B Cell Lymphoma

NEW YORK – Ibrutinib, and now moxetumomab pasudotox, are two novel therapies that can be tried in patients with previously treated hairy cell leukemia, although data and experience with them are so far limited in this rare disease, experts said during a panel discussion at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Since there are so few patients, data on the BTK inhibitor ibrutinib in hairy cell leukemia is largely “anecdotal,” said Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

The anti-CD22 monoclonal antibody moxetumomab pasudotox – approved for hairy cell leukemia in September – isn’t yet on the formulary at Memorial Sloan Kettering, Dr. Zelenetz added in a panel discussion of treatment options for a patient previously treated with purine analogueues and vemurafenib.

Between the two agents, moxetumomab pasudotox has more robust data in this disease, said John N. Allan, MD, of Weill Cornell Medicine, New York.

“I think if you can get access to the drug, that’s probably the best answer,” Dr. Allan said in the case discussion.

Hairy cell leukemia is an indolent B-cell lymphoma that makes up just 2% of all lymphoid leukemias, according to NCCN guidelines.

It is a chronic disease that requires long-term management, according to Dr. Allan.

First-line treatment is usually a purine analogue, either cladribine or pentostatin, and multiple treatments are possible as long as responses of greater than 2 years are achieved, he told attendees at the NCCN conference.

For relapses more than 2 years after first-line treatment, patients can be retreated with the same purine analogue, with or without rituximab, or can be switched to the alternative purine analogue, he said.

Vemurafenib, the BRAF inhibitor, is “surprisingly” effective in 90% of classic hairy cell leukemia patients with the BRAF V600E mutation, Dr. Allan added, though only about 40% of patients achieve complete response.

In discussing therapy options for a hairy cell leukemia patient previously treated with purine analogues and vemurafenib, Dr. Allan noted that the data behind ibrutinib includes case reports and early clinical investigations.

Several phase 1 studies with small numbers of patients show response rates “in the 50% range,” he said.

“This is an option,” he said. “It’s in the guidelines, and it’s something to consider.”

Moxetumomab pasudotox was recently approved for intravenous use in adults with relapsed or refractory hairy cell leukemia who have had at least two previous systemic treatments, including a purine nucleoside analogue. The CD22-directed cytotoxin is the first of its kind for treating patients with hairy cell leukemia, according to the Food and Drug Administration.

In a single-arm, open-label clinical trial including 80 patients with hairy cell leukemia who had previous treatment in line with that indication, 75% had a partial or complete response, of whom 30% had a durable complete response (CR), defined as maintaining hematologic remission for at least 180 days following CR.

Following the FDA’s approval of moxetumomab pasudotox, the NCCN updated its hairy cell leukemia clinical practice guidelines to include the drug as a category 2A recommendation for relapsed/refractory treatment. Other category 2A options in that setting include ibrutinib, vemurafenib with or without rituximab, or a clinical trial.

Along with that, NCCN guideline authors added a full page on special considerations for use of moxetumomab pasudotox. That includes advice on monitoring for capillary leak syndrome and hemolytic uremic syndrome, along with guidance on capillary leak syndrome grading and management by grade.

Dr. Zelenetz reported financial disclosures related to Adaptive Biotechnology, Amgen, AstraZeneca, Celgene, Genentech, Gilead, Hoffman La Roche, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Pharmacyclics, Roche, and Verastem Oncology. Dr. Allan reported disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis, and Verastem Oncology.

NEW YORK – Ibrutinib, and now moxetumomab pasudotox, are two novel therapies that can be tried in patients with previously treated hairy cell leukemia, although data and experience with them are so far limited in this rare disease, experts said during a panel discussion at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Since there are so few patients, data on the BTK inhibitor ibrutinib in hairy cell leukemia is largely “anecdotal,” said Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

The anti-CD22 monoclonal antibody moxetumomab pasudotox – approved for hairy cell leukemia in September – isn’t yet on the formulary at Memorial Sloan Kettering, Dr. Zelenetz added in a panel discussion of treatment options for a patient previously treated with purine analogueues and vemurafenib.

Between the two agents, moxetumomab pasudotox has more robust data in this disease, said John N. Allan, MD, of Weill Cornell Medicine, New York.

“I think if you can get access to the drug, that’s probably the best answer,” Dr. Allan said in the case discussion.

Hairy cell leukemia is an indolent B-cell lymphoma that makes up just 2% of all lymphoid leukemias, according to NCCN guidelines.

It is a chronic disease that requires long-term management, according to Dr. Allan.

First-line treatment is usually a purine analogue, either cladribine or pentostatin, and multiple treatments are possible as long as responses of greater than 2 years are achieved, he told attendees at the NCCN conference.

For relapses more than 2 years after first-line treatment, patients can be retreated with the same purine analogue, with or without rituximab, or can be switched to the alternative purine analogue, he said.

Vemurafenib, the BRAF inhibitor, is “surprisingly” effective in 90% of classic hairy cell leukemia patients with the BRAF V600E mutation, Dr. Allan added, though only about 40% of patients achieve complete response.

In discussing therapy options for a hairy cell leukemia patient previously treated with purine analogues and vemurafenib, Dr. Allan noted that the data behind ibrutinib includes case reports and early clinical investigations.

Several phase 1 studies with small numbers of patients show response rates “in the 50% range,” he said.

“This is an option,” he said. “It’s in the guidelines, and it’s something to consider.”

