AMSTERDAM – Crizotinib has shown significant antitumor activity in adult patients with lymphomas that express the anaplastic lymphoma kinase gene and who were resistant to the effects of at least three lines of previous therapy.
During a compassionate use program, eight of nine patients with anaplastic lymphoma kinase (ALK)–positive lymphoma responded to crizotinib (Xalkori). Six patients had complete responses, and four achieved durable responses lasting more than 6 months.
Sara Freeman/IMNG Medical Media
Dr. Carlo Gambacorti-Passerini
These data mirror positive early results already seen in pediatric anaplastic large cell lymphoma (ALCL). Seven of eight children treated with crizotinib had complete and durable responses, investigators reported at the American Society of Clinical Oncology annual meeting.
"Clinically, ALK+ lymphomas are known for their aggressiveness," said Dr. Carlo Gambacorti-Passerini, who presented the adult findings June 17 at the annual congress of the European Hematology Association. These data give a strong signal that further investigation in ALK-positive lymphomas is warranted.
Crizotinib was approved by the Food and Drug Administration for the treatment of ALK-driven non–small cell lung cancer (NSCLC) last August, but these new data suggest that responses may be even better in these lymphoma patients.
"It looks like, compared to EMF4-ALK-positive non–small cell lung cancer, the responses are much more durable," observed Dr. Matthias Theobald of Medizinische Klinik und Poliklink in Mainz, Germany, who chaired the session in which the adult findings were presented.
"Why lung cancer patients only have a median duration of responses of 10-12 months is not very clear," responded Dr. Carlo Gambacorti-Passerini, professor of internal medicine at the University of Milan–Bicocca and director of the clinical research unit at S. Gerardo Hospital, both in Monza, Italy.
It is also not apparent why some patients with ALK-positive lymphoma initially benefit while others develop resistance with time. "The main issue here is that [nearly] everybody responds, but after 2-3 months we see a divide," Dr. Gambacorti-Passerini said.
Four men and five women aged between 20 and 56 years (median age, 31 years) received crizotinib at a dose of 250 mg twice daily as part of a compassionate protocol. Seven patients had ALCL, and two patients had diffuse large cell lymphoma according to WHO criteria.
The median number of previous lines of therapy they had collectively received was three, although some had received up to five prior chemotherapy regimens, three had undergone autologous bone marrow transplant, and one patient an allogenic bone marrow transplant. While on crizotinib, steroid use or the use of drugs with antineoplastic activity was not allowed.
The effects of crizotinib were carefully assessed via physical exam, examination of bone marrow aspirate, positron-emission tomography and computed tomography scans, and blood tests before treatment initiation and at monthly intervals for the first 3 months, then every 3 months for up to 2 years. Disease status was also evaluated according to standard RECIST criteria.
After a median follow-up of 8 months, six patients had achieved a complete response to crizotinib, lasting for 2, 5, 8, 13, 18, or 24 months or more, respectively. A further two patients had a partial response.
Dr. Gambacorti-Passerini reported responses to treatment were "very rapid," with alleviation of fever within 2-10 days and time to normalization of serum lactate dehydrogenase within a month.
Furthermore, three patients were still on treatment with crizotinib. Six patients had discontinued: one because of patient request and five because of disease progression. The patient who discontinued by request did so because of severe gastroparesis unrelated to crizotinib and after a planned stoppage of the drug for a stem cell transplant.
Importantly, overall survival at 24 months appears to be just over 40%.
The most common side effects and lab abnormalities were ocular flashes, which all nine patients experienced, but these were of grade 1 or 2 and usually a temporary effect; one patient each had a grade 1-2 peripheral edema, a grade 3 neutropenia, and a grade 2 liver function test abnormality.
"These data show that crizotinib was well tolerated in this population of heavily pretreated patients," Dr. Gambacorti-Passerini concluded. He noted that patients have been treated with crizotinib for 2 years or more, which is the longest anyone has received the drug.
"Now, crizotinib is being evaluated in a registration study, which will start after this compassionate use," he added. This international phase I study (NCT01121588) is currently enrolling patients, and there are also suggestions of using crizotinib as first-line treatment or in combination with other agents for ALK+ lymphomas.
Dr. Gambacorti-Passerini has received research funding from Pfizer, which supported the compassionate use program.