B Cell Lymphoma

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

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

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

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

The Food and Drug Administration has approved zanubrutinib (Brukinsa) capsules for use in the treatment of adult patients with Waldenström’s macroglobulinemia (WM), a rare non-Hodgkin lymphoma, according to an approval letter from the agency to BeiGene, the drug’s maker.

The FDA stipulated that the company conduct an additional clinical trial (rather than an observational study) to assess the “known serious risk of second primary malignancies” associated with use of zanubrutinib. The study should further characterize the clinical benefit and safety of zanubrutinib for the treatment of patients with newly diagnosed WM with MYD88 mutation, the agency said.

The drug, which is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), previously received accelerated approval for use in patients with mantle cell lymphoma who have received one prior therapy. It is also being studied for the treatment of chronic lymphocytic leukemia.

The new approval is primarily based on results from ASPEN, a randomized, active control, open-label trial that compared zanubrutinib and ibrutinib.

The ASPEN trial provided “compelling evidence” that zanubrutinib is a highly active BTK inhibitor in WM and that it showed improved tolerability across a number of clinically important side effects in comparison with the first-generation BTK inhibitor ibrutinib, said study investigator Steven Treon, MD, PhD, director of the Bing Center for Waldenström’s Macroglobulinemia Research at the Dana-Farber Cancer Institute, Boston. “The approval of [zanubrutinib] provides an important new option for targeted therapy in Waldenström’s macroglobulinemia,” he added in a company press statement.

The recommended dosage is 160 mg orally twice daily or 320 mg orally once; the drug should be swallowed whole with water with or without food.

In ASPEN, all patients had MYD88 mutation WM. Patients in cohort 1 (n = 201) were randomly assigned in a 1:1 ratio to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. A total of 82% of patients had relapsed/refractory disease.

The major efficacy outcome was the response rate, defined as partial response or better (i.e., partial response, very good partial response, and complete response), as determined on the basis of standard consensus response criteria from the International Workshop on Waldenström’s Macroglobulinemia (IWWM-6) criteria.

The drugs had nearly identical response rates (roughly 77%). There were no complete responses with either drug. However, zanubrutinib had twice the rate of very good partial responses compared with ibrutinib (15.7% vs. 7.1%). In addition, on the basis of modified IWWM-6 criteria, the very good partial response rate was 28% with zanubrutinib, compared to 19% with ibrutinib.

An additional efficacy outcome measure was duration of response, which was measured by the percentage of patients who were event free at 12 months. Zanubrutinib bested ibrutinib in this measure (94.4% vs. 87.9%).

The safety of zanubrutinib was also investigated in the ASPEN trial. Among patients who received zanubrutinib, 93% were exposed for 6 months or longer, and 89% were exposed for longer than 1 year. In cohort 1, serious adverse reactions occurred in 44% of patients who received zanubrutinib. Serious adverse reactions that occurred in > 2% of patients included influenza (3%), pneumonia (4%), neutropenia and decreased neutrophil count (3%), hemorrhage (4%), pyrexia (3%), and febrile neutropenia (3%).

In the FDA’s prescribing information for the drug, which includes approved indications and pooled safety data, the most common adverse reactions for zanubrutinib (≥ 20%) are listed as decreased neutrophil count, upper respiratory tract infection, decreased platelet count, rash, hemorrhage, musculoskeletal pain, decreased hemoglobin, bruising, diarrhea, pneumonia, and cough.
 

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

The risk of in-hospital complications and poor birth outcomes were greater in pregnant women with current or historical cancer diagnoses, new research suggests.

The study, published in Mayo Clinic Proceedings, found that women with current and historical cancer diagnoses had an increased risk of death, kidney injury, and stroke during delivery hospitalizations, compared with those with no cancer. When it came to delivery outcomes, this group also had a higher risk for preterm birth and postpartum hemorrhage. Those with a current cancer diagnoses had a 1.7-fold increase in odds for a preterm birth, compared with women without cancer.

“Our study found that metastases increased the odds of mortality, cesarean delivery, preterm birth, and stillbirth,” the researchers noted. “Coupled with previous research reporting that pregnant women are more likely to be diagnosed with advanced disease, this implies that pregnant women with newly diagnosed cancer have poor prognoses.”

However, although women with prior cancer had increased odds of mortality, the researchers said it was not statistically significant.

“The study really did not show an increase of mortality [for women with prior cancer diagnosis],” said Justin Chura, MD, a specialist in gynecologic oncology who was not involved in the study. “And the reason might be because there is not or the reason might be because it’s such a rare event. You would need 100 million births to assess that. So I would actually use caution in that interpretation.”

Researchers analyzed more than 43 million delivery hospitalizations of women with or without current or historical cancer diagnoses between January 2004 and December 2014. They found that the most common cancer diagnoses were hematologic, thyroid, cervical, skin, and breast.

Of the five most common cancers, the prevalence of all maternal complications and negative delivery outcomes was the highest among women with hematologic cancers. They were more likely to experience peripartum cardiomyopathy, acute kidney injury, and arrhythmia, compared with other cancers. Postpartum hemorrhage, maternal mortality, and placental abruption was also more likely to occur in those with this type of cancer.

“I was surprised that it was the hematologic cancers that were worse when they did it by cancer type,” said Dr. Chura, who is the chief of surgery and the director of gynecologic oncology and robotic surgery at the Cancer Treatment Centers of America’s Eastern Regional Medical Center in Philadelphia. “I think this is a useful bit of information for counseling our patients and also to identify the cohort with the highest risk.”

The findings also suggested that those with skin cancer had the highest odds for stroke, while women with cervical and breast cancers were more likely to experience acute kidney injury and preterm birth.

Dr. Chura said cancer treatments can have an impact on a woman’s health when she’s giving birth. For example, if a woman is diagnosed with cervical cancer, doctors may perform a cone biopsy on her where they remove a large portion of the cervix and still leave them with the ability to conceive and become pregnant. However, those patients are left with a higher risk of a preterm delivery.

