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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.
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
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.
'New benchmark' set in phase-3 blood cancer study
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
The phase 3 SHINE study was conducted in 520 older patients (aged ≥ 65 years) with newly diagnosed mantle cell lymphoma who were randomized to receive ibrutinib or placebo plus bendamustine-rituximab (BR) and rituximab maintenance.
After 7 years of follow-up, median PFS was 80.6 months with the ibrutinib combination versus 52.9 years with placebo, offering patients an additional 2.3 years of disease-free life.
Complete response rates were higher with ibrutinib versus placebo, and importantly, there were no new safety signals with the combination.
“We believe this phase 3 clinical trial sets a new benchmark for patients with newly diagnosed mantle cell lymphoma and the elderly,” commented lead investigator Dr. Michael Wang, department of lymphoma & myeloma, University of Texas MD Anderson Cancer Center, Houston.
He was speaking during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented. It was also simultaneously published in the New England Journal of Medicine.
These results “bring new hope to newly diagnosed, older patients with this rare cancer, who have had too few treatment options” and are “generally underrepresented in clinical trials,” commented Dr. Julie R. Gralow, ASCO chief medical officer.
She described the difference in PFS between the two treatment groups as “profound” and “clinically meaningful,” and said the combination can be considered a “new standard of care as initial treatment of older patients with mantle cell lymphoma.”
Some lymphoma experts not impressed
The study got pushback from several lymphoma experts commenting on Twitter.
Lymphoma specialist and consultant hematologist Toby Eyre, MBChB, from Oxford University, London, highlighted the fact that although there was a PFS benefit, there was no overall survival benefit and more toxicity.
“I hope no one implements this regimen,” replied “Papa Heme” Dr. Aaron Goodman, a hematologist at UC San Diego Health, California.
“The authors should be congratulated on completing a large RCT in this space. As far as the result adding ibrutinib added about 28 mos to PFS. This is actually the median DoR of BTK inhibitors in the 2nd line. So big question is, whether the extra tox is worth it,” commented another lymphoma specialist, Dr. Tim Fenske, MD, of the Medical College of Wisconsin, Milwaukee, replying in the same Twitter thread.
“I don’t see a benefit in adding continuous ibrutinib upfront to BR, based on these results. Added toxicity + less treatment free interval make this a tough pill to swallow (pun intended),” commented Dr. Alan Skarbnik, MD, of Novant Health, Charlotte, N.C.
Potential for first-line use
Ibrutinib is already approved for use in mantle cell lymphoma, but in patients who have received at least one prior therapy; this is an accelerated approval, based on overall response rate.
These new data could lead to approval for first-line use of the drug.
“There is an urgent need to improve outcomes for older patients with mantle cell lymphoma,” Dr. Wang commented in a company press release. “Given the median progression-free survival of 6.7 years, the ibrutinib combination demonstrated the potential to be a first-line treatment in this population.”
Mantle cell lymphoma, a form of non-Hodgkin’s lymphoma, affects men more than women and is more common in people aged over 65 years. Older patients often cannot tolerate intensive chemotherapy or stem cell transplants, so they often have poor outcomes, Dr. Wang explained during the press briefing.
He noted that SHINE is the first phase 3 study to examine ibrutinib plus BR as a first-line therapy in mantle cell lymphoma and involved patients with previously untreated stage II-IV disease aged ≥ 65 years not planning to undergo stem cell transplant.
Participants were a median age of 71 years, and 68%-71% were male. Most were White (76%-79%), and median time from initial diagnosis to randomization was 1.4-1.5 months.
At the data cut-off of June 30, 2021, median follow-up was 84.7 months. Disease progression or death had occurred in 44.4% of patients given ibrutinib and 58.0% of those given placebo.
Dr. Wang noted that the PFS curves “separated early, indicating the benefit that was achieved early within the first year and also that those benefits remained durable” throughout follow-up.
The percentage of patients with a complete response was 65.5% among patients treated with ibrutinib and 57.6% among those in the placebo group.
At the current analysis, there was no significant difference in overall survival between the two treatment arms, with a hazard ratio of 1.07 (P = .06).
Dr. Wang explained that “even though the study has been going on for 10 years, we don’t have enough deaths ... to evaluate overall survival yet.”
Furthermore, the median age of patients at enrollment was 71 years and is currently 78 years, with “half of them over 80 years,” so they are more likely to die of “other causes” than from mantle cell lymphoma, he commented.
He added that if the study had been designed to assess overall survival, it would have been “very different,” requiring 1,500 patients and a follow-up of 15-20 years.
The safety profile of the novel combination was “no surprise,” Dr. Wang said, and “consistent with what we’re seeing in daily practice.”
Grade 3/4 treatment-related adverse events were seen in 81.5% of patients treated with ibrutinib and 77.3% of those given placebo, and 47.1% and 48.1%, respectively, experienced grade 3/4 neutropenia.
In the post-presentation discussion, Dr. Wang said that approximately 40% of the patients in the placebo group received a BTK inhibitor at progression, and most were given ibrutinib.
He cautioned that the current results cannot be generalized to “other subtypes of lymphoma,” as they are “very different,” with different prognostic factors and different underlying biologies.
The study was funded by Janssen Pharmaceuticals and Pharmacyclics, an AbbVie Company. Dr. Wang has reported relationships with multiple companies, as listed in the article. Dr. Gralow has reported relationships with Genentech, AstraZeneca, Hexal, Puma Biotechnology, Roche, Novartis, Seagen, and Genomic Health.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
Third-generation Black woman physician makes cancer research history
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
When Jane Cooke Wright, MD, entered the medical profession in 1945, the notion that toxic drugs could target tumors struck many physicians and patients as outlandish. How could one poison be weaponized against another poison – a cancerous tumor – without creating more havoc? Let alone a combination of two or more chemicals?
Dr. Wright’s story would be extraordinary enough if she’d looked like most of her colleagues, but this surgeon and researcher stood apart. An African American woman at a time when medicine and science – like politics and law – were almost entirely the domain of White men, Dr. Wright had determination in her blood. Her father, once honored by a crowd of dignitaries that included a First Lady, persevered despite his horrific encounters with racism. She shared her father’s commitment to progress and added her own personal twists. She balanced elegance and beauty with scientific savvy, fierce ambition, and a refusal to be defined by anything other than her accomplishments.
“She didn’t focus on race, not at all,” her daughter Alison Jones, PhD, a psychologist in East Lansing, Mich., said in an interview. “Wherever she was, she wanted to be the best, not the best Black person. It was not about how she performed in a category, and she would get upset if someone said she was good as a Black physician.”
On the road to being the best, Dr. Jones said, her mother set a goal of curing cancer. National Cancer Research Month is a fitting opportunity to look back on a scientist dedicated to bringing humanity closer to that elusive achievement.
Medical legacy blazed in toil and trauma
A strong case could be made that Dr. Jane C. Wright and her father Louis Tompkins Wright, MD, are the most accomplished father-and-daughter team in all of medicine.
The elder Dr. Wright, son of a formerly enslaved man turned physician and a stepson of the first African American to graduate from Yale University, New Haven, Conn., himself graduated from Harvard Medical School in 1915. He earned a Purple Heart while serving in World War I, then went on to become the first Black surgeon to join the staff at Harlem Hospital.
Dr. Wright, who had witnessed mob violence and the aftermath of a lynching as a young man, became a supporter of the Harlem Renaissance and a prominent advocate for civil rights and integration. He served as chairman of the National Association for the Advancement of Colored People and was only the second Black member of the American College of Surgeons.
According to the 2009 book “Black Genius: Inspirational Portraits of African American Leaders,” he successfully treated the rare but devastating venereal disease lymphogranuloma venereum with a new antibiotic developed by his former colleague Yellapragada SubbaRow, MD. Dr. Wright even tried the drug himself, “as a lot of doctors in the olden days did,” according to another of his daughters, the late Barbara Wright Pierce, MD, who was quoted in “Black Genius.” She, too, was a physician.
