Phase ii study with crizotinib in patients with anaplastic lymphoma kinase (alk)-positive lymphoma relapsed/refractory to chemotherapy

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK) and cros oncogene 1 (ROS1), is approved for treatment of patients with ALKpositive or ROS1-positive advanced non-small-cell lung cancer. However, ALK rearrangements, are also implicated in anaplastic largecell lymphoma, mainly the fusion-protein NPM-ALK. ALK-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, develop in more than 50% of patients. In this ongoing, single-center, single-arm, phase II study, Crizotinib was administered as monotherapy with a starting dose of 250 mg twice daily to 11 ALK+ lymphoma patients who had progression of disease after at least one line of cytotoxic therapy. Patients were enrolled at the Department of Haematology, San Gerardo Hospital, Monza (Italy) from April 2015 to October 2018. Median number of previous cytotoxic treatments was 3 (range 2-6). Median age at diagnosis was 32 years (range 18-58 years) and 5/11 patients were male. The overall response rate (ORR) was 7 of 11 (63.6%; 95% CI = 35% to 85%). All responding patients achieved complete remission and negativity for the NPM-ALK transcript by Real Time Polymerase Chain Reaction (RT-PCR). Median follow up is 10 months (range 2-48). Disease status at the latest follow up is as follows: 6 patients are in complete response under continuous crizotinib administration, 4 patients had progression of disease and died, 1 patient stopped the treatment and was in complete response after allogenic bone marrow transplantation. All relapses developed within the first 3 months of therapy. The two-years Progression Free Survival (PFS) and Overall Survival (OS, see attached Figure 1) are 65% (95% CI = 53% to 77%) and 70% (CI = 61% to 79%), respectively. The most common treatment related adverse events were diarrhea (90.9%), oedema lower legs (100%), vomiting (72.7%) and visual disorders (36.4%). All adverse events were Grade 1 or 2 and most of them were transient in nature. Crizotinib shows a good safety profile and carries out a potent antitumor activity with durable responses in advanced pretreated ALK+ lymphoma patients. Crizotinib should be made available for patients with relapsed/refractory ALK+ lymphoma.