Crizotinib in Advanced, Chemoresistant Anaplastic Lymphoma Kinase–Positive Lymphoma Patients

Abstract

Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression-free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile.

Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK–Positive Anaplastic Large Cell Lymphoma

“…Housekeeping genes used for normalization were murine HPRT FW: 5 0 -TCAGTCAACGGGGGACATAAA-3 0 ; REV: 5 0 -GGGGC-TGTACTGCTTAACCAG-3 0 or human GAPDH FW: 5 0 -Tgcaccaccacctgcttagc-3 0 ; REV: 5 0 -GGCATGGACTGTGGTCATGAG-3 0 . Deep sequencing was performed as previously described (20).…”

“…Very limited data are available on ALCL patients (19). The first long-term follow-up of ALCL patients who received Crizotinib reported, after 2 years, a PFS of 63.7% and an OS of 72.7%, and the drug was in general well tolerated (20). However, despite great success, as expected from previous experience with tyrosine kinase inhibitors (TKI; refs.…”

“…However, despite great success, as expected from previous experience with tyrosine kinase inhibitors (TKI; refs. 21,22), the first cases of relapse due to the positive selection of mutant clones have already been detected in several Crizotinib-treated NSCLC and ALCL patients (20,(23)(24)(25)(26). To effectively overcome Crizotinib resistance, the development of second-generation ALK inhibitors is exponentially growing (27).…”

Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects

“…207 Gambacorti-Passerini et al reported nine adult patients with refractory ALK-positive ALCL treated with crizotinib. 201 All patients obtained response, and, at the time of the report, four of the patients were on crizotinib and in CR without stem cell transplantation (duration of response: > 21, > 30, > 35, and > 40 months). The estimated 2-year PFS and OS rates were 63.7% and 72.7%, respectively.…”

“…[200][201][202][203][204][205][206] In a pediatric phase I trial evaluating crizotinib for refractory solid tumors or ALCL, seven of nine (78%) patients with ALK-positive ALCL achieved CR. 207 Gambacorti-Passerini et al reported nine adult patients with refractory ALK-positive ALCL treated with crizotinib.…”