Phase II Study of Hyper-Cmad with Liposomal Vincristine (Marqibo) for Patients with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

Background: Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy for patients with relapsed / refractory ALL. Replacement of regular vincristine with liposomal vincristine might lead to improve response rate and survival as well as reduced toxicity.

Methods: Patients ≥18 years with newly-diagnosed B-cell ALL were eligible for the phase II clinical trial consisting of hyper-CMAD (cyclophosphamide 300 mg/m2 IV every 12 hours on days 1-3; liposomal vincristine 2.0 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, 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. Imatinib 600 mg PO daily or dasatinib 100 mg PO daily days 1-14 on course 1 and continuously (imatinib 600 mg PO or dasatinib 70 mg PO) daily starting day 1 after the first cycle in Philadelphia chromosome positive (Ph+) ALL.

Results: Thirty-one patients (16 men, 15 women) have been treated. Patient characteristic and response are described in Table 1. Median follow-up is 33 months (5-46) with a median cycle of 4 cycles (1-8). Median age is 53 years (range 19-80). Thirteen patients (42%) had CD-20 positive ALL, and 21 (68%) had Ph+ ALL. Thirty (97%) achieved complete remission (CR). Early death was observed in 1 patient (3%) with Ph+ ALL. Of 26 patients evaluable for response, 26 (100%) achieved complete cytogenetic response (3 patients, diploid at start; 1 patient, not performed), and 27 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable patients with Ph+ ALL, major molecular response was achieved in 19 patients (95%); complete molecular response in 14 (70%). Grade 3/4 toxicity ≥10% included infections in 28 (90%); hyperglycemia, 16 (52%); hypokalemia, 15 (48%); hypophosphatemia, 15 (45%); hypocalcemia, 10 (32%); DVT, 7 (23%); hyponatremia, 7 (23%); hypoalbuminemia, 6 (19%); peripheral neuropathy, 5 (16%); elevated ALT, 5 (16%); and acute kidney injury 4 (13%). All grade peripheral neuropathy was observed in 21 (68%). With a median follow-up of 33 months, 21 (68%) patients are alive. Ten (32%) patients died: 1, sepsis on C1D10; 4, unknown; 1, post-transplant complications; 4, relapse. The 2-year CR duration and survival rates were 83% and 68%, respectively (Figure 1).

Conclusions: Hyper-CMAD with liposomal vincristine is safe and shows high response and survival rates in patients with newly diagnosed ALL.

View largeDownload slide

View largeDownload slide

Close modal