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‘Molecular map’ of CLL yields fresh genetic insights
Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.
“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.
According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.
For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.
“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”
In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”
The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.
The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”
Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”
While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”
In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”
The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.
“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.
According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.
For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.
“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”
In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”
The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.
The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”
Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”
While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”
In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”
The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
Released in a report in Nature Genetics, the map has doubled the number of genetic traits linked the disease from around 100 to 202, lead author Binyamin A. Knisbacher, PhD, a postdoctoral fellow at the Broad Institute of MIT and Harvard Medical Schoo, Boston, said in an interview.
“It also delineated the molecular landscape of the two immunoglobulin gene (IGHV) subtypes, refined CLL subtyping, and built richer genetic prognostic models,” he said.
According to Dr. Knisbacher, CLL “has been at the forefront of genomic discovery,” and research has shown that there’s a wide variety of somatic mutations that drive CLL initiation across the patient population. However, as many as 10% of cases don’t appear to be driven by any known genetic variation, he said, and there’s a need to identify more subtypes and “build richer prognostic models of patient survival” based on genetics and multiomics such as genomics, transcriptomics, and epigenomics.
For the new study, researchers analyzed RNA and DNA from 1,095 patients with CLL and 54 patients with monoclonal B cell lymphocytosis and built what they say is the largest CLL dataset in existence. It’s twice the size of previous datasets, Dr. Knisbacher said.
“We found that RNA expression data was extremely informative for characterizing CLL,” Dr. Knisbacher said. “The RNA expression subtypes refined the ‘classic’ two IGHV subtypes. It is well documented that patients with U-CLL (IGHV-unmutated CLL) have substantially worse clinical outcome in comparison to M-CLL patients (IGHV-mutated CLLs). We found that M-CLLs that have RNA expression profiles similar to U-CLLs have worse survival than M-CLLs with a typical expression profile. Failure-free survival was 50% shorter – 5.3 versus 10.7 years median failure-free survival.”
In addition, he said, “U-CLLs with expression similar to M-CLLs had better survival than U-CLLs with an RNA expression profile typical to U-CLLs.”
The researchers have made their molecular map publicly available at https://cllmap.org/. Researchers can use it “to discover more about each subtype of CLL, and these future studies can help to improve clinical prognosis for the benefit of the patient,” Dr. Knisbacher said.
The study authors added that “this molecular foundation may allow for better prediction of response to therapy or provide the basis for rational combination of novel agents.”
Lee Greenberger, PhD, chief science officer of the Leukemia & Lymphoma Society, said in an interview that the study “provides foundational data further subtyping CLL patients and outcomes. It identifies new targets for therapy or diagnostic predictions in the future. This type of foundational work has proven invaluable in the development of new medicines for cancer in general.”
While there are many medications that have improved therapeutic outcomes in CLL, he added, “cures – or life-long disease control –remain elusive for many patients. Therefore, new molecular insights are needed that could personalize therapies or even lead to entirely new therapies.”
In addition, he said, although prevention of CLL still remains elusive, “it is conceivable that some of the mutations found in this paper occur early in the CLL trajectory, perhaps even before the disease is presented clinically.”
The study was funded by the National Institutes of Health and the Broad/IBM Cancer Resistance Research Project. Dr. Knisbacher and several other authors disclose that they are inventors on a patent related to CLL. Several authors report various relationships with industry. Dr. Greenberger has no disclosures.
FROM NATURE GENETICS
First drug therapy approved for childhood GVHD
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Specifically, the indication is for pediatric patients with cGVHD who have already been treated with one or more lines of systemic therapy. The manufacturers have also launched a new oral suspension formulation, in addition to capsules and tablets, which were already available.
Ibrutinib is already approved for use in adults with cGVHD.
The drug is also approved for use in several blood cancers, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenström’s macroglobulinemia. All these approvals are for adult patients.
This is the first pediatric indication for the product and is “incredibly meaningful,” said Gauri Sunkersett, DO, associate medical director at AbbVie, which markets the drug together with Jansen. “As a pediatric oncologist, when my patients describe the physical pain they experience from simply hugging their parents, due to their cGVHD, the importance of researching alternative treatment options in this patient population is further validated.”
These children have already been through a lot, having been diagnosed with a leukemia or lymphoma and then undergoing chemotherapy and/or radiotherapy for a stem cell transplant. Just over half (52%-65%) of children who receive allogeneic transplants go on to develop cGVHD, in which the donor bone marrow or stem cells attack the recipient.
“Imagine going through a transplant and then being told you have a moderate to severe chronic disease that can sometimes also be life-threatening,” commented Paul A. Carpenter, MD, attending physician at Seattle Children’s Hospital. “If these children were between 1 and 12 and didn’t respond to steroid treatment, we didn’t have any rigorously studied treatment options – until now.”
The new indication was approved by the U.S. Food and Drug Administration on the basis of results from the iMAGINE trial, for which Dr. Carpenter was a principal investigator.
The phase 1/2 iMAGINE trial was an open-label, multicenter, single-arm trial conducted with 47 patients (mean age, 13 years; range, 1-19 years) with relapsed/refractory cGVHD who had received at least one prior systemic therapy. Ibrutinib was given at a dose of 420 mg orally once daily to patients aged 12 and older and at a dose of 240 mg/m2 orally once daily to patients who were younger than 12 years.
The overall response rate through week 25 was 60% (confidence interval, 95%, 44%-74%). The median duration of response was 5.3 months (95% CI, 2.8-8.8).
The safety profile was consistent with the established profile for ibrutinib. Observed adverse events in pediatric patients were consistent with those observed in adult patients with moderate to severe cGVHD, the companies noted.
The FDA noted that the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were anemia, musculoskeletal pain, pyrexia, diarrhea, pneumonia, abdominal pain, stomatitis, thrombocytopenia, and headache.
Full prescribing information for ibrutinib is available here.
A version of this article first appeared on Medscape.com.
Young children with leukemia are outliving teens
“Outcomes are improving. However, additional efforts, support, and resources are needed to further improve short- and long-term survival for acute leukemia survivors. Targeted efforts focused on populations that face greater disparities in their survival are needed to move the needle faster,” Michael Roth, MD, codirector of the Adolescent and Young Adult Oncology Program at the University of Texas M.D. Anderson Cancer Center, said in an interview.
In one study, released in The Lancet Child & Adolescent Health, an international team of researchers tracked survival outcomes from various types of leukemia in 61 nations. The study focused on the years 2000-2014 and followed patients aged 0-24.
“Age-standardized 5-year net survival in children, adolescents, and young adults for all leukemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia,” the researchers wrote. “Throughout 2000-14, survival from all leukemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries.”
The U.S. data came from 41 states that cover 86% of the nation’s population, lead author Naomi Ssenyonga, a research fellow at London School of Hygiene & Tropical Medicine, said in an interview.
The 5-year survival rate for acute lymphoid leukemia (ALL) rose from 80% during 2000-2004 to 86% during 2010-2014. Survival in patients with acute myeloid leukemia (AML) was lower than for other subtypes: 66% in 2010-2014 vs. 57% in 2000-2004.
In regard to all leukemias, “we noted a steady increase in the U.S. of 6 percentage points in 5-year survival, up from 77% for patients diagnosed during 2000-2004 to 83% for those diagnosed during 2010-2014,” Ms. Ssenyonga said. “The gains were largely driven by the improvements seen among children.”
Why haven’t adolescents and young adults gained as much ground in survival?
“They often have unique clinical needs,” Ms. Ssenyonga said. “Over the past few years, adolescents and young adults with leukemia in some parts of the world, including the U.S., have increasingly been treated under pediatric protocols. This has led to higher survival. However, this approach has not been adopted consistently, and survival for adolescents and young adults with leukemia is still generally lower than survival for children.”
Gwen Nichols, MD, chief medical officer of the Leukemia & Lymphoma Society, agreed that pediatric treatment protocols hold promise as treatments for young adults. However, “because we arbitrarily set an age cutoff for being an adult, many of these patients are treated by an adult [nonpediatric] hematologist/oncologist, and some patients in the 20-39 age group do not receive the more intensive treatment regimens given to children,” she said in an interview.
In another study, published in Cancer Epidemiology, Biomarkers, & Prevention, M.D. Anderson Cancer Center’s Dr. Roth and colleagues tracked 1,938 patients with ALL and 2,350 with AML who were diagnosed at ages 15-39 from 1980 to 2009. All lived at least 5 years after diagnosis. In both groups, about 58% were White, and most of the rest were Hispanic. The median age of diagnosis for ALL was 23 (range: 15-39) and 28 years for AML (range: 15-39).
“For ALL, 10-year survival for those diagnosed in the 1980s, 1990s, and 2000s was 83%, 88%, and 88%, respectively,” the researchers reported. “Ten-year survival for AML was 82%, 90%, and 90% for those diagnosed in the 1980s, 1990s, and 2000s, respectively.”
“Early mortality within 10 years of diagnosis was mostly secondary to leukemia progressing or recurring. We believe that later mortality is secondary to the development of late side effects from their cancer treatment,” Dr. Roth said.
He noted that many adolescents and young adults with ALL or AML receive stem-cell transplants. “This treatment approach is effective. However, it is associated with short- and long-term toxicity that impacts patients’ health for many years after treatment.”
Indeed, up to 80% of acute leukemia survivors have significant health complications after therapy, said the Leukemia & Lymphoma Society’s Dr. Nichols, who wasn’t surprised by the findings. According to the society, “even when treatments are effective, more than 70% of childhood cancer survivors have a chronic health condition and 42% have a severe, disabling or life-threatening condition 30 years after diagnosis.”
“It would be interesting to understand the male predominance better,” she added, noting that the study found that male patients had worse long-term survival than females (survival time ratio: 0.61, 95% confidence interval, 0.45-0.82). “While it is tempting to suggest it is due to difference in cardiac disease, I am not aware of data to support why there is this survival difference.”