Moxetumomab pasudotox was recently approved for intravenous use in adults with relapsed or refractory hairy cell leukemia who have had at least two previous systemic treatments, including a purine nucleoside analogue. The CD22-directed cytotoxin is the first of its kind for treating patients with hairy cell leukemia, according to the Food and Drug Administration.

In a single-arm, open-label clinical trial including 80 patients with hairy cell leukemia who had previous treatment in line with that indication, 75% had a partial or complete response, of whom 30% had a durable complete response (CR), defined as maintaining hematologic remission for at least 180 days following CR.

Following the FDA’s approval of moxetumomab pasudotox, the NCCN updated its hairy cell leukemia clinical practice guidelines to include the drug as a category 2A recommendation for relapsed/refractory treatment. Other category 2A options in that setting include ibrutinib, vemurafenib with or without rituximab, or a clinical trial.

Along with that, NCCN guideline authors added a full page on special considerations for use of moxetumomab pasudotox. That includes advice on monitoring for capillary leak syndrome and hemolytic uremic syndrome, along with guidance on capillary leak syndrome grading and management by grade.

Dr. Zelenetz reported financial disclosures related to Adaptive Biotechnology, Amgen, AstraZeneca, Celgene, Genentech, Gilead, Hoffman La Roche, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Pharmacyclics, Roche, and Verastem Oncology. Dr. Allan reported disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis, and Verastem Oncology.

NEW YORK – Ibrutinib, and now moxetumomab pasudotox, are two novel therapies that can be tried in patients with previously treated hairy cell leukemia, although data and experience with them are so far limited in this rare disease, experts said during a panel discussion at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.

Since there are so few patients, data on the BTK inhibitor ibrutinib in hairy cell leukemia is largely “anecdotal,” said Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.

The anti-CD22 monoclonal antibody moxetumomab pasudotox – approved for hairy cell leukemia in September – isn’t yet on the formulary at Memorial Sloan Kettering, Dr. Zelenetz added in a panel discussion of treatment options for a patient previously treated with purine analogueues and vemurafenib.

Between the two agents, moxetumomab pasudotox has more robust data in this disease, said John N. Allan, MD, of Weill Cornell Medicine, New York.

“I think if you can get access to the drug, that’s probably the best answer,” Dr. Allan said in the case discussion.

Hairy cell leukemia is an indolent B-cell lymphoma that makes up just 2% of all lymphoid leukemias, according to NCCN guidelines.

It is a chronic disease that requires long-term management, according to Dr. Allan.

First-line treatment is usually a purine analogue, either cladribine or pentostatin, and multiple treatments are possible as long as responses of greater than 2 years are achieved, he told attendees at the NCCN conference.

For relapses more than 2 years after first-line treatment, patients can be retreated with the same purine analogue, with or without rituximab, or can be switched to the alternative purine analogue, he said.

Vemurafenib, the BRAF inhibitor, is “surprisingly” effective in 90% of classic hairy cell leukemia patients with the BRAF V600E mutation, Dr. Allan added, though only about 40% of patients achieve complete response.

In discussing therapy options for a hairy cell leukemia patient previously treated with purine analogues and vemurafenib, Dr. Allan noted that the data behind ibrutinib includes case reports and early clinical investigations.

Several phase 1 studies with small numbers of patients show response rates “in the 50% range,” he said.

“This is an option,” he said. “It’s in the guidelines, and it’s something to consider.”

Moxetumomab pasudotox was recently approved for intravenous use in adults with relapsed or refractory hairy cell leukemia who have had at least two previous systemic treatments, including a purine nucleoside analogue. The CD22-directed cytotoxin is the first of its kind for treating patients with hairy cell leukemia, according to the Food and Drug Administration.

In a single-arm, open-label clinical trial including 80 patients with hairy cell leukemia who had previous treatment in line with that indication, 75% had a partial or complete response, of whom 30% had a durable complete response (CR), defined as maintaining hematologic remission for at least 180 days following CR.

Following the FDA’s approval of moxetumomab pasudotox, the NCCN updated its hairy cell leukemia clinical practice guidelines to include the drug as a category 2A recommendation for relapsed/refractory treatment. Other category 2A options in that setting include ibrutinib, vemurafenib with or without rituximab, or a clinical trial.

Along with that, NCCN guideline authors added a full page on special considerations for use of moxetumomab pasudotox. That includes advice on monitoring for capillary leak syndrome and hemolytic uremic syndrome, along with guidance on capillary leak syndrome grading and management by grade.

Dr. Zelenetz reported financial disclosures related to Adaptive Biotechnology, Amgen, AstraZeneca, Celgene, Genentech, Gilead, Hoffman La Roche, MEI Pharma, MorphoSys AG, Novartis, Pfizer, Pharmacyclics, Roche, and Verastem Oncology. Dr. Allan reported disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis, and Verastem Oncology.

Photo courtesy of NCCN

NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.

A third, lisocabtagene maraleucel, will most likely be approved before too long.

Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.

Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.

“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”

“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”

Dr. Karmali outlined those challenges in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

Patient selection

One of the biggest challenges, according to Dr. Karmali, is patient selection.

First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.

Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.

Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.

Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”

Toxicities

The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).

Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.

The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.

The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.

“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”

Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.

“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”

“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.

The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.

Future directions

Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.

“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said.  “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”

“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.

The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.

“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.

“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.” 

Photo courtesy of NCCN

NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.

