Liposomal Vincristine (Marqibo) Combined with Hyper-Cmad As Frontline Therapy for Patients with Acute Lymphoblastic Leukemia: A Result of a Phase II Clinical Trial
Authors: Sasaki Koji , Jabbour Elias , Thomas Deborah A , Khouri Maria R. , Yilmaz Musa , Garcia-Manero Guillermo , Ravandi Farhad , Borthakur Gautam , Garris Rebecca , Gachimova Evguenia , Chahoud Jad , DiNardo Courtney , Pemmaraju Naveen , Cortes Jorge E. , Kantarjian Hagop M. , O'Brien Susan 
Published: October 2019

Abstract
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.
Table 1. Patient characteristic and outcome 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)
Figure 1. Progression-free survival and overall survival 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.