Successful bridging to cell therapy for relapsed/refractory acute lymphoblastic leukaemia with a combination of venetoclax and PEG‐asparaginase

Relapse is still the main cause of treatment failure in adult patients with acute lymphoblastic leukaemia (ALL). A cure for relapsed/refractory (R/R) patients can be obtained only with cell therapy, including allogeneic haematopoietic stem cell transplantation (allo-HSCT) and CAR-T cell therapies for B-ALL. Therapies beyond the second line yield a 10%–20% response rate.1 However, bridging these heavily pretreated patients to cell therapy requires at least transient disease stabilization for CAR-T-cell therapy and complete remission for allo-HSCT, both of which remain challenging. Several studies have highlighted the in vitro efficacy of venetoclax (VEN) in experimental models, which are dependent on BCL2 and BCL-XL for survival.2-4 Synergy has been found between VEN and dexamethasone (DEX), vincristine (VCR), cytarabine and dasatinib in ALL cell lines and xenografts.4 However, few clinical data are available thus far for adult patients with R/R and heavily pretreated ALL. Here, we report the cases of eight patients with R/R ALL treated with a combination of VEN and a PEG-asparaginase (PEG-ASP). The treatment was based on 28-day cycles of VEN 400 to 800 mg daily, DEX 20 mg once daily from Days 1 to 4 and 15 to 18, PEG-ASP 2500 IU/m2 intravenously on Days 2 and 16 and weekly 1.4 mg/m2 VCR. Bone marrow (BM) evaluation was performed between Days 28 and 35 after each cycle. All patients received this VEN/PEG-ASP-based combination on a compassionate basis after receiving counselling about the unapproved nature of the treatment and obtaining verbal consent. Patients were considered for VEN/PEG-ASP only if they had run out of every standard of care option and available early access compassionate program option in France. Informed consent for data collection was obtained in accordance with the principles of the Declaration of Helsinki and the study was approved by the IRB at the Lille Hospital Tumour Bank (certification NF 96900-2014/65453-1). The patient and disease characteristics are shown in Table 1. The median age was 33 years, every patient was heavily pretreated with a median of 4 prior lines of therapy, and 6 of the patients had also received allo-HSCT or CAR-T. When possible, fungal prophylaxis was not given to allow full-dose VEN except for patient 4, who had invasive pulmonary aspergillosis, and patient 5, who was on corticosteroids for acute graft-versus-host disease. Patients 3 and 7 received only 16 days of VEN during the first cycle. Patient 3 had severe coagulopathy before treatment, which was controlled on Day 7. Therefore, DEX was discontinued on Day 4, and VEN was discontinued on Day 16 to avoid excessive lymphopenia and allow leukapheresis to proceed for CAR-T cell production. Patient 7 also received only 16 days of VEN to proceed to leukapheresis. Leukapheresis and CAR-T-cell production were successfully performed for both patients, who then received a second cycle of VEN/PEG-ASP as bridging therapy to CAR-T-cell infusion. GRAAL14; Blina Six patients (75%) achieved complete remission (CR) after one VEN/PEG-ASP cycle and were successfully bridged to cell therapy (second allo-HSCT or donor lymphocyte infusion for three patients and CD19 CAR-T cell therapy for three patients). PET scans were also performed for patients 2 and 5 because of extramedullary relapse and confirmed metabolic remission. Three of the six responders were positive for minimal residual disease after cycle 1. The median number of cycles before allo-HSCT or CAR-T cell therapy was two. Among the responders, three patients ultimately relapsed, and three patients remained in CR. The toxicity of the VEN/PEG-ASP regimen appeared manageable. Mild tumour lysis was observed in every patient during the first week. The most common toxicities were grade 3–4 cytopenia (Table 2). The prolonged cytopenia in patients 4 and 6 was related to treatment failure and to CMV therapy with valganciclovir before starting VEN-PEG-ASP in patient 1. CMV therapy was needed again in cycle 3 and may have contributed to graft dysfunction, leading to prolonged cytopenia and life-threatening infections. Only two patients needed hospitalization after cycle 1: patient 1 experienced febrile neutropenia after 3 cycles, leading to the discontinuation of all chemotherapy, and patient 5 experienced pneumonia. VCR was not used for patient 2 due to peripheral neuropathy sequelae and was discontinued after one cycle in patients 1 and 7 (grade 3 peripheral neuropathy), patient 5 (subocclusive syndrome) and patient 6 (occlusive syndrome). One patient developed grade 3 pancreatitis in cycle 4. The prognosis of patients with R/R ALL is poor, with prolonged survival depending on the possibility of undergoing cell therapy.5-7 To the best of our knowledge, this is the largest real-life cohort of heavily pretreated R/R ALL patients receiving a VEN and PEG-ASP combination as salvage and bridging therapy. The response rate in this cohort was similar to those previously reported for other VEN-based combinations, mostly with intensive chemotherapy but with milder toxicities.8-10 However, MRD was still detectable in three of the patients among six responders, suggesting that responses are unlikely to last. Carpentier and colleagues reported the cases of 13 patients treated with VEN combined with various agents.10 The response rate was similar to that reported in this study (60%), but the median relapse-free survival was 4 months. These data suggest that therapeutic combination regimens including VEN may be most useful as bridges to cell therapy. VEN and PEG-ASP both target cell metabolism. Asparaginases have been shown to deplete the extracellular medium not only of asparagine but also of glutamine and therefore affect mitochondrial metabolism.11 Glutamine depletion is able to overcome BCL2-mediated resistance to apoptosis. VEN not only induces apoptosis through BCL2 inhibition but also modulates mitochondrial metabolism, possibly in leukaemia stem cells.12 Thus, there is a strong biological rationale to investigate such a combination in clinical trials. In summary, the results from this small cohort of VEN/PEG-ASP-treated patients show that this regimen is effective, with manageable toxicity, in heavily pretreated R/R ALL and could represent a last-line option as a bridge to cell therapy. The activity of these drugs targeting cell metabolism deserves further mechanistic and clinical investigations. Laure Goursaud: investigation, writing. Celine Berthon: investigation. Bruno Quesnel: investigation, writing, review and editing, supervision and conceptualization. This work has been supported by Institut pour la Recherche sur le Cancer de Lille. None.