The Role of Dasatinib in Patients with Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL) and Chronic Myeloid Leukemia (CML) Relapsing after Stem Cell Transplantation (SCT).

Abstract

Patients (pts) with CML or Ph+ ALL relapsing after SCT have a poor prognosis and short survival. Dasatinib has shown significant efficacy in patients with Ph+ diseases after imatinib failure. We reviewed the outcome of patients who relapsed after allogeneic SCT and received dasatinib as salvage therapy. Eleven pts were treated (9 CML and 2 Ph+ ALL). The median age was 48 (15–67) and 9 were male. At the time of SCT, the two ALL pts were in CR, one in 1st CR (CR1) and one in 2nd CR (CR2). Of the CML pts, 4 were in chronic phase (CP), 2 in myeloid blast phase (MyBP), 2 in CR1 lymphoid blast phase (LyBP), and 1 in CR1 MyBP. Six pts received SCT from HLA-identical sibling donors and 5 had matched unrelated donors. Two pts had received a T-cell depleted graft and 1 pt had 3 allogeneic transplants prior to dasatinib therapy. The median time from SCT to relapse was 75 days (11–310 days) and median time from SCT to dasatinib was 267 (17 to 4408). All patients had failed prior high-dose imatinib therapy. Ten patients received imatinib prior to SCT and 4 pts achieved complete cytogenetic response (CCyR). At the time dasatinib was started, 5 CML pts were in MyBP, 2 in LyBP, 1 in accelerated phase (AP), and 1 in CP. Both ALL pts had relapsed disease. Ten pts were Ph+ in the bone marrow by cytogenetics (median 63% range 0% to 100%) and 9 had additional chromosomal abnormalities; 1 pt had diploid cytogenetics with detectable bcr/abl transcripts by RT-PCR. Bcr/Abl kinase domain mutations were investigated in 7 patients prior to dasatinib, and a mutation was identified in 4 (E3225G, E255G, G250E and F317L). The starting dose of dasatinib was 50 mg twice daily (BID) in 3 pts, 70 mg BID in 7 and 90mg once daily in one pt. Nine pts (82%) responded as follows: 3 pts achieved complete molecular remission (cMR), 1 CCyR, 2 a partial cytogenetic response (PCyR), 1 minor cytogenetic response (mCyR), 2 partial marrow response; and 2 pts had no response. Two pts had received nilontinib prior to dasatinib: 1 had a mCyR, and one CHR with no cytogenetic response. Three pts had PCR-based microsatellite polymorphism analysis performed after dasatinib therapy, and one pt had 100% donor myeloid and T cells. Two patients received nilontinib post dasatinib: 1 had no response with rapid disease progression and one achieved a CCyR but died of sepsis. All patients receiving dasatinib 70 mg PO BID had treatment interruptions or required dose reductions for gastrointestinal bleeding (3 patients), thrombocytopenia (3 patients), pulmonary complications (2 patients) and liver toxicity (one patient). In the 3 pts starting dasatinib at 50 mg PO BID, one had a dose escalation and the other two had short response durations and did not require dose modifications. At the time of this analysis, 6 pts have died, 3 are alive in cMR, and 2 are alive with disease. The three patients who achieved a cMR had relapsed ALL, CML in AP and MyBP and are alive 15, 17 and 18 months after start of dasatinib, respectively. The median overall survival from start of dasatinib was 381 days and median PFS was 118 days. In summary, despite the advanced stage of these patients at the start of therapy, these results show that dasatinib can induce durable complete remissions in patients with CML and Ph+ ALL who relapse after SCT with acceptable toxicity.