What’s next? “In ALL, we now have a number of new modalities to treat high-risk and relapsed disease such as antibodies and CAR-T,” Dr. Nichols said. “We anticipate that 5-year survival can improve utilizing these modalities due to getting more patients into remission, hopefully while reducing chemotherapeutic toxicity.”
Dr. Nichol’s also highlighted the society’s new genomic-led Pediatric Acute Leukemia (PedAL) Master Clinical Trial, which began enrolling children with acute leukemia in the United States and Canada this year, in an effort to transform medicine’s traditional high-level chemotherapy strategy to their care. The project was launched in collaboration with the National Cancer Institute, Children’s Oncology Group, and the European Pediatric Acute Leukemia Foundation.
As part of the screening process, the biology of each child’s cancer will be identified, and families will be encouraged to enroll them in appropriate targeted therapy trials.
“Until we are able to decrease the toxicity of leukemia regimens, we won’t see a dramatic shift in late effects and thus in morbidity and mortality,” Dr. Nichols said. “The trial is an effort to test newer, less toxic regimens to begin to change that cycle.”
The 5-year survival study was funded by Children with Cancer UK, Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, National Cancer Institute, and the American Cancer Society. One author reports a grant from Macmillan Cancer Support, consultancy fees from Pfizer, and unsolicited small gifts from Moondance Cancer Initiative for philanthropic work. The other authors report no disclosures.
The long-term survival study was funded by the National Cancer Institute, the Archer Foundation and LyondellBasell Industries. Dr. Roth reports no disclosures; other authors report various disclosures. Dr. Nichols reports no disclosures.
“Outcomes are improving. However, additional efforts, support, and resources are needed to further improve short- and long-term survival for acute leukemia survivors. Targeted efforts focused on populations that face greater disparities in their survival are needed to move the needle faster,” Michael Roth, MD, codirector of the Adolescent and Young Adult Oncology Program at the University of Texas M.D. Anderson Cancer Center, said in an interview.
In one study, released in The Lancet Child & Adolescent Health, an international team of researchers tracked survival outcomes from various types of leukemia in 61 nations. The study focused on the years 2000-2014 and followed patients aged 0-24.
“Age-standardized 5-year net survival in children, adolescents, and young adults for all leukemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia,” the researchers wrote. “Throughout 2000-14, survival from all leukemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries.”
The U.S. data came from 41 states that cover 86% of the nation’s population, lead author Naomi Ssenyonga, a research fellow at London School of Hygiene & Tropical Medicine, said in an interview.
The 5-year survival rate for acute lymphoid leukemia (ALL) rose from 80% during 2000-2004 to 86% during 2010-2014. Survival in patients with acute myeloid leukemia (AML) was lower than for other subtypes: 66% in 2010-2014 vs. 57% in 2000-2004.
In regard to all leukemias, “we noted a steady increase in the U.S. of 6 percentage points in 5-year survival, up from 77% for patients diagnosed during 2000-2004 to 83% for those diagnosed during 2010-2014,” Ms. Ssenyonga said. “The gains were largely driven by the improvements seen among children.”
Why haven’t adolescents and young adults gained as much ground in survival?
“They often have unique clinical needs,” Ms. Ssenyonga said. “Over the past few years, adolescents and young adults with leukemia in some parts of the world, including the U.S., have increasingly been treated under pediatric protocols. This has led to higher survival. However, this approach has not been adopted consistently, and survival for adolescents and young adults with leukemia is still generally lower than survival for children.”
Gwen Nichols, MD, chief medical officer of the Leukemia & Lymphoma Society, agreed that pediatric treatment protocols hold promise as treatments for young adults. However, “because we arbitrarily set an age cutoff for being an adult, many of these patients are treated by an adult [nonpediatric] hematologist/oncologist, and some patients in the 20-39 age group do not receive the more intensive treatment regimens given to children,” she said in an interview.
In another study, published in Cancer Epidemiology, Biomarkers, & Prevention, M.D. Anderson Cancer Center’s Dr. Roth and colleagues tracked 1,938 patients with ALL and 2,350 with AML who were diagnosed at ages 15-39 from 1980 to 2009. All lived at least 5 years after diagnosis. In both groups, about 58% were White, and most of the rest were Hispanic. The median age of diagnosis for ALL was 23 (range: 15-39) and 28 years for AML (range: 15-39).
“For ALL, 10-year survival for those diagnosed in the 1980s, 1990s, and 2000s was 83%, 88%, and 88%, respectively,” the researchers reported. “Ten-year survival for AML was 82%, 90%, and 90% for those diagnosed in the 1980s, 1990s, and 2000s, respectively.”
“Early mortality within 10 years of diagnosis was mostly secondary to leukemia progressing or recurring. We believe that later mortality is secondary to the development of late side effects from their cancer treatment,” Dr. Roth said.
He noted that many adolescents and young adults with ALL or AML receive stem-cell transplants. “This treatment approach is effective. However, it is associated with short- and long-term toxicity that impacts patients’ health for many years after treatment.”
Indeed, up to 80% of acute leukemia survivors have significant health complications after therapy, said the Leukemia & Lymphoma Society’s Dr. Nichols, who wasn’t surprised by the findings. According to the society, “even when treatments are effective, more than 70% of childhood cancer survivors have a chronic health condition and 42% have a severe, disabling or life-threatening condition 30 years after diagnosis.”
“It would be interesting to understand the male predominance better,” she added, noting that the study found that male patients had worse long-term survival than females (survival time ratio: 0.61, 95% confidence interval, 0.45-0.82). “While it is tempting to suggest it is due to difference in cardiac disease, I am not aware of data to support why there is this survival difference.”
What’s next? “In ALL, we now have a number of new modalities to treat high-risk and relapsed disease such as antibodies and CAR-T,” Dr. Nichols said. “We anticipate that 5-year survival can improve utilizing these modalities due to getting more patients into remission, hopefully while reducing chemotherapeutic toxicity.”
Dr. Nichol’s also highlighted the society’s new genomic-led Pediatric Acute Leukemia (PedAL) Master Clinical Trial, which began enrolling children with acute leukemia in the United States and Canada this year, in an effort to transform medicine’s traditional high-level chemotherapy strategy to their care. The project was launched in collaboration with the National Cancer Institute, Children’s Oncology Group, and the European Pediatric Acute Leukemia Foundation.
As part of the screening process, the biology of each child’s cancer will be identified, and families will be encouraged to enroll them in appropriate targeted therapy trials.
“Until we are able to decrease the toxicity of leukemia regimens, we won’t see a dramatic shift in late effects and thus in morbidity and mortality,” Dr. Nichols said. “The trial is an effort to test newer, less toxic regimens to begin to change that cycle.”
The 5-year survival study was funded by Children with Cancer UK, Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, National Cancer Institute, and the American Cancer Society. One author reports a grant from Macmillan Cancer Support, consultancy fees from Pfizer, and unsolicited small gifts from Moondance Cancer Initiative for philanthropic work. The other authors report no disclosures.
The long-term survival study was funded by the National Cancer Institute, the Archer Foundation and LyondellBasell Industries. Dr. Roth reports no disclosures; other authors report various disclosures. Dr. Nichols reports no disclosures.
“Outcomes are improving. However, additional efforts, support, and resources are needed to further improve short- and long-term survival for acute leukemia survivors. Targeted efforts focused on populations that face greater disparities in their survival are needed to move the needle faster,” Michael Roth, MD, codirector of the Adolescent and Young Adult Oncology Program at the University of Texas M.D. Anderson Cancer Center, said in an interview.
In one study, released in The Lancet Child & Adolescent Health, an international team of researchers tracked survival outcomes from various types of leukemia in 61 nations. The study focused on the years 2000-2014 and followed patients aged 0-24.
“Age-standardized 5-year net survival in children, adolescents, and young adults for all leukemias combined during 2010-14 varied widely, ranging from 46% in Mexico to more than 85% in Canada, Cyprus, Belgium, Denmark, Finland, and Australia,” the researchers wrote. “Throughout 2000-14, survival from all leukemias combined remained consistently higher for children than adolescents and young adults, and minimal improvement was seen for adolescents and young adults in most countries.”
The U.S. data came from 41 states that cover 86% of the nation’s population, lead author Naomi Ssenyonga, a research fellow at London School of Hygiene & Tropical Medicine, said in an interview.
The 5-year survival rate for acute lymphoid leukemia (ALL) rose from 80% during 2000-2004 to 86% during 2010-2014. Survival in patients with acute myeloid leukemia (AML) was lower than for other subtypes: 66% in 2010-2014 vs. 57% in 2000-2004.
In regard to all leukemias, “we noted a steady increase in the U.S. of 6 percentage points in 5-year survival, up from 77% for patients diagnosed during 2000-2004 to 83% for those diagnosed during 2010-2014,” Ms. Ssenyonga said. “The gains were largely driven by the improvements seen among children.”
Why haven’t adolescents and young adults gained as much ground in survival?
“They often have unique clinical needs,” Ms. Ssenyonga said. “Over the past few years, adolescents and young adults with leukemia in some parts of the world, including the U.S., have increasingly been treated under pediatric protocols. This has led to higher survival. However, this approach has not been adopted consistently, and survival for adolescents and young adults with leukemia is still generally lower than survival for children.”
Gwen Nichols, MD, chief medical officer of the Leukemia & Lymphoma Society, agreed that pediatric treatment protocols hold promise as treatments for young adults. However, “because we arbitrarily set an age cutoff for being an adult, many of these patients are treated by an adult [nonpediatric] hematologist/oncologist, and some patients in the 20-39 age group do not receive the more intensive treatment regimens given to children,” she said in an interview.
