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New Drug Approvals in Leukemia and Lymphoma Presented at ASH 2017

Laura Joszt
The FDA was busy in 2017, with a number of notable approvals, including the first chimeric antigen receptor T-cell treatment. In a session at the 59th American Society of Hematology Annual Meeting and Exposition in Atlanta, Georgia, employees from the FDA presented data on 5 new drug approvals in leukemia and lymphoma in 2017.
Adults with relapsed or refractory large B-cell lymphoma who have been on 2 or more lines of systemic therapy now have another therapeutic option: axicabtagene ciloleucel. The FDA approved axicabtagene based on the ZUMA1 trial, a single-arm, multi-phase study.

In the study, the objective response rate (ORR) was 72% and the CR was 52%. Most of the patients in the trial had diffuse large B-cell lymphoma with approximately 69% having failed 3 prior lines of therapy. Patients with a CR tended to have a durable response, explained Yvette Kasamon, MD, of FDA.

However, there were notably serious adverse reactions in 52% of patients. CRS was near universal with 94% of all patients experiencing it. More than half (55%) experienced grade 2 or higher CRS and 13% had grade 3 or higher CRS. The median time to onset of CRS was 2 days and the median duration was 7 days.

“It is vital to ensure the availability of 2 doses of tocilizumab before the CAR T infusion,” Kasamon noted.

In addition, central nervous system neurotoxicity occurred in the majority of patients. Any grade neurotoxicity occurred in 65% to 87% of patients, depending on definition. The median onset to neurotoxicity was 4 days and the median duration was 9 to 13 days.

The drug was approved with restricted distribution in order to reduce CRS and neurotoxicity. Kasamon also noted the exclusion criteria of ZUMA1, which included history of malignancy other than nonmelanoma skin cancer, carcinoma in situ, or follicular lymphoma unless disease free for at least 3 years; presence of fungal, bacterial, viral, or other infection that is uncontrolled; and a known history of infection with HIV or hepatitis B or C.

“These exclusion criteria were relatively stringent and not necessarily representative of many patients we see in the clinic with relapsed/refractory large B-cell lymphoma,” she said.

Copanlisib was granted accelerated approval in adult patients with relapsed follicular lymphoma who had failed on at least 2 prior systemic therapies. The agent is a phosphatidylinositol-3-kinase (PI3K) inhibitor. It was approved based on results of the CHROOS-1 trial, a multi-center single-arm trial with 104 patients.

The trial reported an ORR of 59% and a CR of 14%. The median duration of response was 12.2 months. During the trial, 21% of patients required a dose reduction and 16% discontinued treatment due to adverse reactions. Copanlisib caused infusion-related hyperglycemia and hypertension.

Overall, the trial demonstrated a magnitude of response and duration of response that predicts clinical benefit in these patients.

“The short-term safety profile of copanlisib is tolerable, yet due to limited exposure to copanlisib, long-term safety information is needed and a postmarketing requirement to prospectively characterize long-term safety was issued,” said Nicholas Richardson, DO, MPH, of FDA.

The last therapy presented was acalabrutinib, which was granted accelerated approval for the treatment of relapsed or refractory mantle cell lymphoma. While patients with mantle cell lymphoma tend to respond to initial therapy, most patients relapse.

“Although the therapeutic landscape for mantle cell lymphoma is changing, with chemo, immunotherapy, and targeted agents, prognosis remains poor in the setting of relapsed disease,” explained Margret Merino, MD, of FDA.

Acalabrutinib is a second-generation inhibitor with less inhibition than ibrutinib, which results in less off-target toxicity. Currently, ORR for approved therapies ranges from 31% to 66% and CR ranges from 8% to 17%. The ACE-LY-004 study, a multicenter, global, single-arm trial of 124 patients reported ORR of 81% and CR of 40%. Further, 73% of patients who responded maintained response at 12 months, and at the 15-month follow-up, median response hadn’t been met.

Acalabrutinib was generally well tolerated, Merino explained. There was a low rate of discontinuation (7%) and of dose reduction (3%). The most common adverse reactions, which were mostly low grade, were cytopenias, headache, diarrhea, fatigue, myalgia, and bruising. Lymphocytosis occurred in 31% of patients, occurred early, and resolved in the majority of patients.

“Additional analysis of safety data with longer follow-up is warranted and is planned as part of the postmarketing requirements,” Merino concluded.

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