Update on GMALL Trial 08/2013 Shows Durable Favorable Outcome of Newly Diagnosed Adult Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) with Imatinib, Dose-Reduced Induction Followed By Stem Cell Transplantation

Background:

Phase II trials with 2nd- or 3nd-generation Tyrosine Kinase Inhibitors (TKI) with or without immunotherapy yield promising results in Ph+ ALL. However, Imatinib (IM) in combination with chemotherapy regimens of different intensity, followed by allogeneic SCT is still the standard treatment in younger patients with newly diagnosed Ph+ALL in many countries.

Aims:

GMALL Trial 08/2013 (NCT02881086), evaluated a concept with dose reduced induction and intensive consolidation in combination with imatinib followed by allogeneic SCT independent of MRD response in patients (pts) aged 18-55 years (yrs). Age-adapted TBI-based conditioning regimen was proposed in all patients (8 Gy TBI vs 12 Gy TBI).

Methods:

Patients received a 6 week induction phase with IM 600 mg/d together with low intensity chemotherapy (VCR, Dexa, PEG-ASP) and intrathecal chemo-prophylaxis. Four doses of Rituximab were added if CD20 expression of blasts was >20%. BM evaluation after 3 weeks separated induction I and II. Consolidation treatment (C1) with Dexa, VCR, HDMTX, HDAC, VP16 followed. Donor search was initiated in all pts at diagnosis. Allogeneic SCT was scheduled after the first consolidation. After an amendment a TKI change was recommended if the MRD value was above >10^-3 BCR::ABL1/ABL1 after C1. MRD was based on quantitative RT-PCR for BCR::ABL1, additional MRD assessment with IG/TCR PCR was recommended.

Results:

Between 09/2016 and 07/2022, 174 patients with a median age of 42 (18-55) years were recruited and evaluable. 70 (40%) patients had a WBC ≥30000/µl. Hematologic CR rates after induction I, II and consolidation I were 85%, 96% and 95%. Early death and failure rates after consolidation 1 were 4% and 1% respectively.

Molecular Remission (MolCR) was defined as PCR negativity for BCR::ABL1 transcripts with at least 10 000 ABL1 copies. The MolCR rate increased from 9% after induction 1 to 24% after induction 2 and was 42% after consolidation 1. Intermediate MRD positivity defined as BCR::ABL1/ABL1 below <10^-4 was observed in 9%, 18% and 21% resp. 38% of the patients were still MRD positive with quantitative MRD >10^-4 BCR::ABL1/ABL1 after the consolidation 1; 9 patients were switched to Dasatinib according to the recommendations after the amendment.

Overall survival (OS) at 3 years was 76%; remission duration at 3 years was 89% with a median follow up of 52 months. 3y-OS was 89%, 73% and 75% for patients aged 18-25, 26-45 and 46-55 years respectively (p>.05). WBC at diagnosis <> 30.000/µl showed no significant difference with 3y-OS of 76% vs 76% (p>.05). 159/174 pts were transplanted in CR1 (98% of CR pts). The median time to SCT was 4 months and the overall survival rate after 3 years was 81%. OS at 3 yrs was similar (79% vs 82%) for matched sibling or matched unrelated SCT. The treatment-related mortality after 3 years was 16% (15% for pts <45yrs and 16% for ≥45 yrs). OS after SCT was not impacted by status of BCR::ABL1 MRD after consolidation 1/before SCT as defined above. Results of IG/TCR MRD and IKZFplus profile will be available.

Summary:

Dose reduced induction including PEG-ASP in combination with IM was feasible and yielded high response rates leading to a molecular CR rate of 42% already after consolidation 1. The SCT realization rate (98%) was extremly high. In conclusion, this multicenter trial for younger patients with Ph+ ALL showed an excellent long term survival rate with imatinib combined with low-intensity chemotherapy followed by allogeneic SCT. It remains open to further trials to determine the prognostic role of BCR::ABL1 MRD in SCT-focused regimens. The role of alternative TKIs and immunotherapies with the goal to reduce SCT indications will be evaluated in the ongoing GMALL EVOLVE trial (NCT06061094).

The trial was funded by Deutsche Krebshilfe.