Pre-Emptive Tyrosine Kinase-Inhibitor Intervention Based On Bcr/Abl1 Monitoring In Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia After Allo-Hsct: Two Independent Observational Cohort Study

Relapse is a major cause of treatment-failure in persons with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) receiving an allogeneic hematopoietic cell transplant. There is controversy whether post-transplant tyrosine kinase-inhibitors (TKIs) reduces relapse risk. We evaluated a pre-emptive strategy in 103 subjects in a prospective study with prophylactic group as historical control. Subjects were tested for measurable residual disease (MRD) by assaying levels of BCRABL1 transcript. MRD was considered positive if the levels of BCRABL1 transcript were >=10-5. Subjects with positive MRD post-transplant received TKI-therapy. The chosen of TKIs was based on BCRABL1 mutation, and donor lymphocyte infusion (DLI) was recommended in those who were not responsive to TKIs. The primary endpoint was relapse (including hematological relapse and central nervous system relapse). Twenty-three of 103 subjects were MRD-positive post-transplant. Seven of whom had BCRABL1 mutations including T315I (N=5). Pre-emptive therapy resulted in 21 subjects being MRD-test negative. The overall 3-year cumulative incidence of relapse (CIR) post-transplantation was 11% (95% confidence interval [CI], 4, 17%) and 34% (22,1, 46.5%) in the pre-emptive and prophylactic maintain group (P=0.030). The 3-year cumulative survival and LFS post-transplants in the pre-emptive and prophylactic group were 87% (80, 94%) and 63% (51, 75%), and 83% (76, 91%) and 58% (46, 70%) (P=0.000 and P=0.000, respectively). The multivariate analysis showed that positive MRD pre-transplantation was the risk factor for relapse, LFS and survival [HRs=8.977(3.344, 24.096; P=0.000), HRs=4.763 (2.153, 10.538; P=0.000) and HRs=7.535 (2.977,19.071; P=0.000], while pre-emptive therapy was the protective factor for relapse, LFS and survival [HRs=0.176 (0.077, 0.339; P=0.000), HRs=0.222 (0.107, 0.462; P=0.000) and HRs=0.188 (0.082,0.43; P=0.000)]. Our data suggest a pre-emptive strategy based on MRD-test monitoring and mutation analyses might reduce CIR and improve survival after allotransplants for Ph+ALL (NCT 01883219).