For women with a hematologic cancer like non-Hodgkin’s lymphoma, chest radiation may cause some subsequent damage to their heart muscles “and now the stress of pregnancy puts more demand on the heart that can lead to cardiac complications for that patient,” Dr. Chura said.

“There are potential long-term effects from radiation and chemotherapy,” Dr. Chura said.

Previous studies have shown that chemotherapy may affect pregnancy and delivery. A 2019 study published in the Journal of Cancer also found that 59 pregnant women with cancer had increased mortality compared with those without the long-term illness. Meanwhile, another 2018 study published in Cancer found that women who conceived less than a year after starting chemotherapy had higher risks of preterm birth in comparison with those who conceived more than a year after starting chemotherapy. The study also found that cancer survivors who conceived more than a year after finishing chemotherapy with or without radiation had no higher risk of a preterm birth than those without cancer.

Dr. Chura said the new study could force doctors to think about the long-term effects of their cancer therapies and make them more apt to think about how to make cancer therapy less toxic with less long-term health consequences, while still curing patients.

“Most oncologists, when dealing with younger patients, are very focused on curing the cancer at hand, but not necessarily thinking 5 or 10 years down the road,” Dr. Chura said. “[This study] could help inform or at least make us aware of the long-term consequences of our cancer therapies.”

Dr. Chura had no relevant financial disclosures.

The risk of in-hospital complications and poor birth outcomes were greater in pregnant women with current or historical cancer diagnoses, new research suggests.

The study, published in Mayo Clinic Proceedings, found that women with current and historical cancer diagnoses had an increased risk of death, kidney injury, and stroke during delivery hospitalizations, compared with those with no cancer. When it came to delivery outcomes, this group also had a higher risk for preterm birth and postpartum hemorrhage. Those with a current cancer diagnoses had a 1.7-fold increase in odds for a preterm birth, compared with women without cancer.

“Our study found that metastases increased the odds of mortality, cesarean delivery, preterm birth, and stillbirth,” the researchers noted. “Coupled with previous research reporting that pregnant women are more likely to be diagnosed with advanced disease, this implies that pregnant women with newly diagnosed cancer have poor prognoses.”

However, although women with prior cancer had increased odds of mortality, the researchers said it was not statistically significant.

“The study really did not show an increase of mortality [for women with prior cancer diagnosis],” said Justin Chura, MD, a specialist in gynecologic oncology who was not involved in the study. “And the reason might be because there is not or the reason might be because it’s such a rare event. You would need 100 million births to assess that. So I would actually use caution in that interpretation.”

Researchers analyzed more than 43 million delivery hospitalizations of women with or without current or historical cancer diagnoses between January 2004 and December 2014. They found that the most common cancer diagnoses were hematologic, thyroid, cervical, skin, and breast.

Of the five most common cancers, the prevalence of all maternal complications and negative delivery outcomes was the highest among women with hematologic cancers. They were more likely to experience peripartum cardiomyopathy, acute kidney injury, and arrhythmia, compared with other cancers. Postpartum hemorrhage, maternal mortality, and placental abruption was also more likely to occur in those with this type of cancer.

“I was surprised that it was the hematologic cancers that were worse when they did it by cancer type,” said Dr. Chura, who is the chief of surgery and the director of gynecologic oncology and robotic surgery at the Cancer Treatment Centers of America’s Eastern Regional Medical Center in Philadelphia. “I think this is a useful bit of information for counseling our patients and also to identify the cohort with the highest risk.”

The findings also suggested that those with skin cancer had the highest odds for stroke, while women with cervical and breast cancers were more likely to experience acute kidney injury and preterm birth.

Dr. Chura said cancer treatments can have an impact on a woman’s health when she’s giving birth. For example, if a woman is diagnosed with cervical cancer, doctors may perform a cone biopsy on her where they remove a large portion of the cervix and still leave them with the ability to conceive and become pregnant. However, those patients are left with a higher risk of a preterm delivery.

For women with a hematologic cancer like non-Hodgkin’s lymphoma, chest radiation may cause some subsequent damage to their heart muscles “and now the stress of pregnancy puts more demand on the heart that can lead to cardiac complications for that patient,” Dr. Chura said.

“There are potential long-term effects from radiation and chemotherapy,” Dr. Chura said.

Previous studies have shown that chemotherapy may affect pregnancy and delivery. A 2019 study published in the Journal of Cancer also found that 59 pregnant women with cancer had increased mortality compared with those without the long-term illness. Meanwhile, another 2018 study published in Cancer found that women who conceived less than a year after starting chemotherapy had higher risks of preterm birth in comparison with those who conceived more than a year after starting chemotherapy. The study also found that cancer survivors who conceived more than a year after finishing chemotherapy with or without radiation had no higher risk of a preterm birth than those without cancer.

Dr. Chura said the new study could force doctors to think about the long-term effects of their cancer therapies and make them more apt to think about how to make cancer therapy less toxic with less long-term health consequences, while still curing patients.

“Most oncologists, when dealing with younger patients, are very focused on curing the cancer at hand, but not necessarily thinking 5 or 10 years down the road,” Dr. Chura said. “[This study] could help inform or at least make us aware of the long-term consequences of our cancer therapies.”

Dr. Chura had no relevant financial disclosures.

The risk of in-hospital complications and poor birth outcomes were greater in pregnant women with current or historical cancer diagnoses, new research suggests.

The study, published in Mayo Clinic Proceedings, found that women with current and historical cancer diagnoses had an increased risk of death, kidney injury, and stroke during delivery hospitalizations, compared with those with no cancer. When it came to delivery outcomes, this group also had a higher risk for preterm birth and postpartum hemorrhage. Those with a current cancer diagnoses had a 1.7-fold increase in odds for a preterm birth, compared with women without cancer.

“Our study found that metastases increased the odds of mortality, cesarean delivery, preterm birth, and stillbirth,” the researchers noted. “Coupled with previous research reporting that pregnant women are more likely to be diagnosed with advanced disease, this implies that pregnant women with newly diagnosed cancer have poor prognoses.”

However, although women with prior cancer had increased odds of mortality, the researchers said it was not statistically significant.