In another study, published in Cancer Epidemiology, Biomarkers, & Prevention, M.D. Anderson Cancer Center’s Dr. Roth and colleagues tracked 1,938 patients with ALL and 2,350 with AML who were diagnosed at ages 15-39 from 1980 to 2009. All lived at least 5 years after diagnosis. In both groups, about 58% were White, and most of the rest were Hispanic. The median age of diagnosis for ALL was 23 (range: 15-39) and 28 years for AML (range: 15-39).
“For ALL, 10-year survival for those diagnosed in the 1980s, 1990s, and 2000s was 83%, 88%, and 88%, respectively,” the researchers reported. “Ten-year survival for AML was 82%, 90%, and 90% for those diagnosed in the 1980s, 1990s, and 2000s, respectively.”
“Early mortality within 10 years of diagnosis was mostly secondary to leukemia progressing or recurring. We believe that later mortality is secondary to the development of late side effects from their cancer treatment,” Dr. Roth said.
He noted that many adolescents and young adults with ALL or AML receive stem-cell transplants. “This treatment approach is effective. However, it is associated with short- and long-term toxicity that impacts patients’ health for many years after treatment.”
Indeed, up to 80% of acute leukemia survivors have significant health complications after therapy, said the Leukemia & Lymphoma Society’s Dr. Nichols, who wasn’t surprised by the findings. According to the society, “even when treatments are effective, more than 70% of childhood cancer survivors have a chronic health condition and 42% have a severe, disabling or life-threatening condition 30 years after diagnosis.”
“It would be interesting to understand the male predominance better,” she added, noting that the study found that male patients had worse long-term survival than females (survival time ratio: 0.61, 95% confidence interval, 0.45-0.82). “While it is tempting to suggest it is due to difference in cardiac disease, I am not aware of data to support why there is this survival difference.”
What’s next? “In ALL, we now have a number of new modalities to treat high-risk and relapsed disease such as antibodies and CAR-T,” Dr. Nichols said. “We anticipate that 5-year survival can improve utilizing these modalities due to getting more patients into remission, hopefully while reducing chemotherapeutic toxicity.”
Dr. Nichol’s also highlighted the society’s new genomic-led Pediatric Acute Leukemia (PedAL) Master Clinical Trial, which began enrolling children with acute leukemia in the United States and Canada this year, in an effort to transform medicine’s traditional high-level chemotherapy strategy to their care. The project was launched in collaboration with the National Cancer Institute, Children’s Oncology Group, and the European Pediatric Acute Leukemia Foundation.
As part of the screening process, the biology of each child’s cancer will be identified, and families will be encouraged to enroll them in appropriate targeted therapy trials.
“Until we are able to decrease the toxicity of leukemia regimens, we won’t see a dramatic shift in late effects and thus in morbidity and mortality,” Dr. Nichols said. “The trial is an effort to test newer, less toxic regimens to begin to change that cycle.”
The 5-year survival study was funded by Children with Cancer UK, Institut National du Cancer, La Ligue Contre le Cancer, Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, Rossy Family Foundation, National Cancer Institute, and the American Cancer Society. One author reports a grant from Macmillan Cancer Support, consultancy fees from Pfizer, and unsolicited small gifts from Moondance Cancer Initiative for philanthropic work. The other authors report no disclosures.
The long-term survival study was funded by the National Cancer Institute, the Archer Foundation and LyondellBasell Industries. Dr. Roth reports no disclosures; other authors report various disclosures. Dr. Nichols reports no disclosures.
Where women’s voices still get heard less
“Our study provides the first analysis of gender and early-career faculty disparities in speakers at hematology and medical oncology board review meetings,” the authors reported in research published in Blood Advances.
“We covered six major board reviews over the last 5 years that are either conducted yearly or every other year, [and] the general trend across all meetings showed skewness toward men speakers,” the authors reported.
Recent data from 2021 suggests a closing of the gender gap in oncology, with women making up 44.6% of oncologists in training. However, they still only represented 35.2% of practicing oncologists and are underrepresented in leadership positions in academic oncology, the authors reported.
With speaking roles at academic meetings potentially marking a key step in career advancement and improved opportunities, the authors sought to investigate the balance of gender, as well as early-career faculty among speakers at prominent hematology and/or oncology board review lecture series taking place in the United States between 2017 and 2021.
The five institutions and one society presenting the board review lecture series included Baylor College of Medicine/MD Anderson Cancer Center, both in Houston; Dana-Farber Brigham Cancer Center, Boston; George Washington University, Washington; Memorial Sloan Kettering Cancer Center, New York; Seattle Cancer Care Alliance; and the hematology board review series from the American Society of Hematology.
During the period in question, among 1,224 board review lectures presented, women constituted only 37.7% of the speakers. In lectures presented by American Board of Internal Medicine–certified speakers (n = 1,016, 83%), women were found to have made up fewer than 50% of speakers in five of six courses.
Men were also more likely to be recurrent speakers; across all courses, 13 men but only 2 women conducted 10 or more lectures. And while 35 men gave six or more lectures across all courses, only 12 women did so.
The lecture topics with the lowest rates of women presenters included malignant hematology (24.8%), solid tumors (38.9%), and benign hematology lectures (44.1%).
“We suspected [the imbalance in malignant hematology] since multiple recurrent roles were concentrated in the malignant hematology,” senior author Samer Al Hadidi, MD, of the Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AK, said in an interview.
He noted that “there are no regulations that such courses need to follow to ensure certain proportions of women and junior faculty are involved.”
Early-career faculty
In terms of early-career representation, more than 50% of lectures were given by faculty who had received their initial certifications more than 15 years earlier. The median time from initial certification was 12.5 years for hematology and 14 years for medical oncology.
The findings that more than half of the board review lectures were presented by faculty with more than 15 years’ experience since initial certification “reflects a lack of appropriate involvement of early-career faculty, who arguably may have more recent experience with board certification,” the authors wrote.
While being underrepresented in such roles is detrimental, there are no regulations that such courses follow to ensure certain proportions of women and junior faculty are involved, Dr. Al Hadidi noted.
Equal representation remains elusive
The study does suggest some notable gains. In a previous study of 181 academic conferences in the United States and Canada between 2007 and 2017, the rate of women speakers was only 15%, compared with 37.7% in the new study.
And an overall trend analysis in the study shows an approximately 10% increase in representation of women in all of the board reviews. However, only the ASH hematology board review achieved more than 50% women in their two courses.
“Overall, the proportion of women speakers is improving over the years, though it remains suboptimal,” Dr. Al Hadidi said.
The authors noted that oncology is clearly not the only specialty with gender disparities. They documented a lack of women speakers at conferences involving otolaryngology head and neck meetings, radiation oncology, emergency medicine, and research conferences.
They pointed to the work of ASH’s Women in Hematology Working Group as an important example of the needed effort to improve the balance of women hematologists.
Ariela Marshall, MD, director of women’s thrombosis and hemostasis at Penn Medicine in Philadelphia and a leader of ASH’s Women in Hematology Working Group, agreed that more efforts are needed to address both gender disparities as well as those of early career speakers. She asserted that the two disparities appear to be connected.
“If you broke down gender representation over time and the faculty/time since initial certification, the findings may mirror the percent of women in hematology-oncology at that given point in time,” Dr. Marshall said in an interview.
“If an institution is truly committed to taking action on gender equity, it needs to look at gender and experience equity of speakers,” she said. “Perhaps it’s the time to say ‘Dr. X has been doing this review course for 15 years. Let’s give someone else a chance.’
“This is not even just from a gender equity perspective but from a career development perspective overall,” she added. “Junior faculty need these speaking engagements a lot more than senior faculty.”
Meanwhile, the higher number of female trainees is a trend that ideally will be sustained as those trainees move into positions of leadership, Dr. Marshall noted.
“We do see that over time, we have achieved gender equity in the percent of women matriculating to medical school. And my hope is that, 20 years down the line, we will see the effects of this reflected in increased equity in leadership positions such as division/department chair, dean, and hospital CEO,” she said. “However, we have a lot of work to do because there are still huge inequities in the culture of medicine (institutional and more broadly), including gender-based discrimination, maternal discrimination, and high attrition rates for women physicians, compared to male physicians.
“It’s not enough to simply say ‘well, we have fixed the problem because our incoming medical student classes are now equitable in gender distribution,’ ”
The authors and Dr. Marshall had no disclosures to report.
“Our study provides the first analysis of gender and early-career faculty disparities in speakers at hematology and medical oncology board review meetings,” the authors reported in research published in Blood Advances.
“We covered six major board reviews over the last 5 years that are either conducted yearly or every other year, [and] the general trend across all meetings showed skewness toward men speakers,” the authors reported.
Recent data from 2021 suggests a closing of the gender gap in oncology, with women making up 44.6% of oncologists in training. However, they still only represented 35.2% of practicing oncologists and are underrepresented in leadership positions in academic oncology, the authors reported.
With speaking roles at academic meetings potentially marking a key step in career advancement and improved opportunities, the authors sought to investigate the balance of gender, as well as early-career faculty among speakers at prominent hematology and/or oncology board review lecture series taking place in the United States between 2017 and 2021.
The five institutions and one society presenting the board review lecture series included Baylor College of Medicine/MD Anderson Cancer Center, both in Houston; Dana-Farber Brigham Cancer Center, Boston; George Washington University, Washington; Memorial Sloan Kettering Cancer Center, New York; Seattle Cancer Care Alliance; and the hematology board review series from the American Society of Hematology.
During the period in question, among 1,224 board review lectures presented, women constituted only 37.7% of the speakers. In lectures presented by American Board of Internal Medicine–certified speakers (n = 1,016, 83%), women were found to have made up fewer than 50% of speakers in five of six courses.
Men were also more likely to be recurrent speakers; across all courses, 13 men but only 2 women conducted 10 or more lectures. And while 35 men gave six or more lectures across all courses, only 12 women did so.
