User login
Mastocytosis: Rare, underdiagnosed, potentially fatal
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.
More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.
Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.
“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”
Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).
In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.
ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.
The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”
Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.
“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.
A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.
The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.
Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.
Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”
Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.
Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.
As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.
How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.
This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.
Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).
Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.
As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.
“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.
“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.
Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.
Adding venetoclax improves ibrutinib outcomes in CLL
Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.
Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.
“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.
However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
Complete remission in over half
The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.
Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.
On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.
The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.
Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.
“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.
There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.
The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.
No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.
The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.
Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.
Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.
“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.
However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
Complete remission in over half
The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.
Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.
On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.
The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.
Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.
“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.
There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.
The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.
No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.
The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.
Investigators led by Philip Thompson, MD, a hematologist/oncologist at the center, explained that CLL patients receiving ibrutinib, a Bruton’s kinase inhibitor, “rarely achieve complete remission with undetectable measurable residual disease,” so they stay on the costly treatment indefinitely or until disease progression or accumulating adverse events force a switch to venetoclax.
Using the two agents together, instead of consecutively, may allow strong responders to stop treatment altogether and suboptimal responders to have longer remissions, they said.
“We would not advocate prolonged Bruton’s kinase inhibitor use prior to starting venetoclax in treatment-naive patients, as the safety and efficacy of commencing venetoclax after a 3-month ibrutinib monotherapy phase has been repeatedly demonstrated,” the team said.
However, the investigators noted that their “study was not intended to directly answer the question of whether combination therapy is superior to the current paradigm of sequential monotherapy.” Randomized trials are looking into the matter. The study was published recently as a preprint on ResearchSquare.com and has not been peer reviewed.
Complete remission in over half
The 45 adult subjects had one or more high-risk features for CLL progression and had received at least 1 year of ibrutinib at 140-420 mg once daily, depending on tolerance. They had bone marrow detectable disease at study entry but did not meet criteria for progression. Median duration of ibrutinib at baseline was 32 months, and about half the subjects were on it as their initial therapy.
Venetoclax, a BCL2 inhibitor with a completely different mechanisms of action, was added to ibrutinib for up to 2 years, escalated up to a target dose of 400 mg once daily.
On intention-to-treat analysis, venetoclax add-on improved ibrutinib response to complete remission in 55% of patients; complete remission was defined as less than 1 CLL cell per 10,000 leukocytes in bone marrow on two consecutive occasions 6 months apart.
The rate of undetectable bone marrow disease was 57% after 1 year of combined treatment and 71% after venetoclax completion, at which point 23 patients with undetectable disease stopped ibrutinib along with venetoclax.
Five patients had disease progression at a median of 41 months after venetoclax initiation, one during combined therapy, three during ibrutinib maintenance afterward, and one with Richter transformation after complete remission and discontinuation of all treatment. No patient had died from CLL.
“There has so far been no significant difference noted in” time to residual disease re-emergence, the team said, based on whether or not patients continued ibrutinib after venetoclax add-on.
There was no significant difference in the rate of bone marrow clearance according to the presence or absence of TP53 abnormalities, complex karyotypes, or prior treatment status.
The most common grade 3/4 adverse event was neutropenia in 20% of patients. Nine patients developed nonmelanoma skin cancer during the trial; six were diagnosed with other solid tumors; three came down with grade 3 infections, and two developed myelodysplastic syndrome, both with a prior history of chemotherapy.
No one stopped venetoclax because of toxicity, but about a third of subjects required dose reductions, most often because of neutropenia.
The study was funded by AbbVie, which is commercializing venetoclax along with Genentech. Investigators disclosed ties to both companies and many others. Dr. Thompson disclosed ties to AbbVie, Pharmacyclics, Lilly, Adaptive Biotechnologies, Janssen, Beigene, and Genentech.
FROM RESEARCHSQUARE
Off their pricey CML meds, many thrive
When imatinib (Gleevec) appeared on the market just over 2 decades ago, it revolutionized the treatment of chronic myelogenous leukemia (CML) and transformed it from a grim diagnosis into a largely treatable form of blood cancer. New generations of tyrosine kinase inhibitors (TKIs) have continued to expand options for patients, and many can look forward to normal lifespans.
But these medications cause side effects and can be expensive. Long-term data doesn’t exist for the newer therapies, so no one knows whether they can harm patients over time. None of this is particularly unusual for medications to treat chronic illness, but now there’s a twist:
“Our focus has changed because the results of treatment are so good,” hematologist-oncologist Ehab L. Atallah, MD, of the Medical College of Wisconsin, Milwaukee, said in an interview. “We’re trying to get people off their medication.”
Still, research estimates that only 20% of patients with CML will be eligible for treatment discontinuation and benefit from it in the long term. As a result, the wide majority of patients will need to be on drugs indefinitely.
Gleevec: A new age dawns
In the early 1990s, before the era of TKIs, the 5-year relative survival rate from CML was just 27%, and the 10-year rate was only 9.5%, according to a 2008 report. “If someone showed up with CML, their only option was to go to a bone marrow transplant. About half survived the transplant, and half of those had significant complications from it,” Dr. Atallah said. According to him, just about everyone who didn’t get transplantation would go on to die.
Then came Gleevec, which received Food and Drug Administration approval in 2001. It ushered in the era of “targeted” cancer treatment by specifically killing CML cells, instead of relying on traditional chemotherapy’s carpet-bombing approach.
“Gleevec and other TKIs have revolutionized how CML is treated, and patients are now living normal lives,” hematologist-oncologist Catherine Lai, MD, MPH, of the University of Pennsylvania, Philadelphia, said in an interview.
Alan Fahnestock, a 68-year-old retired telecommunications specialist in north-central Washington state, is one of the fortunate patients.
He was diagnosed with CML in 2004 after he underwent a thoracic CT scan in light of his tobacco use. “My GP found something odd in my lungs and referred me to a pulmonologist, who couldn’t figure it out either. He transmitted blood samples to my eventual hematologist/oncologist,” Mr. Fahnestock said in an interview. “It’s not clear to me that anybody ever figured out what the ‘oddity’ was. It has since apparently gone away. But the oncologist ran all the tests and came up with CML.”
Mr. Fahnestock hadn’t noticed any symptoms, although “this is, perhaps, because I tend not to pay a lot of attention to such things, having abused my body fairly severely over the years and having been borderline anemic since I was a kid. I don’t really expect to feel great and am a bit of a fatalist: I just get on with things until I no longer can.”
His physician prescribed Gleevec. “I had no particularly notable side effects, and carried on with my life pretty much as if nothing had happened,” Mr. Fahnestock said. He stayed on the drug for almost 20 years.
CML rooted in chromosome swap
It’s not clear exactly what causes CML, although the Mayo Clinic says most cases are linked to an abnormal, extra-short “Philadelphia chromosome,” created when two chromosomes swap material. This happens after birth.
Mr. Fahnestock thinks he happened to develop a random mutation. He also wonders if his work stints in the former Soviet Union in Vladivostok, “where the Soviet nuclear submarine fleet was decomposing,” and in Kiev, Ukraine, “which is not all that far from Chernobyl,” may be responsible.
Most patients, like Mr. Fahnestock, are men. Males will account for about 5,190 of the cases diagnosed in 2023, according to the American Cancer Society, compared to 3,740 in females.
Mr. Fahnestock’s CML diagnosis came at a fairly young age, when he was in his 40s. The average patient is diagnosed at 64. But it’s not unusual that he experienced no apparent symptoms when the cancer was found. In fact, that’s the norm.
Most patients with the disease – which is diagnosed in about 8,900 patients in the United States each year – are asymptomatic or have mild symptoms, Dr. Lai said. Their disease is discovered when “an elevated white count is found on routine blood work,” she said.
“The other group of patients typically present with very elevated white blood cell counts and splenomegaly with symptoms of fatigue and other constitutional symptoms. When the WBC count is very high, it is important to rule out transformation to accelerated or blast phase and also rule out an acute leukemia.”
Polymerase chain reaction is an especially important test during diagnosis, Dr. Atallah said, since it provides baseline data about the cancer that can be tracked.
TKIs: Mainstay of treatment
Four drugs are FDA approved for initial treatment of CML: imatinib (Gleevec), the second-generation TKIs dasatinib (Sprycel) and the third-generation TKI nilotinib (Tasigna). The third-generation TKIs bosutinib (Bosulif) and ponatinib (Iclusig) are approved for use as first-line treatments for patients who cannot tolerate the other drugs or are resistant to them.
The first-in-class drug asciminib (Scemblix), approved by the FDA in 2021, is a third-line drug for patients who failed treatment with two other TKIs and certain patients with the T315I mutation.
Dr. Lai said that it’s crucial to avoid side effects as much as possible “since the goal is for patients to be compliant and take the pill every day and not miss doses.” In younger patients, “I typically choose a second-generation TKI as my first choice, since there is a higher likelihood of getting into a deep molecular remission more quickly. If treatment-free remission is something a patient is interested in, a second-generation TKI is more likely to make this happen.”
