Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia

Abstract

ABSTRACTconventional chemotherapy, we conducted a retrospective comparative study assessing the outcome of 473 adult patients with Ph + ALL who, between 2000 and 2010, underwent allo-SCT in CR1 with HLA-identical siblings or matched unrelated donors, with a special emphasis on the impact of TKIs. Methods Study design, data collection and selection criteriaPatients with Ph + ALL reported to the registry of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) were included in this study. For the purpose of this specific analysis, participating centers were requested to enroll consecutive Ph+ALL cases diagnosed between January 2000 and December 2010. The study aimed to include cases of Ph+ B-ALL receiving first allo-SCT from an HLA-identical sibling donor (MSD) or HLA-matched unrelated donor (at least 6/6 HLA matching) (MUD) who: i) were aged 18 years or over at time of transplant; ii) were in CR1; iii) were transplanted between 2000 and 2010; iv) received allogeneic unmanipulated bone marrow (BM) or peripheral blood stem cells (PBSC) as stem cell source; v) received a standard myeloablative conditioning (MAC) regimen or a reduced-intensity conditioning (RIC) regimen according to Bacigalupo's criteria; 28 and vi) whose complete clinical data and outcomes were available. A total of 473 allo-SCT recipients from 77 participating centers met these eligibility criteria. Institutional review board approval was obtained from all participating institutions. Minimal residual disease assessmentInvestigators were asked to provide minimal residual disease (MRD) data at time of transplant. As the most commonly accepted level of sensitivity for a given sample to be considered PCR negative is 10 -4 BCR/ABL copies, we distinguished two groups for the purpose of this analysis: a "low-risk" group with MRD ≤10 -4, and a "high-risk" group with a ratio >10 -4 . 29,30 Statistical analyses and definitionsThe primary end points were leukemia-free survival (LFS), relapse incidence (RI), and non-relapse mortality (NRM). Secondary end points were overall survival (OS), acute graft-versus-host disease (aGvHD) and chronic graft-versus-host-disease (cGvHD).Patient-related, disease-related, and transplant-related variables were compared between the 2 groups receiving or not TKI before transplantation using the χ 2 statistics for categorical variables and the Mann-Whitney test for continuous variables. Factors that differed significantly between the two groups with P values less than 0.05, and all factors associated with a P value less than 0.10 by univariate analysis were included in the final models. Cumulative incidence functions (CIF) were used to estimate RI and NRM in a competing risk setting, because death and relapse compete with each other. To study cGvHD, we considered relapse and death to be competing events. Probabilities of LFS and OS were calculated using Kaplan-Meier estimates. Univariate analyses were performed using Gray's test for CIF and the log rank test for LFS and OS. Association...

Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study

“…4 A retrospective analysis in the posttransplantation setting has shown that use of prophylactic TKIs is associated with a significantly lower incidence of relapse among patients with Ph 1 ALL. 5 However, relapse remains clinically challenging and is frequently associated with resistance substitutions in the ABL kinase domain, particularly within the threonine 315 residue (T315I). 6,7 Although alternative TKIs for salvage therapy may be effective in some patients, 8,9 remission is short.…”

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

“…Philadelphia chromosome positive (Ph+) ALL is the most common cytogenetic abnormality found in adults with ALL as it accounts for 25% of ALL cases in adulthood [71][72][73]. However, the prevalence of Ph+ ALL increases with age as follows: ˂ 5% in children, 12%-30% in patients between 18 and 35 years, 40%-44% in patients between 35 and 50 years, and ˃ 50% in patients > 60 years of age [71,[74][75][76].…”

“…The administration of TKIs before allogeneic HSCT has significantly improved the long-term outcome of allogeneic HSCT in patients with Ph+ ALL [76]. However, international multicenter studies with long-term follow-up are needed to determine whether consolidation followed by maintenance chemotherapy plus TKIs are equivalent to allogeneic HSCT from related or unrelated donors [74].…”

“…Although allogeneic HSCT is a potentially curative therapeutic modality, it has its own limitations and it requires availability of a healthy human leukocyte antigen (HLA) matching donor and it is associated with relatively high rates of relapse and non-relapse mortality [76]. Haploidentical allogeneic HSCT represents an alternative option for patients with Ph+ ALL who lack an HLA matching donor and its use has been associated with lower relapse rate [82].…”

“…Treatment of patients having Ph+ ALL includes: cytotoxic chemotherapy like other ALL subtypes, TKIs such as imatinib and dasatinib, and allogeneic HSCT particularly in adults [72,75,76]. Although allogeneic HSCT is a potentially curative therapeutic modality, it has its own limitations and it requires availability of a healthy human leukocyte antigen (HLA) matching donor and it is associated with relatively high rates of relapse and non-relapse mortality [76].…”