Factors Associated with Relapse-Free Survival in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Imatinib-Combined Chemotherapy.
Authors: Yanada Masamitsu , Takeuchi Jin , Sugiura Isamu , Akiyama Hideki , Usui Noriko , Yagasaki Fumiharu , Nishii Kazuhiro , Ueda Yasunori , Takeuchi Makoto , Miyawaki Shuichi , Maruta Atsuo , Narimatsu Hiroto , Miyazaki Yasushi , Ohtake Shigeki , Jinnai Itsuro , Matsuo Keitaro , Naoe Tomoki , Ohno Ryuzo 
Published: October 2019

Abstract
Imatinib-combined chemotherapy is highly effective for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, a substantial proportion of patients experience relapse. Here, we evaluated 80 patients enrolled in the phase II study by the Japan Adult Leukemia Study Group (JALSG) with extended follow-up with the aim of identifying factors associated with relapse-free survival (RFS). For remission induction therapy, imatinib was administered from day 8 to day 63 in combination with daunorubicin, cyclophosphamide, vincristine (VCR) and prednisolone (PSL). Consolidation therapy consisted of an odd course (C1) comprising high-dose methotrexate (MTX), high-dose cytarabine (Ara-C) and methylprednisolone, and an even course (C2) with single-agent imatinib for 28 days. C1 and C2 were alternated for 4 cycles each. After completion of the consolidation therapy, patients received maintenance therapy consisting of VCR, PSL and imatinib up to 2 years from the date they had attained complete remission (CR). The daily dose of imatinib used in this study was 600 mg. The protocol was reviewed and approved by the institutional review board of each of the participating centers and was conducted in accordance with the Declaration of Helsinki. A total of 80 patients aged between 15 and 63 years were recruited between September 2002 and January 2005. For a median follow-up of 26.7 months (maximum, 52.5 months), 28 of the 77 CR patients showed relapse. Of the 17 relapses observed during the consolidation therapy, 13 occurred during the imatinib course. The probability of RFS was 50.5% at 2 years. Allogeneic transplantation was performed for 60 patients, including 44 in first CR, 12 in second CR, and 12 in non-CR. Neither transcript types nor copy numbers at diagnosis were associated with RFS (p=0.763 and 0.912). Furthermore, RFS for those with an undetectable BCR-ABL level at the end of induction therapy was similar to that for the other CR patients (p=0.707). In contrast, the presence of secondary chromosome aberrations in addition to t(9;22) or variant translocations detected at diagnosis, particularly +der(22)t(9;22) and abn(9p), was significantly associated with inferior RFS (p=0.003). Multivariate analysis revealed that the presence of additional chromosome aberrations was the only significant prognostic factor for RFS (HR, 2.84; 95% CI, 1.12–7.19; p=0.027). Even after allogeneic HSCT, patients with additional aberrations appeared to have a trend for shorter RFS than those without (p=0.080), but this might reflect a larger proportion of transplantation beyond first CR in the former (31% vs 17%). Although these results need to be validated in the context of the ABL kinase domain mutations, our findings may be of clinical importance for the future treatment of Ph+ ALL.