According to Dr. Atallah, about half of patients end up using more than one drug because their initial choices either don’t work or cause intolerable side effects. Nevertheless, Dr. Lai noted: “Overall, patients do extremely well if compliant with their medication.”
Exceptions include the noncompliant and patients with more aggressive disease, like an accelerated or a blast phase, she said. For the latter patients, “allogenic bone marrow transplant should be considered once the patient is in remission.”
In remission, consider drug omission
How should patients be monitored if they are doing well?
“In general, I tend to follow patients monthly for the first six months after starting therapy, to make sure they are tolerating it well and to help manage side effects,” Dr. Lai said. “After that, I follow once every three months, and then often space out visits depending on whether they hit their molecular milestones and how long they’re in remission.”
In certain cases, patients may be taken off medication. The most recent National Comprehensive Cancer Network guidelines for treatment of CML, published in 2021, say that “discontinuation of TKI therapy (with close monitoring) is feasible in carefully selected, consenting patients” with early stage CML who’ve reached remission, defined as deep molecular response (DMR) of at least MR 4.0 for at least 2 years.
The guidelines caution that disease recurrence appears in “approximately 40%-60% of patients who discontinue TKI therapy after achieving DMR experience recurrence within 12 months of treatment cessation, in some cases as early as one month after discontinuation of TKI therapy.”
Still, the guidelines add that “resumption of TKI therapy immediately after recurrence results in the achievement of DMR in almost all patients.”
Dr. Atallah said stopping medication can be especially helpful for patients who grapple with side effects such as fatigue, diarrhea, and muscle aches. Some patients who take the drugs fear losing their health insurance and facing sky-high drug expenses. In 2018, average daily TKI costs for patients with CML were over $350, a 2020 report found.
Many patients were prescribed hugely expensive second-line treatments rather than inexpensive generic imatinib, the report said, despite “no evidence that later-generation TKIs provide superior progression free or overall survival.”
Many patients, however, refuse to consider stopping their medication, Dr. Atallah said. More data about treatment-free remission is needed, and the 21 U.S. academic medical centers in the H. Jean Khoury Cure CML Consortium are gathering information about patient outcomes.
Mr. Fahnestock is a fan of treatment-free remission. He stopped taking Gleevec about 2 years ago on the advice of his physician after he reached undetectable levels of disease.
“It was sort of a nonevent, really, with no discernible physical effects beyond exacerbation of the osteoarthritis in my hands,” he said. According to him, it’s not clear if this effect is linked to his eliminating the medication.
“I also vaguely hoped I’d feel better, even though I’d never been able to nail down any deleterious side effects,” he said. “No such luck, as it happens.”
Blood work has indicated no resurgence of the disease, and Mr. Fahnestock continues to volunteer as a rural firefighter.
“In general, I’m apparently reasonably healthy for my age, despite my folly [in younger years], and firefighting requires me to stay in reasonable shape,” he said. “I’ve recently been made aware of minor kidney issues and prediabetes. But, hell, I’m genetically scheduled to croak within 5 years or so, so why worry?”
National survival statistics in CML vary by factors such as gender and age, as a 2021 study revealed, and men have worse outcomes. Still, there’s a good chance Mr. Fahnestock won’t need to worry about CML ever again.
Dr. Atallah disclosed research support from Novartis and Takeda and has served both of those firms and Bristol-Myers Squibb as a consultant advisor. Dr. Lai discloses tied with Bristol-Myers Squibb, Jazz, Genentech, Novartis, Abbvie, Daiichi Sankyo, Astellas, MacroGenics, Servier, and Taiho. Mr. Fahnestock has no disclosures.
When imatinib (Gleevec) appeared on the market just over 2 decades ago, it revolutionized the treatment of chronic myelogenous leukemia (CML) and transformed it from a grim diagnosis into a largely treatable form of blood cancer. New generations of tyrosine kinase inhibitors (TKIs) have continued to expand options for patients, and many can look forward to normal lifespans.
But these medications cause side effects and can be expensive. Long-term data doesn’t exist for the newer therapies, so no one knows whether they can harm patients over time. None of this is particularly unusual for medications to treat chronic illness, but now there’s a twist:
“Our focus has changed because the results of treatment are so good,” hematologist-oncologist Ehab L. Atallah, MD, of the Medical College of Wisconsin, Milwaukee, said in an interview. “We’re trying to get people off their medication.”
Still, research estimates that only 20% of patients with CML will be eligible for treatment discontinuation and benefit from it in the long term. As a result, the wide majority of patients will need to be on drugs indefinitely.
Gleevec: A new age dawns
In the early 1990s, before the era of TKIs, the 5-year relative survival rate from CML was just 27%, and the 10-year rate was only 9.5%, according to a 2008 report. “If someone showed up with CML, their only option was to go to a bone marrow transplant. About half survived the transplant, and half of those had significant complications from it,” Dr. Atallah said. According to him, just about everyone who didn’t get transplantation would go on to die.
Then came Gleevec, which received Food and Drug Administration approval in 2001. It ushered in the era of “targeted” cancer treatment by specifically killing CML cells, instead of relying on traditional chemotherapy’s carpet-bombing approach.
“Gleevec and other TKIs have revolutionized how CML is treated, and patients are now living normal lives,” hematologist-oncologist Catherine Lai, MD, MPH, of the University of Pennsylvania, Philadelphia, said in an interview.
Alan Fahnestock, a 68-year-old retired telecommunications specialist in north-central Washington state, is one of the fortunate patients.
He was diagnosed with CML in 2004 after he underwent a thoracic CT scan in light of his tobacco use. “My GP found something odd in my lungs and referred me to a pulmonologist, who couldn’t figure it out either. He transmitted blood samples to my eventual hematologist/oncologist,” Mr. Fahnestock said in an interview. “It’s not clear to me that anybody ever figured out what the ‘oddity’ was. It has since apparently gone away. But the oncologist ran all the tests and came up with CML.”
Mr. Fahnestock hadn’t noticed any symptoms, although “this is, perhaps, because I tend not to pay a lot of attention to such things, having abused my body fairly severely over the years and having been borderline anemic since I was a kid. I don’t really expect to feel great and am a bit of a fatalist: I just get on with things until I no longer can.”
His physician prescribed Gleevec. “I had no particularly notable side effects, and carried on with my life pretty much as if nothing had happened,” Mr. Fahnestock said. He stayed on the drug for almost 20 years.
CML rooted in chromosome swap
It’s not clear exactly what causes CML, although the Mayo Clinic says most cases are linked to an abnormal, extra-short “Philadelphia chromosome,” created when two chromosomes swap material. This happens after birth.
Mr. Fahnestock thinks he happened to develop a random mutation. He also wonders if his work stints in the former Soviet Union in Vladivostok, “where the Soviet nuclear submarine fleet was decomposing,” and in Kiev, Ukraine, “which is not all that far from Chernobyl,” may be responsible.
Most patients, like Mr. Fahnestock, are men. Males will account for about 5,190 of the cases diagnosed in 2023, according to the American Cancer Society, compared to 3,740 in females.
Mr. Fahnestock’s CML diagnosis came at a fairly young age, when he was in his 40s. The average patient is diagnosed at 64. But it’s not unusual that he experienced no apparent symptoms when the cancer was found. In fact, that’s the norm.
Most patients with the disease – which is diagnosed in about 8,900 patients in the United States each year – are asymptomatic or have mild symptoms, Dr. Lai said. Their disease is discovered when “an elevated white count is found on routine blood work,” she said.
“The other group of patients typically present with very elevated white blood cell counts and splenomegaly with symptoms of fatigue and other constitutional symptoms. When the WBC count is very high, it is important to rule out transformation to accelerated or blast phase and also rule out an acute leukemia.”
Polymerase chain reaction is an especially important test during diagnosis, Dr. Atallah said, since it provides baseline data about the cancer that can be tracked.
TKIs: Mainstay of treatment
Four drugs are FDA approved for initial treatment of CML: imatinib (Gleevec), the second-generation TKIs dasatinib (Sprycel) and the third-generation TKI nilotinib (Tasigna). The third-generation TKIs bosutinib (Bosulif) and ponatinib (Iclusig) are approved for use as first-line treatments for patients who cannot tolerate the other drugs or are resistant to them.
The first-in-class drug asciminib (Scemblix), approved by the FDA in 2021, is a third-line drug for patients who failed treatment with two other TKIs and certain patients with the T315I mutation.
Dr. Lai said that it’s crucial to avoid side effects as much as possible “since the goal is for patients to be compliant and take the pill every day and not miss doses.” In younger patients, “I typically choose a second-generation TKI as my first choice, since there is a higher likelihood of getting into a deep molecular remission more quickly. If treatment-free remission is something a patient is interested in, a second-generation TKI is more likely to make this happen.”