“The study really did not show an increase of mortality [for women with prior cancer diagnosis],” said Justin Chura, MD, a specialist in gynecologic oncology who was not involved in the study. “And the reason might be because there is not or the reason might be because it’s such a rare event. You would need 100 million births to assess that. So I would actually use caution in that interpretation.”

Researchers analyzed more than 43 million delivery hospitalizations of women with or without current or historical cancer diagnoses between January 2004 and December 2014. They found that the most common cancer diagnoses were hematologic, thyroid, cervical, skin, and breast.

Of the five most common cancers, the prevalence of all maternal complications and negative delivery outcomes was the highest among women with hematologic cancers. They were more likely to experience peripartum cardiomyopathy, acute kidney injury, and arrhythmia, compared with other cancers. Postpartum hemorrhage, maternal mortality, and placental abruption was also more likely to occur in those with this type of cancer.

“I was surprised that it was the hematologic cancers that were worse when they did it by cancer type,” said Dr. Chura, who is the chief of surgery and the director of gynecologic oncology and robotic surgery at the Cancer Treatment Centers of America’s Eastern Regional Medical Center in Philadelphia. “I think this is a useful bit of information for counseling our patients and also to identify the cohort with the highest risk.”

The findings also suggested that those with skin cancer had the highest odds for stroke, while women with cervical and breast cancers were more likely to experience acute kidney injury and preterm birth.

Dr. Chura said cancer treatments can have an impact on a woman’s health when she’s giving birth. For example, if a woman is diagnosed with cervical cancer, doctors may perform a cone biopsy on her where they remove a large portion of the cervix and still leave them with the ability to conceive and become pregnant. However, those patients are left with a higher risk of a preterm delivery.

For women with a hematologic cancer like non-Hodgkin’s lymphoma, chest radiation may cause some subsequent damage to their heart muscles “and now the stress of pregnancy puts more demand on the heart that can lead to cardiac complications for that patient,” Dr. Chura said.

“There are potential long-term effects from radiation and chemotherapy,” Dr. Chura said.

Previous studies have shown that chemotherapy may affect pregnancy and delivery. A 2019 study published in the Journal of Cancer also found that 59 pregnant women with cancer had increased mortality compared with those without the long-term illness. Meanwhile, another 2018 study published in Cancer found that women who conceived less than a year after starting chemotherapy had higher risks of preterm birth in comparison with those who conceived more than a year after starting chemotherapy. The study also found that cancer survivors who conceived more than a year after finishing chemotherapy with or without radiation had no higher risk of a preterm birth than those without cancer.

Dr. Chura said the new study could force doctors to think about the long-term effects of their cancer therapies and make them more apt to think about how to make cancer therapy less toxic with less long-term health consequences, while still curing patients.

“Most oncologists, when dealing with younger patients, are very focused on curing the cancer at hand, but not necessarily thinking 5 or 10 years down the road,” Dr. Chura said. “[This study] could help inform or at least make us aware of the long-term consequences of our cancer therapies.”

Dr. Chura had no relevant financial disclosures.

Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.

Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.

“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).

“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.

“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.

Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.

Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”

She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.

“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.

Dr. Grover was not involved in the study.
 

More data, s’il vous plait

The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.

Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.

Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.

Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.

That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).

Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.

Patients treated with each CAR T product had a median of three prior lines of therapy.
 

Manageable toxicities

Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.

Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.

Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
 

Favorable outcomes

Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).

The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.

Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.

Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.

The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.

The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.

He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.

The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.

The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.

Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.

Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.

“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).

“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.

“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.

Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.

Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”

She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.

“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.

Dr. Grover was not involved in the study.
 

More data, s’il vous plait

The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.

Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.

Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.

Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.

That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).

Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.

Patients treated with each CAR T product had a median of three prior lines of therapy.
 

Manageable toxicities

Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.

Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.

Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
 

Favorable outcomes

Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).

The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.

Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.

Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.

The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.

The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.

He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.

The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.

The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.

Data from a large French registry on a multicenter experience with chimeric antigen receptor T-cell (CAR T) therapy for aggressive lymphoma suggests that the favorable outcomes seen in clinical trials can be replicated in the real world.

Among 481 patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with either of two commercially available CAR T products – tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) – the duration of responses, progression-free survival (PFS), and overall survival (OS) rates at 6 months mirror those seen in clinical trials, reported Steven LeGouill, MD, PhD, from the University of Nantes (France), on behalf of colleagues in the DESCAR-T (Dispositive d’Evaluation et de Suivi des CAR-T) registry.

“CAR T has now become a standard of care in a lot of French centers, with more than 640 patients treated with CAR T in less than 2 years. The DESCAR-T real-life experience mimics the experience that had been previously by other real-life registries but also in clinical trials. We didn’t see new emerging toxicity signals in real life,” he said in an oral abstract session during the European Hematology Association annual congress (Abstract S216).

“I am convinced that a population registry about CAR T–treated patients is needed,” commented Pieter Sonneveld, MD, from Erasmus Medical Center in Rotterdam, the Netherlands, who was not involved in the study.

“Selection criteria for CAR T trials have been incredibly restrictive, and academic trials have not gained ground yet. It is important to collect and analyze more data, include non-trial patients and analyze long-term follow-up in order to determine the real effects of this innovative treatment in lymphoma and other diseases,” he said.

Dr. Sonneveld, EHA past president, was the moderator a briefing where Dr. LeGouill presented the DESCAR-T study findings.

Natalie Sophia Grover, MD, a leukemia and lymphoma specialist at the University of North Carolina at Chapel Hill, noted in an interview that “there have been several publications recently that have shown that these promising outcomes for these really refractory, high-risk patients with diffuse large B-cell lymphoma seem to be similar with what we’ve seen in trials, which is definitely exciting.”

She noted that the median time from CAR T order to treatment in the study, 50 days, was longer than in her experience.

“Generally, from collection to treatment is less than a month. Looking at that, I would have expected more patients not to make it CAR T, but nearly 90% of patients who had collections got treatment, which is pretty good. Those patients that didn’t make it to treatment had really poor outcomes,” she said.

Dr. Grover was not involved in the study.
 

