Impact of Posttransplant Imatinib Administration on Philadelphia-Chromosome Positive Acute Lymphocytic Leukemia

Philadelphia-chromosome positive acute lymphocytic leukemia (Ph+ALL) is an intractable disease. After the development of imatinib, a tyrosine kinase inhibitor, the outcome of chemotherapy, especially remission induction rate, has been improved. Its long-term prognosis is, however, still poor, mainly because of high relapse rate, and therefore allogeneic stem cell transplantation (allo-SCT) is considered to be the only curative option. Recently, adopting the idea of minimal residual disease (MRD) in a treatment strategy of Ph+ALL as well as chronic myeloid leukemia (CML), it was reported that even in hematologically complete remission (CR), positive MRD at allo-SCT was a strong predictor for relapse after allo-SCT. Although it is ideal to perform allo-SCT in MRD-negative condition, it is sometimes difficult to achieve such treatment effect, despite the administration of imatinib. There are some reports dealing with posttransplant imatinib administration, but its efficacy and administration methods are still controversial. To evaluate the effect of posttransplant imatinib administration, we retrospectively analyzed 34 Ph+ALL patients who received allo-SCT at 7 transplant centers in Japan between January 1989 and September 2007. Study admission criteria were allo-SCT for the first time, non-manipulation and MRD positive at allo-SCT. Median age at allo-SCT was 40 years old, 18 patients were transplanted in hematological CR, 14 patients were transplanted from unrelated donors and 20 patients from relative donors. Seven out of 34 patients received posttransplant imatinib administration. We proposed two strategies for posttransplant imatinib administration. One was early administration, where imatinib was administered upon detecting MRD after allo-SCT. The other was prophylactic administration, where imatinib was administered as soon after allo-SCT as possible. Overall survival was significantly better in patients with posttransplant administration (29.6% in patients without posttransplant imatinib vs. 66.7% in those with posttransplant imatinib at 3 years, p=0.03). In contrst, there was no significant difference in event-free survival (EFS) between two groups (29.6% in patients without posttransplant imatinib vs. 0% in those with posttransplant imatinib at 3 years, p=0.29).(Figure) As for details of MRD in patients with posttransplant imatinib administration, the duration of negative MRD was 9 months, 6 months, and 2 months or more in the early administration group, while in the prophylactic administration group it was 29 months, 12 months, and 9 months or more. It seemed that the duration of negative MRD was longer in the prophylactic group, but in all patients whose observation periods were longer than 1 year, MRD became positive in both groups and this lead to hematological relapse. The fact that posttransplant imatinib administration, even prophylactic administration, was no significant effect on event-free survival revealed the limitation of imatinib administration after allo-SCT. Although it is a great thing to achieve longer duration of negative MRD, posttransplant imatinib administration could not be a fundamental solution for Ph+ALL patients whose MRD was positive at allo-SCT. Considering the cure for Ph+ALL, MRD at allo-SCT has a profound impact on long-term EFS and posttransplant intervention seems to have limitation. To achieve a fundamental solution, the key would be to achieve negative MRD at allo-SCT, for example, by using new drugs, like nilotinib, dasatinib and other secondgeneration tyrosine inhibitors in case imatinib was inadequate to achieve negative MRD. MRD-based strategy is essential for a cure of Ph+ALL.