 monoclonal rituximab which we know can cause neutropenia, as well as the CD37 and the target payload. I don’t know if we have enough information to attribute it to one specific component of the therapy,” he said.

The study was funded by Debiopharm International. Dr. Levy disclosed speaker activities for multiple companies, not including Debiopharm. Dr. Lei and Dr. Davies had no disclosures relevant to the study.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.

Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.

The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).

“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
 

A low bar

But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.

“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.

“This is like comparing a mule cart to a Tesla,” he said.

Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.

“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.

Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.

“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.

Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”

But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.

“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
 

GLOW details

Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.

The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.

The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.

After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.

About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
 

Superior PFS

As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).

PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).

IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).

Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.

Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259). ­

One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
 

Safety

In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.

There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.

Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.

Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.

In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.

The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.

Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.

To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).

Cutoff at 80 years of age

Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.

However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.

“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.

However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”

Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.

[email protected]

Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.

To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).

Cutoff at 80 years of age

Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.

However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.

“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.

However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”

Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.

[email protected]

Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.

To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).

Cutoff at 80 years of age

Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.

However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.

“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.

However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”

Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.

[email protected]

Patients with chronic lymphocytic leukemia (CLL) have increased risk for severe COVID-19 disease as well as mortality.

South_agency/Getty Images

Such patients are likely to have compromised immune systems, making them respond poorly to vaccines, as has been seen in studies involving pneumococcal, hepatitis B, and influenza A and B vaccination. 

In order to determine if vaccination against COVID-19 disease will be effective among these patients, researchers performed a study to determine the efficacy of a single COVID-19 vaccine in patients with CLL. They found that the response rate of patients with CLL to vaccination was significantly lower than that of healthy controls, according to the study published in Blood Advances.

Study details

The study (NCT04746092) assessed the humoral immune responses to BNT162b2 mRNA COVID-19 (Pfizer) vaccination in adult patients with CLL and compared responses with those obtained in age-matched healthy controls. Patients received two vaccine doses, 21 days apart, and antibody titers were measured 2-3 weeks after administration of the second dose, according to Yair Herishanu, MD, of the Tel-Aviv Sourasky Medical Center, Tel Aviv University, and colleagues.

Troubling results

The researchers found an antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in only 66 of 167 (39.5%) of all patients with CLL. The response rate of 52 of these responding patients with CLL to the vaccine was significantly lower than that occurring in 52 age- and sex-matched healthy controls (52% vs. 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). 

Among the patients with CLL, the response rate was highest in those who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients, and it was only 16% in patients under treatment at the time of vaccination. 

In patients treated with either BTK inhibitors or venetoclax with and without anti-CD20 antibody, response rates were low (16.0% and 13.6%, respectively). In particular, none of the patients exposed to anti-CD20 antibodies less than 12 months prior to vaccination responded, according to the researchers.

Multivariate analysis showed that the independent predictors of a vaccine response were age (65 years or younger; odds ratio, 3.17; P = .025), sex (women; OR, 3.66; P = .006), lack of active therapy (including treatment naive and previously treated patients; OR 6.59; P < .001), IgG levels 550 mg/dL or greater (OR, 3.70; P = .037), and IgM levels 40mg/dL or greater (OR, 2.92; P = .017). 

Within a median follow-up period of 75 days since the first vaccine dose, none of the CLL patients developed COVID-19 infection, the researchers reported.

“Vaccinated patients with CLL should continue to adhere to masking, social distancing, and vaccination of their close contacts should be strongly recommended. Serological tests after the second injection of the COVID-19 vaccine can provide valuable information to the individual patient and perhaps, may be integrated in future clinical decisions,” the researchers concluded.

The study was sponsored by the Tel-Aviv Sourasky Medical Center. The authors reported that they had no conflicts of interest. 

[email protected] 

Patients with chronic lymphocytic leukemia (CLL) have increased risk for severe COVID-19 disease as well as mortality.

South_agency/Getty Images

Such patients are likely to have compromised immune systems, making them respond poorly to vaccines, as has been seen in studies involving pneumococcal, hepatitis B, and influenza A and B vaccination. 

In order to determine if vaccination against COVID-19 disease will be effective among these patients, researchers performed a study to determine the efficacy of a single COVID-19 vaccine in patients with CLL. They found that the response rate of patients with CLL to vaccination was significantly lower than that of healthy controls, according to the study published in Blood Advances.

Study details

The study (NCT04746092) assessed the humoral immune responses to BNT162b2 mRNA COVID-19 (Pfizer) vaccination in adult patients with CLL and compared responses with those obtained in age-matched healthy controls. Patients received two vaccine doses, 21 days apart, and antibody titers were measured 2-3 weeks after administration of the second dose, according to Yair Herishanu, MD, of the Tel-Aviv Sourasky Medical Center, Tel Aviv University, and colleagues.