In 1948, Dr. Jane C. Wright joined her father at Harlem Hospital’s Cancer Research Foundation. There the duo explored the cancer-fighting possibilities of a nitrogen mustard–like chemical agent that had been known since World War I to kill white blood cells. Ironically, Dr. Louis Wright himself suffered lifelong health problems because of an attack from the poisonous gas phosgene during his wartime service.
“Remissions were observed in patients with sarcoma, Hodgkin disease, and chronic myelogenous leukemia, mycosis fungoides, and lymphoma,” reported a 2013 obituary in the journal Oncology of the younger Dr. Wright. “They also performed early research into the clinical efficacy and toxicity of folic acid antagonists, documenting responses in 93 patients with various forms of incurable blood cancers and solid tumors.”
This research appears in a study that was authored by three Dr. Wrights – Dr. Louis T. Wright and his daughters Jane and Barbara.
“The elder Dr. Wright died in 1952, just months after 1,000 people – including Eleanor Roosevelt – honored him at a dinner to dedicate a Harlem Hospital library named after him. He was 61.
Scientific savvy mixed with modesty and elegance
After her father’s death, Dr. Janet C. Wright became director of the hospital’s cancer foundation. From the 1950s to the 1970s, she “worked out ways to use pieces of a patient’s own tumor, removed by surgery and grown in a nutrient culture medium in the laboratory, as a ‘guinea pig for testing drugs,’ ” according to the 1991 book “Black Scientists.” Previously, researchers had focused on mice as test subjects.
This approach also allowed Dr. Wright to determine if specific drugs such as methotrexate, a folic acid antagonist, would help specific patients. “She was looking for predictive activity for chemotherapeutic efficacy in vitro at a time when no one had good predictive tests,” wrote James F. Holland, MD, the late Mount Sinai School of Medicine oncologist, who was quoted in Dr. Wright’s 2013 Oncology obituary.
“Her strict attention to detail and concern for her patients helped determine effective dosing levels and establish treatment guidelines,” the Oncology obituary reported. “She treated patients that other physicians had given up on, and she was among the first small cadre of researchers to carefully test the effects of drugs against cancer in a clinical trial setting.”
Dr. Wright also focused on developing ways to administer chemotherapy, such using a catheter to reach difficult-to-access organs like the spleen without surgery, according to “Black Scientists.”
Along with her work, Dr. Wright’s appearance set her apart. According to “Black Genius,” a newspaper columnist dubbed her one of the 10 most beautiful Back woman in America, and Ebony Magazine in 1966 honored her as one of the best-dressed women in America. It featured a photograph of her in a stunning ivory and yellow brocade gown, noting that she was “in private life Mrs. David J. Jones.” (She’d married the Harvard University Law School graduate in 1946.)
Dr. Wright had a sense of modesty despite her accomplishments, according to her daughter Alison Jones. She even downplayed her own mental powers in a newspaper interview. “I know I’m a member of two minority groups,” she told The New York Post in 1967, “but I don’t think of myself that way. Sure, a woman has to try twice as hard. But – racial prejudice? I’ve met very little of it. It could be I met it – and wasn’t intelligent enough to recognize it.”
Sharp-eyed readers might have glimpsed her modesty nearly 2 decades later. In a 1984 article for the Journal of the National Medical Association, a society of African American physicians, she wrote about the past, present, and future of chemotherapy without noting her own prominent role in its development.
‘Global medical pioneer’ cofounds ASCO – and more
In the 1960s, Dr. Wright joined the influential President’s Commission on Heart Disease, Cancer, and Stroke and was named associate dean at New York Medical College, her alma mater, a first for a black woman at a prominent U.S. medical school. Even more importantly, Dr. Wright was the sole woman among seven physicians who founded the American Society of Clinical Oncology in Chicago in 1964. She served as ASCO’s first Secretary-Treasurer and was honored as its longest surviving founder when she passed away 9 years ago.
“Jane Wright had the vision to see that oncology was an important separate discipline within medicine with far-reaching implications for research and discovery,” Georgetown University Medical Center, Washington, oncologist Sandra M. Swain, MD, a former president of the ASCO and author of the 2013 Oncology obituary of Dr. Wright, said in an interview. “It is truly remarkable that, as a woman and an African American woman, she had a seat at the very small table for the formation of such an important group.”
As her friend and fellow oncologist Edith Mitchell, MD, said in a eulogy, “Dr. Wright led delegations of oncologists to China and the Soviet Union, and countries in Africa and Eastern Europe. She led medical teams providing medical and cancer care and education to other nurses and physicians in Ghana in 1957 and Kenya in 1961. From 1973 to 1984, she served as vice-president of the African Research and Medical foundation.”
Dr. Wright also raised two daughters. A 1968 Ebony article devoted to her career and family declared that neither of her teenagers was interested in medical careers. Their perspectives shifted, however – as had Dr. Wright’s. An undergraduate at Smith College, Dr. Wright majored in art, swam on the varsity team, and had a special affinity for German language studies before she switched to premed.
Like their mother, Dr. Wright’s daughters also changed paths, and they ultimately became the fourth generation of their family to enter the medical field. Dr. Alison Jones, the psychologist, currently works in a prison, while Jane Jones, MD, became a clinical psychiatrist. She’s now retired and lives in Guttenberg, N.J.
Both fondly remember their mother as a supportive force who insisted on excellence. “There couldn’t be any excuses for you not getting where you wanted to go,” Dr. Jane Jones recalled in an interview.
Nevertheless, Dr. Wright was still keenly aware of society’s limits. “She told me I had to be a doctor or lawyer,” Dr. Alison Jones said, “because that’s how you need to survive when you’re Black in America.”
Dr. Wright passed away in 2013 at age 93. “Dr. Jane C. Wright truly has made contributions that have changed the practice of medicine,” noted her friend Dr. Mitchell, an oncologist and a retired brigadier general with the U.S. Air Force who now teaches at Thomas Jefferson University, Philadelphia. “A true pioneer. A concerned mentor. A renowned researcher. A global teacher. A global medical pioneer. A talented researcher, beloved sister, wife, and mother, and a beautiful, kind, and loving human being.”
Ex–hospital porter a neglected giant of cancer research
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
We have a half-forgotten Indian immigrant to thank – a hospital night porter turned biochemist –for revolutionizing treatment of leukemia, the once deadly childhood scourge that is still the most common pediatric cancer.
Dr. Yellapragada SubbaRow has been called the “father of chemotherapy” for developing methotrexate, a powerful, inexpensive therapy for leukemia and other diseases, and he is celebrated for additional scientific achievements. Yet Dr. SubbaRow’s life was marked more by struggle than glory.
Born poor in southeastern India, he nearly succumbed to a tropical disease that killed two older brothers, and he didn’t focus on schoolwork until his father died. Later, prejudice dogged his years as an immigrant to the United States, and a blood clot took his life at the age of 53.
Scientifically, however, Dr. SubbaRow (pronounced sue-buh-rao) triumphed, despite mammoth challenges and a lack of recognition that persists to this day. National Cancer Research Month is a fitting time to look back on his extraordinary life and work and pay tribute to his accomplishments.
‘Yella,’ folic acid, and a paradigm shift
No one appreciates Dr. SubbaRow more than a cadre of Indian-born physicians who have kept his legacy alive in journal articles, presentations, and a Pulitzer Prize-winning book. Among them is author and oncologist Siddhartha Mukherjee, MD, who chronicled Dr. SubbaRow’s achievements in his New York Times No. 1 bestseller, “The Emperor of All Maladies: A Biography of Cancer.”