More data, s’il vous plait

The DESCAR-T registry was created in response to a request from French health authorities for data beyond that provided in the EBMT patient registry. The health authorities asked for characterization of the CAR T–eligible population in an intention to treat, 15-year follow-up of both CAR T recipients and candidates who were not treated for whatever reasons, and a full accounting of previous lines of therapy.

Dr. LeGouill presented the first analysis of data from the registry involving 19 enrolling site and 647 patients with DLBCL for whom CAR T cells were ordered from January 2018 to March 2021.

Of the 647 candidates, 10 did not have CAR T ordered for reasons that included patient deaths or disease progression, infection, and patient refusal. An additional 30 patients either had leukapheresis performed or pending, and 607 had CAR T ordered.

Of the 607 patients, 53 did not receive CAR T infusions because of disease progression, death before product administration, manufacturing or leukapheresis failures, uncontrolled infections, patient choice, or progression of other malignancies.

That left 550 patients (85%) who received a CAR T product, either tisagenlecleucel (200 patients) or axicabtagene ciloleucel (350 patients).

Among all patients, the median age at CAR T order was 63 for patients who received tisagenlecleucel, and 65 for patients receiving axicabtagene ciloleucel. Patients 65 and older comprised 44% and 51% of the population, respectively.

Patients treated with each CAR T product had a median of three prior lines of therapy.
 

Manageable toxicities

Toxicities within 10 days of CAR T infusion included 418 cases among 515 patients (81.2%) of cytokine release syndrome, with most being grade 1 or 2 in severity; 44 patients had grade 3 or 4 CRS.

Any-grade neurotoxicity was seen in 184 patients (35.7%), primarily grade 1 or 2 in severity; 50 patients had grade 3 or greater neurotoxicity.

Of 427 patients with at least one CAR T–specific toxicity within 10 days, 139 (32.8%) required ICU admission, 325 (76,1%) were treated for CAR T–specific toxicities, 278 (65.1%) received tocilizumab, 13 (3%) received siltuximab, and 176 (41.2%) received corticosteroids.
 

Favorable outcomes

Overall response rates, at 1, 3, and 6 months post infusions were 70.6%, 56.3%, and 60%, respectively, with the majority of response at each time point being complete responses (CR).

The 6-month overall survival (OS) rate among all patients who were treated was 83.7%, compared with 5.5% for patients who did not receive CAR T infusions.

Progression-free survival (PFS) at 6 months was 44.5%, and 57.7% of patients had an ongoing response at the same time point.

Among patients who received bridging therapy between leukapheresis and CAR T infusion, the 6-month PFS was 58.4% for patients with either a CR, partial response, or stable disease, compared with 63.3% for patients who did not receive bridging therapy, and 29.8% for those with disease progression.

The respective 6 months OS rates were 87.4%, 82.3%, and 65.5%.

The results showed that patients who do not have at least stable disease at the time of CAR T infusion are at risk for early relapse, but approximately 30% of these patients still had long-term disease control, Dr. LeGouill said.

He acknowledged that longer follow-up will be need to see whether the plateaus in the PFS and OS curves the investigators observed can be maintained over time. Questions that still need to be answered include the impact of bridging therapy or disease status at the start of treatment on outcomes, and how to improve CAR T efficacy based on individual patient characteristics.

The registry will be extended to include data on patients treated with CAR T for mantle cell lymphoma and multiple myeloma, investigators announced.

The study is supported by participating centers and Gilead/Kite and Novartis. Dr. LeGouill disclosed advisory board activity and honoraria from the companies and others. Dr. Grover disclosed advisory board participating for Kite and others. Dr. Sonneveld has disclosed research grants and honoraria from several companies, not including Kite or Novartis.

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

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

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

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

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

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

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

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

DLBCL and others

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

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

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

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

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

DLBCL efficacy

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

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

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

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

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

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

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

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

Q 3 weeks suffices

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

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

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

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

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

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

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

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

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

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

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

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

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

DLBCL and others

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

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

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

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

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

DLBCL efficacy

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

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

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

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

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

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

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

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

Q 3 weeks suffices

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

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

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

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

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

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

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

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

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

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

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

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

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

DLBCL and others

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

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

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

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

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

DLBCL efficacy

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

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

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

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

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

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

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

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

Q 3 weeks suffices

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

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

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

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

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

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

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

Cutoff at 80 years of age

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

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

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

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

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

[email protected]

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

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

Cutoff at 80 years of age

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

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

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

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

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

[email protected]

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

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

Cutoff at 80 years of age

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

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

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

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

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

[email protected]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.

Nephron/Wikimedia Commons/CC BY-SA 3.0

However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.

The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.

A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.

Equivalent results

The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.

One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.

The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.

“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.

“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.

The authors reported that they had no competing financial interests.

[email protected]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.

Nephron/Wikimedia Commons/CC BY-SA 3.0

However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.

The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.

A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.

Equivalent results

The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.

One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.

The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.

“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.

“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.

The authors reported that they had no competing financial interests.

[email protected]

Patients with high-risk diffuse large B-cell lymphoma (DLBCL) have a greater than 10% risk of central nervous system (CNS) relapse, and the use of prophylactic high-dose methotrexate (HD-MTX) has been proposed as a preventative measure.

Nephron/Wikimedia Commons/CC BY-SA 3.0

However, the use of prophylactic HD-MTX did not improve CNS or survival outcomes of patients with high-risk DLBCL, but instead was associated with increased toxicities, according to the results of a retrospective study by Hyehyun Jeong, MD, of University of Ulsan College of Medicine, Seoul, Republic of Korea, and colleagues.

The researchers evaluated the effects of prophylactic HD-MTX on CNS relapse and survival outcomes in newly diagnosed R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–treated patients with high-risk DLBCL. The assessment was based on the initial treatment intent (ITT) of the physician on the use of prophylactic HD-MTX.

A total of 5,130 patients were classified into an ITT HD-MTX group and an equal number into a non-ITT HD-MTX group, according to the report, published online in Blood Advances.