A third, lisocabtagene maraleucel, will most likely be approved before too long.

Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.

Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.

“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”

“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”

Dr. Karmali outlined those challenges in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

Patient selection

One of the biggest challenges, according to Dr. Karmali, is patient selection.

First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.

Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.

Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.

Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”

Toxicities

The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).

Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.

The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.

The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.

“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”

Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.

“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”

“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.

The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.

Future directions

Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.

“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said.  “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”

“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.

The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.

“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.

“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.” 

Photo courtesy of NCCN

NEW YORK—Two chimeric antigen receptor (CAR) T-cell therapies—axicabtagene ciloleucel (Yescarta ®) and tisagenlecleucel (Kymriah™)—are already approved in B-cell lymphoma by the U.S. Food and Drug Administration.

A third, lisocabtagene maraleucel, will most likely be approved before too long.

Despite differences in their costimulatory molecules, persistence, efficacy, and toxicity profiles, they all have high overall response rates and a fall-out of response during the first 3 to 6 months.

Longer-term follow-up is necessary to determine whether CAR T-cell therapy is actually curative.

“But based on the way things are looking,” said Reem Karmali, MD, of Robert H. Lurie Comprehensive Cancer Center of Northwestern University, “it seems this might be a realistic expectation.”

“CAR T-cell therapy is clearly effective and has been a ground-breaking form of therapy,” she said, “but there seems to be two sides to the coin. There are a number of challenges that we face with CAR T-cell therapy.”

Dr. Karmali outlined those challenges in a presentation at the NCCN 13^th Annual Congress: Hematologic Malignancies.

Patient selection

One of the biggest challenges, according to Dr. Karmali, is patient selection.

First, patients must have an adequate hematopoietic reserve to ensure successful CAR T-cell manufacture.

Dr. Karmali referred to the JULIET study, in which 7% of patients failed the manufacturing process due to insufficient apheresis.

Second, the patient’s disease must be stable enough to make it through the time it takes to manufacturing the CAR product, which is typically 2 to 4 weeks.

Third, the patient’s overall health must be good enough to tolerate CAR T toxicities. "The patient needs good major organ function as well as preserved neurologic function,” she explained, “to withstand the unique toxicities that come with CAR T-cell therapy, specifically CRS [cytokine release syndrome] and neurotoxicity.”

Toxicities

The major toxicities are CRS and CAR‑T‑cell‑related encephalopathy syndrome (CRES).

Dr. Karmali pointed out there is also a theoretical risk of insertional oncogenesis from viral transduction used in manufacturing the T cells, and an off-tumor on target-effect that can result in B-cell aplasia and hypogammaglobulinemia.

The profiles of inflammatory cytokines and inflammation markers differ for each CAR construct and are driven in different ways. However, IL-6 is an important mediator for CRS and IL-6 receptor blockade is effective in managing the toxicity.

The drug of choice is tocilizumab, Dr. Karmali said, and for patients who are refractory to tocilizumab, siltuximab can be used.

“Steroids are extremely useful for CRS,” she added, “because they hold down inflammation and prevent immune activation.”

Steroids are also the mainstay for managing the neurotoxicity of CAR T-cell therapy because they help stabilize the blood-brain barrier.

“It’s important to make a note,” she said, “that there actually have been a number of analyses that have looked at the impact of using IL-6 receptor blockade and steroids on CAR T-cell expansion and persistence and there really doesn’t seem to be an impact.”

“So we really ought to use these quite liberally for grade 2 or higher toxicity without worrying about dampening the effect of CAR T-cell therapy,” she emphasized.

The Lee grading criteria for the management of CRS and the CTCAE 4.03 and CARTOX-10 for CRES provide guidance in assessing and managing the toxicities.

Future directions

Dr. Karmali outlined a few new directions to address the challenges with CAR T-cell therapy, such as switchable CARs that can be turned on or off and potentially improve safety; development of new constructs that may improve homing; improvement in persistence; use of combination and sequencing strategies; and improved antigen selection that may be effective with other lymphoproliferative diseases.

“A provocative question is whether CAR T-cell therapy can actually replace autologous stem cell transplant as second-line therapy,” she said.  “This is actually being actively evaluated in a number of clinical trials including ZUMA-7 (NCT03391466).”

“I think another provocative question is whether CAR T-cell therapy can be used as consolidation in CR1 [first complete remission],” she added.

The rationale for using CAR Ts as either a replacement for autologous stem cell transplant or in CR1 is that there may be minimal residual disease present that would be enough to elicit a CAR T-cell effect, she explained.

“Ultimately, one envisions the following paradigm for the treatment of lymphomas across the board,” Dr. Karmali concluded.

“Specifically, chemotherapy with a targeted agent for rapid cytoreduction, followed by CAR T-cell consolidation in combination with either other cellular therapies or immunotherapy as a means of eradicating the minimal residual disease and ensuring a pathway to cure.” 

Ilustration: Niklas Elmehed. (c) Nobel Media AB 2018

Two immunologists have been awarded the Nobel Prize in Physiology or Medicine for discoveries that represent a “paradigmatic shift in the fight against cancer,” the Nobel committee said.

James P. Allison, PhD, of MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University, shared the prize for their discovery of cancer therapies that work by inhibiting negative immune regulation.

Dr. Allison studied the protein CTLA-4 found on T cells, which acts as a T-cell brake, and Dr. Honjo discovered a protein on immune cells called PD-1 that also acts as a T-cell brake.