As Dr. Mukherjee wrote, Dr. SubbaRow was a “pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology.” (Per Indian tradition, SubbaRow is the doctor’s first name, and Yellapragada is his surname, but medical literature uses SubbaRow as his cognomen, with some variations in spelling. Dr. Mukherjee wrote that his friends called him “Yella.”)
Dr. SubbaRow came to the United States in 1923, after enduring a difficult childhood and young adulthood. He’d survived bouts of religious fervor, childhood rebellion (including a bid to run away from home and become a banana trader), and a failed arranged marriage. His wife bore him a child who died in infancy. He left it all behind.
In Boston, medical officials rejected his degree. Broke, he worked for a time as a night porter at Brigham and Women’s Hospital in Boston, changing sheets and cleaning urinals. To a poor but proud high-caste Indian Brahmin, the culture shock of carrying out these tasks must have been especially jarring.
Dr. SubbaRow went on to earn a diploma from Harvard Medical School, also in Boston, and became a junior faculty member. As a foreigner, Dr. Mukherjee wrote, Dr. SubbaRow was a “reclusive, nocturnal, heavily accented vegetarian,” so different from his colleagues that advancement seemed impossible. Despite his pioneering biochemistry work, Harvard later declined to offer Dr. SubbaRow a tenured faculty position.
By the early 1940s, he took a job at an upstate New York pharmaceutical company called Lederle Labs (later purchased by Pfizer). At Lederle, Dr. SubbaRow strove to synthesize the vitamin known as folic acid. He ended up creating a kind of antivitamin, a lookalike that acted like folic acid but only succeeded in gumming up the works in receptors. But what good would it do to stop the body from absorbing folic acid? Plenty, it turned out.
Discoveries pile up, but credit and fame prove elusive
Dr. SubbaRow was no stranger to producing landmark biological work. He’d previously codiscovered phosphocreatine and ATP, which are crucial to muscular contractions. However, “in 1935, he had to disown the extent of his role in the discovery of the color test related to phosphorus, instead giving the credit to his co-author, who was being considered for promotion to a full professorship at Harvard,” wrote author Gerald Posner in his 2020 book, “Pharma: Greed, Lies and the Poisoning of America.”
Houston-area oncologist Kirtan Nautiyal, MD, who paid tribute to Dr. SubbaRow in a 2018 article, contended that “with his Indian instinct for self-effacement, he had irreparably sabotaged his own career.”
Dr. SubbaRow and his team also developed “the first effective treatment of filariasis, which causes elephantiasis of the lower limbs and genitals in millions of people, mainly in tropical countries,” Dr. Nautiyal wrote. “Later in the decade, his antibiotic program generated polymyxin, the first effective treatment against the class of bacteria called Gram negatives, and aureomycin, the first “broad-spectrum’ antibiotic.” (Aureomycin is also the first tetracycline antibiotic.)
Dr. SubbaRow’s discovery of a folic acid antagonist would again go largely unheralded. But first came the realization that folic acid made childhood leukemia worse, not better, and the prospect that this process could potentially be reversed.
Rise of methotrexate and fall of leukemia
In Boston, Sidney Farber, MD, a Boston pathologist, was desperate to help Robert Sandler, a 2-year-old leukemia patient. Dr. Farber contacted his ex-colleague Dr. SubbaRow to request a supply of aminopterin, an early version of methotrexate that Dr. SubbaRow and his team had developed. Dr. Farber injected Robert with the substance and within 3 days, the toddler’s white blood count started falling – fast. He stopped bleeding, resumed eating, and once again seemed almost identical to his twin brother, as Dr. Mukherjee wrote in his book.
Leukemia had never gone into remission before. Unfortunately, the treatment only worked temporarily. Robert, like other children treated with the drug, relapsed and died within months. But Dr. Farber “saw a door open” – a chemical, a kind of chemotherapy, that could turn back cancer. In the case of folic acid antagonists, they do so by stopping cancer cells from replicating.
Methotrexate, a related agent synthesized by Dr. SubbaRow, would become a mainstay of leukemia treatment and begin to produce long-term remission from acute lymphoblastic leukemia in 1970, when combination chemotherapy was developed.
Other cancers fell to methotrexate treatment. “Previous assumptions that cancer was nearly always fatal were revised, and the field of medical oncology (treatment of cancer with chemotherapy), which had not previously existed, was formally established in 1971,” according to the National Cancer Institute’s history of methotrexate. This account does not mention Dr. SubbaRow.
Death takes the doctor, but his legacy remains
In biographies, as well as his own words, Dr. SubbaRow comes across as a prickly, hard-driving workaholic who had little interest in intimate human connections. “It is not good to ask in every letter when I will be back,” he wrote to his wife back in India, before cutting off ties completely in the early 1930s. “I will come as early as possible. ... I do not want to write anything more.”
It seems, as his biographer S.P.K. Gupta noted, that “he was quite determined that the time allotted to him on Earth should be completely devoted to finding cures for ailments that plagued mankind.”
Still, Dr. SubbaRow’s research team was devoted to him, and he had plenty of reasons to be bitter, such as the prejudice and isolation he encountered in the United States and earlier, in British-run India. According to Mr. Posner’s book, even as a young medical student, Dr. SubbaRow heeded the call of Indian independence activist Mohandas Gandhi. He “refused the British surgical gown given him at school and instead donned a traditional and simple cotton Khadi. That act of defiance cost SubbaRow the college degree that was necessary for him to get into the State Medical College.”
During the last year of his life, Dr. SubbaRow faced yet another humiliation: In his landmark 1948 study about aminopterin as a treatment for leukemia, his colleague Dr. Farber failed to credit him, an “astonishing omission” as Yaddanapudi Ravindranath, MBBS, a pediatric hematologist/oncologist at Wayne State University, Detroit, put it. “From everything I know, Dr. Farber spent the rest of his career apologizing and trying to make amends for it,” Dr. Ravindranath said in an interview.
A career cut short, and a lasting legacy
In 1948, at the age of 53, Dr. SubbaRow suddenly died. “Many think Dr. SubbaRow would have won [the] Nobel Prize had he lived a few years longer,” said Dr. Ravindranath.
Like Dr. SubbaRow, Dr. Ravindranath was born in Andhra Pradesh state, near the city of Chennai formerly known as Madras. “Being a compatriot, in a way I continue his legacy, and I am obviously proud of him,” said Dr. Ravindranath, who has conducted his own landmark research regarding methotrexate and leukemia.
Nearly 75 years after Dr. SubbaRow’s death, Indian-born physicians like Dr. Ravindranath continue to honor him in print, trying to ensure that he’s not forgotten. Methotrexate remains a crucial treatment for leukemia, along with a long list of other ailments, including psoriasis.
Recognition for “Yella” may have come late and infrequently, but a Lederle Laboratories research library named after him offered Dr. SubbaRow a kind of immortality. A plaque there memorialized him in stone as a scientist, teacher, philosopher, and humanitarian, featuring the quote: “Science simply prolongs life. Religion deepens it.”
By all accounts, Dr. SubbaRow was a man of science and faith who had faith in science.
New trials in lymphoma and MM: Could your patient benefit?
A number of late-phase clinical trials in lymphoma and multiple myeloma (MM) have opened in recent months. Maybe one of your patients could benefit from being enrolled?
Untreated peripheral T-cell lymphoma
Adult patients with peripheral T-cell lymphoma who have received no therapy except corticosteroids are invited to join a phase 2 study testing duvelisib (Copiktra) added to usual chemotherapy. Duvelisib is currently used in relapsed/refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or follicular lymphoma; this study explores first-line use in a different type of lymphoma, so it may be a potential new indication for the drug. All participants will receive a 5-month chemotherapy regimen of cyclophosphamide, doxorubicin (Adriamycin, Rubex), vincristine (Oncovin), prednisone, and etoposide (VePesid). One group will also take oral azacitidine (Vidaza) while the third (experimental) group has oral duvelisib. The primary outcome is complete remission rate; overall survival (OS) is a secondary outcome. Quality of life (QoL) is not measured apart from mood and fatigue. The study opened at Memorial Sloan Kettering Cancer Center on July 30 for up to 170 participants.
