Crizotinib Yields High Response Rates in ALK-positive Lymphoma
NEW ORLEANS—Crizotinib exerted “potent antitumor activity” and produced durable responses in heavily pretreated patients with advanced ALK-positive lymphoma, a study presented at the 55th American Society of Hematology Annual Meeting and Exposition concluded.
The activity of crizotinib in ALK-positive lung cancer has been documented; however, with the exception of “impressive” short-term therapeutic activity in two patients, there have been no reports on the long-term effects of crizotinib in ALK-positive lymphomas, said Carlo Gambacorti Passerini, MD, of the University of Milano-Bicocca and San Gerardo Hospital, Monza, Italy, and colleagues.
In this study, the investigators administered crizotinib 250 mg twice daily as monotherapy until disease progression to 11 patients with ALK-positive lymphoma, which was diagnosed as ALK-positive non-Hodgkin lymphoma (NHL) by immunohistochemistry and/or fluorescence in situ hybridization. Median age was 28 years (range, 19-55 years).
Nine patients had anaplastic large cell lymphoma (ALCL) histology and two, diffuse large B-cell lymphoma (DLCBL). Patients were refractory or had relapsed disease after at least one prior chemotherapy regimen (median, 3, including three patients who received an autologous bone marrow transplant [BMT] and two, an allogeneic BMT) and measurable disease. All had involvement at multiple sites (nodal and extranodal), B symptoms, and an Eastern Cooperative Oncology Group performance score of 1 to 4. Response to therapy was assessed by Response Evaluation Criteria in Solid Tumors.
Ten patients responded; overall response rate (ORR) was 90.5% (95% CI: 58.7%-99.8%) and included nine complete responses (CR, 81.8%; 95% CI: 48.2%-97.8%) and one partial response (10%; 95% CI: 0.2%-44.5%). “Evidence of response by PET/CAT scan was present as early as 12 days,” Dr. Gambacorti Passerini reported. “B symptoms disappeared promptly and LDH levels normalized within 30 days after the start of crizotinib.”
At 40-month follow-up, four patients remained in CR under continuous crizotinib treatment and all tested negative by quantitative polymerase chain reaction for NPM/ALK. Four patients (two with DLBCL and two with ALCL) had disease progression and three died. Three of 11 patients received crizotinib before/after allogeneic BMT (alloBMT). The two-year progression-free survival rate was 63.7% (95% CI: 30.8%-89.15%) and the two-year overall survival rate, 72.7% (95% CI: 39.1%-94.0%), “with a plateau in the curve after the initial 6 months,” Dr. Gambacorti Passerini reported.
Toxicities, all of which were grade 1/2, included ocular flashes in 10 patients, peripheral edema in three, skin rash in one, and erectile dysfunction in one. Laboratory abnormalities, all of which were also grade 1/2. Included neutropenia in two patients, thrombocytosis in one patient, and elevated liver function tests in one patient. None died from a cause related to treatment.
In two patients who relapsed, the kinase domain of NPM-ALK could be amplified from peripheral blood samples obtained at the time of relapse, months 5 and 2,” he said. “Deep sequencing of these products revealed the presence of different mutations: Q1064R at high prevalence (95%) in patient #2 and I1171N (33%) plus M1328I (14%) in patient #6.” None of the mutations were present in samples obtained before treatment with crizotinib was initiated.
Of the three mutations, I1171N had previously been discovered during in vitro screening. I1171N “commands an intermediate level of resistance to crizotinib (RI: 5.8) which, however, is cross-resistant with other anti-ALK TKIs such as AP26113 and NVP-TAE684,” Gambacorti Passerini explained.
The other two mutations had not previously been described and present a RI to crizotinib of 2.4 (M1328I) and 8.5 (Q1064R). Since these do not form direct contact with crizotinib, they are believed to interact with structures within the catalytic domain, such as the hydrophobic R-spine (I1171N), the activation loop (M1328I), or as yet unidentified regions (Q1064R).
“Crizotinib in combination with other agents for first-line treatment is under discussion,” he concluded, adding that second-generation ALK inhibitors should be tested in patients failing crizotinib.