In addition to sharing the honor, the scientists will split the 9 million Swedish kronor ($1.01 million) that comes with the prize.

Drs. Allison and Honjo, working in parallel, pursued different strategies for inhibiting the brakes on the immune system. Both strategies produced effective checkpoint inhibitors in the treatment of cancer.

James P. Allison

Dr. Allison was one of several scientists during the 1990s who noticed that CTLA-4 functions as a brake on T cells. Unlike other scientists, however, he set out to investigate whether blocking CTLA-4 with an antibody he had already developed could release the brake on the immune system.

The antibody had “spectacular” effects in curing mice with cancer. Despite little interest from the pharmaceutical industry, Dr. Allison continued efforts to develop the antibody therapy for humans.

The antibody turned out to be ipilimumab, which was approved in 2011 by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.

Tasuko Honjo

A few years prior to Dr. Allison’s finding, Dr. Honjo discovered PD-1 and set out to determine its function. PD-1 also operates as a T-cell brake, but it uses a different mechanism than does CTLA-4.

Dr. Honjo and others demonstrated in animal experiments that PD-1 blockade could be an effective anticancer therapy. Over the years he demonstrated the efficacy of targeting PD-1 in different types of human cancers.

The first two PD-1 checkpoint inhibitors—pembrolizumab and nivolumab—were approved by the FDA in 2014 for the treatment of melanoma.

Nivolumab is also approved to treat classical Hodgkin lymphoma (HL), non-small cell lung cancer (NSCLC), small cell lung cancer, squamous cell carcinoma of the head and neck, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, and microsatellite instability-high or mismatch repair deficient colorectal cancer.

Pembrolizumab is also approved to treat primary mediastinal large B-cell lymphoma, advanced NSCLC, classical HL, advanced gastric cancer, advanced cervical cancer, head and neck squamous cell cancer, advanced urothelial bladder cancer, and microsatellite instability-high cancer.

And targeting both CTLA-4 and PD-1 in combination therapy together may prove to be even more effective in eliminating cancer cells than either strategy alone, as is being demonstrated in patients with melanoma.

The Nobel organization wrote in a press release, “Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.” 

Ilustration: Niklas Elmehed. (c) Nobel Media AB 2018

Two immunologists have been awarded the Nobel Prize in Physiology or Medicine for discoveries that represent a “paradigmatic shift in the fight against cancer,” the Nobel committee said.

James P. Allison, PhD, of MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University, shared the prize for their discovery of cancer therapies that work by inhibiting negative immune regulation.

Dr. Allison studied the protein CTLA-4 found on T cells, which acts as a T-cell brake, and Dr. Honjo discovered a protein on immune cells called PD-1 that also acts as a T-cell brake.

In addition to sharing the honor, the scientists will split the 9 million Swedish kronor ($1.01 million) that comes with the prize.

Drs. Allison and Honjo, working in parallel, pursued different strategies for inhibiting the brakes on the immune system. Both strategies produced effective checkpoint inhibitors in the treatment of cancer.

James P. Allison

Dr. Allison was one of several scientists during the 1990s who noticed that CTLA-4 functions as a brake on T cells. Unlike other scientists, however, he set out to investigate whether blocking CTLA-4 with an antibody he had already developed could release the brake on the immune system.

The antibody had “spectacular” effects in curing mice with cancer. Despite little interest from the pharmaceutical industry, Dr. Allison continued efforts to develop the antibody therapy for humans.

The antibody turned out to be ipilimumab, which was approved in 2011 by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.

Tasuko Honjo

A few years prior to Dr. Allison’s finding, Dr. Honjo discovered PD-1 and set out to determine its function. PD-1 also operates as a T-cell brake, but it uses a different mechanism than does CTLA-4.

Dr. Honjo and others demonstrated in animal experiments that PD-1 blockade could be an effective anticancer therapy. Over the years he demonstrated the efficacy of targeting PD-1 in different types of human cancers.

The first two PD-1 checkpoint inhibitors—pembrolizumab and nivolumab—were approved by the FDA in 2014 for the treatment of melanoma.

Nivolumab is also approved to treat classical Hodgkin lymphoma (HL), non-small cell lung cancer (NSCLC), small cell lung cancer, squamous cell carcinoma of the head and neck, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, and microsatellite instability-high or mismatch repair deficient colorectal cancer.

Pembrolizumab is also approved to treat primary mediastinal large B-cell lymphoma, advanced NSCLC, classical HL, advanced gastric cancer, advanced cervical cancer, head and neck squamous cell cancer, advanced urothelial bladder cancer, and microsatellite instability-high cancer.

And targeting both CTLA-4 and PD-1 in combination therapy together may prove to be even more effective in eliminating cancer cells than either strategy alone, as is being demonstrated in patients with melanoma.

The Nobel organization wrote in a press release, “Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.” 

Ilustration: Niklas Elmehed. (c) Nobel Media AB 2018

Two immunologists have been awarded the Nobel Prize in Physiology or Medicine for discoveries that represent a “paradigmatic shift in the fight against cancer,” the Nobel committee said.

James P. Allison, PhD, of MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University, shared the prize for their discovery of cancer therapies that work by inhibiting negative immune regulation.

Dr. Allison studied the protein CTLA-4 found on T cells, which acts as a T-cell brake, and Dr. Honjo discovered a protein on immune cells called PD-1 that also acts as a T-cell brake.