Untreated CLL/SLL
Patients with CLL/SLL, no 17p deletions, and no prior systemic therapy can join a phase 3 study of pirtobrutinib, an investigational oral tyrosine-kinase inhibitor. Pirtobrutinib targets Bruton's tyrosine kinase, an intracellular signaler that is crucial to the proliferation and survival of leukemic cells. The trial will involve treatment for up to 5 years, with either oral pirtobrutinib or a standard combination of intravenous bendamustine (Treakisym, Treanda, Ribomustin) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera). Investigators at the study site, the California Research Institute in Los Angeles, started recruiting on Sept. 23 hoping for 250 participants. Progression-free survival is the primary outcome, OS is a secondary measure, and QoL will not be tracked.
Relapsed or refractory follicular lymphoma after one line of therapy
Adult patients who have CD20-positive follicular lymphoma (grades 1-3A) who have received at least one prior systemic lymphoma therapy can join a phase 3 trial of investigational drug mosunetuzumab combined with lenalidomide (Revlimid, Linamide). Participants in the mosunetuzumab group will be treated with the drug combo for approximately 1 year then followed for 8 years. People in the comparator group will receive a rituximab-lenalidomide combination instead. The trial planned to start enrolling on Oct. 31, looking for a total of 400 people in 144 study locations worldwide, including in nine U.S. states. The primary outcome is progression-free survival. OS is a secondary outcome and, apart from fatigue, QoL parameters will not be assessed.
Relapsed or refractory follicular lymphoma after two lines of therapy
Adults with follicular lymphoma (grades 1-3A) despite two or more treatment regimens, including at least one anti-CD20 therapy, are eligible for a phase 2 study of loncastuximab tesirine (Zynlonta). The drug already has an FDA accelerated approval this year for a different lymphoma, relapsed/refractory large B-cell lymphoma, so this could be a new indication. In this trial, it will be compared with idelalisib (Zydelig), which is already approved for follicular lymphoma. Participants will get either an infusion of loncastuximab every 3 weeks or a twice-daily tablet of idelalisib for up to 30 months. Investigators started recruiting on Oct. 30 and hope for 150 participants in Nevada and New Jersey. Complete response rate is the primary outcome. OS and QoL are secondary outcome measures.
Untreated multiple myeloma not eligible for autologous stem-cell transplant (ASCT)
Adults with untreated multiple myeloma who are not eligible for stem-cell transplantation are sought for a phase 2 study testing the performance of selinexor (Xpovio) plus dexamethasone. (Prior treatment with emergency steroids and radiation therapy is allowed.) Selinexor plus dexamethasone was approved in 2019 for multiple myeloma after four prior therapies; the goal of this study is to assess its performance as frontline treatment. Participants will receive oral selinexor and dexamethasone for up to 3 years in addition to subcutaneous daratumumab (Darzalex) and capsules of lenalidomide. The study opened Sept. 10, aiming for 100 participants at sites in Arizona, Colorado, Maryland, New York, Oregon, Texas, and Virginia. OS is a secondary outcome measure; QoL will not be assessed.
Newly diagnosed multiple myeloma where ASCT not planned
Patients with newly diagnosed multiple myeloma who are not having ASCT as initial therapy are eligible for a phase 3 study of the investigational CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel). This product targets B-cell maturation antigen (BCMA), which is expressed on the surface of mature B lymphocytes and malignant plasma cells; it is in late-stage clinical trials for multiple myeloma but has not yet been approved. In this study, the control-group participants will receive standard therapy for up to approximately 4 years - a regimen of bortezomib (Velcade), lenalidomide, and dexamethasone. Patients destined for cilta-cel will undergo apheresis to garner their T cells, which will then be genetically engineered to express the synthetic antigen receptor, duplicated, and re-infused. During the 6-month wait between apheresis and the cilta-cel infusion, the CAR T patients will receive similar treatment to the control group. Recruitment started for 650 patients across 12 U.S. states and 24 countries on August 19. The primary outcome is progression-free survival. OS and QoL are secondary measures and will be tracked for approximately 12 years.
All trial information is from the National Institutes of Health U.S. National Library of Medicine.
A version of this article first appeared on Medscape.com
A number of late-phase clinical trials in lymphoma and multiple myeloma (MM) have opened in recent months. Maybe one of your patients could benefit from being enrolled?
Untreated peripheral T-cell lymphoma
Adult patients with peripheral T-cell lymphoma who have received no therapy except corticosteroids are invited to join a phase 2 study testing duvelisib (Copiktra) added to usual chemotherapy. Duvelisib is currently used in relapsed/refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or follicular lymphoma; this study explores first-line use in a different type of lymphoma, so it may be a potential new indication for the drug. All participants will receive a 5-month chemotherapy regimen of cyclophosphamide, doxorubicin (Adriamycin, Rubex), vincristine (Oncovin), prednisone, and etoposide (VePesid). One group will also take oral azacitidine (Vidaza) while the third (experimental) group has oral duvelisib. The primary outcome is complete remission rate; overall survival (OS) is a secondary outcome. Quality of life (QoL) is not measured apart from mood and fatigue. The study opened at Memorial Sloan Kettering Cancer Center on July 30 for up to 170 participants.
Untreated CLL/SLL
Patients with CLL/SLL, no 17p deletions, and no prior systemic therapy can join a phase 3 study of pirtobrutinib, an investigational oral tyrosine-kinase inhibitor. Pirtobrutinib targets Bruton's tyrosine kinase, an intracellular signaler that is crucial to the proliferation and survival of leukemic cells. The trial will involve treatment for up to 5 years, with either oral pirtobrutinib or a standard combination of intravenous bendamustine (Treakisym, Treanda, Ribomustin) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera). Investigators at the study site, the California Research Institute in Los Angeles, started recruiting on Sept. 23 hoping for 250 participants. Progression-free survival is the primary outcome, OS is a secondary measure, and QoL will not be tracked.
Relapsed or refractory follicular lymphoma after one line of therapy
Adult patients who have CD20-positive follicular lymphoma (grades 1-3A) who have received at least one prior systemic lymphoma therapy can join a phase 3 trial of investigational drug mosunetuzumab combined with lenalidomide (Revlimid, Linamide). Participants in the mosunetuzumab group will be treated with the drug combo for approximately 1 year then followed for 8 years. People in the comparator group will receive a rituximab-lenalidomide combination instead. The trial planned to start enrolling on Oct. 31, looking for a total of 400 people in 144 study locations worldwide, including in nine U.S. states. The primary outcome is progression-free survival. OS is a secondary outcome and, apart from fatigue, QoL parameters will not be assessed.
Relapsed or refractory follicular lymphoma after two lines of therapy
Adults with follicular lymphoma (grades 1-3A) despite two or more treatment regimens, including at least one anti-CD20 therapy, are eligible for a phase 2 study of loncastuximab tesirine (Zynlonta). The drug already has an FDA accelerated approval this year for a different lymphoma, relapsed/refractory large B-cell lymphoma, so this could be a new indication. In this trial, it will be compared with idelalisib (Zydelig), which is already approved for follicular lymphoma. Participants will get either an infusion of loncastuximab every 3 weeks or a twice-daily tablet of idelalisib for up to 30 months. Investigators started recruiting on Oct. 30 and hope for 150 participants in Nevada and New Jersey. Complete response rate is the primary outcome. OS and QoL are secondary outcome measures.