The lecture topics with the lowest rates of women presenters included malignant hematology (24.8%), solid tumors (38.9%), and benign hematology lectures (44.1%).
“We suspected [the imbalance in malignant hematology] since multiple recurrent roles were concentrated in the malignant hematology,” senior author Samer Al Hadidi, MD, of the Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AK, said in an interview.
He noted that “there are no regulations that such courses need to follow to ensure certain proportions of women and junior faculty are involved.”
Early-career faculty
In terms of early-career representation, more than 50% of lectures were given by faculty who had received their initial certifications more than 15 years earlier. The median time from initial certification was 12.5 years for hematology and 14 years for medical oncology.
The findings that more than half of the board review lectures were presented by faculty with more than 15 years’ experience since initial certification “reflects a lack of appropriate involvement of early-career faculty, who arguably may have more recent experience with board certification,” the authors wrote.
While being underrepresented in such roles is detrimental, there are no regulations that such courses follow to ensure certain proportions of women and junior faculty are involved, Dr. Al Hadidi noted.
Equal representation remains elusive
The study does suggest some notable gains. In a previous study of 181 academic conferences in the United States and Canada between 2007 and 2017, the rate of women speakers was only 15%, compared with 37.7% in the new study.
And an overall trend analysis in the study shows an approximately 10% increase in representation of women in all of the board reviews. However, only the ASH hematology board review achieved more than 50% women in their two courses.
“Overall, the proportion of women speakers is improving over the years, though it remains suboptimal,” Dr. Al Hadidi said.
The authors noted that oncology is clearly not the only specialty with gender disparities. They documented a lack of women speakers at conferences involving otolaryngology head and neck meetings, radiation oncology, emergency medicine, and research conferences.
They pointed to the work of ASH’s Women in Hematology Working Group as an important example of the needed effort to improve the balance of women hematologists.
Ariela Marshall, MD, director of women’s thrombosis and hemostasis at Penn Medicine in Philadelphia and a leader of ASH’s Women in Hematology Working Group, agreed that more efforts are needed to address both gender disparities as well as those of early career speakers. She asserted that the two disparities appear to be connected.
“If you broke down gender representation over time and the faculty/time since initial certification, the findings may mirror the percent of women in hematology-oncology at that given point in time,” Dr. Marshall said in an interview.
“If an institution is truly committed to taking action on gender equity, it needs to look at gender and experience equity of speakers,” she said. “Perhaps it’s the time to say ‘Dr. X has been doing this review course for 15 years. Let’s give someone else a chance.’
“This is not even just from a gender equity perspective but from a career development perspective overall,” she added. “Junior faculty need these speaking engagements a lot more than senior faculty.”
Meanwhile, the higher number of female trainees is a trend that ideally will be sustained as those trainees move into positions of leadership, Dr. Marshall noted.
“We do see that over time, we have achieved gender equity in the percent of women matriculating to medical school. And my hope is that, 20 years down the line, we will see the effects of this reflected in increased equity in leadership positions such as division/department chair, dean, and hospital CEO,” she said. “However, we have a lot of work to do because there are still huge inequities in the culture of medicine (institutional and more broadly), including gender-based discrimination, maternal discrimination, and high attrition rates for women physicians, compared to male physicians.
“It’s not enough to simply say ‘well, we have fixed the problem because our incoming medical student classes are now equitable in gender distribution,’ ”
The authors and Dr. Marshall had no disclosures to report.
“Our study provides the first analysis of gender and early-career faculty disparities in speakers at hematology and medical oncology board review meetings,” the authors reported in research published in Blood Advances.
“We covered six major board reviews over the last 5 years that are either conducted yearly or every other year, [and] the general trend across all meetings showed skewness toward men speakers,” the authors reported.
Recent data from 2021 suggests a closing of the gender gap in oncology, with women making up 44.6% of oncologists in training. However, they still only represented 35.2% of practicing oncologists and are underrepresented in leadership positions in academic oncology, the authors reported.
With speaking roles at academic meetings potentially marking a key step in career advancement and improved opportunities, the authors sought to investigate the balance of gender, as well as early-career faculty among speakers at prominent hematology and/or oncology board review lecture series taking place in the United States between 2017 and 2021.
The five institutions and one society presenting the board review lecture series included Baylor College of Medicine/MD Anderson Cancer Center, both in Houston; Dana-Farber Brigham Cancer Center, Boston; George Washington University, Washington; Memorial Sloan Kettering Cancer Center, New York; Seattle Cancer Care Alliance; and the hematology board review series from the American Society of Hematology.
During the period in question, among 1,224 board review lectures presented, women constituted only 37.7% of the speakers. In lectures presented by American Board of Internal Medicine–certified speakers (n = 1,016, 83%), women were found to have made up fewer than 50% of speakers in five of six courses.
Men were also more likely to be recurrent speakers; across all courses, 13 men but only 2 women conducted 10 or more lectures. And while 35 men gave six or more lectures across all courses, only 12 women did so.
The lecture topics with the lowest rates of women presenters included malignant hematology (24.8%), solid tumors (38.9%), and benign hematology lectures (44.1%).
“We suspected [the imbalance in malignant hematology] since multiple recurrent roles were concentrated in the malignant hematology,” senior author Samer Al Hadidi, MD, of the Myeloma Center, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AK, said in an interview.
He noted that “there are no regulations that such courses need to follow to ensure certain proportions of women and junior faculty are involved.”
Early-career faculty
In terms of early-career representation, more than 50% of lectures were given by faculty who had received their initial certifications more than 15 years earlier. The median time from initial certification was 12.5 years for hematology and 14 years for medical oncology.
The findings that more than half of the board review lectures were presented by faculty with more than 15 years’ experience since initial certification “reflects a lack of appropriate involvement of early-career faculty, who arguably may have more recent experience with board certification,” the authors wrote.
While being underrepresented in such roles is detrimental, there are no regulations that such courses follow to ensure certain proportions of women and junior faculty are involved, Dr. Al Hadidi noted.
Equal representation remains elusive
The study does suggest some notable gains. In a previous study of 181 academic conferences in the United States and Canada between 2007 and 2017, the rate of women speakers was only 15%, compared with 37.7% in the new study.
And an overall trend analysis in the study shows an approximately 10% increase in representation of women in all of the board reviews. However, only the ASH hematology board review achieved more than 50% women in their two courses.
“Overall, the proportion of women speakers is improving over the years, though it remains suboptimal,” Dr. Al Hadidi said.
The authors noted that oncology is clearly not the only specialty with gender disparities. They documented a lack of women speakers at conferences involving otolaryngology head and neck meetings, radiation oncology, emergency medicine, and research conferences.
They pointed to the work of ASH’s Women in Hematology Working Group as an important example of the needed effort to improve the balance of women hematologists.
Ariela Marshall, MD, director of women’s thrombosis and hemostasis at Penn Medicine in Philadelphia and a leader of ASH’s Women in Hematology Working Group, agreed that more efforts are needed to address both gender disparities as well as those of early career speakers. She asserted that the two disparities appear to be connected.
“If you broke down gender representation over time and the faculty/time since initial certification, the findings may mirror the percent of women in hematology-oncology at that given point in time,” Dr. Marshall said in an interview.
“If an institution is truly committed to taking action on gender equity, it needs to look at gender and experience equity of speakers,” she said. “Perhaps it’s the time to say ‘Dr. X has been doing this review course for 15 years. Let’s give someone else a chance.’
“This is not even just from a gender equity perspective but from a career development perspective overall,” she added. “Junior faculty need these speaking engagements a lot more than senior faculty.”
Meanwhile, the higher number of female trainees is a trend that ideally will be sustained as those trainees move into positions of leadership, Dr. Marshall noted.
“We do see that over time, we have achieved gender equity in the percent of women matriculating to medical school. And my hope is that, 20 years down the line, we will see the effects of this reflected in increased equity in leadership positions such as division/department chair, dean, and hospital CEO,” she said. “However, we have a lot of work to do because there are still huge inequities in the culture of medicine (institutional and more broadly), including gender-based discrimination, maternal discrimination, and high attrition rates for women physicians, compared to male physicians.
“It’s not enough to simply say ‘well, we have fixed the problem because our incoming medical student classes are now equitable in gender distribution,’ ”
The authors and Dr. Marshall had no disclosures to report.
FROM BLOOD ADVANCES
Phase 3 data: Zanubrutinib bests standard CLL treatment
At a median follow-up of 26.2 months, progression to worsening disease or death was much lower in patients with these conditions who took zanubrutinib (Brukinsa), compared with those who took bendamustine-rituximab (hazard ratio. 0.42; 95% confidence interval, 0.28-0.63; P < .00011). The study was published in The Lancet Oncology.
Researchers already knew that ibrutinib, another BTKi, improves progression-free survival, study coauthor Paolo Ghia, MD, PhD, professor of medical oncology at Vita-Salute San Raffaele University, Milan, said in an interview. “Now we confirmed that the same advantage can be seen” in zanubrutinib.
According to Dr. Ghia, bendamustine-rituximab has long been a standard treatment in blood cancers and is considered well tolerated and inexpensive. But BTKis such as first-in-line ibrutinib have shown better results, he said, “and progressively, we are going to abandon bendamustine-rituximab.”
However, ibrutinib causes significant adverse effects such as bleeding, worsening hypertension and arrhythmia, he noted. As a result, second-generation BTKi such as zanubrutinib have entered the picture. The Food and Drug Administration approved it in 2019 for mantle cell lymphoma, and it has since been approved for Waldenström’s macroglobulinemia and marginal zone lymphoma.
In 2021, an interim analysis in a trial of the drug in patients with previously treated CLL, compared with ibrutinib, found that “zanubrutinib was shown to have a superior response rate, an improved PFS, and a lower rate of atrial fibrillation/flutter.”