Troubling results

The researchers found an antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in only 66 of 167 (39.5%) of all patients with CLL. The response rate of 52 of these responding patients with CLL to the vaccine was significantly lower than that occurring in 52 age- and sex-matched healthy controls (52% vs. 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). 

Among the patients with CLL, the response rate was highest in those who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients, and it was only 16% in patients under treatment at the time of vaccination. 

In patients treated with either BTK inhibitors or venetoclax with and without anti-CD20 antibody, response rates were low (16.0% and 13.6%, respectively). In particular, none of the patients exposed to anti-CD20 antibodies less than 12 months prior to vaccination responded, according to the researchers.

Multivariate analysis showed that the independent predictors of a vaccine response were age (65 years or younger; odds ratio, 3.17; P = .025), sex (women; OR, 3.66; P = .006), lack of active therapy (including treatment naive and previously treated patients; OR 6.59; P < .001), IgG levels 550 mg/dL or greater (OR, 3.70; P = .037), and IgM levels 40mg/dL or greater (OR, 2.92; P = .017). 

Within a median follow-up period of 75 days since the first vaccine dose, none of the CLL patients developed COVID-19 infection, the researchers reported.

“Vaccinated patients with CLL should continue to adhere to masking, social distancing, and vaccination of their close contacts should be strongly recommended. Serological tests after the second injection of the COVID-19 vaccine can provide valuable information to the individual patient and perhaps, may be integrated in future clinical decisions,” the researchers concluded.

The study was sponsored by the Tel-Aviv Sourasky Medical Center. The authors reported that they had no conflicts of interest. 

[email protected] 

Patients with chronic lymphocytic leukemia (CLL) have increased risk for severe COVID-19 disease as well as mortality.

South_agency/Getty Images

Such patients are likely to have compromised immune systems, making them respond poorly to vaccines, as has been seen in studies involving pneumococcal, hepatitis B, and influenza A and B vaccination. 

In order to determine if vaccination against COVID-19 disease will be effective among these patients, researchers performed a study to determine the efficacy of a single COVID-19 vaccine in patients with CLL. They found that the response rate of patients with CLL to vaccination was significantly lower than that of healthy controls, according to the study published in Blood Advances.

Study details

The study (NCT04746092) assessed the humoral immune responses to BNT162b2 mRNA COVID-19 (Pfizer) vaccination in adult patients with CLL and compared responses with those obtained in age-matched healthy controls. Patients received two vaccine doses, 21 days apart, and antibody titers were measured 2-3 weeks after administration of the second dose, according to Yair Herishanu, MD, of the Tel-Aviv Sourasky Medical Center, Tel Aviv University, and colleagues.

Troubling results

The researchers found an antibody-mediated response to the BNT162b2 mRNA COVID-19 vaccine in only 66 of 167 (39.5%) of all patients with CLL. The response rate of 52 of these responding patients with CLL to the vaccine was significantly lower than that occurring in 52 age- and sex-matched healthy controls (52% vs. 100%, respectively; adjusted odds ratio, 0.010; 95% confidence interval, 0.001-0.162; P < .001). 

Among the patients with CLL, the response rate was highest in those who obtained clinical remission after treatment (79.2%), followed by 55.2% in treatment-naive patients, and it was only 16% in patients under treatment at the time of vaccination. 

In patients treated with either BTK inhibitors or venetoclax with and without anti-CD20 antibody, response rates were low (16.0% and 13.6%, respectively). In particular, none of the patients exposed to anti-CD20 antibodies less than 12 months prior to vaccination responded, according to the researchers.

Multivariate analysis showed that the independent predictors of a vaccine response were age (65 years or younger; odds ratio, 3.17; P = .025), sex (women; OR, 3.66; P = .006), lack of active therapy (including treatment naive and previously treated patients; OR 6.59; P < .001), IgG levels 550 mg/dL or greater (OR, 3.70; P = .037), and IgM levels 40mg/dL or greater (OR, 2.92; P = .017). 

Within a median follow-up period of 75 days since the first vaccine dose, none of the CLL patients developed COVID-19 infection, the researchers reported.

“Vaccinated patients with CLL should continue to adhere to masking, social distancing, and vaccination of their close contacts should be strongly recommended. Serological tests after the second injection of the COVID-19 vaccine can provide valuable information to the individual patient and perhaps, may be integrated in future clinical decisions,” the researchers concluded.