Equivalent results

The study showed that the CNS relapse rate was not significantly different between the two groups, with 2-year CNS relapse rates of 12.4% and 13.9%, respectively (P = .96). Three-year progression-free survival and overall survival rates in the ITT HD-MTX and non-ITT HD-MTX groups were 62.4% vs. 64.5% (P = .94) and 71.7% vs. 71.4% (P = .7), respectively. In addition, the propensity score–matched analyses showed no significant differences in the time-to-CNS relapse, progression-free survival, or overall survival, according to the researchers.

One key concern, however, was the increase in toxicity seen in the HD-MTX group. In this study, the ITT HD-MTX group had a statistically higher incidence of grade 3/4 oral mucositis and elevated alanine aminotransferase (ALT) levels, a marker for liver damage. In addition, the ITT HD-MTX group tended to have a higher incidence of elevated creatinine levels during treatment compared with the non-ITT HD-MTX group.

The HD-MTX group also showed a more common treatment delay or a dose reduction in R-CHOP, which might be attributable to toxicities related to intercalated HD-MTX treatments between R-CHOP cycles, the researchers suggested, potentially resulting in a reduced dose intensity of R-CHOP that could play a role in the lack of an observed survival benefit with additional HD-MTX.

“Another vital issue to consider is that HD-MTX treatment requires hospitalization because intensive hydration and leucovorin rescue is needed, which increases the medical costs,” the authors added.

“This real-world experience, which is unique in its scope and analytical methods, should provide insightful information on the role of HD-MTX prophylaxis to help guide current practice, given the lack of prospective clinical evidence in this patient population,” the researchers concluded.

The authors reported that they had no competing financial interests.

[email protected]

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Survivors of childhood cancers are at increased risk for prescription opioid misuse compared with their peers, a review of a claims database revealed.

Among more than 8,000 patients age 21 or younger who had completed treatment for hematologic, central nervous system, bone, or gonadal cancers, survivors were significantly more likely than were their peers to have an opioid prescription, longer duration of prescription, and higher daily doses of opioids, and to have opioid prescriptions overlapping for a week or more, reported Xu Ji, PhD, of Emory University in Atlanta.

Teenage and young adult patients were at higher risk than were patients younger than 12, and the risk was highest among patients who had been treated for bone malignancies, as well as those who had undergone any hematopoietic stem cell transplant.

“These findings suggest that health care providers who regularly see survivors should explore nonopioid options to help prevent opioid misuse, and screen for potential misuse in those who actually receive opioids,” she said in an oral abstract presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a really important topic, and something that’s probably been underinvestigated and underexplored in our patient population,” said session comoderator Sheri Spunt, MD, Endowed Professor of Pediatric Cancer at Stanford (Calif.) University.
 

Database review

Dr. Ji and colleagues used the IBM MarketScan Commercial Claims and Encounters database from 2009 to 2018 to examine prescription opioid use, potential misuse, and substance use disorders in pediatric cancer survivors in the first year after completion of therapy, and to identify factors associated with risk for misuse or substance use disorders. Specifically, the period of interest was the first year after completion of all treatments, including surgery, chemotherapy, radiation, and stem cell transplant (Abstract 2015).

They looked at deidentified records on any opioid prescription and for treatment of any opioid use or substance use disorder (alcohol, psychotherapeutic drugs, marijuana, or illicit drug use disorders).

They defined indicators of potential misuse as either prescriptions for long-acting or extended-release opioids for acute pain conditions; opioid and benzodiazepine prescriptions overlapping by a week or more; opioid prescriptions overlapping by a week or more; high daily opioid dosage (prescribed daily dose of 100 or greater morphine milligram equivalent [MME]; and/or opioid dose escalation (an increase of at least 50% in mean MMEs per month twice consecutively within 1 year).

They compared outcomes between a total of 8,635 survivors and 44,175 controls, matched on a 1:5 basis with survivors by age, sex, and region, and continuous enrollment during the 1-year posttherapy period.

In each of three age categories – 0 to 11 years, 12 to 17 years, and 18 years and older – survivors were significantly more likely to have received an opioid prescription, at 15% for the youngest survivors vs. 2% of controls, 25% vs. 8% for 12- to 17-year-olds, and 28% vs. 12% for those 18 and older (P < .01 for all three comparisons).

Survivors were also significantly more likely to have any indicator of potential misuse (1.6% vs. 0.1%, 4.6% vs. 0.5%, and 7.4% vs. 1.2%, respectively, P < .001 for all) and both the youngest and oldest groups (but not 12- to 17-year-olds) were significantly more like to have opioid or substance use disorder (0.4% vs. 0% for 0-11 years, 5.76% vs. 4.2% for 18 years and older, P < .001 for both).

Among patients with any opioid prescription, survivors were significantly more likely than were controls of any age to have indicators for potential misuse. For example, 13% of survivors aged 18 years and older had prescriptions for high opioid doses, compared with 5% of controls, and 12% had prescription overlap, vs. 2%.

Compared with patients with leukemia, patients treated for bone malignancies had a 6% greater risk for having any indicator of misuse, while patients with other malignancies were at slightly lower risk for misuse than those who completed leukemia therapy.

Patients who received any stem cell transplant had an 8.4% greater risk for misuse compared with patients who had surgery only.
 

Opioids pre- and posttreatment?

“Being someone who takes care of a lot of bone cancer patients, I do see patients with these issues,” Dr. Spunt said.

Audience member Jack H. Staddon, MD, PhD, of the Billings (Montana) Clinic, noted the possibility that opioid use during treatment may have been carried on into the posttreatment period, and asked whether use of narcotics during treatment was an independent risk factor for posttreatment narcotic use or misuse.

The researchers plan to investigate this question in future studies, Dr. Ji replied.

They did not report a study funding source. Dr. Ji and coauthors and Dr. Staddon reported no relevant disclosures.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

Adding ibrutinib to chemotherapy did not improve outcomes for children and young adults with relapsed or refractory mature B-cell non-Hodgkin lymphoma (B-NHL), an interim analysis of the SPARKLE trial showed.

