Allogeneic Transplantation for Ph+ Acute Lymphoblastic Leukemia (ALL): Impact of Conditioning Intensity, Tyrosine Kinase Inhibitors (TKI) and Minimal Residual Disease (MRD)

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for Ph+ ALL. Reduced intensity conditioning (RIC) has been explored to limit transplant related mortality (TRM) while allowing engraftment and the graft-versus- leukemia effect, perhaps enhanced by use of TKI and monitoring for MRD by cytogenetic and molecular techniques. Data on TKI and pre-transplant MRD on RIC HCT outcomes are lacking.

We analyzed 197 adults with Ph+ ALL in CR1 reported to CIBMTR between 2001-2009 and collected data on pre- and post-HCT TKI administration and pre-transplant MRD. Sixty-seven patients receiving RIC were matched with 130 myeloablative (MA) HCT recipients (matched for age, donor type and transplant year). Median age in RIC (54 years) was older than MA (50 years). The RIC group had more frequent pre-HCT fungal infections and a longer time from diagnosis to CR. The majority in both groups received TKI pre-transplant (RIC: 76% vs MA: 78%) while only 31% (RIC) and 17% (MA) received TKI post-transplant. Most patients had MRD monitored pre-HCT by cytogenetic testing (89%) or BCR/ABL PCR (64%).

TRM at 1 year was almost 3-fold lower following RIC compared to MA HCT (13% vs 36%; p<0.001). In contrast, the 3-yr relapse rate was higher after RIC HCT (49% vs 28%; p=0.058) resulting in similar 3 year overall survival (OS) and disease-free survival (DFS) following RIC and MA allograft (OS: 39% vs 35%, p=0.62; DFS: 26% vs 28%, p=0.75). In multivariate analysis, RIC was associated with 2 fold increased relapse risk, but had no significant impact on survival. Post-transplant TKI use and younger age (< 40 years) associated with significantly lower TRM and improved OS. Probability of grade II-IV acute GVHD was 30% and 47% in RIC and MA groups respectively (p=0.014), while conditioning intensity did not alter the incidence of chronic GVHD.

Pre-transplant TKI therapy might influence clearance of MRD pre-HCT and risk of relapse. Among 153 patients who received pre-HCT TKI, complete molecular and cytogenetic remission was 22% (RIC) and 26% (MA); similar to pre-HCT MRD status of patients without TKI (RIC 19%; MA 18%). Importantly, in adjusted multivariate analysis, positive BCR/ABL pre-HCT was strongly associated with increased relapse (HR 2.72; p=0.003) and use of pre-HCT TKI was associated with a 2-fold reduction in relapse (HR 0.49; p=0.003). MRD positivity or pre-transplant TKI had no significant influence on survival. 

In this matched case-control study, we demonstrated that RIC HCT yields similar survival of adults with Ph+ALL in CR1 compared to MA allografts. Importantly, relapse remains higher after RIC HCT. TKI administration prior to HCT can reduce the relapse to achieve the negative MRD status – which is the strongest predictor of leukemia recurrence. MRD reduction pre-allograft therefore remains the important target for future clinical trials, particularly for patients who are candidates for RIC HCT.