In addition to sharing the honor, the scientists will split the 9 million Swedish kronor ($1.01 million) that comes with the prize.

Drs. Allison and Honjo, working in parallel, pursued different strategies for inhibiting the brakes on the immune system. Both strategies produced effective checkpoint inhibitors in the treatment of cancer.

James P. Allison

Dr. Allison was one of several scientists during the 1990s who noticed that CTLA-4 functions as a brake on T cells. Unlike other scientists, however, he set out to investigate whether blocking CTLA-4 with an antibody he had already developed could release the brake on the immune system.

The antibody had “spectacular” effects in curing mice with cancer. Despite little interest from the pharmaceutical industry, Dr. Allison continued efforts to develop the antibody therapy for humans.

The antibody turned out to be ipilimumab, which was approved in 2011 by the U.S. Food and Drug Administration (FDA) for the treatment of advanced melanoma.

Tasuko Honjo

A few years prior to Dr. Allison’s finding, Dr. Honjo discovered PD-1 and set out to determine its function. PD-1 also operates as a T-cell brake, but it uses a different mechanism than does CTLA-4.

Dr. Honjo and others demonstrated in animal experiments that PD-1 blockade could be an effective anticancer therapy. Over the years he demonstrated the efficacy of targeting PD-1 in different types of human cancers.

The first two PD-1 checkpoint inhibitors—pembrolizumab and nivolumab—were approved by the FDA in 2014 for the treatment of melanoma.

Nivolumab is also approved to treat classical Hodgkin lymphoma (HL), non-small cell lung cancer (NSCLC), small cell lung cancer, squamous cell carcinoma of the head and neck, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, urothelial carcinoma, and microsatellite instability-high or mismatch repair deficient colorectal cancer.

Pembrolizumab is also approved to treat primary mediastinal large B-cell lymphoma, advanced NSCLC, classical HL, advanced gastric cancer, advanced cervical cancer, head and neck squamous cell cancer, advanced urothelial bladder cancer, and microsatellite instability-high cancer.

And targeting both CTLA-4 and PD-1 in combination therapy together may prove to be even more effective in eliminating cancer cells than either strategy alone, as is being demonstrated in patients with melanoma.

The Nobel organization wrote in a press release, “Checkpoint therapy has now revolutionized cancer treatment and has fundamentally changed the way we view how cancer can be managed.” 

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

[email protected]

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

[email protected]

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

[email protected]

CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.

These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

Age

“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.

The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.

“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).

Stage

Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.

“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.

An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.

The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
 

Location

“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”

Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.

“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
 

MIPI

MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.

MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.

“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”

Biology

Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).

The prognostic effect was independent of induction treatment, Dr. Blum said.

Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
 

Histology

Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.

“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”

In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).

TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).

Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).

Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”

“I consider all of these factors with each patient that I see with mantle cell,” she said.

Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.

[email protected]

CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.

These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

Age

“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.

The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.

“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).

Stage

Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.

“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.

An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.

The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
 

Location

“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”

Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.

“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
 

MIPI

MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.

MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.

“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”

Biology

Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).

The prognostic effect was independent of induction treatment, Dr. Blum said.

Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
 

Histology

Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.

“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”

In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).

TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).

Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).

Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”

“I consider all of these factors with each patient that I see with mantle cell,” she said.

Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.

[email protected]

CHICAGO – The treatment options for patients with mantle cell lymphoma (MCL) vary based on age, but several prognostic factors can help guide treatment decision making in all patients, according to Kristie A. Blum, MD.

These include age, disease stage, disease sites, Mantle Cell Lymphoma International Prognostic Index (MIPI), biologic factors, and histology, Dr. Blum said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

Age

“I think the most important thing to recognize is there really isn’t any randomized transplant data for patients that are over 65. … There are very few transplant studies for patients [aged] 66-70,” said Dr. Blum, acting professor of hematology and medical oncology at Emory University in Atlanta.

The SWOG 0213 study did examine rituximab-hyperCVAD (R-HCVAD) in this age group, and showed that it has higher toxicity and lower efficacy in older versus younger patients, she said.

“Of course this is not typically a transplant approach, but an intensive-therapy approach,” she said, noting that progression-free and overall survival in patients aged 66-70 years were just 29% and 57%, respectively (Ann Oncol. 2013 Jun; 24[6]:1587-93).

Stage

Like age, disease stage in MCL patients has not been well studied, Dr. Blum said.

“Most of the randomized transplant studies have been conducted in patients stage II-IV, so we don’t have a lot of data about the early-stage patients,” she said, adding, however, that there are some retrospective data on radiation therapy for stage I-II MCL in older adults.

An International Lymphoma Radiation Oncology Group study of 179 patients, for example, showed that overall survival was “really the same whether they got chemo, chemo plus radiation, or radiation alone,” she said.

The 10-year freedom from progression was 46%, 43%, and 31%, respectively (P = .64).
 

Location

“What about where the disease presents? We’ve all heard about indolent mantle cell – so there’s this leukemic ‘non-nodal’ variant that’s been described,” she said, noting that this variant has a chronic lymphocytic leukemia–like presentation (no nodal disease, blood and marrow involvement, and splenic involvement). “And they tend to be SOX11-negative with mutated [immunoglobulin variable region heavy chain gene].”

Another variant involves primarily nodal disease that typically presents without elevated white blood cell count, with low Ki-67 (10% or lower), with SOX11 positivity, and without TP53 mutations.