Untreated multiple myeloma not eligible for autologous stem-cell transplant (ASCT)
Adults with untreated multiple myeloma who are not eligible for stem-cell transplantation are sought for a phase 2 study testing the performance of selinexor (Xpovio) plus dexamethasone. (Prior treatment with emergency steroids and radiation therapy is allowed.) Selinexor plus dexamethasone was approved in 2019 for multiple myeloma after four prior therapies; the goal of this study is to assess its performance as frontline treatment. Participants will receive oral selinexor and dexamethasone for up to 3 years in addition to subcutaneous daratumumab (Darzalex) and capsules of lenalidomide. The study opened Sept. 10, aiming for 100 participants at sites in Arizona, Colorado, Maryland, New York, Oregon, Texas, and Virginia. OS is a secondary outcome measure; QoL will not be assessed.
Newly diagnosed multiple myeloma where ASCT not planned
Patients with newly diagnosed multiple myeloma who are not having ASCT as initial therapy are eligible for a phase 3 study of the investigational CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel). This product targets B-cell maturation antigen (BCMA), which is expressed on the surface of mature B lymphocytes and malignant plasma cells; it is in late-stage clinical trials for multiple myeloma but has not yet been approved. In this study, the control-group participants will receive standard therapy for up to approximately 4 years - a regimen of bortezomib (Velcade), lenalidomide, and dexamethasone. Patients destined for cilta-cel will undergo apheresis to garner their T cells, which will then be genetically engineered to express the synthetic antigen receptor, duplicated, and re-infused. During the 6-month wait between apheresis and the cilta-cel infusion, the CAR T patients will receive similar treatment to the control group. Recruitment started for 650 patients across 12 U.S. states and 24 countries on August 19. The primary outcome is progression-free survival. OS and QoL are secondary measures and will be tracked for approximately 12 years.
All trial information is from the National Institutes of Health U.S. National Library of Medicine.
A version of this article first appeared on Medscape.com
A number of late-phase clinical trials in lymphoma and multiple myeloma (MM) have opened in recent months. Maybe one of your patients could benefit from being enrolled?
Untreated peripheral T-cell lymphoma
Adult patients with peripheral T-cell lymphoma who have received no therapy except corticosteroids are invited to join a phase 2 study testing duvelisib (Copiktra) added to usual chemotherapy. Duvelisib is currently used in relapsed/refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or follicular lymphoma; this study explores first-line use in a different type of lymphoma, so it may be a potential new indication for the drug. All participants will receive a 5-month chemotherapy regimen of cyclophosphamide, doxorubicin (Adriamycin, Rubex), vincristine (Oncovin), prednisone, and etoposide (VePesid). One group will also take oral azacitidine (Vidaza) while the third (experimental) group has oral duvelisib. The primary outcome is complete remission rate; overall survival (OS) is a secondary outcome. Quality of life (QoL) is not measured apart from mood and fatigue. The study opened at Memorial Sloan Kettering Cancer Center on July 30 for up to 170 participants.
Untreated CLL/SLL
Patients with CLL/SLL, no 17p deletions, and no prior systemic therapy can join a phase 3 study of pirtobrutinib, an investigational oral tyrosine-kinase inhibitor. Pirtobrutinib targets Bruton's tyrosine kinase, an intracellular signaler that is crucial to the proliferation and survival of leukemic cells. The trial will involve treatment for up to 5 years, with either oral pirtobrutinib or a standard combination of intravenous bendamustine (Treakisym, Treanda, Ribomustin) and rituximab (Ruxience, Riabni, Truxima, Rituxan, MabThera). Investigators at the study site, the California Research Institute in Los Angeles, started recruiting on Sept. 23 hoping for 250 participants. Progression-free survival is the primary outcome, OS is a secondary measure, and QoL will not be tracked.
Relapsed or refractory follicular lymphoma after one line of therapy
Adult patients who have CD20-positive follicular lymphoma (grades 1-3A) who have received at least one prior systemic lymphoma therapy can join a phase 3 trial of investigational drug mosunetuzumab combined with lenalidomide (Revlimid, Linamide). Participants in the mosunetuzumab group will be treated with the drug combo for approximately 1 year then followed for 8 years. People in the comparator group will receive a rituximab-lenalidomide combination instead. The trial planned to start enrolling on Oct. 31, looking for a total of 400 people in 144 study locations worldwide, including in nine U.S. states. The primary outcome is progression-free survival. OS is a secondary outcome and, apart from fatigue, QoL parameters will not be assessed.
Relapsed or refractory follicular lymphoma after two lines of therapy
Adults with follicular lymphoma (grades 1-3A) despite two or more treatment regimens, including at least one anti-CD20 therapy, are eligible for a phase 2 study of loncastuximab tesirine (Zynlonta). The drug already has an FDA accelerated approval this year for a different lymphoma, relapsed/refractory large B-cell lymphoma, so this could be a new indication. In this trial, it will be compared with idelalisib (Zydelig), which is already approved for follicular lymphoma. Participants will get either an infusion of loncastuximab every 3 weeks or a twice-daily tablet of idelalisib for up to 30 months. Investigators started recruiting on Oct. 30 and hope for 150 participants in Nevada and New Jersey. Complete response rate is the primary outcome. OS and QoL are secondary outcome measures.
Untreated multiple myeloma not eligible for autologous stem-cell transplant (ASCT)
Adults with untreated multiple myeloma who are not eligible for stem-cell transplantation are sought for a phase 2 study testing the performance of selinexor (Xpovio) plus dexamethasone. (Prior treatment with emergency steroids and radiation therapy is allowed.) Selinexor plus dexamethasone was approved in 2019 for multiple myeloma after four prior therapies; the goal of this study is to assess its performance as frontline treatment. Participants will receive oral selinexor and dexamethasone for up to 3 years in addition to subcutaneous daratumumab (Darzalex) and capsules of lenalidomide. The study opened Sept. 10, aiming for 100 participants at sites in Arizona, Colorado, Maryland, New York, Oregon, Texas, and Virginia. OS is a secondary outcome measure; QoL will not be assessed.
Newly diagnosed multiple myeloma where ASCT not planned
Patients with newly diagnosed multiple myeloma who are not having ASCT as initial therapy are eligible for a phase 3 study of the investigational CAR T-cell therapy ciltacabtagene autoleucel (cilta-cel). This product targets B-cell maturation antigen (BCMA), which is expressed on the surface of mature B lymphocytes and malignant plasma cells; it is in late-stage clinical trials for multiple myeloma but has not yet been approved. In this study, the control-group participants will receive standard therapy for up to approximately 4 years - a regimen of bortezomib (Velcade), lenalidomide, and dexamethasone. Patients destined for cilta-cel will undergo apheresis to garner their T cells, which will then be genetically engineered to express the synthetic antigen receptor, duplicated, and re-infused. During the 6-month wait between apheresis and the cilta-cel infusion, the CAR T patients will receive similar treatment to the control group. Recruitment started for 650 patients across 12 U.S. states and 24 countries on August 19. The primary outcome is progression-free survival. OS and QoL are secondary measures and will be tracked for approximately 12 years.
All trial information is from the National Institutes of Health U.S. National Library of Medicine.
A version of this article first appeared on Medscape.com
ZUMA-2, TRANSCEND data pique interest in earlier CAR T for R/R MCL
The “remarkable” efficacy of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory mantle cell lymphoma as observed in recent trials supports its evaluation earlier in the course of treatment, according to Roch Houot, MD, PhD.
Patients with relapsed or refractory mantle cell lymphoma (MCL) who progress after treatment with a Bruton’s tyrosine kinase inhibitor (BTKi) have poor clinical outcomes, Dr. Houot, professor of hematology at Rennes (France) University Hospital, explained at the 3rd European CAR T-cell meeting.