According to Dr. Atallah, about half of patients end up using more than one drug because their initial choices either don’t work or cause intolerable side effects. Nevertheless, Dr. Lai noted: “Overall, patients do extremely well if compliant with their medication.”
Exceptions include the noncompliant and patients with more aggressive disease, like an accelerated or a blast phase, she said. For the latter patients, “allogenic bone marrow transplant should be considered once the patient is in remission.”
In remission, consider drug omission
How should patients be monitored if they are doing well?
“In general, I tend to follow patients monthly for the first six months after starting therapy, to make sure they are tolerating it well and to help manage side effects,” Dr. Lai said. “After that, I follow once every three months, and then often space out visits depending on whether they hit their molecular milestones and how long they’re in remission.”
In certain cases, patients may be taken off medication. The most recent National Comprehensive Cancer Network guidelines for treatment of CML, published in 2021, say that “discontinuation of TKI therapy (with close monitoring) is feasible in carefully selected, consenting patients” with early stage CML who’ve reached remission, defined as deep molecular response (DMR) of at least MR 4.0 for at least 2 years.
The guidelines caution that disease recurrence appears in “approximately 40%-60% of patients who discontinue TKI therapy after achieving DMR experience recurrence within 12 months of treatment cessation, in some cases as early as one month after discontinuation of TKI therapy.”
Still, the guidelines add that “resumption of TKI therapy immediately after recurrence results in the achievement of DMR in almost all patients.”
Dr. Atallah said stopping medication can be especially helpful for patients who grapple with side effects such as fatigue, diarrhea, and muscle aches. Some patients who take the drugs fear losing their health insurance and facing sky-high drug expenses. In 2018, average daily TKI costs for patients with CML were over $350, a 2020 report found.
Many patients were prescribed hugely expensive second-line treatments rather than inexpensive generic imatinib, the report said, despite “no evidence that later-generation TKIs provide superior progression free or overall survival.”
Many patients, however, refuse to consider stopping their medication, Dr. Atallah said. More data about treatment-free remission is needed, and the 21 U.S. academic medical centers in the H. Jean Khoury Cure CML Consortium are gathering information about patient outcomes.
Mr. Fahnestock is a fan of treatment-free remission. He stopped taking Gleevec about 2 years ago on the advice of his physician after he reached undetectable levels of disease.
“It was sort of a nonevent, really, with no discernible physical effects beyond exacerbation of the osteoarthritis in my hands,” he said. According to him, it’s not clear if this effect is linked to his eliminating the medication.
“I also vaguely hoped I’d feel better, even though I’d never been able to nail down any deleterious side effects,” he said. “No such luck, as it happens.”
Blood work has indicated no resurgence of the disease, and Mr. Fahnestock continues to volunteer as a rural firefighter.
“In general, I’m apparently reasonably healthy for my age, despite my folly [in younger years], and firefighting requires me to stay in reasonable shape,” he said. “I’ve recently been made aware of minor kidney issues and prediabetes. But, hell, I’m genetically scheduled to croak within 5 years or so, so why worry?”
National survival statistics in CML vary by factors such as gender and age, as a 2021 study revealed, and men have worse outcomes. Still, there’s a good chance Mr. Fahnestock won’t need to worry about CML ever again.
Dr. Atallah disclosed research support from Novartis and Takeda and has served both of those firms and Bristol-Myers Squibb as a consultant advisor. Dr. Lai discloses tied with Bristol-Myers Squibb, Jazz, Genentech, Novartis, Abbvie, Daiichi Sankyo, Astellas, MacroGenics, Servier, and Taiho. Mr. Fahnestock has no disclosures.
When imatinib (Gleevec) appeared on the market just over 2 decades ago, it revolutionized the treatment of chronic myelogenous leukemia (CML) and transformed it from a grim diagnosis into a largely treatable form of blood cancer. New generations of tyrosine kinase inhibitors (TKIs) have continued to expand options for patients, and many can look forward to normal lifespans.
But these medications cause side effects and can be expensive. Long-term data doesn’t exist for the newer therapies, so no one knows whether they can harm patients over time. None of this is particularly unusual for medications to treat chronic illness, but now there’s a twist:
“Our focus has changed because the results of treatment are so good,” hematologist-oncologist Ehab L. Atallah, MD, of the Medical College of Wisconsin, Milwaukee, said in an interview. “We’re trying to get people off their medication.”
Still, research estimates that only 20% of patients with CML will be eligible for treatment discontinuation and benefit from it in the long term. As a result, the wide majority of patients will need to be on drugs indefinitely.
Gleevec: A new age dawns
In the early 1990s, before the era of TKIs, the 5-year relative survival rate from CML was just 27%, and the 10-year rate was only 9.5%, according to a 2008 report. “If someone showed up with CML, their only option was to go to a bone marrow transplant. About half survived the transplant, and half of those had significant complications from it,” Dr. Atallah said. According to him, just about everyone who didn’t get transplantation would go on to die.
Then came Gleevec, which received Food and Drug Administration approval in 2001. It ushered in the era of “targeted” cancer treatment by specifically killing CML cells, instead of relying on traditional chemotherapy’s carpet-bombing approach.
“Gleevec and other TKIs have revolutionized how CML is treated, and patients are now living normal lives,” hematologist-oncologist Catherine Lai, MD, MPH, of the University of Pennsylvania, Philadelphia, said in an interview.
Alan Fahnestock, a 68-year-old retired telecommunications specialist in north-central Washington state, is one of the fortunate patients.
He was diagnosed with CML in 2004 after he underwent a thoracic CT scan in light of his tobacco use. “My GP found something odd in my lungs and referred me to a pulmonologist, who couldn’t figure it out either. He transmitted blood samples to my eventual hematologist/oncologist,” Mr. Fahnestock said in an interview. “It’s not clear to me that anybody ever figured out what the ‘oddity’ was. It has since apparently gone away. But the oncologist ran all the tests and came up with CML.”
Mr. Fahnestock hadn’t noticed any symptoms, although “this is, perhaps, because I tend not to pay a lot of attention to such things, having abused my body fairly severely over the years and having been borderline anemic since I was a kid. I don’t really expect to feel great and am a bit of a fatalist: I just get on with things until I no longer can.”
His physician prescribed Gleevec. “I had no particularly notable side effects, and carried on with my life pretty much as if nothing had happened,” Mr. Fahnestock said. He stayed on the drug for almost 20 years.
CML rooted in chromosome swap
It’s not clear exactly what causes CML, although the Mayo Clinic says most cases are linked to an abnormal, extra-short “Philadelphia chromosome,” created when two chromosomes swap material. This happens after birth.
Mr. Fahnestock thinks he happened to develop a random mutation. He also wonders if his work stints in the former Soviet Union in Vladivostok, “where the Soviet nuclear submarine fleet was decomposing,” and in Kiev, Ukraine, “which is not all that far from Chernobyl,” may be responsible.
Most patients, like Mr. Fahnestock, are men. Males will account for about 5,190 of the cases diagnosed in 2023, according to the American Cancer Society, compared to 3,740 in females.
Mr. Fahnestock’s CML diagnosis came at a fairly young age, when he was in his 40s. The average patient is diagnosed at 64. But it’s not unusual that he experienced no apparent symptoms when the cancer was found. In fact, that’s the norm.
Most patients with the disease – which is diagnosed in about 8,900 patients in the United States each year – are asymptomatic or have mild symptoms, Dr. Lai said. Their disease is discovered when “an elevated white count is found on routine blood work,” she said.
“The other group of patients typically present with very elevated white blood cell counts and splenomegaly with symptoms of fatigue and other constitutional symptoms. When the WBC count is very high, it is important to rule out transformation to accelerated or blast phase and also rule out an acute leukemia.”
Polymerase chain reaction is an especially important test during diagnosis, Dr. Atallah said, since it provides baseline data about the cancer that can be tracked.
TKIs: Mainstay of treatment
Four drugs are FDA approved for initial treatment of CML: imatinib (Gleevec), the second-generation TKIs dasatinib (Sprycel) and the third-generation TKI nilotinib (Tasigna). The third-generation TKIs bosutinib (Bosulif) and ponatinib (Iclusig) are approved for use as first-line treatments for patients who cannot tolerate the other drugs or are resistant to them.
The first-in-class drug asciminib (Scemblix), approved by the FDA in 2021, is a third-line drug for patients who failed treatment with two other TKIs and certain patients with the T315I mutation.
Dr. Lai said that it’s crucial to avoid side effects as much as possible “since the goal is for patients to be compliant and take the pill every day and not miss doses.” In younger patients, “I typically choose a second-generation TKI as my first choice, since there is a higher likelihood of getting into a deep molecular remission more quickly. If treatment-free remission is something a patient is interested in, a second-generation TKI is more likely to make this happen.”