The study was sponsored by the Tel-Aviv Sourasky Medical Center. The authors reported that they had no conflicts of interest. 

[email protected] 

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease associated with several known genetic abnormalities, including 17p deletion (del[17p]), 11q deletion (del[11q]), and TP53 gene mutations, which are adverse prognostic markers among patients treated with chemoimmunotherapy.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is approved for patients with untreated, relapsed, or refractory disease, including those with del(17p). Clinicians will soon have the chance to pair it with ublituximab, a next-generation, glycoengineered, type I, anti-CD20 monoclonal antibody that binds to a unique epitope on CD20, differentiating it from rituximab, ofatumumab, and obinutuzumab. Results from the phase 3 GENUINE trial, which were recently published in The Lancet Haematology, showed that ublituximab plus ibrutinib was superior to ibrutinib alone for patients with relapsed or refractory high-risk CLL.

This news organization spoke with Jennifer R. Brown, MD, PhD, director of the CLL Center and institute physician at the Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, both in Boston, about the GENUINE trial and its potential impact on treatment choices going forward.
 

What type of patients were treated in the GENUINE trial?

Dr. Brown: This is a trial among relapsed/refractory CLL patients with 17p or 11q deletion or TP53 mutation. Patients aged 18 years or older with CLL who warranted treatment, as defined by International Workshop on CLL criteria, were eligible if they had previously received at least two cycles of at least one standard treatment regimen, had an Eastern Cooperative Oncology Group performance status of 2 or lower, and had high-risk cytogenetics, defined as the presence of at least one of del(17p), del(11q), or TP53 mutation confirmed by a central laboratory with fluorescence in situ hybridization and/or next-generation sequencing.

What were the main outcomes of the trial?

Originally, the GENUINE trial had coprimary endpoints of progression-free survival (PFS) and overall response rate. Because of slow accrual, it was amended to have one primary endpoint of independent review committee (IRC)–assessed ORR.

IRC-assessed ORR was improved from 65% to 83% with the addition of ublituximab. PFS also improved significantly in the ublituximab group, with an even greater improvement when the analysis was limited to those with del(17p) or TP53 aberrancy, but this outcome was limited by the reduced sample size of the study as well as the relatively short PFS of the ibrutinib arm.

After a median follow-up of 41.6 months, the median IRC-assessed PFS in all treated patients was not reached in the ublituximab plus ibrutinib group after 15 PFS events but was 35.9 months in the ibrutinib group after 25 PFS events (hazard ratio, 0.46; 95% confidence interval, 0.24-0.87; P = .016).

Undetectable minimal residual disease was also seen in 42% of the combination arm, compared with 6% of the ibrutinib arm.
 

What types of adverse events were found in the trial?

The researchers found mostly mild and known side effects of ibrutinib. More atrial fibrillation and neutropenia were seen in the antibody group, but this was not marked.

Most adverse events were of grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and 7 [12%] in the ibrutinib group), anemia (5 [8%] and 5 [9%], respectively), and diarrhea (6 [10%] and 3 [5%], respectively).
 

What about serious adverse events?

Hospitalization from infection was seen, as expected. There were two cardiac arrests and an unexplained death, across both arms, which was concerning, given the known association of ibrutinib with ventricular arrhythmia and sudden death. There were also several hemorrhages, including one fatal one, which was again consistent with the known side effects of ibrutinib.

Are there treatments comparable with ublituximab plus ibrutinib that clinicians should perhaps first consider using?

In terms of other anti-CD20 antibodies, we have two randomized trials that have failed to show a benefit from adding rituximab to ibrutinib.

Obinutuzumab, like ublituximab, is also a next-generation glycoengineered antibody, and it is reasonably likely that it might lead to similar results. However, the only data we have on ibrutinib with obinutuzumab are from a single arm in a more heterogeneous, lower-risk patient population, and it is unlikely that a randomized comparison will ever be done.
 

On the basis of these trial results, how would you use the combination of ublituximab and ibrutinib for your patients?

I would consider the addition of ublituximab to a BTK inhibitor in high-risk patients (once ublituximab is approved). I already usually use a next-generation BTK inhibitor rather than ibrutinib.

Are there any other implications of the GENUINE trial?

I think this trial underscores the importance of studying genetic subgroups of patients separately. In this case, that was done in high-risk patients, but this observation likely also applies to low-risk patients.

Most trials to date have enrolled unselected patient populations, often without stratification, and their results therefore tend to obscure the outcomes in both the very high risk (as studied here) and in the low risk (patients with immunoglobulin heavy chain variable region gene mutations).

