A Phase II Study of Methotrexate (M), Vincristine (O), Pegylated L-Asparaginase (pA), and Dexamethasone (MOpAD) in Patients with Relapsed and/or Refractory Acute Lymphoblastic Leukemia (ALL)

Adults with relapsed or refractory (R/R) ALL have a poor prognosis, with low rates of complete remission (CR) to standard salvage therapy and long term survival of less than 5%. L-asparaginase has a unique mechanism of action and is highly active in ALL, but its use in adults has been limited by concerns for side effects. A new pegylated (peg) preparation bestows a longer half-life, less immunogenicity, and better tolerance. Additionally L-asparaginase has a significant synergy when combined with methotrexate in schedule-dependent manner.

Patients with previously treated, R/R ALL (including Burkitt's and Philadelphia [Ph] positive) with adequate organ function, and PS ≤ 3 were enrolled on a phase II clinical trial to determine the efficacy and safety of MOpAD. Patients were stratified in two groups: 1^st salvage or³ 2^nd salvage. They were treated on the following schedule: methotrexate 200 mg/m²/d IV on days 1 & 15; vincristine 1.4 mg/m²/d (max 2 mg) IV on days 1,8, & 15; peg-asparaginase 2500 IU/m²/d on days 2 and 16; and dexamethasone 40 mg IV or PO daily on days 1–4 and 15–18. Patients with CD20+ ALL could receive rituximab 375 mg/m²/d IV on days 1 & 15 for the first 4 cycles (1 cycle=28 d). A later amendment allowed patients with Ph+ ALL to also receive daily imatinib, dasatinib, or nilotinib in conjunction with MOAD.

A total of 27 patients (37% female) with R/R ALL have been enrolled thus far, with a median age of 41 (range, 24–68) and median PS of 1 (0–3). Eighteen pts (67%) had B-ALL (including 6 with Ph+ ALL), and 9 (33%) had T-ALL. The median number of prior therapies is 2 (1–6), and the breakdown by salvage is as follows: 1^st salvage: 10 (37%); ≥ 2^nd salvage: 17 (63%). 5 pts received rituximab, and 2 of 6 Ph+ pts received a tyrosine kinase inhibitor (TKI) (1 each of dasatinib and nilotinib). The overall response rate (ORR) was (12/27) 44%, with 8 CR (30%), 1 CRi (4%), and 3 CRp (11%). The ORR by salvage status was 25% in 1^st salvage and 47% in ≥ 2^nd salvage. The ORR by phenotype: Ph(−) B-ALL: 17%, Ph+ B-ALL: 67%, and T-ALL: 67%. All 6 patients (100%) with T-ALL who responded were able to go on to stem cell transplant. Response predicted for improved OS: median 9 months vs. 1 month in responders vs. non-responders. The most common grade 3/4 adverse events included low fibrinogen (44%), elevated bilirubin (37%), transaminitis (26%), elevated amylase/lipase without pancreatitis (15%), and thrombosis (11%). Side effects were manageable overall, myelosuppression was universal, and there were 3 early deaths (11%).

The non-anthracycline-based combination of MOpAD is a safe and effective salvage regimen in adult patients with relapsed ALL, particularly those with T-ALL or Ph+ disease. The chemotherapy backbone can be combined safely with rituximab and TKIs in this setting. Patients continue to be enrolled and updated results will be presented.

Kadia:GSK: Research Funding. Borthakur:Sigma Tau: Research Funding.