Outcome of Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) for Philadelphia Chromosome Acute Lymphoblastic Leukemia (Ph+ALL) in First Complete Remission (CR1) At the Era of Tyrosine Kinase Inhibitors (TKI): A Survey From the Acute Leukemia Working Party (ALWP) of EBMT,
Authors: Brissot Eolia , Labopin Myriam , Socié Gérard , Volin Liisa , Rambaldi Alessandro , Beelen Dietrich , Kroeger Nicolaus , Lenhoff Stig , Finke Jurgen , Esteve Jordi , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 4107
In the recent years, tyrosine kinase inhibitors (TKIs) emerged as major drugs as part of Ph+ALL treatment armamentarium. Indeed, treatment with TKIs may allow for increased rate of complete response (CR) and greater opportunity for patients to proceed to alloHSCT, which remains the only curative option in those eligible patients. The current survey from the ALWP of EBMT aimed to assess the outcome [overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM), and relapse incidence (RI)] of a cohort of 1041 Ph+ALL patients who received allo-HSCT in CR1 between 2000 and 2010 from an HLA-matched related or unrelated donor (HLA matching at least 6/6). The primary endpoint of the study was to assess the impact of the use of TKIs prior to alloHSCT considering the time period before and after 2007 when TKIs were made available in most EBMT centers for the treatment of adult Ph+ALL according to the European label extension for TKIs in adult Ph+ALL.
In this series, the median age as 42 y. (range, 18–73) and 58% were males. Median time from diagnosis to CR1 was 42 days and from diagnosis to alloHSCT 162 days. 552 patients (53%) received alloHSCT from an HLA-matched related donor, while 489 patients (47%) received an HLA-matched unrelated graft. Prior to alloHSCT, 869 patients (83%) underwent a myeloablative conditioning (MAC) regimen, while 172 (17%) received a reduced intensity conditioning (RIC) regimen. The MAC regimens included high-dose TBI in 719 cases (83%) and the RIC regimens included low-dose TBI in 47 cases (27%).
With a median follow-up of 20 months (range, 1–132) after alloHSCT, in the whole cohort, the 2-years OS and LFS were 54±2% and 42±2%, respectively. In multivariate analysis, NRM was significantly influenced by age>37 y. in the MAC subgroup (P<0.0001, HR=1.90, 95%CI, 1.40–2.57). No significant predictive factors for NRM were found in the RIC subgroup. On the other hand, multivariate analysis showed that the year of alloHSCT (≥2007) was a strong factor predictive of an improved LFS (P=0.001, HR=0.75, 95%, 0.63–0.89), while age>42 y. was associated with a lower LFS (P=0.001, HR=1.34, 95%CI, 1.12–1.6).
In the MAC alloHSCT subgroup, TBI and year of transplant ≥2007 were associated with significantly improved LFS (P=0.01, HR=0.75, 95%CI, 0.59–0.94; and P=0.005, HR=0.76, 95%CI, 0.62–0.92, respectively), while age>37 y. was a negative predictive factor for LFS (P=0.001, HR=1.38, 95%CI, 1.14–1.68). In the RIC alloHSCT subgroup, no significantly predictive factors were found for LFS.
When considering RI, multivariate analysis showed that the year of transplant ≥2007 was also associated with decreased relapse in both the MAC and RIC subgroups (P=0.003, HR=0.67, 95%CI, 0.51–0.88 and P=0.007, HR=0.50, 95%CI, 0.31–0.83, respectively). In the MAC subgroups, the use of TBI and an HLA-matched unrelated graft were found to be factors associated with decreased RI (P=0.008, HR=0.66, 95%CI, 0.48–0.90 and P=0.03, HR=0.75, 95%CI, 0.58–0.97, respectively).
In all, this large survey suggests that the introduction of TKIs after the year 2007 within European centers, has likely improved the outcome of adult Ph+ALL patients eligible for alloHSCT. Prospective evaluation are needed since further improvement would be expected in the next few years with the wider use of minimal residual disease assessment associated to TKI-based preemptive and/or maintenance strategies after alloHSCT.

Disclosures:
No relevant conflicts of interest to declare.