Dr. Brown has served as a consultant for AbbVie, Acerta/AstraZeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Genentech/Roche, Janssen, MEI Pharma, Morphosys, and Novartis, and has received research funding from Gilead, Loxo/Lilly, TG Therapeutics, Verastem/SecuraBio.

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

Chronic lymphocytic leukemia (CLL) patients present significant problems with regard to COVID-19 disease, according to a literature review by Yousef Roosta, MD, of Urmia (Iran) University of Medical Sciences, and colleagues.

Diagnostic interaction between CLL and COVID-19 provides a major challenge. CLL patients have a lower rate of anti–SARS-CoV-2 IgG development, and evidence shows worse therapeutic outcomes in these patients, according to study published in Leukemia Research Reports.

The researchers assessed 20 retrieved articles, 11 of which examined patients with CLL and with concomitant COVID-19; and 9 articles were designed as prospective or retrospective case series of such patients. The studies were assessed qualitatively by the QUADAS-2 tool.
 

Troubling results

Although the overall prevalence of CLL and COVID-19 concurrence was low, at 0.6% (95% confidence interval 0.5%-0.7%) according to the meta-analysis, the results showed some special challenges in the diagnosis and care of these patients.

Diagnostic difficulties are a unique problem. Lymphopenia is common in patients with COVID-19, while lymphocytosis may be considered a transient or even rare finding. The interplay between the two diseases is sometimes very misleading for specialists, and in patients with lymphocytosis, the diagnosis of CLL may be completely ignored, according to the researchers. They added that when performing a diagnostic approach for concurrent COVID-19 and CLL, due to differences in the amount and type of immune response, “relying on serological testing, and especially the evaluation of the anti–SARS-CoV-2 IgG levels may not be beneficial,” they indicated.

In addition, studies showed unacceptable therapeutic outcome in patients with concurrent CLL and COVID-19, with mortality ranging from 33% to 41.7%, showing a need to revise current treatment protocols, according to the authors. In one study, 85.7% of surviving patients showed a considerable decrease in functional class and significant fatigue, with such a poor prognosis occurring more commonly in the elderly.

With regard to treatment, “it is quite obvious that despite the use of current standard protocols, the prognosis of these patients will be much worse than the prognosis of CLL patients with no evidence of COVID-19. Even in the first-line treatment protocol for these patients, there is no agreement in combination therapy with selected CLL drugs along with management protocols of COVID-19 patients,” the researchers stated.

“[The] different hematological behaviors of two diseases might mimic the detection of COVID-19 in the CLL state and vise versa. Also, due to the low level of immune response against SARS-CoV-2 in CLL patients, both scheduled immunological-based diagnosis and treatment may fail,” the researchers added.

The authors reported that they had no disclosures.

[email protected]

Chronic lymphocytic leukemia (CLL) patients present significant problems with regard to COVID-19 disease, according to a literature review by Yousef Roosta, MD, of Urmia (Iran) University of Medical Sciences, and colleagues.

Diagnostic interaction between CLL and COVID-19 provides a major challenge. CLL patients have a lower rate of anti–SARS-CoV-2 IgG development, and evidence shows worse therapeutic outcomes in these patients, according to study published in Leukemia Research Reports.

The researchers assessed 20 retrieved articles, 11 of which examined patients with CLL and with concomitant COVID-19; and 9 articles were designed as prospective or retrospective case series of such patients. The studies were assessed qualitatively by the QUADAS-2 tool.
 

Troubling results

Although the overall prevalence of CLL and COVID-19 concurrence was low, at 0.6% (95% confidence interval 0.5%-0.7%) according to the meta-analysis, the results showed some special challenges in the diagnosis and care of these patients.

Diagnostic difficulties are a unique problem. Lymphopenia is common in patients with COVID-19, while lymphocytosis may be considered a transient or even rare finding. The interplay between the two diseases is sometimes very misleading for specialists, and in patients with lymphocytosis, the diagnosis of CLL may be completely ignored, according to the researchers. They added that when performing a diagnostic approach for concurrent COVID-19 and CLL, due to differences in the amount and type of immune response, “relying on serological testing, and especially the evaluation of the anti–SARS-CoV-2 IgG levels may not be beneficial,” they indicated.

In addition, studies showed unacceptable therapeutic outcome in patients with concurrent CLL and COVID-19, with mortality ranging from 33% to 41.7%, showing a need to revise current treatment protocols, according to the authors. In one study, 85.7% of surviving patients showed a considerable decrease in functional class and significant fatigue, with such a poor prognosis occurring more commonly in the elderly.