Objective response rates in patients who relapse after BTKi therapy range from 25% to 42%, and median overall survival (OS) is less than 10 months with standard therapies, he said at the meeting, which is jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
The recent ZUMA-2 and TRANSCEND NHL 001 trials evaluating the CD19 CAR T-cell products brexucabtagene autoleucel (brexu-cel; Tecartus) and lisocabtagene maraleucel (liso-cel; Breyanzi), respectively, in patients with relapsed or refractory MCL after BTKi therapy, showed dramatically improved outcomes, compared with outcomes seen previously with standard salvage therapies.
The ORR in 68 patients treated with brexu-cel in ZUMA-2 was 92%, including complete response (CR) in 40 patients (67%) and partial response (PR) in 15 patients (25%) with the rare, aggressive subtype of B-cell lymphoma.
“Interestingly, among patients who achieved a CR, 70% remained in remission after a median follow-up of 17.5 months,” he said.
Median duration of response, progression-free survival, and overall survival were not reached at that time, and ongoing responses were consistent across prognostic subgroups, he added.
The ZUMA-2 findings led to accelerated approval of brexu-cel by the Food and Drug Administration in July 2020, as well as priority medicine designation by the European Medicines Agency in December 2020, for the treatment of MCL after two or more prior lines of systemic therapy including a BTKi.
The TRANSCEND study also included patients with MCL who were relapsed or refractory after two or more lines of therapy.
The ORR was 84% in 32 patients who completed treatment – including CRs in 66% and PRs in 19%. An additional 3% had stable disease and 9% of patients progressed, Dr. Houot said.
“The follow-up of the TRANSCEND study is still very short – the median is 5.9 months – so we don’t have survival data yet for these patients,” he noted.
Still, the efficacy in these studies is excellent, particularly considering the challenges of treating MCL patients who relapse or are refractory after BTKi treatment, he said, noting that most patients in both studies had poor prognostic factors.
Toxicities in both studies were similar to those seen in studies of patients with aggressive B-cell lymphomas who were treated with these drugs, he added.
“Longer follow-up is needed to better evaluate long-term efficacy,” he said, concluding that the results nonetheless “support evaluation of CAR T-cell therapy earlier in the therapeutic strategy of mantle cell lymphoma.”
Dr. Houot reported having no disclosures.
The “remarkable” efficacy of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory mantle cell lymphoma as observed in recent trials supports its evaluation earlier in the course of treatment, according to Roch Houot, MD, PhD.
Patients with relapsed or refractory mantle cell lymphoma (MCL) who progress after treatment with a Bruton’s tyrosine kinase inhibitor (BTKi) have poor clinical outcomes, Dr. Houot, professor of hematology at Rennes (France) University Hospital, explained at the 3rd European CAR T-cell meeting.
Objective response rates in patients who relapse after BTKi therapy range from 25% to 42%, and median overall survival (OS) is less than 10 months with standard therapies, he said at the meeting, which is jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
The recent ZUMA-2 and TRANSCEND NHL 001 trials evaluating the CD19 CAR T-cell products brexucabtagene autoleucel (brexu-cel; Tecartus) and lisocabtagene maraleucel (liso-cel; Breyanzi), respectively, in patients with relapsed or refractory MCL after BTKi therapy, showed dramatically improved outcomes, compared with outcomes seen previously with standard salvage therapies.
The ORR in 68 patients treated with brexu-cel in ZUMA-2 was 92%, including complete response (CR) in 40 patients (67%) and partial response (PR) in 15 patients (25%) with the rare, aggressive subtype of B-cell lymphoma.
“Interestingly, among patients who achieved a CR, 70% remained in remission after a median follow-up of 17.5 months,” he said.
Median duration of response, progression-free survival, and overall survival were not reached at that time, and ongoing responses were consistent across prognostic subgroups, he added.
The ZUMA-2 findings led to accelerated approval of brexu-cel by the Food and Drug Administration in July 2020, as well as priority medicine designation by the European Medicines Agency in December 2020, for the treatment of MCL after two or more prior lines of systemic therapy including a BTKi.
The TRANSCEND study also included patients with MCL who were relapsed or refractory after two or more lines of therapy.
The ORR was 84% in 32 patients who completed treatment – including CRs in 66% and PRs in 19%. An additional 3% had stable disease and 9% of patients progressed, Dr. Houot said.
“The follow-up of the TRANSCEND study is still very short – the median is 5.9 months – so we don’t have survival data yet for these patients,” he noted.
Still, the efficacy in these studies is excellent, particularly considering the challenges of treating MCL patients who relapse or are refractory after BTKi treatment, he said, noting that most patients in both studies had poor prognostic factors.
Toxicities in both studies were similar to those seen in studies of patients with aggressive B-cell lymphomas who were treated with these drugs, he added.
“Longer follow-up is needed to better evaluate long-term efficacy,” he said, concluding that the results nonetheless “support evaluation of CAR T-cell therapy earlier in the therapeutic strategy of mantle cell lymphoma.”
Dr. Houot reported having no disclosures.
The “remarkable” efficacy of chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory mantle cell lymphoma as observed in recent trials supports its evaluation earlier in the course of treatment, according to Roch Houot, MD, PhD.
Patients with relapsed or refractory mantle cell lymphoma (MCL) who progress after treatment with a Bruton’s tyrosine kinase inhibitor (BTKi) have poor clinical outcomes, Dr. Houot, professor of hematology at Rennes (France) University Hospital, explained at the 3rd European CAR T-cell meeting.
Objective response rates in patients who relapse after BTKi therapy range from 25% to 42%, and median overall survival (OS) is less than 10 months with standard therapies, he said at the meeting, which is jointly sponsored by the European Society for Blood and Marrow Transplantation and the European Hematology Association.
The recent ZUMA-2 and TRANSCEND NHL 001 trials evaluating the CD19 CAR T-cell products brexucabtagene autoleucel (brexu-cel; Tecartus) and lisocabtagene maraleucel (liso-cel; Breyanzi), respectively, in patients with relapsed or refractory MCL after BTKi therapy, showed dramatically improved outcomes, compared with outcomes seen previously with standard salvage therapies.
The ORR in 68 patients treated with brexu-cel in ZUMA-2 was 92%, including complete response (CR) in 40 patients (67%) and partial response (PR) in 15 patients (25%) with the rare, aggressive subtype of B-cell lymphoma.
“Interestingly, among patients who achieved a CR, 70% remained in remission after a median follow-up of 17.5 months,” he said.
Median duration of response, progression-free survival, and overall survival were not reached at that time, and ongoing responses were consistent across prognostic subgroups, he added.
The ZUMA-2 findings led to accelerated approval of brexu-cel by the Food and Drug Administration in July 2020, as well as priority medicine designation by the European Medicines Agency in December 2020, for the treatment of MCL after two or more prior lines of systemic therapy including a BTKi.
The TRANSCEND study also included patients with MCL who were relapsed or refractory after two or more lines of therapy.
The ORR was 84% in 32 patients who completed treatment – including CRs in 66% and PRs in 19%. An additional 3% had stable disease and 9% of patients progressed, Dr. Houot said.
“The follow-up of the TRANSCEND study is still very short – the median is 5.9 months – so we don’t have survival data yet for these patients,” he noted.
Still, the efficacy in these studies is excellent, particularly considering the challenges of treating MCL patients who relapse or are refractory after BTKi treatment, he said, noting that most patients in both studies had poor prognostic factors.
Toxicities in both studies were similar to those seen in studies of patients with aggressive B-cell lymphomas who were treated with these drugs, he added.
“Longer follow-up is needed to better evaluate long-term efficacy,” he said, concluding that the results nonetheless “support evaluation of CAR T-cell therapy earlier in the therapeutic strategy of mantle cell lymphoma.”
Dr. Houot reported having no disclosures.