According to Dr. Atallah, about half of patients end up using more than one drug because their initial choices either don’t work or cause intolerable side effects. Nevertheless, Dr. Lai noted: “Overall, patients do extremely well if compliant with their medication.”
Exceptions include the noncompliant and patients with more aggressive disease, like an accelerated or a blast phase, she said. For the latter patients, “allogenic bone marrow transplant should be considered once the patient is in remission.”
In remission, consider drug omission
How should patients be monitored if they are doing well?
“In general, I tend to follow patients monthly for the first six months after starting therapy, to make sure they are tolerating it well and to help manage side effects,” Dr. Lai said. “After that, I follow once every three months, and then often space out visits depending on whether they hit their molecular milestones and how long they’re in remission.”
In certain cases, patients may be taken off medication. The most recent National Comprehensive Cancer Network guidelines for treatment of CML, published in 2021, say that “discontinuation of TKI therapy (with close monitoring) is feasible in carefully selected, consenting patients” with early stage CML who’ve reached remission, defined as deep molecular response (DMR) of at least MR 4.0 for at least 2 years.
The guidelines caution that disease recurrence appears in “approximately 40%-60% of patients who discontinue TKI therapy after achieving DMR experience recurrence within 12 months of treatment cessation, in some cases as early as one month after discontinuation of TKI therapy.”
Still, the guidelines add that “resumption of TKI therapy immediately after recurrence results in the achievement of DMR in almost all patients.”
Dr. Atallah said stopping medication can be especially helpful for patients who grapple with side effects such as fatigue, diarrhea, and muscle aches. Some patients who take the drugs fear losing their health insurance and facing sky-high drug expenses. In 2018, average daily TKI costs for patients with CML were over $350, a 2020 report found.
Many patients were prescribed hugely expensive second-line treatments rather than inexpensive generic imatinib, the report said, despite “no evidence that later-generation TKIs provide superior progression free or overall survival.”
Many patients, however, refuse to consider stopping their medication, Dr. Atallah said. More data about treatment-free remission is needed, and the 21 U.S. academic medical centers in the H. Jean Khoury Cure CML Consortium are gathering information about patient outcomes.
Mr. Fahnestock is a fan of treatment-free remission. He stopped taking Gleevec about 2 years ago on the advice of his physician after he reached undetectable levels of disease.
“It was sort of a nonevent, really, with no discernible physical effects beyond exacerbation of the osteoarthritis in my hands,” he said. According to him, it’s not clear if this effect is linked to his eliminating the medication.
“I also vaguely hoped I’d feel better, even though I’d never been able to nail down any deleterious side effects,” he said. “No such luck, as it happens.”
Blood work has indicated no resurgence of the disease, and Mr. Fahnestock continues to volunteer as a rural firefighter.
“In general, I’m apparently reasonably healthy for my age, despite my folly [in younger years], and firefighting requires me to stay in reasonable shape,” he said. “I’ve recently been made aware of minor kidney issues and prediabetes. But, hell, I’m genetically scheduled to croak within 5 years or so, so why worry?”
National survival statistics in CML vary by factors such as gender and age, as a 2021 study revealed, and men have worse outcomes. Still, there’s a good chance Mr. Fahnestock won’t need to worry about CML ever again.
Dr. Atallah disclosed research support from Novartis and Takeda and has served both of those firms and Bristol-Myers Squibb as a consultant advisor. Dr. Lai discloses tied with Bristol-Myers Squibb, Jazz, Genentech, Novartis, Abbvie, Daiichi Sankyo, Astellas, MacroGenics, Servier, and Taiho. Mr. Fahnestock has no disclosures.
Multiple myeloma diagnosed more via emergency care during COVID
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
The study covered in this summary was published on Research Square as a preprint and has not yet been peer reviewed.
Key takeaway
Why this matters
While trying to avoid COVID-19 infection, patients ultimately diagnosed with multiple myeloma may have delayed interactions with healthcare professionals and consequently delayed their cancer diagnosis.
Study design
Researchers collected data on newly diagnosed patients with multiple myeloma from January 2019 until July 2021 across five institutions (three universities and two hospitals) in England. In total, 323 patients with multiple myeloma were identified.
Patients were divided into two groups: those diagnosed between Jan. 1, 2019, until Jan. 31, 2020, or pre-COVID, and those diagnosed from Feb. 1, 2020, to July 31, 2021, or post COVID.
Key results
Among all patients, 80 (24.8%) were diagnosed with smoldering multiple myeloma and 243 (75.2%) were diagnosed with multiple myeloma requiring treatment.
Significantly more patients in the post-COVID group were diagnosed with myeloma through the emergency route (45.5% post COVID vs. 32.7% pre-COVID; P = .03).
Clinical complications leading to emergency admission prior to a myeloma diagnosis also differed between the two cohorts: Acute kidney injury accounted for most emergency admissions in the pre-COVID cohort while skeletal-related events, including spinal cord compression, were the major causes for diagnosis through the emergency route in the post-COVID cohort.
Patients who were diagnosed with symptomatic myeloma pre-COVID were more likely to be treated with a triplet rather than doublet combination compared with those diagnosed in the post-COVID period (triplet pre-COVID 79.1%, post COVID 63.75%; P = .014).
Overall survival at 1 year was not significantly different between the pre-COVID and post-COVID groups: 88.2% pre-COVID, compared with 87.8% post COVID.
Overall, the authors concluded that the COVID pandemic “resulted in a shift in the symptomatology, disease burden, and routes of diagnosis of patients presenting with myeloma” and “this may have significant consequences” over the long term.
Limitations
The study does not provide a clear time frame of delays in diagnosis.
Disclosures
The study authors did not report any conflicts of interest.
A version of this article first appeared on Medscape.com .
High cost and demand for old cancer drug sparks crisis
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
At Oregon Health and Science University, for example, an extensive algorithm now offers guidance through a thicket of alternative options, from adjusting doses and using substitutes to delaying treatment. Meanwhile, some institutions have enlisted ethicists and attorneys to guide their decisions on which patients will have to wait for potentially life-saving treatment.
Even as surgeons turn to alternatives, advocates for transplantation in hematology have warned about the potential for harm.
“This continued fludarabine shortage is forcing centers to use non–[Food and Drug Administration] approved lymphodepleting regimens that may negatively impact the success of a possibly lifesaving CAR-T therapy,” Brenda Sandmaier, MD, president of the Transplantation and Cellular Therapy American Society, and Jeffery Auletta, MD, a senior vice president with the National Marrow Donor, said in a June 30 letter to the FDA. The physicians added that they “request the FDA to take immediate action on this critical shortage. Many centers currently have no ability to purchase fludarabine through their suppliers and have no estimated time frame for return of availability. Other centers are limited to mere weeks of supply, with continued uncertainty of future availability.”
In October, less than 4 months after that letter was sent, one of the manufacturers of fludarabine – Areva Pharmaceuticals – marked up the price of fludarabine to $2,736 per vial, 10-20 times that of two other makers of the drug.
In new treatment era, fludarabine remains crucial
In 2015, ASH Clinical News – a publication of the American Society of Hematology – invited a pair of hematologists to discuss whether fludarabine is “dead” as a front-line treatment for chronic lymphocytic leukemia (CLL). “Fludarabine is not dead yet, but the data from those and other long-term trials may be the final nail in its coffin,” said Mitchell Smith, MD, PhD, who was then with Cleveland Clinic and now works for George Washington University.
Seven years later, the role of fludarabine as a long-term chemotherapeutic agent in blood cancer has definitely evolved. Just as oncologists predicted back in 2015, “the use of fludarabine declined for the primary management of CLL and other B cell malignancies, due to the development of targeted therapies such as BTK inhibitors, venetoclax, and other agents,” Memorial Sloan Kettering hematologic oncologist Anthony Mato, MD, said in an interview.
But the drug “remains a critical agent for conditioning the immune system for cellular therapies such as allogeneic stem cell transplantation and CAR-T cells,” Dr. Mato said.
Nirav Shah, MD, a hematologic oncologist at the Medical College of Wisconsin, explained in an interview that “conditioning” in the stem-cell transplant context refers to “wiping out” the immune system, allowing the donor’s stem cells to avoid rejection. “It’s a commonly used drug,” he said, “and shortage was not really a concern that people faced until this year.”
As shortage continues, price hike brings yet another hit
The first reports of fludarabine being in short supply surfaced about a year ago. According to a Nov. 2 update from the American Society of Health-System Pharmacists, five companies now manufacture fludarabine, and all of them report shortages. Areva, which dramatically raised its price, is accepting direct orders. Leucadia and Teva don’t know when the drug will be available; and Fresenius Kabi and Sagent expect availability in early 2023.