With regard to treatment, “it is quite obvious that despite the use of current standard protocols, the prognosis of these patients will be much worse than the prognosis of CLL patients with no evidence of COVID-19. Even in the first-line treatment protocol for these patients, there is no agreement in combination therapy with selected CLL drugs along with management protocols of COVID-19 patients,” the researchers stated.

“[The] different hematological behaviors of two diseases might mimic the detection of COVID-19 in the CLL state and vise versa. Also, due to the low level of immune response against SARS-CoV-2 in CLL patients, both scheduled immunological-based diagnosis and treatment may fail,” the researchers added.

The authors reported that they had no disclosures.

[email protected]

Chronic lymphocytic leukemia (CLL) patients present significant problems with regard to COVID-19 disease, according to a literature review by Yousef Roosta, MD, of Urmia (Iran) University of Medical Sciences, and colleagues.

Diagnostic interaction between CLL and COVID-19 provides a major challenge. CLL patients have a lower rate of anti–SARS-CoV-2 IgG development, and evidence shows worse therapeutic outcomes in these patients, according to study published in Leukemia Research Reports.

The researchers assessed 20 retrieved articles, 11 of which examined patients with CLL and with concomitant COVID-19; and 9 articles were designed as prospective or retrospective case series of such patients. The studies were assessed qualitatively by the QUADAS-2 tool.
 

Troubling results

Although the overall prevalence of CLL and COVID-19 concurrence was low, at 0.6% (95% confidence interval 0.5%-0.7%) according to the meta-analysis, the results showed some special challenges in the diagnosis and care of these patients.

Diagnostic difficulties are a unique problem. Lymphopenia is common in patients with COVID-19, while lymphocytosis may be considered a transient or even rare finding. The interplay between the two diseases is sometimes very misleading for specialists, and in patients with lymphocytosis, the diagnosis of CLL may be completely ignored, according to the researchers. They added that when performing a diagnostic approach for concurrent COVID-19 and CLL, due to differences in the amount and type of immune response, “relying on serological testing, and especially the evaluation of the anti–SARS-CoV-2 IgG levels may not be beneficial,” they indicated.

In addition, studies showed unacceptable therapeutic outcome in patients with concurrent CLL and COVID-19, with mortality ranging from 33% to 41.7%, showing a need to revise current treatment protocols, according to the authors. In one study, 85.7% of surviving patients showed a considerable decrease in functional class and significant fatigue, with such a poor prognosis occurring more commonly in the elderly.

With regard to treatment, “it is quite obvious that despite the use of current standard protocols, the prognosis of these patients will be much worse than the prognosis of CLL patients with no evidence of COVID-19. Even in the first-line treatment protocol for these patients, there is no agreement in combination therapy with selected CLL drugs along with management protocols of COVID-19 patients,” the researchers stated.

“[The] different hematological behaviors of two diseases might mimic the detection of COVID-19 in the CLL state and vise versa. Also, due to the low level of immune response against SARS-CoV-2 in CLL patients, both scheduled immunological-based diagnosis and treatment may fail,” the researchers added.

The authors reported that they had no disclosures.

[email protected]

COVID vaccines do not work well for patients with hematologic malignancies, new data suggest.

A small study involving 67 such patients shows that nearly half did not produce antibodies and were therefore still at risk of contracting COVID-19, even though they had all received both doses of one of the new mRNA COVID vaccines (Moderna or Pfizer).

“[This] is in stark contrast with the results of phase 1 mRNA vaccine immunogenicity trials, in which robust antibody responses were seen in essentially 100% of participants,” said the authors, led by Mounzer Agha, MD, director of the Mario Lemieux Center for Blood Cancers at the University of Pittsburgh Medical Center’s Hillman Cancer Center.

“Clinicians caring for patients with hematological malignancies and other immunocompromising conditions should be aware of the possibility of COVID-19 vaccine failure,” they emphasized.

“It’s critically important for these patients to be aware of their continued risk [for SARS-CoV-2 infection] and to seek prompt medical attention if they have COVID-19 symptoms, even after vaccination,” Dr. Agha said in a statement.

The study was published online on April 9 as preprint in medRxiv and has not yet undergone peer review.


 

Antibody responses

The authors analyzed responses in a group of 67 patients who had a hematologic malignancy, including chronic lymphocytic leukemia (CLL), lymphoma, and multiple myeloma. Approximately 45% of the patients were receiving therapy for their cancer at the time of vaccination; the rest were under observation.

All patients received two doses of an mRNA COVID vaccine and so were considered to be fully vaccinated.

Antibody responses for these fully vaccinated patients were then analyzed. The median duration between receipt of the second dose of the vaccine and the antibody test was 23 days.

“In total ... 46.3% ... had a negative antibody result after vaccination and were therefore considered to be vaccine nonresponders,” the authors reported.

