BCR-ABL translocation as a favorable prognostic factor in elderly patients with acute lymphoblastic leukemia in the era of potent tyrosine kinase inhibitors

The clinical outcome of acute lymphoblastic leukemia (ALL) depends strongly on the dose-intensity of chemotherapy delivered. The importance of dose-intensity resulted in the establishment of pediatric-inspired regimens for the treatment of fit adults with ALL. ALL patients with the BCR-ABL translocation, the so-called Philadelphia chromosome-positive ALL (Ph+ ALL), form a distinct subgroup, accounting for 20-30% of the adult ALL population. Although the BCR-ABL translocation is a well-known adverse prognostic factor in ALL, treatment of Ph+ ALL has improved dramatically with the advent of tyrosine kinase inhibitors (TKI) targeting ABL kinase. Imatinib, nilotinib, dasatinib, and ponatinib have all shown promising efficacy in terms of increased complete remission achievement and prolonged relapse-free survival and overall survival in Ph+ ALL. Allogeneic stem cell transplantation (ASCT) remains the recommended consolidative treatment for fit Ph+ ALL patients, but recent evidence suggests that newer ABL TKI are capable of long-term disease control without ASCT in certain Ph+ ALL populations. Some reports have even suggested the possibility of using these secondand thirdgeneration TKI as the sole consolidation modality without cytotoxic chemotherapy. Epidemiologically, patients over 60 years of age account for a significant proportion of ALL patients. These elderly patients are often unfit for either dose-intensive chemotherapy or ASCT and their clinical outcomes have, therefore, been dismal. The increased incidence of BCR-ABL translocation with older age also contributes to the poor prognosis of elderly ALL patients. However, we conjectured that, with the introduction of potent TKI targeting ABL, the BCR-ABL translocation might not have a negative prognostic impact in elderly ALL. Considering that many elderly PhALL patients do not tolerate the cytotoxic chemotherapy required for effective tumor control, we supposed that the efficacy of ABL TKI and their combination with lowdose cytotoxic chemotherapy would result in better survival for elderly Ph+ ALL patients compared to their Phcounterparts. Through our study we confirmed our hypothesis and found that Ph chromosome positivity may actually be a better prognostic factor in elderly patients in the era of potent TKI. This study was a multicenter, retrospective, longitudinal cohort study of elderly patients (≥60 years) with de novo ALL recruited from 13 hospitals in Korea between January 2006 and December 2015. Overall 114 patients were identified and after exclusion of 11 with incomplete data, 103 cases were finally evaluated. Five patients in the Ph+ group did not receive a TKI (1 due to poor oral intake, 1 due to the patient’s refusal and 3 for unknown reasons), and they were excluded from the analyses. This study was conducted according to the Declaration of Helsinki and was approved by the institutional review boards of all the participating hospitals. We considered a patient to have Ph+ ALL if the translocation was found by at least one of three techniques: conventional cytogenetics, fluorescence in situ hybridization, or quantitative real-time polymerase chain reaction. Differences between groups were assessed using the Student t-test or one-way analysis of variance for continuous variables, and the Pearson chi-square test for categorical variables, as indicated. Complete remission was defined as less than 5% blasts in bone marrow, while relapse was defined by recurrence of a bone marrow blast count above 5% or extramedullary disease after a previously documented complete remission. The overall and relapse-free survival curves were estimated using the Kaplan-Meier method. Overall survival was defined as the time from ALL diagnosis to death, and relapse-free survival as the time from ALL diagnosis to relapse or death. If patients survived without progression, survival was censored on the latest date of follow-up. If the patient underwent ASCT, overall and relapse-free survival were censored at the time of transplantation. Univariate and multivariate proportional hazards regression models were used to identify independent risk factors for relapse-free survival and overall survival. Factors associated with ALL prognosis, including age, white blood cell count at diagnosis, Philadelphia chromosome status, ALL subtype, and induction regimen were included in multivariate analyses. All data were analyzed using the Statistical Package for the Social Sciences software (IBM® SPSS®Statistics, version 22.0). Of the 98 patients analyzed, 51 (52.0%) had PhALL and 47 (48.0%) had Ph+ ALL. There were no differences between the two groups with regards to age, sex distribution, performance status, and induction regimens (Table 1). Ph+ ALL patients had higher peripheral and bone marrow blast counts at diagnosis. MLL rearrangement status was available for 37 (72.5%) of the PhALL patients, and four (10.8%) were positive for the genetic