Areva, Leucadia, and Teva didn’t provide reasons for their shortages. Fresenius Kabi blamed increased demand, and Sagent pointed to manufacturing delays. Pfizer, another manufacturer, had a tiny market share and stopped making fludarabine in 2020, according to the pharmacist society.
In a May 12 press release, a company called Lannett announced it would take over U.S. distribution of fludarabine for Areva and suggested that the supply shortage would be lucrative: “While total U.S. sales for the 12 months ended March 2022 of Fludarabine Phosphate for injection, USP, 50 mg/2mL were approximately $4.9 million, according to IQVIA, the current market value is believed to be higher due to the recent market disruptions.”
“We were all shocked and outraged when Areva came out with the new, dramatically higher prices,” Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, said in a recent interview.
In a prior interview, conducted during the summer of 2022, Dr. Greene addressed the topic of hematologic drug shortages. Back then he noted that he was seeking emergency supplies of fludarabine, since all five manufacturers reported having no stock available.
Interviewed again in November 2022, Dr. Greene noted that the hospital “had been able to stay ahead of the need and meet the needs of our patients” through arrangements with Teva and Fresenius Kabi. “In cases of patient need, we certainly are willing to pay a higher product price if that’s what it takes to get it – assuming the product is a quality product.”
The Medical College of Wisconsin’s Dr. Shah said insurers may refuse to cover the higher price, sticking medical institutions with the bill.
Alternatives abound, but do they suffice?
There is some good news on the fludarabine shortage front. Areva recently alerted providers that it was releasing fludarabine from non-FDA-approved suppliers with the agency’s permission, and Accord Healthcare said it received permission to sell fludarabine that was marketed in Canada.
Another option – oral fludarabine instead of the standard IV version – remains unavailable in the United States. According to the June letter to the FDA from the American Society for Transplantation and Cellular Therapy and National Marrow Donor Program, it “might be an appropriate alternative” and is available in Europe, Canada and Australia.
The letter warns that “transplant centers have also been forced to move away from fludarabine-based regimens and use alternative drugs such as cladribine or clofarabine, which are both significantly less studied and rely on single-center experience or limited phase II data. ... The limited availability of fludarabine is leading to the use of alternative regimens that are known to be more toxic or understudied alternatives with unknown long-term clinical effects or harms to patients.”
In a November 2022 report published in Transplantation and Cellular Therapy, Dr. Shah and colleagues noted that institutions are adopting strategies such as “(1) pharmacy dose banding and rounding down to save vials, even if a >5% reduction was required; (2) administering all dosing of fludarabine based not on actual body weight but on adjusted body weight; and (3) switching the billing of fludarabine from single-dose vials to billing by dose delivery.”
If the shortage continues, “it becomes necessary for centers to establish algorithms for management now,” they wrote. “Substitution of such agents as bendamustine and cladribine can be considered ... [and] another acceptable solution could be the substitution of clofarabine for fludarabine.”
Still, there are many unanswered questions. “The challenge is that these alternative regimens have not been extensively studied in a large population,” Dr. Shah said. “You have to be more mindful of potential side effects and risks, and the biggest concern is efficacy. Is changing the drug going to be detrimental to a patient’s outcome? To be honest, we don’t know the answer to that.”
Dr. Mato disclosed ties with TG Therapeutics, Pharmacyclics, AbbVie, Acerta, Adaptive Biotechnologies, AstraZeneca, BeiGene, BioPharma, BMS, Curio, Dava, DTRM, Genentech, Genmab, Janssen, Johnson & Johnson, LOXO, Medscape, Nurix, Octapharma, PER, PerView, and Pfizer. Dr. Greene and Dr. Shah have no disclosures.
Pandemic caused treatment delay for half of patients with CTCL, study finds
showed. However, among patients with CTCL diagnosed with COVID-19 during that time, no cases were acquired from outpatient visits.
“Delays in therapy for patients with cutaneous lymphomas should likely be avoided,” two of the study authors, Larisa J. Geskin, MD, of the department of dermatology at Columbia University Irving Medical Center, New York, and Bradley D. Kwinta, a medical student at Columbia University, told this news organization in a combined response via email.
“Continuing treatment and maintenance therapy appears critical to avoiding disease progression, highlighting the importance of maintenance therapy in CTCL,” they said. “These patients can be safely treated according to established treatment protocols while practicing physical distancing and using personal protective equipment without significantly increasing their risk of COVID-19 infection.”
The United States Cutaneous Lymphoma Consortium and the European Organization for Research and Treatment of Cancer developed emergency guidelines for the management of patients with cutaneous lymphomas during the pandemic to ensure patient safety, and the International Society for Cutaneous Lymphomas created an International Cutaneous Lymphomas Pandemic Section to collect data to assess the impact of these guidelines.
“Using this data, we can determine if these measures were effective in preventing COVID-19 infection, what the impact was of maintenance therapy, and how delays in treatment affected disease outcomes in CTCL patients,” the authors and their colleagues wrote in the study, which was published in the Journal of the American Academy of Dermatology.
They retrospectively analyzed data from the electronic medical records of 149 patients with CTCL who were being managed at one of nine international academic medical centers in seven countries from March to October 2020. Slightly more than half (56%) were male, 70% were White, 18% were Black, 52% had stage IA-IIA disease, and 19% acquired COVID-19 during the study period.
Of the 149 patients, 79 (53%) experienced a mean treatment delay of 3.2 months (range, 10 days to 10 months). After adjusting for age, race, biological sex, COVID-19 status, and disease stage, treatment delay was associated with a significant risk of disease relapse or progression across all stages (odds ratio, 5.00; P < .001). Specifically, for each additional month that a patient experienced treatment delay, the odds of disease progression increased by 37% (OR, 1.37; P < .001).
A total of 28 patients with CTCL (19%) were diagnosed with COVID-19, but none were acquired from outpatient office visits. Patients who contracted COVID-19 did not have a statistically significant increase in odds of disease progression, compared with COVID-negative patients (OR, 0.41; P = .07).
According to Dr. Geskin, who is also director of the Comprehensive Skin Cancer Center in the division of cutaneous oncology in the department of dermatology at Columbia, and Mr. Kwinta, no clinical trials exist to inform maintenance protocols in patients with cutaneous lymphomas. “There are also no randomized and controlled observational studies that demonstrate the impact that therapy delay may have on disease outcomes,” they said in the email. “In fact, the need for maintenance therapy for CTCL is often debated. Our findings demonstrate the importance of continuing treatment and the use of maintenance therapy in avoiding disease progression in these incurable lymphomas.”
They acknowledged certain limitations of the study, including its retrospective observational design. “Therefore, we cannot establish a definitive causal link between treatment delay and disease progression,” they said. “Our cohort of patients were on various and often multiple therapies, making it hard to extrapolate our data to discern which maintenance therapies were most effective in preventing disease progression.”
In addition, their data only includes patients from March to October 2020, “before the discovery of new variants and the development of COVID-19 vaccines,” they added. “Additional studies would be required to draw conclusions on how COVID-19 vaccines may affect patients with CTCL, including outcomes in the setting of new variants.”
The authors reported having no financial disclosures.
showed. However, among patients with CTCL diagnosed with COVID-19 during that time, no cases were acquired from outpatient visits.
“Delays in therapy for patients with cutaneous lymphomas should likely be avoided,” two of the study authors, Larisa J. Geskin, MD, of the department of dermatology at Columbia University Irving Medical Center, New York, and Bradley D. Kwinta, a medical student at Columbia University, told this news organization in a combined response via email.
“Continuing treatment and maintenance therapy appears critical to avoiding disease progression, highlighting the importance of maintenance therapy in CTCL,” they said. “These patients can be safely treated according to established treatment protocols while practicing physical distancing and using personal protective equipment without significantly increasing their risk of COVID-19 infection.”
The United States Cutaneous Lymphoma Consortium and the European Organization for Research and Treatment of Cancer developed emergency guidelines for the management of patients with cutaneous lymphomas during the pandemic to ensure patient safety, and the International Society for Cutaneous Lymphomas created an International Cutaneous Lymphomas Pandemic Section to collect data to assess the impact of these guidelines.
“Using this data, we can determine if these measures were effective in preventing COVID-19 infection, what the impact was of maintenance therapy, and how delays in treatment affected disease outcomes in CTCL patients,” the authors and their colleagues wrote in the study, which was published in the Journal of the American Academy of Dermatology.
They retrospectively analyzed data from the electronic medical records of 149 patients with CTCL who were being managed at one of nine international academic medical centers in seven countries from March to October 2020. Slightly more than half (56%) were male, 70% were White, 18% were Black, 52% had stage IA-IIA disease, and 19% acquired COVID-19 during the study period.
Of the 149 patients, 79 (53%) experienced a mean treatment delay of 3.2 months (range, 10 days to 10 months). After adjusting for age, race, biological sex, COVID-19 status, and disease stage, treatment delay was associated with a significant risk of disease relapse or progression across all stages (odds ratio, 5.00; P < .001). Specifically, for each additional month that a patient experienced treatment delay, the odds of disease progression increased by 37% (OR, 1.37; P < .001).