The worst responses occurred in patients with CLL, of whom only 23% produced measurable antibodies to either vaccine, although approximately 70% of these patients were not receiving any form of cancer therapy at the time of vaccination.

Older patients were more likely not to have a response to either vaccine compared with younger patients, the investigators added.

In contrast, gender, immunoglobulin G levels, the number of days between the second dose and the measurement of antibodies, and status of cancer therapy did not differ among patients who had a response to the vaccines and those who did not.

“Our findings underscore the importance of adherence to nonpharmaceutical interventions to prevent COVID-19 in hematological malignancy patients,” the authors wrote. This is particularly important, given the fact that among patients with hematologic malignancies who become infected with SARS-CoV-2, the mortality rate is in excess of 30%.

Moreover, among such patients, viral shedding may be prolonged, often lasting several months. As such, “these patients should be advised to wear masks and observe social distancing regardless of vaccination status,” the investigators advised.

As of March 2021, guidance from the Centers for Disease Control and Prevention has allowed gatherings of unmasked people who have been vaccinated and of those at low risk for COVID-19 who have not yet been vaccinated. “As we see more national guidance allowing for unmasked gatherings among vaccinated people, clinicians should counsel their immunocompromised patients about the possibility that COVID-19 vaccines may not fully protect them against SARS-CoV-2,” coauthor Ghady Haidar, MD, assistant professor of medicine at the University of Pittsburgh, said in a statement.

“Our results show that the odds of the vaccine producing an antibody response in people with hematologic malignancies are the equivalent of a coin flip,” he said.

The authors have disclosed no relevant financial relationships.
 

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

COVID vaccines do not work well for patients with hematologic malignancies, new data suggest.

A small study involving 67 such patients shows that nearly half did not produce antibodies and were therefore still at risk of contracting COVID-19, even though they had all received both doses of one of the new mRNA COVID vaccines (Moderna or Pfizer).

“[This] is in stark contrast with the results of phase 1 mRNA vaccine immunogenicity trials, in which robust antibody responses were seen in essentially 100% of participants,” said the authors, led by Mounzer Agha, MD, director of the Mario Lemieux Center for Blood Cancers at the University of Pittsburgh Medical Center’s Hillman Cancer Center.

“Clinicians caring for patients with hematological malignancies and other immunocompromising conditions should be aware of the possibility of COVID-19 vaccine failure,” they emphasized.

“It’s critically important for these patients to be aware of their continued risk [for SARS-CoV-2 infection] and to seek prompt medical attention if they have COVID-19 symptoms, even after vaccination,” Dr. Agha said in a statement.

The study was published online on April 9 as preprint in medRxiv and has not yet undergone peer review.


 

Antibody responses

The authors analyzed responses in a group of 67 patients who had a hematologic malignancy, including chronic lymphocytic leukemia (CLL), lymphoma, and multiple myeloma. Approximately 45% of the patients were receiving therapy for their cancer at the time of vaccination; the rest were under observation.

All patients received two doses of an mRNA COVID vaccine and so were considered to be fully vaccinated.

Antibody responses for these fully vaccinated patients were then analyzed. The median duration between receipt of the second dose of the vaccine and the antibody test was 23 days.

“In total ... 46.3% ... had a negative antibody result after vaccination and were therefore considered to be vaccine nonresponders,” the authors reported.

The worst responses occurred in patients with CLL, of whom only 23% produced measurable antibodies to either vaccine, although approximately 70% of these patients were not receiving any form of cancer therapy at the time of vaccination.

Older patients were more likely not to have a response to either vaccine compared with younger patients, the investigators added.

In contrast, gender, immunoglobulin G levels, the number of days between the second dose and the measurement of antibodies, and status of cancer therapy did not differ among patients who had a response to the vaccines and those who did not.

“Our findings underscore the importance of adherence to nonpharmaceutical interventions to prevent COVID-19 in hematological malignancy patients,” the authors wrote. This is particularly important, given the fact that among patients with hematologic malignancies who become infected with SARS-CoV-2, the mortality rate is in excess of 30%.

Moreover, among such patients, viral shedding may be prolonged, often lasting several months. As such, “these patients should be advised to wear masks and observe social distancing regardless of vaccination status,” the investigators advised.

As of March 2021, guidance from the Centers for Disease Control and Prevention has allowed gatherings of unmasked people who have been vaccinated and of those at low risk for COVID-19 who have not yet been vaccinated. “As we see more national guidance allowing for unmasked gatherings among vaccinated people, clinicians should counsel their immunocompromised patients about the possibility that COVID-19 vaccines may not fully protect them against SARS-CoV-2,” coauthor Ghady Haidar, MD, assistant professor of medicine at the University of Pittsburgh, said in a statement.

