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Introduction: Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE. Methods: Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21. Conclusion: This trial will answer several major questions in the treatment of Ph+ALL.

Here, we report a current trial from the German Multicenter ALL Study Group for Adult ALL (GMALL) which aims to answer several major questions in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL). The current standard of care (SoC) in younger patients with Ph+ALL is imatinib in combination with low-dose chemotherapy, change of tyrosine kinase inhibitor (TKI) in case of persistent BCR::ABL1-based minimal residual disease (MRD) measurement above 10−3 after consolidation I (CONS I), and indication for allogeneic stem cell transplantation (SCT) [1, 2]. The phase II, open-label, double-randomized trial is entitled “A Multicentre, Randomized Trial in Adults with de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia to Assess the Efficacy of Ponatinib versus Imatinib in Combination with Low-Intensity Chemotherapy, to Compare End of Therapy with Indication for Stem Cell Transplantation versus Tyrosine Kinase Inhibitor, Blinatumomab, and Chemotherapy in Optimal Responders, and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE).” The primary objective was to prove non-inferiority in the overall survival (OS) of patients with Ph+ALL and molecular complete remission (MolCR) treated with TKI, chemotherapy alternating with blinatumomab (blina) (TKI-chemo-blina) versus end of therapy (EOT) with indication for SCT. The key secondary objective was to compare the rate of MolCR after induction and first consolidation with chemo and ponatinib versus imatinib. Secondary objectives were to evaluate the MolCR rate after blina in patients with molecular failure (MolFail), the OS in subgroups in comparison with groups from previous GMALL trials, the safety and efficacy of the treatment elements and the quality of life, Patient-Reported Adverse Events, and comorbidities. The exploratory objectives were to evaluate the biological and prognostic meaning of MRD assessed by two different methods (BCR::ABL1 vs. IG/TCR-based MRD measurement), to analyse ABL1-tyrosine kinase domain mutation status, and to document and describe patients’ course after EOT including further treatment lines in SoC.

The EVOLVE trial aims to answer three current major questions in Ph+ALL treatment: firstly, use of ponatinib compared to imatinib both in combination with low-dose chemotherapy and CONS I (randomization I [RI]; see Fig. 1); secondly, in patients with MolCR (defined as undetectable BCR::ABL1 with ABL1 copies >10,000 copies and Ig/TCR negative measured with a sensitivity of at least 10−4) omit indication for SCT but continue therapy with TKI, chemotherapy [3], and blina [4, 5] as additional antileukemic compound (randomization II [RII]; see Fig. 1), with the option for later indication for SCT, e.g., in case of molecular relapse or non-tolerability of experimental therapy; and finally, in patients with a MolFail or MRD positivity after CONS I to omit the indication for a TKI change but give instead blina followed by EOT and indication for SCT (non-randomized). Therefore, the trial addresses the optimization of primary treatment, the assessment of MRD-based risk stratification, and the potential omission of SCT.

Fig. 1.

Overview of study design. Description of the trial design illustrating interventional and observational part of trial phase. RI, randomization I; CONS I, consolidation I; MolNE, molecular response not evaluable; MolFail, molecular failure; MolCR, molecular complete remission; RII, randomization II; blina I, blinatumomab I; C 2, consolidation II; blina II, blinatumomab II; C 3, consolidation 3; blina III, blinatumomab III; C 4, consolidation 4; EOT-Soc, end of therapy-standard of care; SCT*, stem cell transplantation.

Fig. 1.

Overview of study design. Description of the trial design illustrating interventional and observational part of trial phase. RI, randomization I; CONS I, consolidation I; MolNE, molecular response not evaluable; MolFail, molecular failure; MolCR, molecular complete remission; RII, randomization II; blina I, blinatumomab I; C 2, consolidation II; blina II, blinatumomab II; C 3, consolidation 3; blina III, blinatumomab III; C 4, consolidation 4; EOT-Soc, end of therapy-standard of care; SCT*, stem cell transplantation.

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Patients are stratified according to their response after CONS I: optimal responders with complete MolCR proceed to RII (see above), and suboptimal responders with MolFail or molecular response not evaluable proceed to rescue with TKI plus blina followed by EOT with indication for SCT. The described study scheme results in five treatment arms: (I) imatinib + low-dose chemotherapy induction and CONS I (standard arm of RI), (II) ponatinib + low-dose chemotherapy induction and CONS I (experimental arm of RI), (III) patients with MolCR: EOT with indication for SCT (standard arm of RII), (IV) patients with MolCR: no EOT with indication for SCT but continuation with imatinib/ponatinib (per RI), chemotherapy, and blina (experimental arm of RII), and (V) patients with MolFail/molecular response not evaluable: continuation with imatinib/ponatinib (per RI) and addition of blina followed by EOT with indication for SCT. In case of SCT, patients will be treated according to GMALL recommendations regarding conditioning regimen and conduction of SCT. Imatinib will be dosed at 600 mg QD, and ponatinib will be dosed with 45 mg QD with a consecutive dose reduction to 30 mg QD after induction. The chemotherapy cycles are designed analog to the scheme already described [6]. The trial consists of an interventional phase, an observational phase, and a follow-up phase. The observational phase consists of management according to SoC after EOT in all arms until end of study visit (week 130) or end of trial, whatever occurs earlier, and the follow-up phase includes collection of survival data at minimum up to month 18 (week 77) or end of trial. The trial was designed in collaboration with the patient organization (Deutsche Leukämie- & Lymphomhilfe) and aimed to involve patients directly through web-based questionnaires.

