Imatinib 400mg Daily Combined with Vindesine and Dexamethasone As Induction and Maintenance Therapy for Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia

Imatinib combined with intensive chemotherapy protocol markedly has markedly improved the prognosis of patients with Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ALL), and has become the standard therapy for this disease. Based on experience from patients with chronic myelogenous leukemia in blast crisis or accelerated phase, this highly specific tyrosine kinase inhibitor was given 600mg or 800mg daily in most clinical trials. However, some pilot study and case report implied that either lower dose of imatinib or less intensive chemotherapy could also achieve a satisfying remission rate. We carried out this pilot study to testify whether a lower dose of imatinib and less intensive chemotherapy could generate similar outcome, especially for patient who are unwilling to or unsuitable for allogeneic hematopoietic stem cell transplantation.

Thirty six patients with de novo Ph+ALL were enrolled between Dec-2008 and Dec-2010. All patients received imatinib 400mg daily, vindesine 4 mg weekly and dexamethasone 10 mg/m²/day for 4 days per week as induction therapy. After complete remission, these patients received 3 courses chemotherapy of protocols adapted from China Acute Lymphocytic Leukemia Group (CALLG) as intensification. Those who were unwilling to receive or unsuitable for allo-HSCT received maintenance therapy with imatinib 400mg daily with chemotherapy by vindesine 4 mg on D1 and D11, dexamethasone 10mg/m²/day on D1-5 and D11-15 with or without interferon-α 3 million unit every other day. Patients over 55 year old skipped the intensification therapy. The maintenance chemotherapy was given once a month in the first year, once per 2 months in the second year, and once per 3 months in the third year. Sixteen cycles of intrathecal chemotherapy with cytarabine and dexamethasone +/− methotrexate was scheduled for central nervous system leukemia (CNSL) prophylaxis.

Thirty six patients were enrolled, and the median age of this group of patients was 33.5 years (shown in table 1). All but one patients (97.2%) achieved complete remission after 4 weeks of induction therapy. One patient was loss of follow-up and one patient quit from this study because of severe hepatic dysfunction thought to be caused by imatinib. Three patients (8.3%) died of infections (pneumonia or sepsis) within intensification cycles. Three (8.3%) patients received allo-HSCT either from a sibling or an unrelated donor at CR1 after 3–4 courses of intensification therapy. The median time of follow-up was 8 months. The median overall survival was were 22.1 (shown in figure 1A.). For patients who received imatinib and chemotherapy only, the median overall survival was 20.4 months (shown in figure 1B). Although there was no evidence for CNSL at diagnosis in all patient, four (11.1%) patients had CNS relapse and three died despite of regular CNSL prophylaxis.

In this pilot study, our data showed that imatinib combined with less intensive chemotherapy could also achieve a over 90% remission rate in patients with de novo Ph+ALL. With the short time of follow-up, the long term effect of this strategy on survival and relapse can not determined yet, and a prospective randomized study is warranted. With reduced chemotherapy intensity, a more intensive protocol for CNS prophylaxis or new generation of TKI (e.g. dasatinib) with higher blood-brain barrier permeability may be considered.

No relevant conflicts of interest to declare.