Outcomes in younger patients (pts) with Philadelphia-positive Acute Lymphoblastic Leukemia (Ph+ ALL) have improved by using tyrosine kinase inhibitors (TKI) and stem cell transplantation (SCT), but the optimal first-line TKI, the role of chemotherapy (CTX), antibody therapies and the value of SCT remain debatable. The German Multicenter Center Study Group for Adult ALL (GMALL) conducts a phase II trial EVOLVE (NCT06061094): Patients (pts) aged 18–65 years (y) are randomized to receive imatinib (Ima) or ponatinib (Pona) as frontline TKI (randomization I). Pts with molecular failure (Molfail) or intermediate measurable residual disease (MRD) after consolidation (C) I receive blinatumomab (Blina). Pts in molecular remission (MolCR) after C I are randomized to receive SCT or a Blina/CTX alternating regimen (randomization II) (Lang et al, Oncol Res Treat. 2024). Key points addressed are: efficacy of Ima vs Pona as frontline treatment, Blina in MolFail pts before SCT, SCT vs. Blina/CTX as consolidation. This is an independent study of the Goethe University, funded by the Bundesministerium für Bildung und Forschung (grant nr: KS2020-028) and supported by drug supply by Incyte and Amgen.

Therapy starts after prephase (Dexa, Cyclo) with induction (Ind) I/II (Dexa, VCR, ±Peg ASP), followed by C I (HDMTX, HDAraC, VND, Dexa). In pts randomized to the CTX/Blina arm further treatment includes C II (HDMTX, 6-MP, ±Peg ASP), reinduction (PND, VND, ±Peg ASP), and C III/IV (HDAraC, Cyclo, HDMTX, 6-MP, ±Peg ASP), with regular intrathecal prophylaxis and maintenance (6-MP/MTX). Blina is given in three alternating cycles with CTX. Pona starts at 45 mg, reduced to 30 mg after Ind II; Ima dosage is 600 mg; Blina is administered at standard dosing. 80 sites across Germany participate. MRD is centrally assessed using quantitative analysis of clonal IG/TR rearrangements and BCR::ABL1 transcripts. MolCR is defined as MRD negativity with a sensitivity of at least 10-4 or positive MRD below 10-4.

From 8/23 to 3/25 51 pts from 35 sites were included. Median age was 46 (19-63) y, 45% were aged 18-44 y, 19% were 45-54 y and 36% 55-65 y (male/female: 45%/55%). 69% had at least one comorbidity (defined by Sorror Score); 23% had ≥3. 23% were smokers and 23% suffered from any cardiac disease.

The hematologic CR rate after Ind I was 92% (no early death) and 100% before and after C I. The MolCR rate (combined MRD BCR::ABL1 and IG/TR) was 12% after Ind I, 40% after Ind II and 52% after C I. Combined MolCR rates after C I were 59% vs 33% in pts with p190 vs p210 breakpoint (p>.05). Interestingly, the MolCR rate was significantly higher regarding IG/TR only vs BCR::ABL1 at all timepoints (after C I MolCR rates IG/TR vs BCR::ABL1 95% vs 57% (p<.0001)). The rate of MRD-negativity after C I was 81% vs 29% respectively (p<.0001).

All pts with MolCR (52%) were randomized to proceed with SCT or experimental arm (CTX + Blina). All pts in MolFail (MRD positivity ≥10-4) /Intermediate (MRD positivity <10-4) (48%) were stratified to Blina plus SCT. Data on the impact of Blina in MolFail patients without change of TKI will be presented. The SCT realization rate was 83%.

With a median follow up of 8 (1-16) months, overall survival (OS) in the total cohort is 100%. The probability of continuous hematological remission is 100%, with a median remission duration (RD) of 5.8 months (range 0-16). Three pts experienced molecular relapse (two during standard therapy and one following SCT). To date, 38 serious adverse events (SAEs) have been reported, most commonly infections (n=19), followed by neurologic events (n=5), immune-related events (n=4), bleeding complications (n=3, including two subdural hematomas), gastrointestinal (n=3) and other causes (n=4: Blina interruption, pleural effusion, tachyarrhytmia, anorexia). No cardiovascular events occurred.

The excellent results in the EVOLVE trial underscore its relevance in the evolving treatment landscape of Ph+ ALL. The regimen demonstrated acceptable tolerability across a large multicenter cohort including pts of advanced age and with comorbidities. Notably, the pronounced differences in molecular response rates between the two MRD measurement methods, highlight the biological complexity of the disease and may inform refinement of MRD-based treatment guidance. The use of Blina in pts with Mol fail prior to SCT (no TKI switch) will provide insights into the additive benefit of immunotherapy in optimizing outcomes in this population.

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2025
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