“But I would caution you that this is really not very well defined; there’s no clear marker that predicts for indolent disease,” Dr. Blum said. “If you have one of these patients and you’re thinking about observing them, my experience has been that the most important thing to do is make sure you look at their [gastrointestinal] tract. I’ve had a lot of these patients progress with colon masses over time.”
 

MIPI

MIPI is basically a risk score calculated based on age, performance status, lactate dehydrogenase levels, and white cell count, she said.

MIPI less than 5.70 indicates low risk, MIPI of 5.70-6.2 is considered intermediate risk, and MIPI greater than 6.2 is considered high risk. High-risk patients who were transplanted in one study had a median overall survival of about 2.8 years and a median time to treatment failure of 1.4 years (J Clin Oncol. 2014 May 1;32[13]:1338-46). Even among patients under age 65 with high risk, the median time to treatment failure was 2 years, she said.

“So I do wonder, are we really helping these patients by transplanting them?” she added. “Similarly, the low-risk patients had a median time to treatment failure of 6 years; I wonder if they didn’t need a transplant.”

Biology

Ki-67 protein, a cellular marker for proliferation, is another important prognostic factor. A European Mantle Cell network study showed that median overall survival for patients with a Ki-67 proliferation index of less than 30% was not reached, and 5-year survival was 75%. At the same time, the median overall survival (OS) for those with Ki-67 proliferation index of 30% or greater was just 3.4 years, and 5-year OS was only 41% (J Clin Oncol. 2016 Apr 20;34[12]:1386-94).

The prognostic effect was independent of induction treatment, Dr. Blum said.

Combining MIPI and the Ki-67 index (MIPI-C) provides further value in defining a very high-risk group; those with both high MIPI and high Ki-67 had a median overall survival of only 1.5 years, and those with both, but who were under age 65, had median OS of only 1.7 years.
 

Histology

Patients with blastoid MCL variants were shown in that same study to have median OS of about 2.8 years, compared with 8 years in those with nonblastoid variants. The 5-year OS and progression-free survival (PFS) for blastoid variants were 35% and 29%, respectively, and for nonblastoid variants were 68% and 44%, respectively.

“But when you look at this with respect to the Ki-67 – so those patients that were called nonblastoid, that had a high Ki-67 index – their median overall survival is still lower at 5 years,” she said, noting that median OS was not reached in blastic variant (low-Ki-67) patients. “So it seems like the prognostic effect of cytology is largely explained by the Ki-67 index.”

In terms of karyotype, several studies have shown that complex karyotype is associated with poorer outcomes. One recent multicenter study of 274 patients showed that median OS in 53 patients with at least three cytogenetic abnormalities versus the remaining patients was 4.5 years vs. 11.6 years, and median PFS was 1.9 vs. 4.4 years (Cancer. 2018 Jun 1;124[11]:2306-15).

TP53 deletions (which affect about 20% of MCL patients) and mutations (which affect about 10%), are also useful prognostic factors, she said, noting that each is associated with inferior outcomes, and in one study patients with both appeared to have the worst outcomes (Blood. 2017;130:1903-10).

Another study showed that high TP53 staining (greater than 50% positive) is also associated with inferior outcomes, including reduced time to treatment failure and lower overall survival (Blood. 2018;131:417-20).

Finally, the most important factor is the patient’s wishes, Dr. Blum said, noting that she has “a lot of long discussions with these patients.”

“I consider all of these factors with each patient that I see with mantle cell,” she said.

Dr. Blum is a consultant for Acerta, AstraZeneca, and Molecular Templates and has received research funding from Acerta, AstraZeneca, Celgene, Cephalon, Immunomedics, Janssen, Merck, Millennium, Molecular Templates, Novartis, Pharmacyclics, and Seattle Genetics.

[email protected]

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

NEW YORK – The cell therapy landscape increasingly involves strategies beyond chimeric antigen receptor (CAR) T-cell therapy, but those studies still predominate among investigational trials, according to Frederick L. Locke, MD, of Moffitt Cancer Center in Tampa.

Researchers are looking at CAR T-cell therapy for earlier lines of treatment, especially in patients with aggressive lymphomas, Dr. Locke said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

Of 753 trials examining cell therapies and listed at ClinicalTrials.gov as of March 30, 2018, about half (404) were CAR T-cell therapies. The others included T-cell receptor therapies, tumor infiltrating lymphocyte therapies, dendritic cell vaccines, and natural killer cell–based therapies, according to an article in Nature Reviews.

“The development isn’t just here in the United States,” Dr. Locke said. “It’s really global. We see a lot of activity in Europe, but also in China. We’re seeing medical advances across the world through molecular biology and gene engineering of T cells and other immune cells which can be adoptively transferred into patients.”

That activity includes studies seeking to move CAR T-cell therapy earlier in the treatment paradigm for some diseases, he added. “CAR T-cell therapy in non-Hodgkin lymphoma is really beginning a paradigm shift, at least in my mind.”

Several large, randomized trials that are now comparing CD19 CAR T-cell therapy with second-line standard-of-care therapies for patients with aggressive B-cell lymphomas. Among those trials is ZUMA-7, a phase 3, randomized trial comparing axicabtagene ciloleucel with standard-of-care treatment in patients with relapsed or refractory diffuse large B-cell lymphoma.

While prognosis remains poor for relapsed or progressing aggressive B-cell lymphomas treated with chemotherapy, data to date suggest CAR T-cell therapy produces durable, long-term remissions in about 40% of patients at “a year out and counting,” Dr. Locke said.

