Phase two study of crizotinib in patients with anaplastic lymphoma kinase (<scp>ALK</scp>)‐positive anaplastic large cell lymphoma relapsed/refractory to chemotherapy
Authors: Elisa Bossi, Andrea Aroldi, Filippo A. Brioschi, Carolina Steidl, Silvia Baretta, Rossella Renso, Luisa Verga, Diletta Fontana, Geeta G. Sharma, Luca Mologni, Lara Mussolin, Rocco Piazza, Carlo Gambacorti‐Passerini
Journal: American Journal of Hematology (2020)

To the Editor: Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), is approved for the treatment of patients with ALK-positive (ALK+) or ROS1-positive (ROS1+) advanced non-small-cell lung cancer (NSCLC). The ALK rearrangements are also implicated in anaplastic large-cell lymphoma (ALCL), which is characterized by the presence of the fusion-protein NPM-ALK. Note, ALK+ ALCL responds to chemotherapy, but relapses are frequent and progression-free survival (PFS) at 4 years is <50%.1 Brentuximab-vedotin (BV) is considered a standard treatment for patients with relapsed/refractory ALCL2 and is currently used in many countries even as first line treatment. Due to the need for intravenous infusion and the cumulative peripheral neuropathy, prolonged treatment with BV may be difficult to manage in the setting of refractory/relapsed (R/R) patients. Crizotinib has previously been shown to have therapeutic activity in R/R refractory ALK+ lymphomas with a favorable tolerability profile3, 4 and could therefore represent a potential treatment option in this setting. However, no formal phase two study has been performed in adult patients. We herein present the results of a single-center, single-arm, phase two study (CRU1; ClinicalTrials.gov Identifier: NCT02419287) with crizotinib administered as monotherapy (dosage 250 mg BID) to 12 ALK+ ALCL patients R/R to at least one line of previous cytotoxic therapy. Median age at the enrollment was 31 years (range 18-83); six patients were male and median number of previous lines of chemotherapy was two (range 1-6) (Table S1 in Appendix S1). The primary endpoint was the overall response rate (ORR), according to Response Evaluation Criteria in Lymphoma (RECIL) 2017. In the analysis set, the proportion of patients with CR or partial response (PR) as the best response is regarded as the ORR. Tumor assessments were performed with CT or CT/PET at baseline, after 4 weeks, 12 weeks and then every 12 weeks (Table S2 in Appendix S1). Since the NPM-ALK fusion protein detected by immunohistochemistry exhibited a nuclear and cytoplasmatic staining pattern in all ALCL patients, qualitative real time polymerase chain reaction (RT-PCR) was used to measure NPM-ALK fusion transcript in peripheral blood samples at the same time points, and then every 12 weeks throughout the study (supplementary information methods in Appendix S1). The Overall Response Rate (ORR) was 10/12, or 83.3% (95% CI, 55.2%-95.3%). Seven patients (58.3%; 95% CI, 32.0%-80.7%) achieved complete remission (CR) and three patients (25%; 95% CI, 8.9%-53.2%) achieved partial remission (PR) (Table S1 and S3 in Appendix S1). Interestingly, three patients who obtained CR were resistant to previous BV administration. One patient in CR stopped crizotinib after only 1 month of treatment, then underwent an allogenic-HSCT and was therefore censored. Only one of three patients in PR is still alive and in response at the latest follow up under continuous crizotinib administration. The other two patients in PR had PD in the CNS after 2 and 3 months of therapy, respectively. Two patients (16.7%; 95% CI, 4.7%-44.8%) did not respond to crizotinib. One patient obtained a stable disease (SD) after the first month of treatment, then had a rapid systemic disease progression and died. The second patient progressed early after the start of treatment and died quickly. Real-time polymerase chain Reaction (RT-PCR) for NPM-ALK became negative within 1 month in 6/8 evaluable patients (75%; 95% CI 40.9%-92.8%) (Table S1 and S3 in Appendix S1). Early negativity by RT-PCR for NPM-ALK in previously positive NPM-ALK patients seemed to correlate with the depth and durability of response; RT-PCR could indeed represent an effective method to monitor minimal residual disease in adult ALK+ lymphoma, similar to what has previously been observed in pediatric patients..5 Crizotinib may therefore offer a potential long-term treatment option in patients with relapsed/refractory ALCL, with a 2-year PFS and OS of 65% and 66%, respectively (Figure 1). All responding patients obtained their best response after only 1 month of treatment and almost all patients with only one previous line of cytotoxic therapy (4/5, 80%; 95% CI 37.6%-96.4%) showed durable responses; this fact could indicate that an early treatment with crizotinib after the failure of first-line treatment may produce better results than when administered later on. Moreover, all patients who progressed/relapsed did it within the initial 90 days of treatment and no further progressions/relapses were noted thereafter. Median duration of treatment (DOT) is 16.5 months (range 0.5-66 months), but for patients with durable response median DOT exceeds 40 months (range 12-66 months) (Table S3 in Appendix S1). To our knowledge, the treatment duration (up to 66 months) in this study is currently the longest reported in literature in adult patients and therefore provides new information about the long-term safety of crizotinib. Treatment was generally well-tolerated and no patient dropped out in association with any adverse event. The safety profile observed was similar to that reported previously6; the most common treatment related adverse events were transient gastrointestinal and visual disorders graded 1/2 (Table S4). The needed duration of treatment is presently unknown; however, abrupt relapses of ALK+ lymphoma following crizotinib discontinuation have been reported, so caution must be exercised when interrupting treatment in patients with ALK+ lymphomas, since ALCL may recur rapidly.7 The EORTC-QL questionnaire (version 3.0) data collected among patients on treatment with crizotinib revealed no negative impact on quality of life, with a decrease of disease-related symptoms and improvement in general wellbeing (Figure S2, and Tables S5, S6, and S7 in Appendix S1). Only diarrhea (Figure S2 and Table S5 in Appendix S1) showed an increase during treatment but never proved substantial in our patients. At the latest follow up seven patients (six CR and one PR, 58.3%; 95% CI, 32.0%-80.7%) were still in response under continuous crizotinib administration with a median duration of response of 39 months (range 11-63 months) (Table S3 in Appendix S1). In conclusion, our study shows notable and durable antitumor activity of crizotinib as monotherapy for patients with relapsed or refractory ALK+ ALCL, together with a favorable safety profile maintained over long-term treatment. Crizotinib should be made available for patients with relapsed/refractory ALK+ lymphoma, including those pretreated with BV. Combining crizotinib with other novel therapies, especially those that target the key effectors of the NPM-ALK-induced malignant cell transformation, could improve the overall response rates without exposing patients to long-term toxicities.8 We would like to thank all of the participating patients and their families, as well as the investigators, research nurses, study coordinators, and operations staff. The authors have no relevant conflict of interest to report. This study was supported by Italian Association for Cancer Research (AIRC) (grant number IG 2017 id 20112), by University of Milano-Bicocca and by a grant from Pfizer Inc. 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