Among 51 patients aged 1-30 years with mature B-NHL that had been diagnosed before age 18, there was no significant difference in the primary endpoint of event-free survival (EFS) between patients assigned on a 2:1 basis to receive either ibrutinib (Imbruvica) plus one of two chemotherapy regimens or to chemotherapy alone. In fact, EFS was shorter among patients assigned to ibrutinib, although a larger proportion of these patients had previously received rituximab, a known factor for poor prognosis, reported Amos Burke, MD, from Cambridge (England) University.

The trial was stopped for futility in May 2020, after a median follow-up of 17.97 months.

“Further studies are required to determine the optimal therapy for patients with relapsed, mature B-NHL, especially those who have received prior rituximab,” he said in an audio walk-through of a scientific poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.

“This is a very challenging patient population because they historically have had a very poor survival rate,” commented Paul J. Galardy, MD, a pediatric hematologist/oncologist at the Mayo Clinic in Rochester, Minn., who was not involved in the study.

“The field has struggled to improve outcomes for these patients in part because there are relatively few patients per year with relapsed refractory mature B-cell lymphoma due to the very effective nature of the up-front therapy. This makes new clinical trials difficult to perform,” he said.
 

Poor prognosis

Ibrutinib, an inhibitor of Bruton tyrosine kinase, is approved in the United States for treatment of marginal zone lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma, as well as other indications, all in adults only. It has also been shown to have activity against B-NHL in preclinical and early human trials, Dr. Burke said.

Given the poor prognosis of children and young adults with relapsed/refractory mature B-NHL – a 2-year overall survival (OS) of 30% or less with chemoimmunotherapy – the investigators tested whether adding ibrutinib to the standard of care could improve outcomes.

They enrolled patients with relapsed/refractory B-NHL in first relapse or primarily refractory to conventional therapy, with measurable disease (greater than 1 cm) by CT, bone marrow involvement, or cerebrospinal fluid with blasts. The patients were required to have Karnofsky-Lansky performance scores of 50 or greater.

The histologies included Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt-like lymphoma, Burkitt leukemia, primary mediastinal B-cell lymphoma, and other unspecified types.

Dr. Burke reported results on 48 patients included in the May 2020 analysis, plus 3 additional patients who were enrolled between the data cutoff for the first analysis and the meeting of the independent data monitoring committee where the decision was made to stop the trial.

A total of 35 patients were randomized to receive ibrutinib with either the RICE (rituximab plus ifosfamide, carboplatin, and etoposide) or RVICI (rituximab plus vincristine, ifosfamide, carboplatin, idarubicin, and dexamethasone) regimen. All of these patients received treatment on study.

Of the 18 patients randomized to receive either RICE or RVICI alone, 1 did not receive any cycles of chemoimmunotherapy.

At the data cutoff for the updated analysis in November 2020, 14 patients assigned to ibrutinib and 4 assigned to chemoimmunotherapy alone remained on study; no patients in either arm were still receiving therapy.

A total of 17 patients assigned to the combination arm died and 4 withdrew consent. In the chemoimmunotherapy-alone arm, 10 died and 2 withdrew consent.

In both arms, patients were treated until either completing three cycles of therapy, start of conditioning treatment prior to stem cell transplantation, disease progression, or unacceptable toxicity.

In the ibrutinib arm, the median EFS was 5.36 months, compared with 6.97 months with chemoimmunotherapy alone, translating into a hazard ratio for EFS with ibrutinib of 1.078 (nonsignificant).

The respective median overall survival was 13.44 versus 11.07 months,

Subgroup analysis showed that EFS and OS did not differ significantly by age, histology, background regimen, or central nervous system or bone marrow involvement. ­

Overall response rates were 68.6% in the ibrutinib arm, and 81.3% in the chemoimmunotherapy arm. The respective complete response rates were 8.6% and 18.8%, and partial response rates were 60% and 62.5%.

The overall treatment-emergent adverse event (TEAE) profile was similar between the treatment arms, although six patients in the ibrutinib arm versus one in the chemoimmunotherapy arm experienced a major hemorrhage. One patients in the ibrutinib arm died from pulmonary hemorrhage.

Dr. Burke noted that, although the numbers were small, the failure to see a difference in efficacy between study arms may have been caused in part by a greater number of patients assigned to ibrutinib who had received prior treatment with rituximab (85.7% vs. 56.3%).
 

Not the right partner?

“The results of this study would suggest that ibrutinib is not the right agent. This is not altogether unexpected,” Dr. Galardy said. “The benefit of ibrutinib in adults with mature B-cell lymphoma is primarily based on biological characteristics of lymphomas that develop in older individuals.”

He noted that mature B-cell lymphoma in older adults is often of the activated B-cell subtype, which frequently has mutations that make it sensitive to ibrutinib. In contrast, children, adolescents, and young adults more commonly have the germinal center B-cell subtype that doesn’t have similarly targetable mutations.

He added that, although the reasons for poor prognosis in patients with prior rituximab exposure are unclear, “it is likely that patients who have recurrent or refractory disease after therapy that included rituximab may have developed resistance to this drug. Since both arms of this study included rituximab as a component of the therapy, the patients with prior exposure to this drug may have had reduced benefit of the additional rituximab, compared with those who had not received the drug before.”

The SPARKLE trial was funded by Janssen Research & Development. Dr. Burke disclosed consultancy fees from Janssen and others. Dr. Galardy is an equity holder in Abbott and AbbVie.

The Food and Drug Administration granted an accelerated approval April 24, 2021, for a new drug for use in patients with relapsed/refractory diffuse large B-cell lymphomas (DLBCL) who have tried at least two prior systemic therapies.

The new product, loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics), is the first and only CD19-targeted antibody-drug conjugate approved for this disease.

DLBCL is the most common type of non-Hodgkin lymphoma in the United States, but the indication also includes DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

“There is a significant unmet need for treatment options for patients with [relapsed or refractory] DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, said in a company press release.

The company also cited data from previous clinical trials showing that more than 40% of first-line DLBCL treatments fail, and that these patients have a poor prognosis, worsening with each line of therapy that is tried.
 

Accelerated approval based on ORR

The accelerated approval was based on overall response rate data from the single-arm LOTIS-2 trial. All patients received the new drug, administered as a 30-minute infusion once every 3 weeks for 1 year.