The drug’s manufacturer, BeiGene, launched the new open-label, multicenter study, in a bid for FDA approval of the drug as a frontline treatment for CLL and SLL. More than 150 hospitals in 14 countries participated in the trial from 2017 to 2019.
The subjects were all adults and at least 65 years old or with comorbidities; None had the genetic trait del(17)(p13.1); 241 were assigned to take zanubrutinib and 238 to bendamustine-rituximab. Another group consisted of 111 patients with CLL and del(17)(p13·1). According to the study authors, these patients are especially difficult to treat.
The vast majority of patients were White (92%-95% depending on group) and male (61%-71%); 90%-92% had CLL.
At follow-up, there was no difference in overall survival between the main zanubrutinib and bendamustine-rituximab groups; 29 (12%) of the 241 patients in the zanubrutinib group and 57 (24%) of 238 patients in the bendamustine-rituximab group had progressed or died (HR, 0.42; 95% CI, 0.27-0.66; P < .00011). Adverse events leading to discontinuation were more common in the bendamustine-rituximab group (14%) versus zanubrutinib (8%).
In the third group, which only received zanubrutinib, 14% of patients died at median follow-up of 30.5 months; 98% of patients had adverse effects, and 5% discontinued treatment.
The researchers wrote that “zanubrutinib showed superior progression-free survival versus bendamustine-rituximab in older patients or those with comorbidities with untreated CLL, with a low incidence of cardiac arrhythmia. Similar efficacy was observed in patients with del(17p)–positive disease.”
The study didn’t examine cost; zanubrutinib is quite expensive.
In an interview, hematologist-oncologist Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York said the new study is important although not surprising, since other medications in the same class have shown similar results. Zanubrutinib is an alternative to ibrutinib, although the latter remains “an excellent drug,” he said.
“The era of chemotherapy being a first choice is over,” he said. “We’ve had several randomized studies that show targeted therapies are better tolerated and have better outcomes. We now need to look through the choices to decide which one of these good options are the best for our patients.”
In an interview, hematologist-oncologist Joanna Rhodes, MD, of Northwell Health in Hempstead, N.Y., highlighted the side effect profile of zanubrutinib, noting that it is low and resembles that of other BTKis, making it “another excellent treatment option.”
“We are seeing that bruising, upper respiratory tract infections, diarrhea, and arthralgias are the most common side effects,” she said. “Bleeding also is a common side effect, which is consistent across the class of BTKis, with 5% of patients developing a major bleed. Also, 3% of patients treated with zanubrutinib developed atrial fibrillation, which is consistent with data from other trials. Treatment discontinuation rates were low (8%).”
The study was funded by BeiGene. The authors reported multiple disclosures. Dr. Mato reported research or consulting relationships with BeiGene, AstraZeneca, and AbbVie. Dr. Rhodes reported multiple research or consulting relationships with Abbvie, BeiGene, Genentech, and others.
At a median follow-up of 26.2 months, progression to worsening disease or death was much lower in patients with these conditions who took zanubrutinib (Brukinsa), compared with those who took bendamustine-rituximab (hazard ratio. 0.42; 95% confidence interval, 0.28-0.63; P < .00011). The study was published in The Lancet Oncology.
Researchers already knew that ibrutinib, another BTKi, improves progression-free survival, study coauthor Paolo Ghia, MD, PhD, professor of medical oncology at Vita-Salute San Raffaele University, Milan, said in an interview. “Now we confirmed that the same advantage can be seen” in zanubrutinib.
According to Dr. Ghia, bendamustine-rituximab has long been a standard treatment in blood cancers and is considered well tolerated and inexpensive. But BTKis such as first-in-line ibrutinib have shown better results, he said, “and progressively, we are going to abandon bendamustine-rituximab.”
However, ibrutinib causes significant adverse effects such as bleeding, worsening hypertension and arrhythmia, he noted. As a result, second-generation BTKi such as zanubrutinib have entered the picture. The Food and Drug Administration approved it in 2019 for mantle cell lymphoma, and it has since been approved for Waldenström’s macroglobulinemia and marginal zone lymphoma.
In 2021, an interim analysis in a trial of the drug in patients with previously treated CLL, compared with ibrutinib, found that “zanubrutinib was shown to have a superior response rate, an improved PFS, and a lower rate of atrial fibrillation/flutter.”
The drug’s manufacturer, BeiGene, launched the new open-label, multicenter study, in a bid for FDA approval of the drug as a frontline treatment for CLL and SLL. More than 150 hospitals in 14 countries participated in the trial from 2017 to 2019.
The subjects were all adults and at least 65 years old or with comorbidities; None had the genetic trait del(17)(p13.1); 241 were assigned to take zanubrutinib and 238 to bendamustine-rituximab. Another group consisted of 111 patients with CLL and del(17)(p13·1). According to the study authors, these patients are especially difficult to treat.
The vast majority of patients were White (92%-95% depending on group) and male (61%-71%); 90%-92% had CLL.
At follow-up, there was no difference in overall survival between the main zanubrutinib and bendamustine-rituximab groups; 29 (12%) of the 241 patients in the zanubrutinib group and 57 (24%) of 238 patients in the bendamustine-rituximab group had progressed or died (HR, 0.42; 95% CI, 0.27-0.66; P < .00011). Adverse events leading to discontinuation were more common in the bendamustine-rituximab group (14%) versus zanubrutinib (8%).
In the third group, which only received zanubrutinib, 14% of patients died at median follow-up of 30.5 months; 98% of patients had adverse effects, and 5% discontinued treatment.
The researchers wrote that “zanubrutinib showed superior progression-free survival versus bendamustine-rituximab in older patients or those with comorbidities with untreated CLL, with a low incidence of cardiac arrhythmia. Similar efficacy was observed in patients with del(17p)–positive disease.”
The study didn’t examine cost; zanubrutinib is quite expensive.
In an interview, hematologist-oncologist Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York said the new study is important although not surprising, since other medications in the same class have shown similar results. Zanubrutinib is an alternative to ibrutinib, although the latter remains “an excellent drug,” he said.
“The era of chemotherapy being a first choice is over,” he said. “We’ve had several randomized studies that show targeted therapies are better tolerated and have better outcomes. We now need to look through the choices to decide which one of these good options are the best for our patients.”
In an interview, hematologist-oncologist Joanna Rhodes, MD, of Northwell Health in Hempstead, N.Y., highlighted the side effect profile of zanubrutinib, noting that it is low and resembles that of other BTKis, making it “another excellent treatment option.”
“We are seeing that bruising, upper respiratory tract infections, diarrhea, and arthralgias are the most common side effects,” she said. “Bleeding also is a common side effect, which is consistent across the class of BTKis, with 5% of patients developing a major bleed. Also, 3% of patients treated with zanubrutinib developed atrial fibrillation, which is consistent with data from other trials. Treatment discontinuation rates were low (8%).”
The study was funded by BeiGene. The authors reported multiple disclosures. Dr. Mato reported research or consulting relationships with BeiGene, AstraZeneca, and AbbVie. Dr. Rhodes reported multiple research or consulting relationships with Abbvie, BeiGene, Genentech, and others.
At a median follow-up of 26.2 months, progression to worsening disease or death was much lower in patients with these conditions who took zanubrutinib (Brukinsa), compared with those who took bendamustine-rituximab (hazard ratio. 0.42; 95% confidence interval, 0.28-0.63; P < .00011). The study was published in The Lancet Oncology.
Researchers already knew that ibrutinib, another BTKi, improves progression-free survival, study coauthor Paolo Ghia, MD, PhD, professor of medical oncology at Vita-Salute San Raffaele University, Milan, said in an interview. “Now we confirmed that the same advantage can be seen” in zanubrutinib.
According to Dr. Ghia, bendamustine-rituximab has long been a standard treatment in blood cancers and is considered well tolerated and inexpensive. But BTKis such as first-in-line ibrutinib have shown better results, he said, “and progressively, we are going to abandon bendamustine-rituximab.”
However, ibrutinib causes significant adverse effects such as bleeding, worsening hypertension and arrhythmia, he noted. As a result, second-generation BTKi such as zanubrutinib have entered the picture. The Food and Drug Administration approved it in 2019 for mantle cell lymphoma, and it has since been approved for Waldenström’s macroglobulinemia and marginal zone lymphoma.
In 2021, an interim analysis in a trial of the drug in patients with previously treated CLL, compared with ibrutinib, found that “zanubrutinib was shown to have a superior response rate, an improved PFS, and a lower rate of atrial fibrillation/flutter.”
The drug’s manufacturer, BeiGene, launched the new open-label, multicenter study, in a bid for FDA approval of the drug as a frontline treatment for CLL and SLL. More than 150 hospitals in 14 countries participated in the trial from 2017 to 2019.
The subjects were all adults and at least 65 years old or with comorbidities; None had the genetic trait del(17)(p13.1); 241 were assigned to take zanubrutinib and 238 to bendamustine-rituximab. Another group consisted of 111 patients with CLL and del(17)(p13·1). According to the study authors, these patients are especially difficult to treat.
The vast majority of patients were White (92%-95% depending on group) and male (61%-71%); 90%-92% had CLL.
At follow-up, there was no difference in overall survival between the main zanubrutinib and bendamustine-rituximab groups; 29 (12%) of the 241 patients in the zanubrutinib group and 57 (24%) of 238 patients in the bendamustine-rituximab group had progressed or died (HR, 0.42; 95% CI, 0.27-0.66; P < .00011). Adverse events leading to discontinuation were more common in the bendamustine-rituximab group (14%) versus zanubrutinib (8%).
In the third group, which only received zanubrutinib, 14% of patients died at median follow-up of 30.5 months; 98% of patients had adverse effects, and 5% discontinued treatment.