FROM CART21
Don’t delay: Cancer patients need both doses of COVID vaccine
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The new findings, which are soon to be published as a preprint, cast doubt on the current U.K. policy of delaying the second dose of the vaccine.
Delaying the second dose can leave most patients with cancer wholly or partially unprotected, according to the researchers. Moreover, such a delay has implications for transmission of SARS-CoV-2 in the cancer patient’s environs as well as for the evolution of virus variants that could be of concern, the researchers concluded.
The data come from a British study that included 151 patients with cancer and 54 healthy control persons. All participants received the COVID-19 mRNA BNT162b2 vaccine (Pfizer-BioNTech).
This vaccine requires two doses. The first few participants in this study were given the second dose 21 days after they had received the first dose, but then national guidelines changed, and the remaining participants had to wait 12 weeks to receive their second dose.
The researchers reported that, among health controls, the immune efficacy of the first dose was very high (97% efficacious). By contrast, among patients with solid tumors, the immune efficacy of a single dose was strikingly low (39%), and it was even lower in patients with hematologic malignancies (13%).
The second dose of vaccine greatly and rapidly increased the immune efficacy in patients with solid tumors (95% within 2 weeks of receiving the second dose), the researchers added.
Too few patients with hematologic cancers had received the second dose before the study ended for clear conclusions to be drawn. Nevertheless, the available data suggest that 50% of patients with hematologic cancers who had received the booster at day 21 were seropositive at 5 weeks vs. only 8% of those who had not received the booster.
“Our data provide the first real-world evidence of immune efficacy following one dose of the Pfizer vaccine in immunocompromised patient populations [and] clearly show that the poor one-dose efficacy in cancer patients can be rescued with an early booster at day 21,” commented senior author Sheeba Irshad, MD, senior clinical lecturer, King’s College London.
“Based on our findings, we would recommend an urgent review of the vaccine strategy for clinically extremely vulnerable groups. Until then, it is important that cancer patients continue to observe all public health measures in place, such as social distancing and shielding when attending hospitals, even after vaccination,” Dr. Irshad added.
The paper, with first author Leticia Monin-Aldama, PhD, is scheduled to appear on the preprint server medRxiv. It has not undergone peer review. The paper was distributed to journalists, with comments from experts not involved in the study, by the UK Science Media Centre.
These data are “of immediate importance” to patients with cancer, commented Shoba Amarnath, PhD, Newcastle University research fellow, Laboratory of T-cell Regulation, Newcastle University Center for Cancer, Newcastle upon Tyne, England.
“These findings are consistent with our understanding. … We know that the immune system within cancer patients is compromised as compared to healthy controls,” Dr. Amarnath said. “The data in the study support the notion that, in solid cancer patients, a considerable delay in second dose will extend the period when cancer patients are at risk of SARS-CoV-2 infection.”
Although more data are required, “this study does raise the issue of whether patients with cancer, other diseases, or those undergoing therapies that affect the body’s immune response should be fast-tracked for their second vaccine dose,” commented Lawrence Young, PhD, professor of molecular oncology and director of the Warwick Cancer Research Center, University of Warwick, Coventry, England.
Stephen Evans, MSc, professor of pharmacoepidemiology, London School of Hygiene and Tropical Medicine, underlined that the study is “essentially” observational and “inevitable limitations must be taken into account.
“Nevertheless, these results do suggest that the vaccines may well not protect those patients with cancer as well as those without cancer,” Mr. Evans said. He added that it is “important that this population continues to observe all COVID-19–associated measures, such as social distancing and shielding when attending hospitals, even after vaccination.”
Study details
Previous studies have shown that some patients with cancer have prolonged responses to SARS-CoV-2 infection, with ongoing immune dysregulation, inefficient seroconversion, and prolonged viral shedding.
There are few data, however, on how these patients respond to COVID-19 vaccination. The authors point out that, among the 18,860 individuals who received the Pfizer vaccine during its development trials, “none with an active oncological diagnosis was included.”
To investigate this issue, they launched the SARS-CoV-2 for Cancer Patients (SOAP-02) study.
The 151 patients with cancer who participated in this study were mostly elderly, the authors noted (75% were older than 65 years; the median age was 73 years). The majority (63%) had solid-tumor malignancies. Of those, 8% had late-stage disease and had been living with their cancer for more than 24 months.
The healthy control persons were vaccine-eligible primary health care workers who were not age matched to the cancer patients.
All participants received the first dose of vaccine; 31 (of 151) patients with cancer and 16 (of 54) healthy control persons received the second dose on day 21.
The remaining participants were scheduled to receive their second dose 12 weeks later (after the study ended), in line with the changes in the national guidelines.
The team reported that, approximately 21 days after receiving the first vaccine dose, the immune efficacy of the vaccine was estimated to be 97% among healthy control persons vs. 39% for patients with solid tumors and only 13% for those with hematologic malignancies (P < .0001 for both).
T-cell responses, as assessed via interferon-gamma and/or interleukin-2 production, were observed in 82% of healthy control persons, 71% of patients with solid tumors, and 50% of those with hematologic cancers.
Vaccine boosting at day 21 resulted in immune efficacy of 100% for healthy control persons and 95% for patients with solid tumors. In contrast, only 43% of those who did not receive the second dose were seropositive 2 weeks later.
Further analysis suggested that participants who did not have a serologic response were “spread evenly” across different cancer types, but the reduced responses were more frequent among patients who had received the vaccine within 15 days of cancer treatment, especially chemotherapy, and had undergone intensive treatments.
The SOAP study is sponsored by King’s College London and Guy’s and St. Thomas Trust Foundation NHS Trust. It is funded from grants from the KCL Charity, Cancer Research UK, and program grants from Breast Cancer Now. The investigators have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
New inhibitor shows promise in previously failed B-cell malignancies
who discontinued prior Bruton’s tyrosine kinase (BTK)–inhibitor treatment due to resistance or intolerance, according to the results of the BRUIN trial, a phase 1/2 study.
Pirtobrutinib (formerly known as LOXO-305) is an oral-dose, highly selective, reversible BTK inhibitor, which might address a growing, unmet need for alternative therapies in BTK-inhibitor treatment failure patients, according to Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Their report was published in The Lancet.
The study included 109 women (34%) and 214 men (66%), with a median age of 68 years, who were treated with pirtobrutinib. Of these, 203 patients were assigned to pirtobrutinib (25-300 mg once per day) in the phase 1 portion of the study, and 120 patients were assigned to pirtobrutinib (200 mg once per day) in phase 2.
Promising outcomes
Pirtobrutinib, showed promising efficacy and tolerable safety in patients with CLL or small lymphocytic lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia who were previously treated with a BTK inhibitor. In 121 efficacy-evaluable patients with CLL or SLL treated with a previous covalent BTK inhibitor, the overall response rate with pirtobrutinib was 62% (95% confidence interval, 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481-mutant (71%), and BTK wild-type (66%) disease.
In 52 efficacy-evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI, 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression free to date, the authors stated.
In 19 efficacy-evaluable patients with Waldenström macroglobulinemia, the ORR was 68%. Among eight patients with follicular lymphoma who were efficacy evaluable, responses were observed in four (50%) patients, and six (75%) of eight efficacy evaluable patients with Richter’s transformation identified before enrollment responded to treatment, the authors stated.
No dose-limiting toxicities were observed and the maximum tolerated dose was not reached, according to the researchers. The recommended phase 2 dose was 200 mg daily. The adverse events, which occurred in at least 10% of 323 patients, were fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia (10%). Five patients (1%) discontinued treatment because of a treatment-related adverse event.
In this “first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma. Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment. Global randomized phase 3 studies in CLL or SLL, and MCL are planned,” the researchers concluded.
Birth of a third generation?