He presented a proposed treatment algorithm that included R-CHOP chemotherapy up front and CAR T-cell therapy in later lines of treatment, an approach that Dr. Locke speculated could result in a cure rate of perhaps 80% in large-cell lymphomas.

Encouraging longer-term data is emerging, with some patients with aggressive T-cell lymphomas now without recurrence for 5 years or more following a single infusion of CAR T-cell therapy, he said.

Dr. Locke reported a financial disclosure related to Cellular Biomedicine Group.

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

Photo by Esther Dyson

The U.S. Food and Drug Administration (FDA) has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas.

The FDA had placed the hold in April, and this halted U.S.-based enrollment of new patients in tazemetostat clinical trials.

Now, Epizyme, Inc., the company developing tazemetostat, is in the process of reopening enrollment in all company-sponsored trials in the U.S.

The FDA had placed the partial hold on tazemetostat trials after an adverse event was observed in a pediatric patient on a phase 1 study.

The patient, who had advanced poorly differentiated chordoma, developed secondary T-cell lymphoblastic lymphoma (T-LBL) while taking tazemetostat. The patient has since discontinued tazemetostat and responded to treatment for T-LBL.

“This remains the only case of T-LBL we’ve seen in more than 750 patients treated with tazemetostat,” said Robert Bazemore, president and chief executive officer of Epizyme.

Due to this adverse event and the partial clinical hold, Epizyme began to assess the risk of T-LBL and other secondary malignancies potentially associated with tazemetostat.

The company also assessed the overall risks and benefits of tazemetostat treatment, conducting a review of the published literature and an examination of efficacy and safety data across all of its tazemetostat trials.

Epizyme concluded that the benefits of tazemetostat outweigh the risks, and the risk of T-LBL appears confined to pediatric patients who received higher doses of the drug. The phase 1 pediatric study in which the patient developed T-LBL included higher doses of tazemetostat than those used in the phase 2 adult studies.

Epizyme convened a panel of external scientific and medical experts who reviewed and validated the company’s findings.

“The team at Epizyme has worked diligently in collaboration with external experts and FDA over the past several months, culminating in decisions . . . to lift the partial clinical hold and allow re-opening of enrollment in our clinical trials,” Bazemore said.

He noted that the company is not making any substantial changes to trial designs or the patient populations involved in tazemetostat trials.

However, Epizyme is modifying dosing in the pediatric studies, improving patient monitoring, and making changes to exclusion criteria to reduce the potential risk of T-LBL and other secondary malignancies.

Bazemore said the lifting of the partial clinical hold allows Epizyme to turn its full attention to key priorities, including plans to submit a new drug application for tazemetostat in epithelioid sarcoma.

The company also plans to begin preparing for a potential new drug application for tazemetostat in follicular lymphoma.

Tazemetostat is currently under investigation as monotherapy in phase 2 trials of follicular lymphoma and solid tumor malignancies. The drug is also being studied as part of combination therapy for non-small cell lung cancer and diffuse large B-cell lymphoma (DLBCL).

In August, Epizyme announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with DLBCL. However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.

Now that Epizyme has resolved the U.S. hold on tazemetostat trials, the company is working to resolve partial clinical holds placed in France and Germany to resume trial enrollment in those countries.

After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.

After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.

In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.

SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.

After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.

After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.

In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.

SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.

After 5 years, the combination of lenalidomide and rituximab as first-line therapy for mantle cell lymphoma (MCL) continues to show durable responses with manageable toxicities, long-term results from a phase 2 clinical trial show.

After a median follow-up of 64 months, 21 of 33 patients with initial responses remained in durable, minimal residual disease (MRD)-negative remission following induction with lenalidomide and rituximab and maintenance with those same two agents for at least 3 years.

The patients with durable responses included five who opted to discontinue maintenance after 3 years, reported Jia Ruan, MD, PhD, of Cornell University, New York, and her colleagues.

“Our long-term data provide proof of concept that an outpatient-based induction and maintenance strategy free of conventional chemotherapy is effective, safe, and feasible as first-line therapy for MCL,” they wrote. Their report was published in Blood.

In the multicenter, phase 2 single-arm study, 38 patients with untreated MCL were enrolled and treated with lenalidomide 20 mg daily on days 1-21 of each 28-day cycle for 12 cycles during induction, followed by dose reduction to 15 mg during the maintenance phase. Patients also received standard dose rituximab 375 mg/m² weekly for 4 weeks during cycle 1, then once every other cycle.

Patients remained on treatment until disease progression, unacceptable toxicities, or study withdrawal. Patients who remained in remission after 3 years, based on routine surveillance CT scans, had the option to discontinue maintenance.

Of the original 38 patients enrolled, 36 were evaluable for response, including 23 with a complete response (CR) and 10 with a partial response.

At the 64-month median follow-up, neither the median progression-free survival (PFS) nor duration of response had been reached.

Overall, 21 of the 33 patients with responses (64%) had ongoing responses, including six patients with responses beyond 6 years.

Estimated 3-year and 5-year PFS rates were 80.3% and 63.9%, respectively. Respective estimated 3- and 5-year overall survival rates were 89.5% and 77.4%.

Mantle cell lymphoma international prognostic index (MIPI) scores were not associated with either response or PFS rates, but patients with high-risk MIPI scores were significantly more likely to have worse overall survival (P = .04).