The researchers wrote that “zanubrutinib showed superior progression-free survival versus bendamustine-rituximab in older patients or those with comorbidities with untreated CLL, with a low incidence of cardiac arrhythmia. Similar efficacy was observed in patients with del(17p)–positive disease.”
The study didn’t examine cost; zanubrutinib is quite expensive.
In an interview, hematologist-oncologist Anthony Mato, MD, of Memorial Sloan Kettering Cancer Center in New York said the new study is important although not surprising, since other medications in the same class have shown similar results. Zanubrutinib is an alternative to ibrutinib, although the latter remains “an excellent drug,” he said.
“The era of chemotherapy being a first choice is over,” he said. “We’ve had several randomized studies that show targeted therapies are better tolerated and have better outcomes. We now need to look through the choices to decide which one of these good options are the best for our patients.”
In an interview, hematologist-oncologist Joanna Rhodes, MD, of Northwell Health in Hempstead, N.Y., highlighted the side effect profile of zanubrutinib, noting that it is low and resembles that of other BTKis, making it “another excellent treatment option.”
“We are seeing that bruising, upper respiratory tract infections, diarrhea, and arthralgias are the most common side effects,” she said. “Bleeding also is a common side effect, which is consistent across the class of BTKis, with 5% of patients developing a major bleed. Also, 3% of patients treated with zanubrutinib developed atrial fibrillation, which is consistent with data from other trials. Treatment discontinuation rates were low (8%).”
The study was funded by BeiGene. The authors reported multiple disclosures. Dr. Mato reported research or consulting relationships with BeiGene, AstraZeneca, and AbbVie. Dr. Rhodes reported multiple research or consulting relationships with Abbvie, BeiGene, Genentech, and others.
FROM THE LANCET ONCOLOGY
Many die waiting for `last-chance’ therapy
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.
Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.
About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”
But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.
The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.
The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.
“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”
The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.
For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
Shortage affecting mostly myeloma patients
The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.
The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).
“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”
Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.
A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.
“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.
“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”
“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.
He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.
“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
Complex causes behind bottleneck
The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.
While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.
“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”
On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.
Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.
There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”
The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.
“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.
Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”
Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
Pharma companies trying to meet the demand
This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.
“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.
“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.
“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”
Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.
The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.
“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.
Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.
“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”
With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
Incredibly exciting potential
Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.
“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.
But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.
A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.
The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.
At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”
A version of this article first appeared on Medscape.com.
Life and death decisions: What keeps oncologists up at night
It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.
The breast oncologist was thinking about a patient of hers with metastatic cancer.
The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.
Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.
“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).
That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.
“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.
And in the quiet hours of night, these concerns grow louder.
Dr. Shatsky is not alone.
“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”
The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.
Many oncologists carry this baggage home with them because they have no other option.
“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
What am I missing?
Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.
But no matter how many times he checks and rechecks, one question nags at him: What am I missing?
For Dr. Goodman, this exhaustive level of attention is worth it.
“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”
That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.
Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.
“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.
For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.
“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”
That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.
Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.
Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.
“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.
Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.
“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.
Her response: “You’re supposed to give me the answer.”
However, for patients approaching the end of life, there often is no right answer.
“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
The difficult conversation
Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”
It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.
“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.
For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.
“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”
When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.
“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”
The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.
Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.
“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”
He was afraid that if he did, he wouldn’t wake up.
In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
Life outside the clinic
Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.
Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.
“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.
The past few years of the pandemic have added a new layer of worry for Dr. Patel.
“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.
This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?
“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
The inevitable losses and the wins
For patients with metastatic disease, eventually the treatment options will run out.
Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”
For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.
“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.
That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”
Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.
When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.
And there’s a delicate balance.
“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”
What would you do if you had terminal cancer?
Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.
Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.
That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”
A version of this article first appeared on Medscape.com.
It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.
The breast oncologist was thinking about a patient of hers with metastatic cancer.
The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.
Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.
“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).
That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.
“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.
And in the quiet hours of night, these concerns grow louder.
Dr. Shatsky is not alone.
“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”
The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.
Many oncologists carry this baggage home with them because they have no other option.
“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
What am I missing?
Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.
But no matter how many times he checks and rechecks, one question nags at him: What am I missing?
For Dr. Goodman, this exhaustive level of attention is worth it.
“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”
That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.
Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.
“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.
For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.
“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”
That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.
Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.
Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.
“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.
Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.
“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.
Her response: “You’re supposed to give me the answer.”
However, for patients approaching the end of life, there often is no right answer.
“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
The difficult conversation
Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”
It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.
“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.
For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.
“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”
When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.
“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”
The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.
Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.
“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”
He was afraid that if he did, he wouldn’t wake up.
In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
Life outside the clinic
Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.
Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.
“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.
The past few years of the pandemic have added a new layer of worry for Dr. Patel.
“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.
This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?
“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
The inevitable losses and the wins
For patients with metastatic disease, eventually the treatment options will run out.
Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”
For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.
“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.
That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”
Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.
When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.
And there’s a delicate balance.
“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”
What would you do if you had terminal cancer?
Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.
Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.
That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”
A version of this article first appeared on Medscape.com.
It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.
The breast oncologist was thinking about a patient of hers with metastatic cancer.
The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.
Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.
“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).
That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.
“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.
And in the quiet hours of night, these concerns grow louder.
Dr. Shatsky is not alone.
“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”
The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.
Many oncologists carry this baggage home with them because they have no other option.
“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
What am I missing?
Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.
But no matter how many times he checks and rechecks, one question nags at him: What am I missing?
For Dr. Goodman, this exhaustive level of attention is worth it.
“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”
That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.
Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.
“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.
For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.
“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”
That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.
Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.
Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.
“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.
Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.
“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.
Her response: “You’re supposed to give me the answer.”
However, for patients approaching the end of life, there often is no right answer.
“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
The difficult conversation
Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”
It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.
“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.
For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.
“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”
When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.
“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”
The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.
Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.
“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”
He was afraid that if he did, he wouldn’t wake up.
In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
Life outside the clinic
Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.
Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.
“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.
The past few years of the pandemic have added a new layer of worry for Dr. Patel.
“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.
This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?
“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
The inevitable losses and the wins
For patients with metastatic disease, eventually the treatment options will run out.
Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”
For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.
“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.
That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”
Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.
When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.
And there’s a delicate balance.
“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”
What would you do if you had terminal cancer?
Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.
Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.
That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”
A version of this article first appeared on Medscape.com.
CAR T-cell therapy turns 10 and finally earns the word ‘cure’
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Ten years ago, Stephan Grupp, MD, PhD, plunged into an unexplored area of pediatric cancer treatment with a 6-year-old patient for whom every treatment available for her acute lymphoblastic leukemia (ALL) had been exhausted.
Dr. Grupp, a pioneer in cellular immunotherapy at Children’s Hospital of Philadelphia, had just got the green light to launch the first phase 1 trial of chimeric antigen receptor (CAR) T-cell therapy for children.
“The trial opened at the absolute last possible moment that it could have been helpful to her,” he said in an interview. “There was nothing else to do to temporize her further. ... It had to open then or never.”
The patient was Emily Whitehead, who has since become a poster girl for the dramatic results that can be achieved with these novel therapies. After that one CAR T-cell treatment back in 2012, she has been free of her leukemia and has remained in remission for more than 10 years.
Dr. Grupp said that he is, at last, starting to use the “cure” word.
“I’m not just a doctor, I’m a scientist – and one case isn’t enough to have confidence about anything,” he said. “We wanted more patients to be out longer to be able to say that thing which we have for a long time called the ‘c word.’
“CAR T-cell therapy has now been given to hundreds of patients at CHOP, and – we are unique in this – we have a couple dozen patients who are 5, 6, 7, 9 years out or more without further therapy. That feels like a cure to me,” he commented.
First patient with ALL
Emily was the first patient with ALL to receive the novel treatment, and also the first child.
There was a precedent, however. After having been “stuck” for decades, the CAR T-cell field had recently made a breakthrough, thanks to research by Dr. Grupp’s colleague Carl June, MD, and associates at the University of Pennsylvania, Philadelphia. By tweaking two key steps in the genetic modification of T cells, Dr. June’s team had successfully treated three adults with chronic lymphocytic leukemia (CLL), two of whom were in complete remission.
But using the treatment for a child and for a different type of leukemia was a daunting prospect. Dr. Grupp said that he was candid with Emily’s parents, Tom and Kari Whitehead, emphasizing that there are no guarantees in cancer treatment, particularly in a phase 1 trial.
But the Whiteheads had no time to waste and nowhere else to turn. Her father, Tom, recalled saying: “This is something outside the box, this is going to give her a chance.”
Dr. Grupp, who described himself as being “on the cowboy end” of oncology care, was ready to take the plunge.
Little did any of them know that the treatment would make Emily even sicker than she already was, putting her in intensive care. But thanks to a combination of several lucky breaks and a lot of brain power, she would make a breathtakingly rapid recovery.
The ‘magic formula’
CAR T-cell therapy involves harvesting a patient’s T cells and modifying them in the lab with a chimeric antigen receptor to target CD19, a protein found on the surface of ALL cancer cells.
Before the University of Pennsylvania team tweaked the process, clinical trials of the therapy yielded only modest results because the modified T cells “were very powerful in the short term but had almost no proliferative capacity” once they were infused back into the patient, Dr. Grupp explained.
“It does not matter how many cells you give to a patient, what matters is that the cells grow in the patient to the level needed to control the leukemia,” he said.
Dr. June’s team came up with what Dr. Grupp calls “the magic formula”: A bead-based manufacturing process that produced younger T-cell phenotypes with “enormous” proliferative capacity, and a lentiviral approach to the genetic modification, enabling prolonged expression of the CAR-T molecule.
“Was it rogue? Absolutely, positively not,” said Dr. Grupp, thinking back to the day he enrolled Emily in the trial. “Was it risky? Obviously ... we all dived into this pool without knowing what was under the water, so I would say, rogue, no, risky, yes. And I would say we didn’t know nearly enough about the risks.”