The trial was conducted in 145 patients with relapsed/refractory DLBCL who had already tried at least two lines of systemic therapy. Dr. Caimi noted that this included patients who had been heavily pretreated, as the population included patients who previously received stem cell transplant or chimeric antigen receptor T-cell therapy.

The ORR was 48.3% (70/145 patients), which included a complete response rate of 24.1% (35/145 patients) and a partial response rate of 24.1% (35/145 patients).

Patients had a median time to response of 1.3 months and the median duration of response for the 70 responders was 10.3 months.

“Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial,” the company noted.

A phase 3 confirmatory is underway: the LOTIS 5 trial (NCT04384484) compares the combination of loncastuximab tesirine and rituximab versus chemoimmunotherapy in patients with relapsed/refractory DLBCL.

The company also noted that in a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, an increase in levels of the liver enzyme gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In the LOTIS-2 trial, the most common (≥10%) grade 3 or higher treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), GGT increase (17.2%) and anemia (10.3%).

Permanent treatment discontinuation as the result of an adverse reaction occurred in 19% of patients, and these included a GGT increase, edema, and effusion.

Dose reductions because of an adverse reaction occurred in 8% of patients, and most were the result of a GGT increase. Dosage interruptions because of an adverse reaction occurred in 49% of patients, and these included a GGT increase, neutropenia, thrombocytopenia, and edema.
 

Warnings on effusions, infections, and skin reactions

The product carries a warning that serious effusion and edema has been reported. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites), grade 3 pleural effusion occurred in 3%, and grade 3 or 4 pericardial effusion occurred in 1%.

Prescribers are recommended to monitor patients for new or worsening edema or effusions, and to consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating.

The product also carries a warning about fatal and serious infections, including opportunistic infections, and serious cutaneous reactions, including photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.

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

The Food and Drug Administration granted an accelerated approval April 24, 2021, for a new drug for use in patients with relapsed/refractory diffuse large B-cell lymphomas (DLBCL) who have tried at least two prior systemic therapies.

The new product, loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics), is the first and only CD19-targeted antibody-drug conjugate approved for this disease.

DLBCL is the most common type of non-Hodgkin lymphoma in the United States, but the indication also includes DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

“There is a significant unmet need for treatment options for patients with [relapsed or refractory] DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, said in a company press release.

The company also cited data from previous clinical trials showing that more than 40% of first-line DLBCL treatments fail, and that these patients have a poor prognosis, worsening with each line of therapy that is tried.
 

Accelerated approval based on ORR

The accelerated approval was based on overall response rate data from the single-arm LOTIS-2 trial. All patients received the new drug, administered as a 30-minute infusion once every 3 weeks for 1 year.

The trial was conducted in 145 patients with relapsed/refractory DLBCL who had already tried at least two lines of systemic therapy. Dr. Caimi noted that this included patients who had been heavily pretreated, as the population included patients who previously received stem cell transplant or chimeric antigen receptor T-cell therapy.

The ORR was 48.3% (70/145 patients), which included a complete response rate of 24.1% (35/145 patients) and a partial response rate of 24.1% (35/145 patients).

Patients had a median time to response of 1.3 months and the median duration of response for the 70 responders was 10.3 months.

“Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial,” the company noted.

A phase 3 confirmatory is underway: the LOTIS 5 trial (NCT04384484) compares the combination of loncastuximab tesirine and rituximab versus chemoimmunotherapy in patients with relapsed/refractory DLBCL.

The company also noted that in a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, an increase in levels of the liver enzyme gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In the LOTIS-2 trial, the most common (≥10%) grade 3 or higher treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), GGT increase (17.2%) and anemia (10.3%).

Permanent treatment discontinuation as the result of an adverse reaction occurred in 19% of patients, and these included a GGT increase, edema, and effusion.

Dose reductions because of an adverse reaction occurred in 8% of patients, and most were the result of a GGT increase. Dosage interruptions because of an adverse reaction occurred in 49% of patients, and these included a GGT increase, neutropenia, thrombocytopenia, and edema.
 

Warnings on effusions, infections, and skin reactions

The product carries a warning that serious effusion and edema has been reported. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites), grade 3 pleural effusion occurred in 3%, and grade 3 or 4 pericardial effusion occurred in 1%.

Prescribers are recommended to monitor patients for new or worsening edema or effusions, and to consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating.

The product also carries a warning about fatal and serious infections, including opportunistic infections, and serious cutaneous reactions, including photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.

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

The Food and Drug Administration granted an accelerated approval April 24, 2021, for a new drug for use in patients with relapsed/refractory diffuse large B-cell lymphomas (DLBCL) who have tried at least two prior systemic therapies.

The new product, loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics), is the first and only CD19-targeted antibody-drug conjugate approved for this disease.

DLBCL is the most common type of non-Hodgkin lymphoma in the United States, but the indication also includes DLBCL not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.

“There is a significant unmet need for treatment options for patients with [relapsed or refractory] DLBCL, including those who have been heavily pretreated and have difficult-to-treat disease,” Paolo F. Caimi, MD, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, said in a company press release.

The company also cited data from previous clinical trials showing that more than 40% of first-line DLBCL treatments fail, and that these patients have a poor prognosis, worsening with each line of therapy that is tried.
 

Accelerated approval based on ORR

The accelerated approval was based on overall response rate data from the single-arm LOTIS-2 trial. All patients received the new drug, administered as a 30-minute infusion once every 3 weeks for 1 year.

The trial was conducted in 145 patients with relapsed/refractory DLBCL who had already tried at least two lines of systemic therapy. Dr. Caimi noted that this included patients who had been heavily pretreated, as the population included patients who previously received stem cell transplant or chimeric antigen receptor T-cell therapy.

The ORR was 48.3% (70/145 patients), which included a complete response rate of 24.1% (35/145 patients) and a partial response rate of 24.1% (35/145 patients).

Patients had a median time to response of 1.3 months and the median duration of response for the 70 responders was 10.3 months.

“Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial,” the company noted.

