Abstract
Background: Despite the high complete remission (CR) rates, a significant proportion of adult patients (pts) with T-cell acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (T-LL) treated with standard combination cytotoxic regimens will relapse underscoring the need for better therapeutic strategies. Nelarabine combined with intensive chemotherapy has been shown to be safe and effective in the frontline treatment of pediatric T-ALL. There is limited data on the use of nelarabine in the frontline setting in adult T-ALL and T-LL.
Methods: This single-arm phase 2 study was designed to determine the CR rate, overall survival (OS), and safety of adding nelarabine cycles to the standard hyper-CVAD regimen in previously untreated or minimally pretreated (failure to 1 induction course or CR after ≤ 2 cycles) pts with T-ALL and T-LL. Treatment consisted of 8 induction/consolidation cycles of hyper-CVAD (odd courses 1, 3, 5, 7) alternating with high-dose methotrexate (MTX) and cytarabine (Ara-C; even courses 2, 4, 6, 8) followed by 30 months of POMP (monthly vincristine, prednisone, 6-mercaptopurine, and MTX) maintenance therapy. Pts received nelarabine at a dose of 650 mg/m2 IV daily over 2 hrs for 5 days after the 8 cycles of induction/consolidation (Regimen 1). After 30 pts, the protocol was amended to deliver nelarabine after cycles 4 and 5 of induction/consolidation (Regimen 2). All patients also receive nelarabine instead of cycles 6 and 7 of POMP maintenance as early intensification. Late intensification consisted of MTX (100 mg/m2 IV on day 1) plus PEG-asparaginase (2000 IU/m2 IV on day 2) and hyper-CVAD given instead of cycles 18 and 19 of POMP maintenance. CNS prophylaxis consisted of 8 intrathecal treatments of MTX alternating with Ara-C. Pts with initial bulky mediastinal disease or with residual disease after induction were considered for local radiation therapy prior to the start of POMP maintenance.
Results: To date, sixty-seven pts have been enrolled; 40 pts (60%) had T-ALL, 26 pts (39%) had T-LL, and 1 pt (1%) had biphenotypic disease. Median age was 37 years (range, 18-78) with 76% (N=51) of the pts males. Performance status was 2 in 9 pts (13%). Four pts (6%) had CNS involvement and 31 pts (46%) had mediastinal disease at diagnosis. Median WBC count at presentation was 8.1 x109/L (range, 0.8-309.2) and 11 pts (16%) had a WBC count > 100 x109/L. Based on immunophenotype, pts were categorized as thymic (N=24), mature (N=8), early T-cell precursor ALL (ETP; N=24), early non-ETP (N=2), and not otherwise specified (N=9). At diagnosis, 41 pts (61%) had diploid cytogenetics, 19 pts (28%) had miscellaneous karyotypic abnormalities, and 7 pts (10%) had indeterminate karyotype due to lack of testing and insufficient metaphases. Eleven pts were in CR at the time of initial presentation after having received 1-2 prior courses of therapy. Overall response rate was 96% (54/56 pts); with 52 pts (93%) achieving CR, 2 pts (4%) PR, and 2 pts (4%) no response. CR rates were similar for T-ALL and T-LL, 87% and 100%, respectively. There were no early deaths within the first month of treatment. With a median follow-up of 35 months (range, 2-98), 44 pts (66%) remain alive of which 41 pts (93%) are in remission. Ten pts (15%) received SCT after achieving CR and remain alive post-SCT; 8 remained in CR and 2 relapsed post-SCT. Nineteen pts relapsed with a median time to relapse of 6.5 months (range, 1.4-62). The site of relapses were: 10 hematologic (BM + blood), 5 extramedullary (EM), 3 BM + EM, and 1 BM + CNS. Twenty-three pts (34%) died including 17 pts with CR dying after relapse. Probability of CR duration at 3 years was 68% (95% CI 54-79 %). The 3-year probability of OS was 65% (95% CI 50-76 %) with a median OS of 82 months. There was no statistically significant difference in OS among the two different nelarabine regimens (Figure 1; p-value=0.93). Grade 3-4 nonhematological toxicity was reported in 60 (90%) pts, most frequent toxicities being infection (82%), elevated alanine aminotransferase (ALT) (16%), and thrombotic events (12%).
Conclusion: Hyper-CVAD plus nelarabine is safe and effective in the frontline treatmentof adult T-ALL/T-LL and induces durable remissions. Administration of nelarabine earlier during the course of therapy does not appear to influence the outcome.
Disclosures
Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses; Portola: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding. Wierda:Gilead: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Jain:Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Novimmune: Consultancy, Honoraria; Infinity: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Daver:Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.
PDGFRA rearrangement leading to hyper-eosinophilia, T-lymphoblastic lymphoma, myeloproliferative neoplasm and precursor B-cell acute lymphoblastic leukemia
