Results of Treatment with Tyrosine Kinase Inhibitors(TKIs) in Combination with Intensive Chemotherapy in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia(Ph+ALL)
Authors: Kyo Taiichi , Okatani Takeshi , Kyo Kouhei , Imanaka Ryouta , Itagaki Mitsuhiro , Katayama Yuuta , Iwato Koji , Asaoku Hideki 
Published: October 2019

Abstract
Abstract 1503
(Objective) The treatment outcome of patients with Ph+ ALL has significantly improved since the advent of TKIs such as imatinib and dasatinib. However, the long-term survival of these patients is not necessarily high when bone marrow transplantation (BMT) is not performed. The present study was aimed at developing an effective combination of a TKI and chemotherapy for long-term survival of patients with Ph+ ALL but ineligible for BMT. (Subjects and Methods) Forty-three consecutive patients (18 men, 25 women) with previously untreated Ph+ ALL who visited our hospital between June 2001 and February 2011 were treated. The age range was 13 to 84 years (median: 57), and 21 were 60 years or older. Measurement of BCR-ABL fusion transcript levels was performed immediately in these patients, and imatinib (IM) was started at 600 mg/body/day (given daily as a rule) as soon as the patient tested positive. A remission induction regimen (chemotherapy) used commonly in acute myeloblastic leukemia (AML) patients at our hospital was combined with TKIs in the first 14 patients. Another remission induction regimen often used in ALL patients at our hospital was then combined with TKIs in the subsequent 29 patients. The AML remission induction regimen used idarubicin (IDR) at 12 mg/m2 for 4 days, behenoyl-ara-C (BH-AC) at 350 mg/m2 for 10 days, and prednisolone (PSL) at 40 mg/body (P.O.) for 10 days. PSL was initially given at 100 mg/body (P.O.) and then gradually reduced in the ALL remission induction regimen. Vincristine (VCR) at 1.3 mg/m2 (Days 1, 8, 15, and 22), daunorubicin at 60 mg/m2 (Days 1, 2, and 3), cyclophosphamide at 1200 mg/m2 (Day 2), and L-asparaginase at 3000 μ/m2 (Days 11, 13, 16, 18, and 20) were administered. The remission induction therapies were given in a sterile room. Macrophage colony-stimulating factor was given for 7 days from Day 11 and granulocyte colony-simulating factor from Day 19. A post-remission therapy commonly administered to AML patients at our hospital was given after remission for 1 year (ASH, 2009, abstract, no. 1052). High-dose cytarabine (at 2 g/m2 BID for 5 days but at 1 g/m2 BID in patients aged 60 years or older) (HD-AC) and mitoxantrone (MIT) at 7 mg/m2 × 3 were initially administered after remission. Maintenance/consolidation therapy was given by alternating BH-AC at 350 mg/m2 × 4 + aclarubicin at 20 mg/body × 6 and BH-AC at 350 mg/m2 × 4 + IDR at 10 mg/m2 × 1 + VCR at 1.3 mg/m2 (each for 35 days). IM was given daily at 600 mg/day simultaneously with the post-remission therapy. Dasatinib was used in the post-remission therapy of 8 patients at 140 mg/day. All of the TKIs were given to patients for 3 years after completion of chemotherapy. (Results) Complete remission (CR) was achieved in 41/43 (95%). CR was achieved in 13 out of 14 (93%) patients treated with the AML regimen and 28 out of 29 (97%) treated with the ALL regimen. DIC occurred in 31/41 (76%) during remission induction therapy. The follow-ups of patients achieving CR lasted for 5 to 128 months (median: 24 months). Ten patients (aged 25 to 54 years [median: 37]) underwent BMT at first CR. Thirty-one patients (aged 13 to 84 years [median: 63]) were assigned to the chemotherapy group. The 10-year overall survival (OS) calculated by the Kaplan-Meier method was 57% for 41 patients who achieved CR, 66% for 20 patients younger than 60 years, and 49% for 21 patients aged 60 years or older. The OS was 80% for 10 patients who underwent BMT at first CR and 47% for 31 patients in the chemotherapy group. The 50% OS of the chemotherapy group was 36 months. The 10-year event-free survival (EFS) was 50% for patients who achieved CR, 80% for patients who underwent BMT at first CR, and 43% for the chemotherapy group. The 50% EFS of the chemotherapy group was 33 months. Fifteen patients have relapsed, and a new chromosomal aberration was observed at relapse in 11/13 (85%). (Discussion) The results of the present report indicate that BMT is the first choice for post-remission therapy of Ph+ ALL. Fifty percent of patients aged 60 years or older, who account for about half of the patients with Ph+ ALL, have achieved long-term survival with the prolonged TKI + chemotherapy used in the present report. Relapse was also rare among patients who received the combination and maintained CR for 3 years or longer. A combination of an appropriate TKI and a chemotherapy regimen as well as careful monitoring for complications is likely to further extend the survival of patients with Ph+ ALL.

Disclosures:
No relevant conflicts of interest to declare.