Update of the Hyper-CVAD and Imatinib Mesylate Regimen in Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

The intensive combination chemotherapy program hyper-CVAD in newly diagnosed Ph+ ALL yields complete remission (CR) rates of 90%, but remissions are brief with median CR duration of 16 months [Kantarjian et al, JCO 18:547, 2000]. The activity of the tyrosine kinase inhibitor imatinib given as a single agent in relapsed or refractory Ph+ ALL or chronic myelogenous leukemia in lymphoid blast phase was 20% [Druker et al, NEJM 344:1084, 2001]. A phase II trial of imatinib and hyper-CVAD was conducted in newly diagnosed Ph+ ALL. Imatinib was given 400 mg days 1–14 of each course of therapy (fractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate and ara-C). Preliminary results were published in the first 20 patients (pts) treated, with CR rates of 100% in the de novo group, and improvement of disease-free survival (DFS) compared with hyper-CVAD alone [Thomas et al, Blood 103:4396, 2004]. To date, 32 pts with Ph+ ALL have been treated from April 2001 to February 2004. Twenty-six patients had active disease, either untreated (n=21) or refractory (n=5) to one induction course without imatinib. Six pts were in CR at study entry after one induction course without imatinib mesylate. Median age was 48 years (range, 17–75); 59% were male. Five had CNS disease (16%). Twenty-five of 26 pts (96%) with active disease at study entry achieved CR (1 failed to meet platelet criteria for CR). Median days to response was 21 days. Two of 26 pts (8%) required 2 courses to achieve CR. Allogeneic stem cell transplant (SCT) was performed in 13 pts in CR within a median of 3 months from start of therapy (range, 1–12). After a median follow-up of 2 years (range, 4–36 months), 1 primary refractory pt relapsed at 12 mos (bcr-abl/abl RT-PCR ratio <.05 at 9 mos), 1 pt relapsed day 149 after matched related SCT despite negative nested PCR for bcr-abl, and 2 pts changed therapy after 5 mos for persistent marrow Ph+ metaphases without overt leukemia relapse. Five pts died in CR, 3 older pts related to comorbid conditions (2 were negative for bcr-abl by nested PCR) and 2 related to complications of allogeneic SCT. Molecular response rate (negative bone marrow RT-PCR for bcr-abl confirmed by nested PCR) was approximately 50% in 19 pts who did not undergo allogeneic SCT. Outcome appears better with the hyper-CVAD and imatinib regimen with 2-year DFS rates of 87% (all pts) compared with 28% for hyper-CVAD alone or 12% for VAD (p<.001). Unexpected toxicities related to the addition of imatinib mesylate were not observed. The hyper-CVAD and imatinib regimen with or without allogeneic SCT continues to appear promising with additional accrual and longer follow-up.