Imatinib Given Concurrently with Induction Chemotherapy Is Superior to Imatinib Subsequent to Induction and Consolidation in Newly Diagnosed Philadelphia-Positive Acute Lymphoblastic Leukemia (PH+ALL).
Authors: Ottmann Oliver G. , Wassmann Barbara , Pfeifer Heike , Goekbuget Nicola , Bug Gesine , Brueck Patrick , Binckebanck Anja , Gschaidmeier Harald , Hoelzer Dieter 
Published: October 2019

Abstract
Background and study design: Despite intensive chemotherapy (ChThx), preferably followed by allogeneic SCT, the prognosis of adult patients with Ph+ALL is poor. Adding Imatinib to first-line treatment may improve efficacy and outcome and reduce the occurrence of Imatinib-resistance. However, it has not yet been established how Imatinib is best incorporated in front-line treatment of Ph+ALL. In a prospective, multicenter study of the GMALL, we compared the safety, anti-leukemic efficacy and MRD response of two strategies in which Imatinib was incorporated either intercurrently between (cohort 1) or simultaneously with (cohort 2) induction and consolidation cycles. Cohort 1 patients had to have a CR after induction therapy, with persistance of minimal residual disease (MRD) by RT-PCR; in contrast, patients in cohort 2 received Imatinib simultaneously with the 2nd phase of induction irrespective of remission status, with continuation of Imatinib for up to 8 weeks after the first consolidation cycle. Results: Cohort 1 encompasses 48 pts. (median age 47 y, range: 24–72), 46 of whom were in CR and 2 in PR upon starting Imatinib at 400 mg/d (n=36) or 600 mg (n=12). Imatinib was initiated 18 (5–52) days after completion of induction and given for a median of 28 (13–176) days. No patient relapsed during post-induction Imatinib, three pts. relapsed prior to SCT and one death occurred in CR after consolidation therapy due to septicaemia. Hematologic and non-hematologic toxicities were limited to WHO grades I/II. Cohort 2 encompasses 46 pts. (median age 39 y, range: 19–62) enrolled to date; 58% (19/33) had achieved a CR prior to initiation of Imatinib after induction phase I, a PR or non-response was documented in 18% and 24%, respectively. After completion of induction phase II concurrent with Imatinib, 96% (23/24 evaluable) had achieved a CR, one pt. (4%) failed and died. Comparison of median bcr/abl transcripts prior to and after induction II showed no significant decrease in cohort I (ChThx alone) in contrast to a 1.4 log reduction in cohort 2 (ChThx+Imatinib). Comparison of bcr/abl transcripts prior to consolidation I with pre-induction II levels showed a 3.9 log reduction in cohort 2 versus a 1.5 log reduction in cohort 1. Moreover, the frequency with which bcr/abl transcripts became undetectable by RT-PCR prior to consolidation I increased from 10% in cohort 1 to 50% in cohort 2. The duration of grade III/IV thrombocytopenia and neutropenia in cohort 2 was 12 (3–57) days and 16 (3–47) days, respectively, with cytopenias and/or infectious complications entailing Imatinib dose reductions in 40% and interruption of Imatinib in 77% of pts. The most frequent grade III/IV non-hematologic toxicity was hepatic (43% of evaluable pts.). There were no treatment related deaths. Summary: Imatinib given concurrently with and subsequent to induction and consolidation is highly effective first-line treatment for adult Ph+ALL, with a CR rate exceeding 90% and 50% MRD negativity. This strategy is more effective than alternating chemotherapy and Imatinib cycles, but is accompanied by substantial hematologic and non-hematologic toxicity. The overall impact on long-term survival in this very high risk group or patients remains to be determined, particularly in light of subsequent allogeneic SCT in a large proportion of patients.