Cytokine storm
The gravest risk that Dr. Grupp and his team encountered was something they had not anticipated. At the time, they had no name for it.
The three adults with CLL who had received CAR T-cell therapy had experienced a mild version that the researchers referred to as “tumor lysis syndrome”.
But for Emily, on day 3 of her CAR T-cell infusion, there was a ferocious reaction storm that later came to be called cytokine release syndrome.
“The wheels just came off then,” said Mr. Whitehead. “I remember her blood pressure was 53 over 29. They took her to the ICU, induced a coma, and put her on a ventilator. It was brutal to watch. The oscillatory ventilator just pounds on you, and there was blood bubbling out around the hose in her mouth.
“I remember the third or fourth night, a doctor took me in the hallway and said, ‘There’s a one-in-a-thousand chance your daughter is alive when the sun comes up,’” Mr. Whitehead said in an interview. “And I said: ‘All right, I’ll see you at rounds tomorrow, because she’ll still be here.’ ”
“We had some vague notion of toxicity ... but it turned out not nearly enough,” said Dr. Grupp. The ICU “worked flat out” to save her life. “They had deployed everything they had to keep a human being alive and they had nothing more to add. At some point, you run out of things that you can do, and we had run out.”
On the fly
It was then that the team ran into some good luck. The first break was when they decided to look at her cytokines. “Our whole knowledge base came together in the moment, on the fly, at the exact moment when Emily was so very sick,” he recalled. “Could we get the result fast enough? The lab dropped everything to run the test.”
They ordered a broad cytokine panel that included 30 analytes. The results showed that a number of cytokines “were just unbelievably elevated,” he said. Among them was interleukin-6.
“IL-6 isn’t even made by T cells, so nobody in the world would have guessed that this would have mattered. If we’d ordered a smaller panel, it might not even have been on it. Yet this was the one cytokine we had a drug for – tocilizumab – so that was chance. And then, another chance was that the drug was at the hospital, because there are rheumatology patients who get it.
“So, we went from making the determination that IL-6 was high and figuring out there was a drug for it at 3:00 o’clock to giving the drug to her at 8:00 o’clock, and then her clinical situation turned around so quickly – I mean hours later.”
Emily woke up from a 14-day medically induced coma on her seventh birthday.
Eight days later, her bone marrow showed complete remission. “The doctors said, ‘We’ve never seen anyone this sick get better any faster,’ ” Mr. Whitehead said.
She had already been through a battery of treatments for her leukemia. “It was 22 months of failed, standard treatment, and then just 23 days after they gave her the first dose of CAR T-cells that she was cancer free,” he added.
Talking about ‘cure’
Now that Emily, 17, has remained in remission for 10 years, Dr. Grupp is finally willing to use the word “cure” – but it has taken him a long time.
Now, he says, the challenge from the bedside is to keep parents’ and patients’ expectations realistic about what they see as a miracle cure.
“It’s not a miracle. We can get patients into remission 90-plus percent of the time – but some patients do relapse – and then there are the risks [of the cytokine storm, which can be life-threatening].
“Right now, our experience is that about 12% of patients end up in the ICU, but they hardly ever end up as sick as Emily ... because now we’re giving the tocilizumab much earlier,” Dr. Grupp said.
Hearing whispers
Since their daughter’s recovery, Tom and Kari Whitehead have dedicated much of their time to spreading the word about the treatment that saved Emily’s life. Mr. Whitehead testified at the Food and Drug Administration’s advisory committee meeting in 2017 when approval was being considered for the CAR T-cell product that Emily received. The product was tisagenlecleucel-T (Novartis); at that meeting, there was a unanimous vote to recommend approval. This was the first CAR T cell to reach the market.
As cofounders of the Emily Whitehead Foundation, Emily’s parents have helped raise more than $2 million to support research in the field, and they travel around the world telling their story to “move this revolution forward.”
Despite their fierce belief in the science that saved Emily, they also acknowledge there was luck – and faith. Early in their journey, when Emily experienced relapse after her initial treatments, Mr. Whitehead drew comfort from two visions, which he calls “whispers,” that guided them through several forks in the road and through tough decisions about Emily’s treatment.
Several times the parents refused treatment that was offered to Emily, and once they had her discharged against medical advice. “I told Kari she’s definitely going to beat her cancer – I saw it. I don’t know how it’s going to happen, but we’re going to be in the bone marrow transplant hallway [at CHOP] teaching her to walk again. I know a lot of doctors don’t want to hear anything about ‘a sign,’ or what guided us, but I don’t think you have to separate faith and science, I think it takes everything to make something like this to happen.”
Enduring effect
The key to the CAR T-cell breakthrough that gave rise to Emily’s therapy was cell proliferation, and the effect is enduring, beyond all expectations, said Dr. Grupp. The modified T cells are still detectable in Emily and other patients in long-term remission.
“The fundamental question is, are the cells still working, or are the patients cured and they don’t need them?” said Dr. Grupp. “I think it’s the latter. The data that we have from several large datasets that we developed with Novartis are that, if you get to a year and your minimal residual disease testing both by flow and by next-generation sequencing is negative and you still have B-cell aplasia, the relapse risk is close to zero at that point.”
While it’s still not clear if and when that risk will ever get to zero, Emily and Dr. Grupp have successfully closed the chapter.
“Oncologists have different notions of what the word ‘cure’ means. If your attitude is you’re not cured until you’ve basically reached the end of your life and you haven’t relapsed, well, that’s an impossible bar to hit. My attitude is, if your likelihood of having a disease recurrence is lower than the other risks in your life, like getting into your car and driving to your appointment, then that’s what a functional cure looks like,” he said.
“I’m probably the doctor that still sees her the most, but honestly, the whole conversation is not about leukemia at all. She has B-cell aplasia, so we have to treat that, and then it’s about making sure there’s no long-term side effects from the totality of her treatment. Generally, for a patient who’s gotten a moderate amount of chemotherapy and CAR T, that should not interfere with fertility. Has any patient in the history of the world ever relapsed more than 5 years out from their therapy? Of course. Is that incredibly rare? Yes, it is. You can be paralyzed by that, or you can compartmentalize it.”
As for the Whiteheads, they are focused on Emily’s college applications, her new driver’s license, and her project to cowrite a film about her story with a Hollywood filmmaker.
Mr. Whitehead said the one thing he hopes clinicians take away from their story is that sometimes a parent’s instinct transcends science.
A version of this article first appeared on Medscape.com.
Heed cardiac risk of BTKis for CLL
The report discourages the use of the drugs in patients with heart failure, and it specifies that ibrutinib should be avoided in cases of ventricular fibrillation. The consensus statement appeared in the journal Blood Advances.
However, a physician who studies the intersection of cardiology and oncology questioned the report's methodology and said that it goes too far in its warnings about the use of BTKis. Also, the report is funded by AstraZeneca, which produces acalabrutinib, a rival BTKi product to ibrutinib.
“BTK inhibitors have revolutionized treatment outcomes and strategies in both the upfront and refractory CLL disease settings. Led by ibrutinib, the drugs are associated with dramatic improvements in long-term survival and disease outcomes for most CLL patients,” report co-author and cardiologist Daniel Addison, MD, co-director of the cardio-oncology program at the Ohio State University, said in an interview. “The main cardiac concerns are abnormal heart rhythms, high blood pressure, and heart weakness. It is not completely clear at this time why these things develop when patients are treated with these important drugs.”
For the new consensus statement, colleagues met virtually and examined peer-reviewed research. “Generally, this statement reflects available knowledge from cancer clinical trials,” Dr. Addison said. “Because of the design of these trials, cardiac analyses were secondary analyses. In terms of clinic use, this should be balanced against a large number of heart-focused retrospective examinations specifically describing the cardiac effects of these drugs. Most of the available heart-focused studies have not been prospective trials. Primary outcome heart-focused trials with BTK inhibitors are needed. This statement acknowledges this.”
The report recommends that all patients under consideration for BTKi therapy undergo electrocardiograms and blood pressure measurement, and it states that echocardiograms are appropriate for patients with heart disease or at high risk. Patients under 70 without risk factors may take ibrutinib, acalabrutinib, or zanubrutinib, while the latter two drugs are “generally preferred” in patients with established heart disease, well-controlled atrial fibrillation (AFib), hypertension, heart failure, or valvular heart disease.
The authors noted: “If the patient has difficult-to-manage AF[ib], recent acute coronary syndromes, or difficult to control heart failure, alternatives to BTKi treatment, including venetoclax, should be considered.”
As for patients with heart failure, the authors wrote that BTKis should be avoided, “but this is a relative contraindication, not an absolute one.” Ibrutinib should definitely be avoided because of the risk of AFib.
Finally, the authors stated that “the use of BTKis, especially ibrutinib, should be avoided in patients with a history of ventricular arrhythmias and cardiac arrest. Ibrutinib has been shown to increase the incidence of ventricular arrhythmias and sudden cardiac death. Although data are not yet available regarding whether second-generation BTKis [acalabrutinib or zanubrutinib] are also associated with these events, a Bcl-2 antagonist is preferred to any BTKi in these patients.”
Darryl P. Leong, MBBS, PhD, MPH, director of the cardio-oncology program at McMaster University, Hamilton, Ont., and Hamilton Health Sciences, said in an interview that the consensus statement has important limitations.
“The data extracted were not standardized. The authors of the original research were not contacted to provide data that might have been informative,” he said. “Finally and perhaps most importantly, I am uncertain that the quality of the data on which recommendations are made was well evaluated or described.”
Specifically, Dr. Leong said the report’s conclusions about heart failure and arrhythmias are not “necessarily well-supported by the evidence.”
