P355: favorable outcome of philadelphia-positive acute lymphoblastic leukemia with imatinib, dose-reduced induction followed by allogeneic stem cell transplantation –results from the gmall trial 08/13

Background: Phase II trials with 2nd or 3rd generation Tyrosine Kinase Inhibitors (TKI) with/without immunotherapy yield promising results in Ph+ ALL. However, Imatinib (IM) in combination with chemotherapy regimens of different intensities followed by allogeneic SCT is still the standard treatment for younger patients (pts) in many countries. Aims: GMALL Trial 08/2013 (NCT02881086) evaluates a concept with dose-reduced induction (ind) and intensive consolidation (CI) in combination with IM followed by SCT independent of MRD response in patients (pts) aged 18-55 years (yrs). Dose reduced conditioning (8 Gy TBI vs 12 Gy TBI) was recommended in pts older than 45 yrs. Methods: The 6 week ind included IM 600 mg/d together with low intensity chemotherapy (VCR, Dexa, PEG-ASP) and intrathecal prophylaxis. Bone marrow evaluation after 3 weeks separated ind I and II. Four doses of Rituximab were added if CD20 was >20%. C I (Dexa, VCR, HDMTX, HDAC, VP16) followed. Donor search was initiated in all pts at diagnosis. SCT was scheduled after C I; after an amendment, a TKI change was recommended if MRD >10-3 after CI. MRD was assessed by quantitative (RQ)-PCR of BCR::ABL in a central reference laboratory. Additional MRD assessment with IG/TR RQ-PCR was recommended. Results: 163 pts with a median age of 42 (18-55) yrs were evaluable. 64 (39%) pts had a WBC >=30,000/µL. CR rates after ind I, II and CI were 85%, 95% and 93%. Early death and failure rates were 5% and 1% after CI, respectively. Molecular complete remission (MolCR) rates, defined as PCR negativity for BCR::ABL1 transcripts with at least 10000 ABL1 copies, were 10% after ind I, 24% after ind II and 43% after CI. Low positive MRD (≤10-4) was observed in 8%, 19% and 20%, respectively, whereas the remaining pts experienced molecular failure (MolF) with MRD >10-4. 27/48 pts with MolF (59%) had MRD ≥10-3; 10/27 pts were switched to another TKI. Data are yet available from 8/10 pts. These pts. were switched to Dasatinib (n=7) or Ponatinib (n=1). Only 1/8 pts with available data had a molecular remission after 4 weeks of ponatinib. Overall survival (OS) at 1 yr was 82% and 74% at 3 yrs; remission duration (RD) was 92% and 89%, resp. OS at 3 yrs was 88%, 70% and 75% for pts aged 18-25, 26-45 and 46-55 yrs resp (p>0.05). WBC at diagnosis <> 30000/µL had no impact on 3y-OS of 73% vs 76% (p>0.05). 138 pts (85%) were transplanted in CR1 as scheduled after CI (Median time to SCT: 4 mo) with OS 86% and 81% at 1 and 3 yrs. OS was similar (86% vs 79% at 3 yrs, p>0.05) for matched sibling or matched unrelated SCT. The treatment-related mortality was 14%. OS after SCT was not impacted by status of BCR::ABL1 MRD after CI as defined above. Summary/Conclusion: Dose reduced induction including PEG-ASP in combination with IM was feasible and yielded high response rates leading to a molecular CR rate as high as 43% already after CI. A very high SCT realization rate (85%) was obtained at approximately 3 months from diagnosis likely contributing to the favorable overall outcome. It remains open to further trials whether BCR::ABL MRD at all has a prognostic impact in transplant-focused regimens. The role of alternative TKI and immunotherapies with the aim to reduce SCT indications will be evaluated in the upcoming GMALL EVOLVE trial. The trial was funded by Deutsche Krebshilfe.Keywords: Acute lymphoblastic leukemia, Treatment, Philadelphia chromosome