“The pirtobrutinib study, by opening the way for a third generation of BTK inhibitors, could improve such a personalized molecular approach in the treatment of B-cell malignancies,” according to accompanying editorial comment by Jean-Marie Michot, MD, and Vincent Ribrag, MD, both of the Institut de Cancérologie Gustave Roussy, Villejuif, France.
They discussed how BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL and how the three currently approved BTK inhibitors, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at the protein – the C481 binding site. “Ibrutinib was the first approved drug. The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective,” they added. However, the covalency and irreversibility of the drugs, considered therapeutic strengths, have resulted in induced resistance mutations occurring at the covalent binding, rendering the drugs inactive. “Two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased,” they wrote. “Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.”
Several of the study authors reported receiving grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), which sponsored the study, as well as financial relationships with other pharmaceutical and biotechnology companies.
Dr. Michot and Dr. Ribrag reported that they had no disclosures relevant to the discussion.
who discontinued prior Bruton’s tyrosine kinase (BTK)–inhibitor treatment due to resistance or intolerance, according to the results of the BRUIN trial, a phase 1/2 study.
Pirtobrutinib (formerly known as LOXO-305) is an oral-dose, highly selective, reversible BTK inhibitor, which might address a growing, unmet need for alternative therapies in BTK-inhibitor treatment failure patients, according to Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Their report was published in The Lancet.
The study included 109 women (34%) and 214 men (66%), with a median age of 68 years, who were treated with pirtobrutinib. Of these, 203 patients were assigned to pirtobrutinib (25-300 mg once per day) in the phase 1 portion of the study, and 120 patients were assigned to pirtobrutinib (200 mg once per day) in phase 2.
Promising outcomes
Pirtobrutinib, showed promising efficacy and tolerable safety in patients with CLL or small lymphocytic lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia who were previously treated with a BTK inhibitor. In 121 efficacy-evaluable patients with CLL or SLL treated with a previous covalent BTK inhibitor, the overall response rate with pirtobrutinib was 62% (95% confidence interval, 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481-mutant (71%), and BTK wild-type (66%) disease.
In 52 efficacy-evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI, 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression free to date, the authors stated.
In 19 efficacy-evaluable patients with Waldenström macroglobulinemia, the ORR was 68%. Among eight patients with follicular lymphoma who were efficacy evaluable, responses were observed in four (50%) patients, and six (75%) of eight efficacy evaluable patients with Richter’s transformation identified before enrollment responded to treatment, the authors stated.
No dose-limiting toxicities were observed and the maximum tolerated dose was not reached, according to the researchers. The recommended phase 2 dose was 200 mg daily. The adverse events, which occurred in at least 10% of 323 patients, were fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia (10%). Five patients (1%) discontinued treatment because of a treatment-related adverse event.
In this “first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma. Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment. Global randomized phase 3 studies in CLL or SLL, and MCL are planned,” the researchers concluded.
Birth of a third generation?
“The pirtobrutinib study, by opening the way for a third generation of BTK inhibitors, could improve such a personalized molecular approach in the treatment of B-cell malignancies,” according to accompanying editorial comment by Jean-Marie Michot, MD, and Vincent Ribrag, MD, both of the Institut de Cancérologie Gustave Roussy, Villejuif, France.
They discussed how BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL and how the three currently approved BTK inhibitors, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at the protein – the C481 binding site. “Ibrutinib was the first approved drug. The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective,” they added. However, the covalency and irreversibility of the drugs, considered therapeutic strengths, have resulted in induced resistance mutations occurring at the covalent binding, rendering the drugs inactive. “Two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased,” they wrote. “Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.”
Several of the study authors reported receiving grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), which sponsored the study, as well as financial relationships with other pharmaceutical and biotechnology companies.
Dr. Michot and Dr. Ribrag reported that they had no disclosures relevant to the discussion.
who discontinued prior Bruton’s tyrosine kinase (BTK)–inhibitor treatment due to resistance or intolerance, according to the results of the BRUIN trial, a phase 1/2 study.
Pirtobrutinib (formerly known as LOXO-305) is an oral-dose, highly selective, reversible BTK inhibitor, which might address a growing, unmet need for alternative therapies in BTK-inhibitor treatment failure patients, according to Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. Their report was published in The Lancet.
The study included 109 women (34%) and 214 men (66%), with a median age of 68 years, who were treated with pirtobrutinib. Of these, 203 patients were assigned to pirtobrutinib (25-300 mg once per day) in the phase 1 portion of the study, and 120 patients were assigned to pirtobrutinib (200 mg once per day) in phase 2.
Promising outcomes
Pirtobrutinib, showed promising efficacy and tolerable safety in patients with CLL or small lymphocytic lymphoma, mantle cell lymphoma, and Waldenström macroglobulinemia who were previously treated with a BTK inhibitor. In 121 efficacy-evaluable patients with CLL or SLL treated with a previous covalent BTK inhibitor, the overall response rate with pirtobrutinib was 62% (95% confidence interval, 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (67%), covalent BTK inhibitor intolerance (52%), BTK C481-mutant (71%), and BTK wild-type (66%) disease.
In 52 efficacy-evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI, 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but 8 remain progression free to date, the authors stated.
In 19 efficacy-evaluable patients with Waldenström macroglobulinemia, the ORR was 68%. Among eight patients with follicular lymphoma who were efficacy evaluable, responses were observed in four (50%) patients, and six (75%) of eight efficacy evaluable patients with Richter’s transformation identified before enrollment responded to treatment, the authors stated.
No dose-limiting toxicities were observed and the maximum tolerated dose was not reached, according to the researchers. The recommended phase 2 dose was 200 mg daily. The adverse events, which occurred in at least 10% of 323 patients, were fatigue (20%), diarrhea (17%), and contusion (13%). The most common grade 3 or higher adverse event was neutropenia (10%). Five patients (1%) discontinued treatment because of a treatment-related adverse event.
In this “first-in-human trial of pirtobrutinib, we showed promising efficacy and safety in patients with B-cell malignancies, including CLL or SLL, MCL, Waldenström macroglobulinemia, and follicular lymphoma. Activity was observed in heavily pretreated patients, including patients with resistance and intolerance to previous covalent BTK inhibitor treatment. Global randomized phase 3 studies in CLL or SLL, and MCL are planned,” the researchers concluded.
Birth of a third generation?
“The pirtobrutinib study, by opening the way for a third generation of BTK inhibitors, could improve such a personalized molecular approach in the treatment of B-cell malignancies,” according to accompanying editorial comment by Jean-Marie Michot, MD, and Vincent Ribrag, MD, both of the Institut de Cancérologie Gustave Roussy, Villejuif, France.
They discussed how BTK inhibitors have been a considerable therapeutic advance in the treatment of NHL-B and CLL and how the three currently approved BTK inhibitors, namely ibrutinib, acalabrutinib, and zanubrutinib, are all covalent and irreversible inhibitors at the protein – the C481 binding site. “Ibrutinib was the first approved drug. The second-generation inhibitors, acalabrutinib and zanubrutinib, were designed to be more BTK selective,” they added. However, the covalency and irreversibility of the drugs, considered therapeutic strengths, have resulted in induced resistance mutations occurring at the covalent binding, rendering the drugs inactive. “Two advantages of this new drug class are highlighted. First, the selectivity of the drug on BTK appears to be increased,” they wrote. “Second, this class does not bind BTK to the C481 residue, and the efficacy of the drug is therefore not affected by mutations in the BTK binding site.”
Several of the study authors reported receiving grants and personal fees from Loxo Oncology (a wholly owned subsidiary of Eli Lilly), which sponsored the study, as well as financial relationships with other pharmaceutical and biotechnology companies.
Dr. Michot and Dr. Ribrag reported that they had no disclosures relevant to the discussion.
FROM THE LANCET