Liposomal Vincristine (Marqibo) Combined with Hyper-Cmad As Frontline Therapy for Patients with Acute Lymphoblastic Leukemia: A Result of a Phase II Clinical Trial

Background: Liposomal vincristine has been approved as salvage chemotherapy for patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Replacement of regular vincristine with liposomal vincristine might lead to improve outcome with reduced neurotoxicity in patients with newly diagnosed ALL. Methods: Patients ≥18 years with newly-diagnosed B-cell ALL were eligible for the clinical trial consisting of hyper-CMAD (cyclophosphamide 300 mg/m2 IV every 12 hours on Days 1-3; liposomal vincristine 2 mg/m2 IV on Day 1 and day 8; doxorubicin 50 mg/m2 IV on Day 4; dexamethasone 40 mg IV daily on Days 1-4 and Days 11-14) (odd cycles 1, 3, 5, 7) alternating with high-dose methotrexate 1000 mg/m2 IV on Day 1, and cytarabine 3 gm/m2 IV every 12 hours on Days 2 and 3 (even cycles 2, 4, 6, 8). Rituximab 375 mg/m2 IV on Days 1 and 8 for courses 1-4 was administered in CD-20 positive ALL. TKI (imatinib or dasatinib) were concomitantly administered in patients with Philadelphia chromosome positive (Ph+) ALL. Overall survival (OS) was defined as time interval from the start date of hyper-CMAD to the date of death. Progression-free survival (PFS) was defined as time interval from the start date of hyper-CMAD to the date of relapse or death, whichever comes first. Results: Twenty-seven patients have been treated so far. Baseline patient characteristics are described in table 1. Median age is 53 years (range 23-80). Eleven patients (41%) had CD-20 positive ALL, and 17 (63%) had Ph+ ALL. Median follow-up is 12 months (3-22) with a median of 4 cycles (1-8) administered Of 17 patients with Ph+ ALL, 15 patients were received additional dasatinib and 2 imatinib. Twenty-six (96%) achieved complete response (CR). Early death was observed in 1 patient (4%) with Ph+ ALL. Of the 26 patients evaluable for response, 22 (100%) achieved CCyR (3 patients, diploid at start; 1 patient, not performed), and 23 (88%) achieved negative MRD by multicolor flow cytometry. Of the 16 evaluable Ph-positive patients, MMR was observed in 15 (94%) and CMR in 10 (63%). Three patients in CR1 underwent allogeneic stem cell transplantation (ASCT). At the last follow-up, 23 (85%) patients are alive. Four (15%) patients died: 1 from sepsis on C1D10; 1 from unknown cause on C1D135; 1 from post-transplant complications; and 1 from disease progression at the third salvage chemotherapy. Median time to platelet and neutrophil recovery for cycle 1 was 24 and 19 days, respectively. To date, 3 patients relapsed; 1 patient with t(4;11) relapsed at C5D36; 1 Ph-positive patient relapsed post C8 with no maintenance therapy; 1 patient with positive MRD 2 months prior to morphologic relapse while on maintenance therapy C10D32. At the last follow-up, 23 (85%) patients are alive. Four (15%) patients died: 1 from sepsis on C1D10; 1 from unknown cause on C1D135; 1 from post-transplant complications; and 1 from relapse and disease progression at the third salvage chemotherapy. The 1-year PFS and OS rates were 77% and 87%, respectively. Conclusions: The combination ofliposomal vincristine withHyper-CMAD is safe and effective with high response rates in patients with newly diagnosed ALL. | | N (%)/ Median [range] N= 27 | | -------------------------------- | ----------------------------------- | | Age (yrs) | 53 (23-80) | | Age ≥ 60 | 10 (37) | | Male | 12 (44) | | PS 2-3 | 2 (7) | | WBC (x 109/L) | 17.1 (1.4-372.1) | | CNS disease | 6 (22) | | CD20 positivity | 11 (41) | | Cytogenetic Abnormality, No. (%) | | Diploid | 3 (11) | | Philadelphia chromosome | 17 (63) | | Hypodiploid | 2 (7) | | Hyperdiploid | 1 (4) | | t(4;11) | 3 (11) | | Misc | 1 (4) | | Overall response, No. (%) | | CR | 26/27 (96) | | Early death | 1/27 (4) | | CCyR | 22/22 (100) | | MRD by Flow | 23/26 (88) | | MMR:BCR/ABL | 15/16 (94) | | CMR:BCR/ABL | 10/16 (63) | Table 1. Patient characteristic and outcome ![Figure 1.][1] Figure 1. Progression-free survival and overall survival Disclosures Chahoud: American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. DiNardo: Novartis: Research Funding. Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes: BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding. O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. [1]: pending:yes