A selection of key inclusion and exclusion criteria is summarized in Table 1. The primary efficacy endpoint is OS in MolCR patients treated with TKI-chemo-blina versus (vs.) EOT with indication for SCT (SoC). The key secondary endpoint is MRD and ABL1-tyrosine kinase domain mutation status at week 11 (after CONS I). Further selected secondary endpoints are rate of MolCR after use of blina in MolFail patients, remission duration, disease-free survival, OS in subgroups versus historical comparator groups, mortality in CR in the different subgroups after RII and parameters of QoL, Patient-Reported Adverse Events, and comorbidities compared in treatment arms and with historical comparators. Assessment of safety includes incidence and severity of adverse events (AEs) and serious AEs according to CTC-AE [7]. Statistical analyses will be carried out regarding efficacy analysis including OS and MolCR rate for primary and key secondary endpoint.

Table 1.

Selection of inclusion and exclusion criteria

Key inclusion criteria (selection)Key exclusion criteria (selection)
- De novo Ph+ ALL - History of malignancy other than ALL diagnosed within 5 years prior to start of protocol-specified therapy with defined exceptions 
- Age ≥18–65 years - Any other concurrent disease interfering with study treatment 
- ECOG performance status ≤2 - Pregnant and nursing women 
- Normal QTcF interval ≤450 ms for males and ≤470 ms for females - Contraindications against the use of imatinib, ponatinib, chemotherapy, or blina 
 - Known impaired cardiac function, including LVEF <40%, complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bifascicular block, history of or presence of clinically significant ventricular or atrial tachyarrhythmias, clinically significant resting bradycardia, congenital long QT syndrome, myocardial infarction within 12 months prior to starting study treatment, other clinically significant heart diseases 
 - Symptomatic peripheral vascular disease, any history of ischaemic stroke or transient ischaemic attacks (TIAs), uncontrolled hyper-triglyceridemia 
Key inclusion criteria (selection)Key exclusion criteria (selection)
- De novo Ph+ ALL - History of malignancy other than ALL diagnosed within 5 years prior to start of protocol-specified therapy with defined exceptions 
- Age ≥18–65 years - Any other concurrent disease interfering with study treatment 
- ECOG performance status ≤2 - Pregnant and nursing women 
- Normal QTcF interval ≤450 ms for males and ≤470 ms for females - Contraindications against the use of imatinib, ponatinib, chemotherapy, or blina 
 - Known impaired cardiac function, including LVEF <40%, complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bifascicular block, history of or presence of clinically significant ventricular or atrial tachyarrhythmias, clinically significant resting bradycardia, congenital long QT syndrome, myocardial infarction within 12 months prior to starting study treatment, other clinically significant heart diseases 
 - Symptomatic peripheral vascular disease, any history of ischaemic stroke or transient ischaemic attacks (TIAs), uncontrolled hyper-triglyceridemia 

For the primary efficacy analysis, OS will be compared in all patients with MolCR using a non-inferiority log-rank test with α = 5% and non-inferiority margin Δ = 10%. Further safety analysis includes descriptive analysis of incidences of AE and serious AE in patients treated with ponatinib and imatinib, and mortality in CR in patients treated with TKI-chemo-blina versus SCT. Analyses regarding secondary endpoints are comparison of incidences and medians, Cox regression for multivariable analyses, descriptive analyses, Kaplan-Meier analyses (log-rank test). The recruitment period of the trial is scheduled for 54-month period, first patient-in to last patient-out is 72 months, and duration of the entire trial is 84 months. N = 220 patients are planned to be assessed for eligibility, n = 208 patients will be allocated to trial, and n = 208 patients are planned to be analysed. After recruitment of 100 patients, an interim analysis will address the feasibility and safety of ponatinib treatment in induction/CONS I. Up to 100 sites are planned to participate within the trial.

The proposed randomized EVOLVE trial contains a complex study plan with two randomizations and one stratification, which results in a number of 208 patients needed. Given the overall low incidence of Ph+ALL, a network like the GMALL study group is needed with 100 planned sites in order to fulfil this recruitment goal and to answer the important major questions in the treatment of Ph+ALL patients: is there a benefit for ponatinib in first-line Ph+ALL treatment? Is SCT omittable in optimal responders? Is there a role for using blina to rescue suboptimal responders?

This study protocol was reviewed and approved by “Ethikkommission Fachbereich Medizin,” Goethe University Hospital, Frankfurt/M, Germany, under the approval number 2022-876-AMG. Written informed consent will be obtained from all patients participating in this study.

F.L. received consultancy and honoraria from Bristol Myers Squibb, Incyte, and Celgene; and consultancy, honoraria, and research funding from Novartis. N.G. received honoraria (advisory boards, invited talks) from Incyte, Amgen, Novartis, and Pfizer; institutional funding from Incyte, Amgen, and Pfizer. H.P. is a member of advisory board of Incyte; received research funding from Incyte; and received travel support and honoraria from Incyte. M.B. is contracted to carry out research for Affimed, Amgen, and Regeneron and is a member of the advisory boards of Amgen and Incyte and the speaker bureaus of Amgen, Janssen, Pfizer, and Roche. E.H. reported grants from DZHK (Grant from German Federal Ministry of Education and Research). H.S. received honoraria from Novartis, Robert Bosch Gesellschaft für Medizinische Forschung, Gilead Sciences; and consulting or advisory role from Gilead Sciences, IKP Stuttgart (Robert Bosch Gesellschaft für Medizinische Forschung).

The trial is funded by the Bundesministerium für Bildung und Forschung (BMBF) under the Grant No. 01KG2121. The trial is supported by the following drug supply: ponatinib will be supplied by Incyte Pharmaceuticals, and blinatumomab will be supplied by Amgen Pharmaceuticals.

F.L., H.P., and N.G. wrote the manuscript. M.B., E.H., and H.S. reviewed the manuscript.

All data generated or analysed during this study will be included in further articles and reports. Further enquiries can be directed to the corresponding author.

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