“Our results show that the odds of the vaccine producing an antibody response in people with hematologic malignancies are the equivalent of a coin flip,” he said.

The authors have disclosed no relevant financial relationships.
 

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

COVID vaccines do not work well for patients with hematologic malignancies, new data suggest.

A small study involving 67 such patients shows that nearly half did not produce antibodies and were therefore still at risk of contracting COVID-19, even though they had all received both doses of one of the new mRNA COVID vaccines (Moderna or Pfizer).

“[This] is in stark contrast with the results of phase 1 mRNA vaccine immunogenicity trials, in which robust antibody responses were seen in essentially 100% of participants,” said the authors, led by Mounzer Agha, MD, director of the Mario Lemieux Center for Blood Cancers at the University of Pittsburgh Medical Center’s Hillman Cancer Center.

“Clinicians caring for patients with hematological malignancies and other immunocompromising conditions should be aware of the possibility of COVID-19 vaccine failure,” they emphasized.

“It’s critically important for these patients to be aware of their continued risk [for SARS-CoV-2 infection] and to seek prompt medical attention if they have COVID-19 symptoms, even after vaccination,” Dr. Agha said in a statement.

The study was published online on April 9 as preprint in medRxiv and has not yet undergone peer review.


 

Antibody responses

The authors analyzed responses in a group of 67 patients who had a hematologic malignancy, including chronic lymphocytic leukemia (CLL), lymphoma, and multiple myeloma. Approximately 45% of the patients were receiving therapy for their cancer at the time of vaccination; the rest were under observation.

All patients received two doses of an mRNA COVID vaccine and so were considered to be fully vaccinated.

Antibody responses for these fully vaccinated patients were then analyzed. The median duration between receipt of the second dose of the vaccine and the antibody test was 23 days.

“In total ... 46.3% ... had a negative antibody result after vaccination and were therefore considered to be vaccine nonresponders,” the authors reported.

The worst responses occurred in patients with CLL, of whom only 23% produced measurable antibodies to either vaccine, although approximately 70% of these patients were not receiving any form of cancer therapy at the time of vaccination.

Older patients were more likely not to have a response to either vaccine compared with younger patients, the investigators added.

In contrast, gender, immunoglobulin G levels, the number of days between the second dose and the measurement of antibodies, and status of cancer therapy did not differ among patients who had a response to the vaccines and those who did not.

“Our findings underscore the importance of adherence to nonpharmaceutical interventions to prevent COVID-19 in hematological malignancy patients,” the authors wrote. This is particularly important, given the fact that among patients with hematologic malignancies who become infected with SARS-CoV-2, the mortality rate is in excess of 30%.

Moreover, among such patients, viral shedding may be prolonged, often lasting several months. As such, “these patients should be advised to wear masks and observe social distancing regardless of vaccination status,” the investigators advised.

As of March 2021, guidance from the Centers for Disease Control and Prevention has allowed gatherings of unmasked people who have been vaccinated and of those at low risk for COVID-19 who have not yet been vaccinated. “As we see more national guidance allowing for unmasked gatherings among vaccinated people, clinicians should counsel their immunocompromised patients about the possibility that COVID-19 vaccines may not fully protect them against SARS-CoV-2,” coauthor Ghady Haidar, MD, assistant professor of medicine at the University of Pittsburgh, said in a statement.

“Our results show that the odds of the vaccine producing an antibody response in people with hematologic malignancies are the equivalent of a coin flip,” he said.

The authors have disclosed no relevant financial relationships.
 

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

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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

For select older patients, it is safe to switch to a lower dose of lenalidomide maintenance therapy and discontinue dexamethasone after 9 months. The regimen is safe and yields outcomes similar to those of standard, continuous lenalidomide/dexamethasone (Rd), according to new findings.

At a median follow-up of 37 months, event-free survival was 10.4 months in the experimental arm in which dexamethasone therapy was stopped (Rd-R) versus 6.9 months for standard therapy. The tailored approach also resulted in fewer adverse effects.

The authors noted that there was no difference in progression-free survival (PFS) and overall survival between the two groups.

“These results may be useful for the treatment of myeloma patients, since approximately one-third of patients not eligible for stem cell transplantation are intermediate fit, the population in our study,” said lead author Alessandra Larocca, MD, PhD, from the department of hematology-oncology of the University Hospital Città della Salute e della Scienza, Torino, Italy.

She said in an interview that they expect that these findings “may help to optimize the treatment of less-fit elderly patients by reducing the occurrence of adverse events and thus improving outcomes and preserving quality of life of these patients.”

