Novel Tyrosine Kinase Inhibitor Therapy Before Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia.

Background: A significant proportion of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for CML will have received a novel tyrosine kinase inhibitor (NTKI) after failing imatinib mesylate. It is unclear, however, if these drug will influence HSCT outcomes by changing the toxicity profile of transplantation.

Aims: To describe outcomes of patients that received a NTKI prior to HSCT.

Methods: We retrospectively analyzed the outcome of 30 patients (pts) with CML [8 chronic phase (CP), 9 accelerated phase (AP), and 13 in blastic phase (BP)] that were so treated. All pts failed imatinib, and then received a second TKI {dasatinib (n=14), nilotinib (n=13), bosutinib (n=3)}, or a third TKI {dasatinib (n=2), nilotinib (n=1), or INNO-406 (n=1)} prior to HSCT. Preparative regimens were intravenous busulfan-based in 24 pts and fludarabine and melphalan in 6. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate 5 mg/m2 on days 1, 3, 6, and 11 after HSCT. Donors were match related (MRD) in 12, match unrelated (MUD) in 14, haplo-identical in 1, 1-antigen mismatched related in 1, and unrelated cord blood in 2 cases.

Results: Median age at HSCT was 42 years (range, 22–63). The median time on NTKI treatment was 27 weeks (range, 2–86), and the median time from the end of NTKI therapy to HSCT was 10 weeks (range, 1–32). At the time of start of second TKI, 8 were in CP, 9 in AP, and 13 in BP. At the time of start of 3rd TKI, 2 were in AP, and 2 in BP. Twenty-one pts (70%) responded to 2nd TKI; this included: 2 partial hematologic response (PHR; 1 AP, 1 BP), 5 complete hematologic response (CHR; 2 CP, 3 BP), 5 minor cytogenetic response (minor cytogenetic response (mCyR): 1 CP, 2 AP, 2 BP), 2 partial cytogenetic response (PCyR; 1 CP, 1 AP), and 7 complete cytogenetic response (CCyR; 2 CP, 2 AP, 3 BP). Two pts responded to third TKI: 1 PHR and 1 CCyR. Eight of the responders (38%) maintained their response till the HSCT. At the time of HSCT, 9 pts were in CP, 8 were in second CP, 6 were in AP, and 7 in BP. Twenty-eight pts (93%) engrafted neutrophils within a median of 12 days (range, 5–20). Both pts with primary graft failure received cord blood transplants: one was rescued with autologous stem cells and the second received a haplo-identical transplant. Two pts had secondary graft failure 2 and 6 months from the first HSCT, respectively, and were rescued with a related 1-antigen mismatched donor transplant and same MUD transplant, respectively. Acute GVHD was observed in 19 pts (Grade I in 11, Grade II/III in 6, Grade IV in 2). Chronic GVHD was observed in 10 pts (extensive in 5). Of the 28 evaluable pts for response, 5 achieved a complete cytogenetic response (CCyR), 20 achieved a complete molecular response (CMR); 3 did not respond and had disease progression by day 30 post HSCT. Eight (4 CCyR, 4 CMR) patients relapsed within a median of 4 months (range, 3–7) from HSCT. After a median follow-up of 20 months (range, 5–44), 17 patients were alive: 12 in CMR, 2 in CCyR, and 3 with active disease; 13 patients died (2 and 8 within 3 and 12 mos post HSCT, respectively), 8 of disease progression, 4 of GVHD, and one of uncontrollable infection. The estimated 2-year survival was 51%.

Conclusion: Previous treatment with NTKI did not increase early transplant-related morbidity/mortality in this preliminary experience. These drugs may “downstage’ CML prior to HSCT, and this effect may be beneficial. Further follow-up and larger number of patients will be necessary to expand these observations.