A total of 28 patients with CTCL (19%) were diagnosed with COVID-19, but none were acquired from outpatient office visits. Patients who contracted COVID-19 did not have a statistically significant increase in odds of disease progression, compared with COVID-negative patients (OR, 0.41; P = .07).
According to Dr. Geskin, who is also director of the Comprehensive Skin Cancer Center in the division of cutaneous oncology in the department of dermatology at Columbia, and Mr. Kwinta, no clinical trials exist to inform maintenance protocols in patients with cutaneous lymphomas. “There are also no randomized and controlled observational studies that demonstrate the impact that therapy delay may have on disease outcomes,” they said in the email. “In fact, the need for maintenance therapy for CTCL is often debated. Our findings demonstrate the importance of continuing treatment and the use of maintenance therapy in avoiding disease progression in these incurable lymphomas.”
They acknowledged certain limitations of the study, including its retrospective observational design. “Therefore, we cannot establish a definitive causal link between treatment delay and disease progression,” they said. “Our cohort of patients were on various and often multiple therapies, making it hard to extrapolate our data to discern which maintenance therapies were most effective in preventing disease progression.”
In addition, their data only includes patients from March to October 2020, “before the discovery of new variants and the development of COVID-19 vaccines,” they added. “Additional studies would be required to draw conclusions on how COVID-19 vaccines may affect patients with CTCL, including outcomes in the setting of new variants.”
The authors reported having no financial disclosures.
showed. However, among patients with CTCL diagnosed with COVID-19 during that time, no cases were acquired from outpatient visits.
“Delays in therapy for patients with cutaneous lymphomas should likely be avoided,” two of the study authors, Larisa J. Geskin, MD, of the department of dermatology at Columbia University Irving Medical Center, New York, and Bradley D. Kwinta, a medical student at Columbia University, told this news organization in a combined response via email.
“Continuing treatment and maintenance therapy appears critical to avoiding disease progression, highlighting the importance of maintenance therapy in CTCL,” they said. “These patients can be safely treated according to established treatment protocols while practicing physical distancing and using personal protective equipment without significantly increasing their risk of COVID-19 infection.”
The United States Cutaneous Lymphoma Consortium and the European Organization for Research and Treatment of Cancer developed emergency guidelines for the management of patients with cutaneous lymphomas during the pandemic to ensure patient safety, and the International Society for Cutaneous Lymphomas created an International Cutaneous Lymphomas Pandemic Section to collect data to assess the impact of these guidelines.
“Using this data, we can determine if these measures were effective in preventing COVID-19 infection, what the impact was of maintenance therapy, and how delays in treatment affected disease outcomes in CTCL patients,” the authors and their colleagues wrote in the study, which was published in the Journal of the American Academy of Dermatology.
They retrospectively analyzed data from the electronic medical records of 149 patients with CTCL who were being managed at one of nine international academic medical centers in seven countries from March to October 2020. Slightly more than half (56%) were male, 70% were White, 18% were Black, 52% had stage IA-IIA disease, and 19% acquired COVID-19 during the study period.
Of the 149 patients, 79 (53%) experienced a mean treatment delay of 3.2 months (range, 10 days to 10 months). After adjusting for age, race, biological sex, COVID-19 status, and disease stage, treatment delay was associated with a significant risk of disease relapse or progression across all stages (odds ratio, 5.00; P < .001). Specifically, for each additional month that a patient experienced treatment delay, the odds of disease progression increased by 37% (OR, 1.37; P < .001).
A total of 28 patients with CTCL (19%) were diagnosed with COVID-19, but none were acquired from outpatient office visits. Patients who contracted COVID-19 did not have a statistically significant increase in odds of disease progression, compared with COVID-negative patients (OR, 0.41; P = .07).
According to Dr. Geskin, who is also director of the Comprehensive Skin Cancer Center in the division of cutaneous oncology in the department of dermatology at Columbia, and Mr. Kwinta, no clinical trials exist to inform maintenance protocols in patients with cutaneous lymphomas. “There are also no randomized and controlled observational studies that demonstrate the impact that therapy delay may have on disease outcomes,” they said in the email. “In fact, the need for maintenance therapy for CTCL is often debated. Our findings demonstrate the importance of continuing treatment and the use of maintenance therapy in avoiding disease progression in these incurable lymphomas.”
They acknowledged certain limitations of the study, including its retrospective observational design. “Therefore, we cannot establish a definitive causal link between treatment delay and disease progression,” they said. “Our cohort of patients were on various and often multiple therapies, making it hard to extrapolate our data to discern which maintenance therapies were most effective in preventing disease progression.”
In addition, their data only includes patients from March to October 2020, “before the discovery of new variants and the development of COVID-19 vaccines,” they added. “Additional studies would be required to draw conclusions on how COVID-19 vaccines may affect patients with CTCL, including outcomes in the setting of new variants.”
The authors reported having no financial disclosures.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Blenrep for multiple myeloma withdrawn from U.S. market
A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.
The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).
The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).
This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).
The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.
The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.
“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.
The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”
Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.
The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.
However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
For relapsed/refractory disease
Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.
Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.
“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
Details of DREAMM-3 results
DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.
The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).
At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).
A version of this article first appeared on Medscape.com.
A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.
The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).
The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).
This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).
The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.
The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.
“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.
The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”
Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.
The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.
However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
For relapsed/refractory disease
Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.
Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.
“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
Details of DREAMM-3 results
DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.
The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).
At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).
A version of this article first appeared on Medscape.com.
A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.
The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).
The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).
This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).
The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.
The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.
“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.
The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”
Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.
The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.
However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
For relapsed/refractory disease
Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.
Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.
“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
Details of DREAMM-3 results
DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.
The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).
At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).
A version of this article first appeared on Medscape.com.
CAR T-cell therapy neurotoxicity linked to NfL elevations
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
“This is the first study to show NfL levels are elevated even before CAR T treatment is given,” first author Omar H. Butt, MD, PhD, of the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, said in an interview.
“While unlikely to be the sole driver of [the neurotoxicity], neural injury reflected by NfL may aid in identifying a high-risk subset of patients undergoing cellular therapy,” the authors concluded in the study, published in JAMA Oncology.
CAR T-cell therapy has gained favor for virtually revolutionizing the treatment of some leukemias and lymphomas, however, as many as 40%-60% of patients develop the neurotoxicity side effect, called immune effector cell–associated neurotoxicity syndrome (ICANS), which, though usually low grade, in more severe cases can cause substantial morbidity and even mortality.
Hence, “the early identification of patients at risk for ICANS is critical for preemptive management,” the authors noted.
NfL, an established marker of neuroaxonal injury in neurodegenerative diseases including multiple sclerosis and Alzheimer’s disease, has been shown in previous studies to be elevated following the development of ICANS and up to 5 days prior to its peak symptoms.
To further evaluate NfL elevations in relation to ICANS, Dr. Butt and colleagues identified 30 patients undergoing CD19 CART-cell therapy, including 77% for diffuse large B-cell lymphoma, at two U.S. centers: Washington University in St. Louis and Case Western Reserve University, Cleveland.
The patients had a median age of 64 and were 40% female.
Among them, four developed low-grade ICANS grade 1-2, and 7 developed ICANS grade 3 or higher.
Of those developing any-grade ICANS, baseline elevations of NfL prior to the CAR T-cell treatment, were significantly higher, compared with those who did not develop ICANs (mean 87.6 pg/mL vs. 29.4 pg/mL, P < .001), with no significant differences between the low-grade (1 and 2) and higher-grade (3 or higher) ICANS groups.
A receiver operating characteristic analysis showed baseline NfL levels significantly predicted the development of ICANS with high accuracy (area under the ROC curve, 0.96), as well as sensitivity (AUROC, 0.91) and specificity (AUROC, 0.95).
Notably, baseline NfL levels were associated with ICANS severity, but did not correlate with other factors including demographic, oncologic history, nononcologic neurologic history, or history of exposure to neurotoxic therapies.
However, Dr. Butt added, “it is important to note that our study was insufficiently powered to examine those relationships in earnest. Therefore, [a correlation between NfL and those factors] remains possible,” he said.
The elevated NfL levels observed prior to the development of ICANS remained high across the study’s seven time points, up to day 30 post infusion.
Interest in NfL levels on the rise
NfL assessment is currently only clinically validated in amyotrophic lateral sclerosis, where it is used to assess neuroaxonal health and integrity. However, testing is available as interest and evidence of NfL’s potential role in other settings grows.
Meanwhile, Dr. Butt and associates are themselves developing an assay to predict the development of ICANS, which will likely include NfL, if the role is validated in further studies.
