Crizotinib Proves Effective in ALK-Positive Lymphoma


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Carlo Gambacorti-Passerini, MD

Crizotinib in Lymphoma

These data indicate that ALK-positive lymphoma patients have a high chance of responding to crizotinib even when heavily pretreated, with approximately half of them not relapsing within the first months and then enjoying long-lasting responses.

—Carlo Gambacorti-Passerini, MD

Crizotinib (Xalkori) produced promising results in patients with ALK-positive lymphoma in two small studies presented at the 2013 American Society of Hematology (ASH) Annual Meeting. Crizotinib exerted potent antitumor activity in advanced ALK-positive lymphoma and achieved durable responses in heavily pretreated patients, with a benign safety profile.

Crizotinib was the first ALK inhibitor to be approved by the U.S. Food and Drug Administration for the indication of ALK-positive non–small cell lung cancer. These studies support the concept of targeting the tumor abnormality as an important strategy, not just focusing on the type of cancer.

“These data indicate that ALK-positive lymphoma patients have a high chance of responding to crizotinib even when heavily pretreated, with approximately half of them not relapsing within the first months and then enjoying long-lasting responses…. These data will be useful for the management of this aggressive disease,” said Carlo Gambacorti-Passerini, MD, University of Milano Bicocca, Monza, Italy, an investigator in both studies.

Compassionate Use Study

To test the concept of ALK inhibition in ALK-positive lymphoma, Dr. Gambacorti-Passerini and colleagues evaluated crizotinib monotherapy (250 mg twice daily) in a compassionate use study of 11 patients (7 males, 4 females) with ALK-positive non-Hodgkin lymphoma documented by immunohistochemistry and fluorescence in situ hybridization.

“In this study, crizotinib was well tolerated for up to 3 years, with a 91% overall response rate and a 2-year progression-free survival of 63.7%. Durable responses were seen in about half the patients in this study. These promising results will lead to studies of crizotinib earlier in the course of disease and in combinations. Since ALK mutations were identified in relapsed patients, second-generation ALK inhibitors should be tested in relapsed patients,” Dr. Gambacorti-Passerini said.

All 11 patients had relapsed or refractory, heavily pretreated disease, with a median of three prior lines of therapy. Median age was 28 years. Response to crizotinib was evaluated by computed tomography and positron-emission tomography scans according to RECIST criteria. Overall response rate was 91%, including nine complete remissions and one partial remission. ALK rearrangements were documented in all nine complete remissions.

Responses began to emerge as early as 12 days after the first dose of crizotinib. Bulky lymphadenopathy resolved as early as day 16, and bone marrow involvement resolved at 1 month in four patients with bone marrow involvement. B symptoms resolved quickly, normalizing within 30 days, Dr. Gambacorti-Passerini noted.

At 2 years, the overall survival rate was 72.7% and the progression-free survival rate is 63.7%. All four cases of crizotinib treatment failure occurred within the first 3 months of therapy.

“Four patients relapsed, three were able to undergo bone marrow transplantation, and four are alive and happy.” Dr. Gambacorti-Passerini said. “Our observations suggest that within 2 to 3 months of treatment with crizotinib, approximately half the patients relapse and die and half go on to continued complete remission,” he stated.

Registration Study

Dr. Gambacorti-Passerini was lead author of a registration study sponsored by Pfizer and reported at the ASH meeting during a poster session. The registration study had a design and enrollment criteria (including advanced pretreated ALK-positive lymphoma) similar to those of the compassionate use study.

This open-label, multicenter, exploratory trial enrolled 15 patients with advanced ALK-positive lymphoma; 14 had anaplastic large-cell lymphoma (ALCL) and 1 had diffuse large B-cell lymphoma. Median age was 25 years, and 60% were male. All patients had received prior systemic therapy, and 13% had undergone prior radiation therapy. The median number of previous lines of therapy was three.

At the time of data analysis in June 2013, 5 patients had discontinued therapy and 10 were still on treatment. Median duration of treatment was 33 weeks. Overall response rate was 57%, and clinical benefit rate (including complete remission, partial remission, and stable disease) was 64%. Progression-free and overall survival will be reported with longer follow-up.

The most common adverse events were diarrhea and nausea, each observed in 47% of patients. Visual impairment was reported in 40%, and asthenia, cough, and neutropenia each occurred in 27%. Most treatment-emergent adverse events were grade 1.

“These data suggest that ALK inhibition can be effective in patients with ALK-positive hematologic malignancy. Further study is warranted in this setting,” concluded Dr. Gambacorti-Passerini, who was first author of the poster presentation. ■

Disclosure: Dr. Gambacorti-Passerini is a consultant for and has received research funding from Pfizer.

References

1. Redaelli S, et al: ASH Annual Meeting. Abstract 368. Presented December 9, 2013.

2. Gambacorti-Passerini C, et al: ASH Annual Meeting. Abstract 4342. Presented December 9, 2013.


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