A phase 3 confirmatory is underway: the LOTIS 5 trial (NCT04384484) compares the combination of loncastuximab tesirine and rituximab versus chemoimmunotherapy in patients with relapsed/refractory DLBCL.

The company also noted that in a pooled safety population the most common adverse reactions (≥20%) were thrombocytopenia, an increase in levels of the liver enzyme gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain.

In the LOTIS-2 trial, the most common (≥10%) grade 3 or higher treatment-emergent adverse events were neutropenia (26.2%), thrombocytopenia (17.9%), GGT increase (17.2%) and anemia (10.3%).

Permanent treatment discontinuation as the result of an adverse reaction occurred in 19% of patients, and these included a GGT increase, edema, and effusion.

Dose reductions because of an adverse reaction occurred in 8% of patients, and most were the result of a GGT increase. Dosage interruptions because of an adverse reaction occurred in 49% of patients, and these included a GGT increase, neutropenia, thrombocytopenia, and edema.
 

Warnings on effusions, infections, and skin reactions

The product carries a warning that serious effusion and edema has been reported. Grade 3 edema occurred in 3% (primarily peripheral edema or ascites), grade 3 pleural effusion occurred in 3%, and grade 3 or 4 pericardial effusion occurred in 1%.

Prescribers are recommended to monitor patients for new or worsening edema or effusions, and to consider diagnostic imaging in patients who develop symptoms of pleural effusion or pericardial effusion, such as new or worsened dyspnea, chest pain, and/or ascites such as swelling in the abdomen and bloating.

The product also carries a warning about fatal and serious infections, including opportunistic infections, and serious cutaneous reactions, including photosensitivity reaction, rash (including exfoliative and maculopapular), and erythema.

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

A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.

Nephron/Wikimedia Commons/CC BY-SA 3.0

In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
 

Study characteristics

Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.

Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.

In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.

Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.

Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
 

MiniCHOP mattered

Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.

In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.

For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m², doxorubicin 25 mg/m², and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m² on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m² or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.

One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).

“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.

The authors reported that they received no research funds for the study and that they had no disclosures.
 

[email protected]

A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.

Nephron/Wikimedia Commons/CC BY-SA 3.0

In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
 

Study characteristics

Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.

Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.

In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.

Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.

Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
 

MiniCHOP mattered

Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.

In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.

For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m², doxorubicin 25 mg/m², and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m² on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m² or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.

One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).

“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.

The authors reported that they received no research funds for the study and that they had no disclosures.
 

[email protected]

A dose-adjusted R-CHOP may be the best treatment for elderly patients with diffuse large beta-cell lymphoma (DLBCL), according to a review of 38 studies that examined this aged population.

Nephron/Wikimedia Commons/CC BY-SA 3.0

In addition, treatment choices based on new tools such as the Comprehensive Geriatric Assessment appeared to provide useful guidance based on the comorbidities and frailty index of this group of patients, according to Alda Tavares, MD, of Hospital Pedro Hispano, Matosinhos (Portugal) Local Health Unit, and Ilídia Moreira, MD, of the Portuguese Institute of Oncology of Porto.
 

Study characteristics

Of the 38 studies assessed, 13 were retrospective and 25 were phase II/III clinical trials. Most of these studies investigated the efficacy of dose-adjusted R-CHOP regimen, according to the review published online in Critical Reviews in Oncology/Hematology.

Alternative therapeutic drugs as well as the use of geriatric assessment were also investigated.

In terms of the elderly populations assessed, 11 out of 38 studies included at least 30 patients over age 80 years, although 11 other studies did not specify the number of patients older than 80 years. Eight of the studies included exclusively patients aged 80 years and over. Three of these studies were phase II trials.

Only six of the clinical trials required a geriatric assessment tool for inclusion criteria or therapeutic regime choice, using the Cumulative Illness Rating Scale–Geriatric (CIRS-G), the performance in activities of daily living (ADL) and/or instrumental activities of daily living (IADL) tools.

Most of the studies investigated the efficacy of R-CHOP regimen at different doses and variations, with 11 studies using alternative anthracycline in place of doxorubicin.
 

MiniCHOP mattered

Elderly patients over 80 years achieved complete response (CR) rates from 37.2% to 66.7% and 2-year overall survival (OS) from 31.9% to 64.7% across the studies reviewed. Overall, for fit patients aged 80 and over, the strongest evidence favored the use of an R-miniCHOP regimen, according to the authors.

In the 25 studies with treatment based on R-CHOP/modified R-CHOP or immunochemotherapy with an alternative anthracycline, the CR rate was below 50% in three studies and over 60% in the majority. Higher CR rates of 71%-88.9% were achieved in eight studies.

For patients over 80 years, the strongest evidence favored rituximab/ofatumumab-miniCHOP, based on two studies. In both studies, patients over 80 years old, without significant comorbidities, received CHOP regime with a dose reduction of about 50% (miniCHOP: cyclophosphamide 400 mg/m², doxorubicin 25 mg/m², and 1 mg vincristine on day 1 of each cycle, and prednisone 40 mg/m² on days 1-5) plus an anti–CD-20 antibody (rituximab 375 mg/m² or ofatumumab 1,000 mg). The first of these studies obtained CR rate of 62% and 2-year OS of 59% with low toxicities. The second study achieved slightly better results, according to the reviewers, who suggested the difference was possibly because of a prephase treatment and/or the use of ofatumumab.

One study group developed a simple prognostic model based on multivariate analysis of 108 patients aged 80 years and older treated in their study with R-CHOP at full (48%) or reduced dose (51%). Patients with at least two out of three risk factors (age > 85 years, revised International Prognostic Index score 3-5 and CIRS > 5) had worse survival than did those with 0-1 risk factors, with a median OS of 12 months vs. 45 months, P = .001, respectively).

“All these studies results favor the tailored treatment approach,” the reviewers stated. “More prospective studies are still needed to demonstrate and validate the adequate tools for the selection of patients and their optimal treatment. They would provide the grounds for clinical therapeutic decision, aiming for tailored treatment and fulfilling best individual expectations and outcome,” they concluded.

The authors reported that they received no research funds for the study and that they had no disclosures.
 

[email protected]