Grade 3 or greater hematologic toxicities included neutropenia in 42% of patients in both induction and maintenance, anemia in 8% and 3%, thrombocytopenia in 11% and 5%, and febrile neutropenia in 3% and 5%.

Secondary primary malignancies occurred in six patients. These included five noninvasive skin cancers requiring only local therapy without the need for study interruption. Two patients, including one with a skin cancer, died from the secondary malignancies, including one from Merkel cell carcinoma and one from pancreatic cancer.

“The efficacy and survival outcome observed in our study compared favorably to those reported with lenalidomide either as single agent, or in combination with rituximab in relapsed and refractory setting, lending support for prioritizing novel agents such as lenalidomide early in the treatment sequence, to compare to conventional chemotherapy-based approach,” the investigators wrote.

The study was supported in part by Celgene Corporation, a Clinical Translational Science Center grant, and the Lymphoma Foundation. Dr. Ruan has received research support and been a consultant for Celgene, and other coauthors reported research support and consultant relationships with the company.

SOURCE: Ruan J et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-859769.

The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Courtesy Novartis

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.

In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, in draft guidance issued Sept. 19, NICE recommended against using tisagenlecleucel for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

[email protected]

The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Courtesy Novartis

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.

In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, in draft guidance issued Sept. 19, NICE recommended against using tisagenlecleucel for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

[email protected]

The National Institute for Health and Care Excellence (NICE) has issued draft guidance recommending against tisagenlecleucel (Kymriah) as a treatment for adults with diffuse large B-cell lymphoma (DLBCL).

Courtesy Novartis

Tisagenlecleucel is a chimeric antigen receptor (CAR) T-cell therapy that was recently approved by the European Commission to treat adults with relapsed or refractory DLBCL who have received two or more lines of systemic therapy.

Tisagenlecleucel is also European Commission–approved to treat patients up to age 25 years who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse.

In September 2018, the National Health Service (NHS) in England announced tisagenlecleucel will be made available for these ALL patients through the Cancer Drugs Fund.

However, in draft guidance issued Sept. 19, NICE recommended against using tisagenlecleucel for adults with relapsed/refractory DLBCL who have received two or more lines of systemic therapy. NICE noted that there is no standard treatment for this patient group, and that salvage chemotherapy is the most common treatment option.

Although the latest results from the JULIET trial suggest tisagenlecleucel can produce responses in patients with relapsed/refractory DLBCL, there are no data comparing tisagenlecleucel with salvage chemotherapy. Additionally, tisagenlecleucel cannot be considered a life-extending treatment at the end of life, according to NICE criteria.

All cost-effectiveness estimates for tisagenlecleucel are above the range NICE normally considers acceptable, and tisagenlecleucel does not meet criteria for inclusion in the Cancer Drugs Fund.

The list price for tisagenlecleucel is 282,000 pounds. However, Novartis, the company developing tisagenlecleucel, has a confidential commercial arrangement with the NHS that lowers the price of tisagenlecleucel for the ALL indication. This arrangement would apply if tisagenlecleucel were recommended for the DLBCL indication.

In August, NICE issued a similar draft guidance document recommending against use of another CAR T-cell therapy, axicabtagene ciloleucel (Yescarta). Axicabtagene ciloleucel is approved in Europe for the treatment of patients with relapsed/refractory DLBCL or primary mediastinal B-cell lymphoma who have received two or more lines of systemic therapy.

[email protected]

Survival gains among adolescents and young adults with cancer continue to lag behind outcomes for children and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?

“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.

He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.

“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.

In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.

“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.

“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
 

Treatment approach and setting

In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).

Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.

Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.

Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).

Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).

But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).

The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).

Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.

“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.

This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.

The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.

“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”

Disease and developmental biology

As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.

For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).

“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.

The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”

Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”

One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.

In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
 

Psychosocial factors

The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.

“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.

These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.

Courtesy Wake Forest University

Trial enrollment

In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.

“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”

The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.

Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.

The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.

Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.

Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.

Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.

About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.

An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).

Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.

“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.

In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.

Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
 

What’s next?

Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.

Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”

Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.

[email protected]

Survival gains among adolescents and young adults with cancer continue to lag behind outcomes for children and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?

“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.

He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.

“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.

In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.

“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.

“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
 

Treatment approach and setting

In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).

Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.

Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.

Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).

Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).

But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).

The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).

Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.

“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.

This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.

The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.

“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”

Disease and developmental biology

As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.

For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).

“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.

The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”

Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”

One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.

In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
 

Psychosocial factors

The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.

“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.

These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.

Courtesy Wake Forest University

Trial enrollment

In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.

“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”

The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.

Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.

The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.

Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.

Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.

Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.

About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.

An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).

Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.

“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.

In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.

Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
 

What’s next?

Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.

Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”

Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.

[email protected]

Survival gains among adolescents and young adults with cancer continue to lag behind outcomes for children and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?

“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.

He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.

“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.

In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.

“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.

“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
 

Treatment approach and setting

In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).

Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.

Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.

Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).

Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).

But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).

The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).

Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.

“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.

This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.

The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.

“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”

Disease and developmental biology

As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.

For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).

“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.

The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”

Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”

One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.

In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
 

Psychosocial factors

The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.

“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.

These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.

Courtesy Wake Forest University

Trial enrollment

In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.

“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”

The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.

Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.

The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.

Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.

Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.

Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.

About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.

An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).

Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.

“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.

In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.

Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
 

What’s next?

Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.

Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”

Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.

[email protected]