He added: “While there is some evidence to suggest that BTKIs may increase heart failure risk, ibrutinib leads to substantial reductions in mortality. It is a large extrapolation to accept that a mostly theoretic risk of heart failure –with modest supporting empiric data – should outweigh proven reductions in death.”
As for the recommendation against the use of ibrutinib in patients with ventricular arrhythmias and cardiac arrest, he said the evidence cited by the report – an analysis of adverse event data prompted by a case report and a retrospective analysis – is limited. “The statement that ibrutinib increases the risk of ventricular arrhythmias and sudden death is more of a hypothesis at present, and the evidence to support this hypothesis is far from conclusive.”
As for the future, report co-author Dr. Addison said that “additional prospective and lab-based studies of these drugs are needed to guide how to best manage their cardiac effects in the future. This will be critical, as the use of these drugs continues to rapidly expand. Currently, we do not know a lot about why these heart issues really happen.”
The study was funded by AstraZeneca. Several authors reported multiple disclosures. Dr. Addison disclosed funding from AstraZeneca. Dr. Leong reported consulting and speaker fees from Janssen, maker of ibrutinib, as well as AstraZeneca.
The report discourages the use of the drugs in patients with heart failure, and it specifies that ibrutinib should be avoided in cases of ventricular fibrillation. The consensus statement appeared in the journal Blood Advances.
However, a physician who studies the intersection of cardiology and oncology questioned the report's methodology and said that it goes too far in its warnings about the use of BTKis. Also, the report is funded by AstraZeneca, which produces acalabrutinib, a rival BTKi product to ibrutinib.
“BTK inhibitors have revolutionized treatment outcomes and strategies in both the upfront and refractory CLL disease settings. Led by ibrutinib, the drugs are associated with dramatic improvements in long-term survival and disease outcomes for most CLL patients,” report co-author and cardiologist Daniel Addison, MD, co-director of the cardio-oncology program at the Ohio State University, said in an interview. “The main cardiac concerns are abnormal heart rhythms, high blood pressure, and heart weakness. It is not completely clear at this time why these things develop when patients are treated with these important drugs.”
For the new consensus statement, colleagues met virtually and examined peer-reviewed research. “Generally, this statement reflects available knowledge from cancer clinical trials,” Dr. Addison said. “Because of the design of these trials, cardiac analyses were secondary analyses. In terms of clinic use, this should be balanced against a large number of heart-focused retrospective examinations specifically describing the cardiac effects of these drugs. Most of the available heart-focused studies have not been prospective trials. Primary outcome heart-focused trials with BTK inhibitors are needed. This statement acknowledges this.”
The report recommends that all patients under consideration for BTKi therapy undergo electrocardiograms and blood pressure measurement, and it states that echocardiograms are appropriate for patients with heart disease or at high risk. Patients under 70 without risk factors may take ibrutinib, acalabrutinib, or zanubrutinib, while the latter two drugs are “generally preferred” in patients with established heart disease, well-controlled atrial fibrillation (AFib), hypertension, heart failure, or valvular heart disease.
The authors noted: “If the patient has difficult-to-manage AF[ib], recent acute coronary syndromes, or difficult to control heart failure, alternatives to BTKi treatment, including venetoclax, should be considered.”
As for patients with heart failure, the authors wrote that BTKis should be avoided, “but this is a relative contraindication, not an absolute one.” Ibrutinib should definitely be avoided because of the risk of AFib.
Finally, the authors stated that “the use of BTKis, especially ibrutinib, should be avoided in patients with a history of ventricular arrhythmias and cardiac arrest. Ibrutinib has been shown to increase the incidence of ventricular arrhythmias and sudden cardiac death. Although data are not yet available regarding whether second-generation BTKis [acalabrutinib or zanubrutinib] are also associated with these events, a Bcl-2 antagonist is preferred to any BTKi in these patients.”
Darryl P. Leong, MBBS, PhD, MPH, director of the cardio-oncology program at McMaster University, Hamilton, Ont., and Hamilton Health Sciences, said in an interview that the consensus statement has important limitations.
“The data extracted were not standardized. The authors of the original research were not contacted to provide data that might have been informative,” he said. “Finally and perhaps most importantly, I am uncertain that the quality of the data on which recommendations are made was well evaluated or described.”
Specifically, Dr. Leong said the report’s conclusions about heart failure and arrhythmias are not “necessarily well-supported by the evidence.”
He added: “While there is some evidence to suggest that BTKIs may increase heart failure risk, ibrutinib leads to substantial reductions in mortality. It is a large extrapolation to accept that a mostly theoretic risk of heart failure –with modest supporting empiric data – should outweigh proven reductions in death.”
As for the recommendation against the use of ibrutinib in patients with ventricular arrhythmias and cardiac arrest, he said the evidence cited by the report – an analysis of adverse event data prompted by a case report and a retrospective analysis – is limited. “The statement that ibrutinib increases the risk of ventricular arrhythmias and sudden death is more of a hypothesis at present, and the evidence to support this hypothesis is far from conclusive.”
As for the future, report co-author Dr. Addison said that “additional prospective and lab-based studies of these drugs are needed to guide how to best manage their cardiac effects in the future. This will be critical, as the use of these drugs continues to rapidly expand. Currently, we do not know a lot about why these heart issues really happen.”
The study was funded by AstraZeneca. Several authors reported multiple disclosures. Dr. Addison disclosed funding from AstraZeneca. Dr. Leong reported consulting and speaker fees from Janssen, maker of ibrutinib, as well as AstraZeneca.
The report discourages the use of the drugs in patients with heart failure, and it specifies that ibrutinib should be avoided in cases of ventricular fibrillation. The consensus statement appeared in the journal Blood Advances.
However, a physician who studies the intersection of cardiology and oncology questioned the report's methodology and said that it goes too far in its warnings about the use of BTKis. Also, the report is funded by AstraZeneca, which produces acalabrutinib, a rival BTKi product to ibrutinib.
“BTK inhibitors have revolutionized treatment outcomes and strategies in both the upfront and refractory CLL disease settings. Led by ibrutinib, the drugs are associated with dramatic improvements in long-term survival and disease outcomes for most CLL patients,” report co-author and cardiologist Daniel Addison, MD, co-director of the cardio-oncology program at the Ohio State University, said in an interview. “The main cardiac concerns are abnormal heart rhythms, high blood pressure, and heart weakness. It is not completely clear at this time why these things develop when patients are treated with these important drugs.”
For the new consensus statement, colleagues met virtually and examined peer-reviewed research. “Generally, this statement reflects available knowledge from cancer clinical trials,” Dr. Addison said. “Because of the design of these trials, cardiac analyses were secondary analyses. In terms of clinic use, this should be balanced against a large number of heart-focused retrospective examinations specifically describing the cardiac effects of these drugs. Most of the available heart-focused studies have not been prospective trials. Primary outcome heart-focused trials with BTK inhibitors are needed. This statement acknowledges this.”
The report recommends that all patients under consideration for BTKi therapy undergo electrocardiograms and blood pressure measurement, and it states that echocardiograms are appropriate for patients with heart disease or at high risk. Patients under 70 without risk factors may take ibrutinib, acalabrutinib, or zanubrutinib, while the latter two drugs are “generally preferred” in patients with established heart disease, well-controlled atrial fibrillation (AFib), hypertension, heart failure, or valvular heart disease.
The authors noted: “If the patient has difficult-to-manage AF[ib], recent acute coronary syndromes, or difficult to control heart failure, alternatives to BTKi treatment, including venetoclax, should be considered.”
As for patients with heart failure, the authors wrote that BTKis should be avoided, “but this is a relative contraindication, not an absolute one.” Ibrutinib should definitely be avoided because of the risk of AFib.
Finally, the authors stated that “the use of BTKis, especially ibrutinib, should be avoided in patients with a history of ventricular arrhythmias and cardiac arrest. Ibrutinib has been shown to increase the incidence of ventricular arrhythmias and sudden cardiac death. Although data are not yet available regarding whether second-generation BTKis [acalabrutinib or zanubrutinib] are also associated with these events, a Bcl-2 antagonist is preferred to any BTKi in these patients.”
Darryl P. Leong, MBBS, PhD, MPH, director of the cardio-oncology program at McMaster University, Hamilton, Ont., and Hamilton Health Sciences, said in an interview that the consensus statement has important limitations.
“The data extracted were not standardized. The authors of the original research were not contacted to provide data that might have been informative,” he said. “Finally and perhaps most importantly, I am uncertain that the quality of the data on which recommendations are made was well evaluated or described.”
Specifically, Dr. Leong said the report’s conclusions about heart failure and arrhythmias are not “necessarily well-supported by the evidence.”
He added: “While there is some evidence to suggest that BTKIs may increase heart failure risk, ibrutinib leads to substantial reductions in mortality. It is a large extrapolation to accept that a mostly theoretic risk of heart failure –with modest supporting empiric data – should outweigh proven reductions in death.”
As for the recommendation against the use of ibrutinib in patients with ventricular arrhythmias and cardiac arrest, he said the evidence cited by the report – an analysis of adverse event data prompted by a case report and a retrospective analysis – is limited. “The statement that ibrutinib increases the risk of ventricular arrhythmias and sudden death is more of a hypothesis at present, and the evidence to support this hypothesis is far from conclusive.”
As for the future, report co-author Dr. Addison said that “additional prospective and lab-based studies of these drugs are needed to guide how to best manage their cardiac effects in the future. This will be critical, as the use of these drugs continues to rapidly expand. Currently, we do not know a lot about why these heart issues really happen.”
The study was funded by AstraZeneca. Several authors reported multiple disclosures. Dr. Addison disclosed funding from AstraZeneca. Dr. Leong reported consulting and speaker fees from Janssen, maker of ibrutinib, as well as AstraZeneca.
FROM BLOOD ADVANCES
Drug shortages plague hematology, but preparedness helps
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.