Retrospective analysis of Philadelphia chromosome-positive acute lymphoblastic leukemia treated with allogeneic hematopoietic stem cell transplant versus chemotherapy combined with tyrosine kinase inhibitor

Th e prognosis of t(9;22), Philadelphia chromosome-positive, acute lymphoblastic leukemia (Ph ALL) is poor. Despite high complete response (CR) rates with intensive chemo- therapy (Cx) regimens, the response is only transient. Th is is attributed to the requirement for administering allogeneic hematopoietic stem cell transplant (HCT) (1). Concurrently, the prognosis is very poor for patients with no indications for transplant, particularly the elderly. Th e relatively recent introduction of the selective tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) for Cx has signifi cantly improved the prognosis of patients with Ph ALL (2,3), and has improved outcomes after allogeneic HCT (4,5). However, we are aware of only one report that compares prognosis between adult patients treated with intensive Cx followed by HCT and those treated with Cx alone (3). Th erefore, we retrospectively analyzed patients with Ph ALL treated with IM at our institution and compared treatment outcomes between HCT and Cx alone. Twenty-two patients with Ph ALL treated with IM- combined Cx in our institution from March 2002 to June 2011 were retrospectively evaluated. Patient characteristics are summarized in Table I. Twenty-one patients received intensive Cx according to the protocol of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxo- rubicin, dexamethasone) combined with IM (2) and one patient was treated with the Japan Adult Leukemia Study Group (JALSG) IM-combined regimen Ph ALL202 (3). All patients received IM at a dose of 600 mg orally per day. Patients aged more than 60 years were administered doses of cytotoxic agents reduced by 20 - 30%. Allogeneic HCT was administered to 13 patients (HCT cohort), and nine patients received Cx alone (Cx cohort). All patients in the HCT cohort received a transplant during their fi rst CR. IM or other TKI therapy was not administered after transplant. To quantify the levels of minor and major BCR - ABL mRNA transcripts (encoding p190 and p210 oncoproteins, respectively), real-time quantitative polymerase chain reac- tion (PCR) analysis was used to diagnose Ph ALL. Th e copy number of BCR - ABL mRNA transcripts was normalized to that of GAPDH (glyceraldehyde 3-phosphate dehydroge- nase) and converted to molecules/ μ g RNA. Th e detection threshold for quantifi cation was 50 copies/ μ g RNA, which corresponded to a minimal sensitivity of 10 5 (6). Survival of the patients was determined on 31 December 2012 and analyzed using the Kaplan - Meier method. Statistical tests for diff erences in survival were based on the log-rank test. Overall survival (OS) and event-free survival (EFS) were calculated from the date of diagnosis to the date of death by any cause or according to the last known date of follow-up, and to the date of hematological or molecu- lar relapse or death by any cause or the last known date of follow-up, respectively. Th e cumulative incidence of relapse and treatment-related mortality (TRM) were estimated after adjusting for the competing risk of patient death using Gray ' s method (7). Diff erences in variables were compared using independent t -tests. Fisher ' s exact test was performed when appropriate. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (Th e R Foundation for Statistical Computing, Vienna, Austria; version 1.6-3) (8). Despite a higher median age of the Cx cohort compared with the HCT cohort (60 vs. 39 years of age, p 0.001, Table I), there were no signifi cant diff erences between the progno- ses of the Cx and HCT cohorts (5-year OS, 50.8% vs. 48.4%, p 0.76 (Figure 1(A)), 5-year EFS 38.1% vs. 50.5%, p 0.97). We considered that allogeneic HCT should be given to those patients with Ph ALL who would tolerate it well, explaining the advanced median age in the Cx cohort. Th e 5-year prob- abilities of relapse for the Cx and HCT cohorts were 61.1% and 15.4% ( p 0.07, data not shown), respectively, and the 5-year probabilities of TRM were 0% and 34.1% for the Cx and HCT cohorts ( p 0.07, data not shown), respectively. Th ere were no signifi cant diff erences between white blood cell (WBC) counts and levels of BCR - ABL mRNA transcripts at diagnosis between both cohorts (Table I).