Long-Term Outcome of 335 Adult Patients Receiving Different Schedules of Imatinib and Chemotherapy as Front-Line Treatment for Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
Authors: Pfeifer Heike , Goekbuget Nicola , Völp Christian , Hüttmann Andreas , Lübbert Michael , Stuhlmann Reingard , Dengler Julanta , Kreuzer Karl-Anton , Beck Joachim , Stelljes Matthias , Schmid Mathias , Wassmann B. , Leimer Lothar , Spiekermann Karsten , Terwey Theis H , Schäfer-Eckart K. , Ditz D. , Lindemann H. , Morgner A. , Schaich Markus , Burmeister Thomas , Binckebanck A. , Hoelzer Dieter , Ottmann Oliver G. 
Published: October 2019

Abstract
Abstract 173
Imatinib (IM) in combination with either of a variety of chemotherapy regimens has become the mainstay of front-line treatment for younger patients with Ph+ ALL, followed by allogeneic SCT as a curative treatment option. Complete remission (CR) rates generally exceed 90% and overall treatment outcomes have improved as judged on the basis of phase II trials, but there is a paucity of long-term outcome data obtained from a large group of prospectively evaluated patients. Moreover, the impact of different front-line IM schedules on the outcome of patients undergoing allogeneic stem cell transplantation in first CR (CR1) as opposed to non-transplanted patients has not been thoroughly evaluated. We previously reported the results of a GMALL study comparing two alternating and concurrent schedules of IM and chemotherapy in successive patient cohorts (A1 and A2, respectively)(Wassmann et al, Blood 2006;108:1469). In a subsequent cohort (A3), IM was started simultaneously with induction chemotherapy according to the GMALL protocol 07/03, i.e. immediately after confirmation of the presence of a Philadelphia chromosome and/or bcr-abl translocation and completion of prephase therapy.
We here report the long-term results of a prospective multicenter study of the GMALL study group including a total of 335 patients with newly diagnosed Ph+ ALL who received IM given at a single daily oral dose of 600 mg within 3 successive treatment cohorts. A1: IM administered between induction (IND) and first consolidation cycles (CONS1) and again after CONS1 (n=51); A2: IM given during the second half of IND and then continued throughout CONS1 until SCT (n=105); A3: IM initiated together with start of induction chemotherapy and continued throughout CONS1 until SCT (n=179). Minimal residual disease (MRD) was serially assessed by quantitative RT-PCR, mutational analyses was performed by D-HPLC and direct sequencing.
The median age of all patients was 43 years (17-65 y), 57 (17%) patients were 55 years of age or older, 147 (44%) male and 182 (56%) female. CR rates in cohorts A2 and A3 were 89,4% and 85.7%, induction deaths occurred in 5.8% and 11.3% of patients, treatment failure was observed in 4.8% and 3% of pts., respectively. Initial responses are not reported for cohort A1 as only pts. already in CR or PR were eligible for study entry at this stage of the trial. The molecular response rate based on PCR negativity for bcr-abl transcripts after CONS1 was superior in cohort A3 with 33% (26/79) as compared to 12.5% (5/40) and 4.2% (2/47) in cohorts A2 and A1, respectively (p=0.01). Overall treatment outcome improved with earlier initiation and more prolonged administration of IM in the three successive patient cohorts: Overall survival (OS) at 4 years was 31%, 40% and 50% in cohorts A1, A2 and A3, respectively. There was a trend towards lower rates of pre-transplant relapse or treatment discontinuation of patients in CR in cohort A3 (4% and 1.1%, respectively) compared to cohorts A2 (8.7% and 5.8%) or A1 (11.8% and 5.9%). To date, 219 patients (66.4%) underwent SCT in CR1 (A1: n=39; A2: n=74; A3: n=106), with a median age of 39.5 years. The 3 year probability of DFS of pts. in cohort A3 who received myeloablative conditioning regimens combining TBI with cyclophosphamide or etoposide was 72%. DFS was not significantly different between matched sibling and matched unrelated donor SCT. The incidence of relapse after SCT was substantially lower among patients in cohort A3 (11.3%) than those in A2 (24.3%) or A1 (30.8%). Similarly, there was a trend to lower non-relapse mortality after SCT in A3 (20.8%) compared to A2 (25.7%) or A1 (33.3%). For all pts. transplanted in CR1 irrespective of treatment cohort, median OS was 57% after 3 yrs. and 52% after 7 yrs. Patients who did not undergo SCT in CR1 had a dismal outcome, with a median OS of 9.4 months and 14% alive after 3 years.
In conclusion, earlier and more prolonged administration of IM in conjunction with chemotherapy is associated with superior treatment outcomes after SCT in newly diagnosed pts. with Ph+ ALL who are considered eligible for allogeneic SCT. SCT in CR1 remains the treatment of choice even in patients who achieve a good molecular response to initial therapy. Reducing induction as well as post-transplant mortality could have the greatest impact on further improving OS and DFS.

Disclosures:
Ottmann: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.