“Future studies will explore validating NfL for ICANS and additional indications,” he said.
ICANS symptoms can range from headaches and confusion to seizures or strokes in more severe cases.
The current gold standard for treatment includes early intervention with high-dose steroids and careful monitoring, but there is reluctance to use such therapies because of concerns about their blunting the anticancer effects of the CAR T cells.
Importantly, if validated, elevations in NfL could signal the need for more precautionary measures with CAR T-cell therapy, Dr. Butt noted.
“Our data suggests patients with high NfL levels at baseline would benefit most from perhaps closer monitoring with frequent checks and possible early intervention at the first sign of symptoms, a period of time when it may be hard to distinguish ICANS from other causes of confusion, such as delirium,” he explained.
Limitations: Validation, preventive measures needed
Commenting on the study, Sattva S. Neelapu, MD, a professor and deputy chair of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, agreed that the findings have potentially important implications.
“I think this is a very intriguing and novel finding that needs to be investigated further prospectively in a larger cohort and across different CAR T products in patients with lymphoma, leukemia, and myeloma,” Dr. Neelapu said in an interview.
The NfL elevations observed even before CAR T-cell therapy among those who went on to develop ICANS are notable, he added.
“This is the surprising finding in the study,” Dr. Neelapu said. “It raises the question whether neurologic injury is caused by prior therapies that these patients received or whether it is an age-related phenomenon, as we do see higher incidence and severity of ICANS in older patients or some other mechanisms.”
A key caveat, however, is that even if a risk is identified, options to prevent ICANS are currently limited, Dr. Neelapu noted.
“I think it is too early to implement this into clinical practice,” he said. In addition to needing further validation, “assessing NfL levels would be useful when there is an effective prophylactic or therapeutic strategy – both of which also need to be investigated.”
Dr. Butt and colleagues are developing a clinical assay for ICANS and reported a provisional patent pending on the use of plasma NfL as a predictive biomarker for ICANS. The study received support from the Washington University in St. Louis, the Paula and Rodger O. Riney Fund, the Daniel J. Brennan MD Fund, the Fred Simmons and Olga Mohan Fund; the National Cancer Institute, the National Multiple Sclerosis Society, and the National Institute of Neurological Disorders and Stroke. Dr. Neelapu reported conflicts of interest with numerous pharmaceutical companies.
FROM JAMA ONCOLOGY
Drug combo holds promise of better AML outcomes
Adding venetoclax (Venclexta) to a gilteritinib (Xospata) regimen appeared to improve outcomes in refractory/relapsed FLT3-mutated acute myeloid leukemia (AML), a new industry-funded phase 1b study reported.
“.
Outcomes in AML are poor. As the study notes, most patients relapse and face a median overall survival of 4-7 months even with standard chemotherapy. Gilteritinib, a selective oral FLT3 inhibitor, is Food and Drug Administration–approved for the 30% of relapsed/refractory patients with AML who have FLT3 mutations.
“The general sentiment is that, although some patients have great benefit from gilteritinib monotherapy, there is room to improve the quality, frequency, and duration of responses with combinations,” said hematologist Andrew Brunner, MD, of Massachusetts General Hospital in Boston, in an interview. He was not involved with the study research.
For the new open-label, dose-escalation/dose-expansion study, led by hematologist Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, researchers enrolled 61 patients (56 with FLT3 mutations) from 2018 to 2020. The median age was 63 years (range 21-85).
The subjects were assigned to get a recommended phase 2 dose of 400 mg venetoclax once daily and 120 mg gilteritinib once daily.
Over a median follow-up of 17.5 months, the median remission time was 4.9 months (95% confidence interval, 3.4-6.6), and the patients with FLT3 mutations survived a median of 10 months.
“The combination of venetoclax and gilteritinib was tolerable at standard doses of each drug, generated remarkably high response rates, and markedly reduced FLT3-internal tandem duplications mutation burden. … Early mortality was similar to gilteritinib monotherapy,” the authors wrote.
Eighty percent of patients experienced cytopenias, and “adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively.”
About 60% of patients who went on to receive allogeneic hematopoietic stem cell transplantation were alive at the end of follow-up, “suggesting that VenGilt [the combo treatment] could be an effective bridge to transplant in young/fit patients with relapsed FLT3mut AML,” the researchers wrote.
All patients withdrew from the study by November 2021 for several reasons such as death (n=42), adverse events (n=10), and disease progression (29); some had multiple reasons.
Dr. Brunner said the study is “an important step toward evaluating a new potential regimen.”
The remission duration, FLT3 molecular response, and median overall survival “seem quite encouraging for a severe disease like AML in relapse,” he said. However, he added that the drug combo “would need to be evaluated in a randomized and, ideally, placebo-controlled setting to know if this is a significant improvement.”
He also highlighted the high number of severe cyptopenias with associated complications such as death. “Whether this is acceptable depends on the patient and circumstances,” he said. “But it does suggest that this regimen would potentially be for more robust patients, particularly since the group that did best were those who went to transplant later.”
Pending more research, Dr. Brunner said, “I am not sure I would use [the combination treatment] over gilteritinib monotherapy, for instance. But there may be settings where no other options are available, and this could be considered, particularly if a transplant option is a next step.”
The study was funded by AbbVie, Genentech, and Astellas. The study authors report multiple disclosures; some are employed by Astellas, AbbVie, and Genentech/Roche.
Dr. Bronner reports running clinical trials, advisory board service and/or consultation for Acceleron, Agios, Abbvie, BMS/Celgene, Keros Therapeutics, Novartis, Takeda, GSK, AstraZeneca, Janssen, and Gilead.
Adding venetoclax (Venclexta) to a gilteritinib (Xospata) regimen appeared to improve outcomes in refractory/relapsed FLT3-mutated acute myeloid leukemia (AML), a new industry-funded phase 1b study reported.
“.
Outcomes in AML are poor. As the study notes, most patients relapse and face a median overall survival of 4-7 months even with standard chemotherapy. Gilteritinib, a selective oral FLT3 inhibitor, is Food and Drug Administration–approved for the 30% of relapsed/refractory patients with AML who have FLT3 mutations.
“The general sentiment is that, although some patients have great benefit from gilteritinib monotherapy, there is room to improve the quality, frequency, and duration of responses with combinations,” said hematologist Andrew Brunner, MD, of Massachusetts General Hospital in Boston, in an interview. He was not involved with the study research.
For the new open-label, dose-escalation/dose-expansion study, led by hematologist Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, researchers enrolled 61 patients (56 with FLT3 mutations) from 2018 to 2020. The median age was 63 years (range 21-85).
The subjects were assigned to get a recommended phase 2 dose of 400 mg venetoclax once daily and 120 mg gilteritinib once daily.
Over a median follow-up of 17.5 months, the median remission time was 4.9 months (95% confidence interval, 3.4-6.6), and the patients with FLT3 mutations survived a median of 10 months.
“The combination of venetoclax and gilteritinib was tolerable at standard doses of each drug, generated remarkably high response rates, and markedly reduced FLT3-internal tandem duplications mutation burden. … Early mortality was similar to gilteritinib monotherapy,” the authors wrote.
Eighty percent of patients experienced cytopenias, and “adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively.”
About 60% of patients who went on to receive allogeneic hematopoietic stem cell transplantation were alive at the end of follow-up, “suggesting that VenGilt [the combo treatment] could be an effective bridge to transplant in young/fit patients with relapsed FLT3mut AML,” the researchers wrote.
All patients withdrew from the study by November 2021 for several reasons such as death (n=42), adverse events (n=10), and disease progression (29); some had multiple reasons.
Dr. Brunner said the study is “an important step toward evaluating a new potential regimen.”
The remission duration, FLT3 molecular response, and median overall survival “seem quite encouraging for a severe disease like AML in relapse,” he said. However, he added that the drug combo “would need to be evaluated in a randomized and, ideally, placebo-controlled setting to know if this is a significant improvement.”
He also highlighted the high number of severe cyptopenias with associated complications such as death. “Whether this is acceptable depends on the patient and circumstances,” he said. “But it does suggest that this regimen would potentially be for more robust patients, particularly since the group that did best were those who went to transplant later.”
Pending more research, Dr. Brunner said, “I am not sure I would use [the combination treatment] over gilteritinib monotherapy, for instance. But there may be settings where no other options are available, and this could be considered, particularly if a transplant option is a next step.”
The study was funded by AbbVie, Genentech, and Astellas. The study authors report multiple disclosures; some are employed by Astellas, AbbVie, and Genentech/Roche.
Dr. Bronner reports running clinical trials, advisory board service and/or consultation for Acceleron, Agios, Abbvie, BMS/Celgene, Keros Therapeutics, Novartis, Takeda, GSK, AstraZeneca, Janssen, and Gilead.