This approach is a viable option for clinicians to consider for some patient subgroups. “This steroid-sparing approach can also be used in other combinations,” she said. “Ongoing trials are now evaluating steroid sparing in combination with monoclonal antibodies or the role of frailty-guided treatment.”

The study was published March 19, 2021, in Blood.
 

Curtailing steroids

Myeloma patients aged 75 years or older or who have comorbidities and functional impairments are an understudied population. They are more susceptible to adverse events that may negatively affect the duration of treatment and outcomes. Steroids are “scarcely tolerated” in the long term, even among younger patients, and “whether sparing dexamethasone is as effective as prolonged steroid exposure remains an open issue,” the authors wrote. There are still no clear data on the advantage of continuous steroid treatment as opposed to fixed-duration treatment for newly diagnosed patients.

In 2010, a study compared high-dose with low-dose dexamethasone. As expected, the rate of adverse events was lower among patients who received the low-dose steroid, but quite unexpectedly, deaths with high-dose dexamethasone were significantly higher than with low-dose dexamethasone.

The 1-year overall survival was 96% among patients who received the low dose of dexamethasone versus 87% with the standard high dose.

S. Vincent Rajkumar, MD, of the Mayo Clinic, Rochester, Minn., who was the lead author of the 2010 study, spoke with this new organization about the current study. “This is an important and practice-changing study,” he said. “We have already changed our practice and recommendations based on this study.”

He explained that, for transplant-ineligible patients, instead of initial therapy with bortezomib-lenalidomide-dexamethasone followed by Rd, they use lenalidomide alone without steroids.

“After 9 months of initial therapy, I now recommend we stop dexamethasone unless we are having problems controlling the myeloma, such as progressive disease,” Dr. Rajkumar said. “I congratulate the authors on a study that will improve the quality of life for our patients.”
 

Improved event-free survival

In this study, Dr. Larocca and colleagues investigated the efficacy and feasibility of a dose- and schedule-adjusted Rd regimen that was followed by maintenance Rd-R 10 mg/d and compared the regimen with continuous Rd in elderly, intermediate-fit patients who were newly diagnosed with multiple myeloma.

The primary endpoint was event-free survival, defined as progression/death from any cause, lenalidomide discontinuation, and any hematologic grade 4 or nonhematologic grade 3-4 adverse events.

The cohort consisted of 199 patients who were randomly assigned to receive either Rd-R (n = 101) or continuous Rd (n = 98). The median age was 75 years in the Rd-R arm and 76 years in the Rd arm; 52% of patients in the Rd-R group and 43% in the Rd group were classified as being intermediate fit not for age but for geriatric impairments.

With a median follow-up of 37 months, event-free survival was 10.4 months in the Rd-R arm versus 6.9 months in the Rd arm (hazard ratio, 0.70; P = .02). This benefit was maintained beyond nine cycles (median: 19.8 vs. 10.6 months for Rd-R vs. Rd; HR, 0.55; P = .03)

The median PFS was 20.2 months with Rd-R and 18.3 months with Rd (HR, 0.78; P = .16). The median overall survival was not reached. The 3-year overall survival was 74% with Rd-R and 63% with continuous Rd (HR, 0.62; P = .06). Among patients remaining on therapy after nine cycles, no difference in median PFS was observed between the two groups (24.3 vs. 18.7 months; HR, 0.73; P = .19).

Best response was similar for both groups, with an overall response rate of 78% versus 68% (P = .15). The very good partial response rate was 51% in the Rd-R arm versus 39% in the continuous Rd arm (P = .09).

Toxicities were similar between the two groups. Hematologic adverse events of at least grade 3 were reported in 26% of Rd-R patients versus 20% of Rd patients (P = .40). In both groups, the most frequent grade ≥3 hematologic toxicity was neutropenia (21% vs 18%). The most frequent grade ≥3 toxicities were nonhematologic. They occurred in 33% of Rd-R patients and 43% of Rd patients (P = .15). The most frequent nonhematologic toxicities were infections (10% vs. 12%), constitutional (3% vs. 12%), dermatologic (7% vs. 3%), and central nervous toxicities (2% vs. 6%).

The study was sponsored by Fondazione EMN Italy Onlus. Dr. Larocca has received honoraria from Amgen, Bristol-Myers Squibb, Celgene, Janssen, and GlaxoSmithKline, and has served on the advisory boards for Bristol-Myers Squibb, Celgene, Janssen, and Takeda. Several coauthors also have disclosed relationships with industry. Dr. Rajkumar disclosed no relevant financial relationships.

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