Adding venetoclax (Venclexta) to a gilteritinib (Xospata) regimen appeared to improve outcomes in refractory/relapsed FLT3-mutated acute myeloid leukemia (AML), a new industry-funded phase 1b study reported.
“.
Outcomes in AML are poor. As the study notes, most patients relapse and face a median overall survival of 4-7 months even with standard chemotherapy. Gilteritinib, a selective oral FLT3 inhibitor, is Food and Drug Administration–approved for the 30% of relapsed/refractory patients with AML who have FLT3 mutations.
“The general sentiment is that, although some patients have great benefit from gilteritinib monotherapy, there is room to improve the quality, frequency, and duration of responses with combinations,” said hematologist Andrew Brunner, MD, of Massachusetts General Hospital in Boston, in an interview. He was not involved with the study research.
For the new open-label, dose-escalation/dose-expansion study, led by hematologist Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, researchers enrolled 61 patients (56 with FLT3 mutations) from 2018 to 2020. The median age was 63 years (range 21-85).
The subjects were assigned to get a recommended phase 2 dose of 400 mg venetoclax once daily and 120 mg gilteritinib once daily.
Over a median follow-up of 17.5 months, the median remission time was 4.9 months (95% confidence interval, 3.4-6.6), and the patients with FLT3 mutations survived a median of 10 months.
“The combination of venetoclax and gilteritinib was tolerable at standard doses of each drug, generated remarkably high response rates, and markedly reduced FLT3-internal tandem duplications mutation burden. … Early mortality was similar to gilteritinib monotherapy,” the authors wrote.
Eighty percent of patients experienced cytopenias, and “adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively.”
About 60% of patients who went on to receive allogeneic hematopoietic stem cell transplantation were alive at the end of follow-up, “suggesting that VenGilt [the combo treatment] could be an effective bridge to transplant in young/fit patients with relapsed FLT3mut AML,” the researchers wrote.
All patients withdrew from the study by November 2021 for several reasons such as death (n=42), adverse events (n=10), and disease progression (29); some had multiple reasons.
Dr. Brunner said the study is “an important step toward evaluating a new potential regimen.”
The remission duration, FLT3 molecular response, and median overall survival “seem quite encouraging for a severe disease like AML in relapse,” he said. However, he added that the drug combo “would need to be evaluated in a randomized and, ideally, placebo-controlled setting to know if this is a significant improvement.”
He also highlighted the high number of severe cyptopenias with associated complications such as death. “Whether this is acceptable depends on the patient and circumstances,” he said. “But it does suggest that this regimen would potentially be for more robust patients, particularly since the group that did best were those who went to transplant later.”
Pending more research, Dr. Brunner said, “I am not sure I would use [the combination treatment] over gilteritinib monotherapy, for instance. But there may be settings where no other options are available, and this could be considered, particularly if a transplant option is a next step.”
The study was funded by AbbVie, Genentech, and Astellas. The study authors report multiple disclosures; some are employed by Astellas, AbbVie, and Genentech/Roche.
Dr. Bronner reports running clinical trials, advisory board service and/or consultation for Acceleron, Agios, Abbvie, BMS/Celgene, Keros Therapeutics, Novartis, Takeda, GSK, AstraZeneca, Janssen, and Gilead.
FROM JOURNAL OF CLINICAL ONCOLOGY
From B to T: a Case of Concurrent B-Cell and T-Cell Lymphomas Successfully Palliated With Targeted Therapies
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non- Hodgkin lymphoma (NHL), comprising 30% of all NHL. Due to a decreased state of immunosurveillance resulting from the disease itself and its associated therapies, patients are at increased risk of developing a secondary malignancy. Multiple primary malignancies have been reported to occur in up to 15% of patients with DLBCL, retrospectively.
Herein, we review a case of a man with DLBCL who concomitantly developed ALK negative anaplastic large cell lymphoma (ALCL) distinctly of T-cell lineage who was successfully treated with palliative therapy for both diagnoses despite his advanced age and diagnosis associated with a poor prognosis with continued effect and sustained quality of life.
Case Report
An 88-year-old man presented with stage III DLBCL, diagnosed in 12/2018, was deemed not to be an aggressive therapy candidate. As such, he was treated with Rituximab monotherapy for 6 cycles, ending in 02/2019, with remarkably good effect. He remained in a PR with stable disease on serial PET/CTs until 09/2021, at which time he was noted to have Horner’s Syndrome in clinic. CT chest demonstrated a right apical lung mass, not previously seen on prior scans measuring 4.2 x 2.7 cm. Other sites of nodal disease remained stable on PET/CT.
Biopsy of the lesion revealed CD30+ ALK-negative ALCL with distinct T-cell marker positivity on immunohistochemistry and the absence of B-cell lineage markers. After discussion at our treatment planning conference, we decided to treat with brentuximab-vedotin (Bv) monotherapy for 6 cycles. End of treatment PET/CT demonstrated a PR with near resolution in background PET avidity at the lesion. His symptoms of Horner syndrome also improved.
Conclusion
A diagnosis of aggressive lymphoma increases the risk of developing a secondary malignancy and providers should remain vigilant of this. Elderly individuals in whom aggressive therapies may be precluded can still greatly benefit from palliative targeted therapy even in the setting of diseases historically associated with a poor prognosis.
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non- Hodgkin lymphoma (NHL), comprising 30% of all NHL. Due to a decreased state of immunosurveillance resulting from the disease itself and its associated therapies, patients are at increased risk of developing a secondary malignancy. Multiple primary malignancies have been reported to occur in up to 15% of patients with DLBCL, retrospectively.
Herein, we review a case of a man with DLBCL who concomitantly developed ALK negative anaplastic large cell lymphoma (ALCL) distinctly of T-cell lineage who was successfully treated with palliative therapy for both diagnoses despite his advanced age and diagnosis associated with a poor prognosis with continued effect and sustained quality of life.
Case Report
An 88-year-old man presented with stage III DLBCL, diagnosed in 12/2018, was deemed not to be an aggressive therapy candidate. As such, he was treated with Rituximab monotherapy for 6 cycles, ending in 02/2019, with remarkably good effect. He remained in a PR with stable disease on serial PET/CTs until 09/2021, at which time he was noted to have Horner’s Syndrome in clinic. CT chest demonstrated a right apical lung mass, not previously seen on prior scans measuring 4.2 x 2.7 cm. Other sites of nodal disease remained stable on PET/CT.
Biopsy of the lesion revealed CD30+ ALK-negative ALCL with distinct T-cell marker positivity on immunohistochemistry and the absence of B-cell lineage markers. After discussion at our treatment planning conference, we decided to treat with brentuximab-vedotin (Bv) monotherapy for 6 cycles. End of treatment PET/CT demonstrated a PR with near resolution in background PET avidity at the lesion. His symptoms of Horner syndrome also improved.
Conclusion
A diagnosis of aggressive lymphoma increases the risk of developing a secondary malignancy and providers should remain vigilant of this. Elderly individuals in whom aggressive therapies may be precluded can still greatly benefit from palliative targeted therapy even in the setting of diseases historically associated with a poor prognosis.
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non- Hodgkin lymphoma (NHL), comprising 30% of all NHL. Due to a decreased state of immunosurveillance resulting from the disease itself and its associated therapies, patients are at increased risk of developing a secondary malignancy. Multiple primary malignancies have been reported to occur in up to 15% of patients with DLBCL, retrospectively.
Herein, we review a case of a man with DLBCL who concomitantly developed ALK negative anaplastic large cell lymphoma (ALCL) distinctly of T-cell lineage who was successfully treated with palliative therapy for both diagnoses despite his advanced age and diagnosis associated with a poor prognosis with continued effect and sustained quality of life.
Case Report
An 88-year-old man presented with stage III DLBCL, diagnosed in 12/2018, was deemed not to be an aggressive therapy candidate. As such, he was treated with Rituximab monotherapy for 6 cycles, ending in 02/2019, with remarkably good effect. He remained in a PR with stable disease on serial PET/CTs until 09/2021, at which time he was noted to have Horner’s Syndrome in clinic. CT chest demonstrated a right apical lung mass, not previously seen on prior scans measuring 4.2 x 2.7 cm. Other sites of nodal disease remained stable on PET/CT.
Biopsy of the lesion revealed CD30+ ALK-negative ALCL with distinct T-cell marker positivity on immunohistochemistry and the absence of B-cell lineage markers. After discussion at our treatment planning conference, we decided to treat with brentuximab-vedotin (Bv) monotherapy for 6 cycles. End of treatment PET/CT demonstrated a PR with near resolution in background PET avidity at the lesion. His symptoms of Horner syndrome also improved.
Conclusion
A diagnosis of aggressive lymphoma increases the risk of developing a secondary malignancy and providers should remain vigilant of this. Elderly individuals in whom aggressive therapies may be precluded can still greatly benefit from palliative targeted therapy even in the setting of diseases historically associated with a poor prognosis.