Venetoclax-based treatment in adult relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma: a single-center real-world experience

Year 2026, Volume: 9 Issue: 1, 140 - 146, 05.01.2026

Süreyya Yiğit Kaya , Senem Maral , Amir Hossein Abedi , Hüseyin Saffet Beköz , Leylagül Kaynar

https://doi.org/10.32322/jhsm.1825832

Abstract

Aims: Relapsed/refractory (R/R) acute lymphoblastic leukemia and lymphoblastic lymphoma (ALL/LBL) remain clinically challenging entities with limited effective salvage options, particularly in T-cell and early T-cell precursor (ETP) subtypes. Venetoclax has shown encouraging activity in preclinical and early clinical studies; however, real-world data are still scarce. This study aimed to evaluate venetoclax-based regimens in adult patients with R/R ALL/LBL treated at a single-center.
Methods: This retrospective analysis included 13 adults with R/R ALL/LBL who received venetoclax-based therapy between 2019 and 2025. Clinical characteristics, prior treatments, cytogenetics, venetoclax dosing schedules, treatment combinations, response rates and survival outcomes were extracted from institutional records. Responses were assessed using bone marrow evaluation, multiparameter flow cytometry for measurable residual disease (MRD) and PET-CT for extramedullary disease. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier analysis.
Results: The median age was 30 years, and most patients had T-ALL/LBL (61.5%), including two with ETP-ALL/LBL. Patients were heavily pretreated (median 3 prior lines); 38.5% had relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Venetoclax was administered with various backbones, most commonly FLAG (46.2%) or nelarabine/asparaginase (23.1%). Venetoclax treatment duration ranged from 7–28 days per cycle, with shorter schedules frequently used in individualized regimens. The overall CR/CRi rate was 84.6%, including 38.5% MRD-negative CR. Complete metabolic response (CMR) was achieved in 3 patients with extramedullary disease. Both patients with ETP-ALL/LBL achieved deep responses (CMR or MRD negative CR), aligning with the biological venetoclax sensitivity of this subtype. Following venetoclax-based therapy, 7 patients (53.8%) proceeded to allo-HSCT. Median OS was 7 months and median PFS was 5 months, comparable to previously published real-world series. Toxicities were manageable; although Grade ≥3 cytopenias were universal, prolonged cytopenias were infrequent with 7-14-day venetoclax courses. Infectious complications included febrile neutropenia (84.6%), mucormycosis (7.7%) and invasive aspergillosis (7.7%). No patient discontinued therapy due to toxicity.
Conclusion: Venetoclax-based regimens demonstrated substantial activity in a young, heavily pretreated R/R ALL/LBL population, yielding high CR/CRi rates, MRD-negative remissions and successful transition to allo-HSCT in over half of patients. Efficacy in the ETP-ALL/LBL subgroup and manageable toxicity with shorter venetoclax schedules highlight the practicality of individualized real-world use. These findings support venetoclax-based combinations as a promising salvage and bridging strategy in R/R ALL/LBL, warranting further prospective evaluation.

Keywords

Venetoclax , acute lymphoblastic leukemia , lymphoblastic lymphoma , relapsed and refractory , hematopoietic stem cell transplantation

Relaps/refrakter akut lenfoblastik lösemi ve lenfoblastik lenfomada venetoklaks temelli tedavi: tek merkez gerçek yaşam deneyimi

Abstract

Özet
Amaç: Relaps/refrakter (R/R) akut lenfoblastik lösemi ve lenfoblastik lenfoma (ALL/LBL), özellikle T-hücreli ve erken T-hücre prekürsörlü (ETP) alt tiplerde sınırlı etkili kurtarma seçenekleri nedeniyle önemli bir klinik zorluk olmaya devam etmektedir. Venetoklaks, preklinik ve erken klinik çalışmalarda umut verici bir aktivite göstermiş olsa da gerçek yaşam verileri hâlâ sınırlıdır. Bu çalışma, tek merkezde tedavi edilen R/R ALL/LBL’li erişkin hastalarda venetoklaks temelli rejimlerin etkinliğini değerlendirmeyi amaçlamıştır.

Yöntemler: Bu retrospektif analiz, 2019–2025 yılları arasında venetoklaks temelli tedavi alan 13 R/R ALL/LBL’li erişkin hastayı içermektedir. Klinik özellikler, önceki tedaviler, sitogenetik veriler, venetoklaks dozlama şemaları, tedavi kombinasyonları, yanıt oranları ve sağkalım sonuçları kurum kayıtlarından elde edilmiştir. Yanıtlar kemik iliği değerlendirmesi, ölçülebilir kalıntı hastalık (ÖKH) için çok parametreli akım sitometrisi ve ekstramedüller hastalık için PET-BT ile değerlendirilmiştir. Genel sağkalım ve progresyonsuz sağkalım Kaplan–Meier analizi ile hesaplanmıştır.

Bulgular: Medyan yaş 30 olup hastaların çoğu T-ALL/LBL’di (%61,5); bunların ikisi ETP-ALL/LBL idi. Hastalar yoğun şekilde ön tedavi almıştı (medyan 3 basamak); %38,5’i allojenik hematopoietik kök hücre nakli (allo-HKHN) sonrası relaps olmuştu. Venetoklaks çeşitli tedavi omurgalarıyla birlikte uygulanmış olup en sık FLAG (%46,2) veya nelarabin/asparaginaz (%23,1) ile kombine edilmiştir. Venetoklaks tedavi süresi kür başına 7–28 gün arasında değişmiş, bireyselleştirilmiş şemalarda daha kısa uygulamalar tercih edilmiştir. Genel tam yanıt/tam yanıt-hematolojik iyileşme olmaksızın (TY/TYi) oranı %84,6 olup bunun %38,5’i ÖKH-negatif tam yanıttı. Ekstramedüller hastalığı olan üç hastada tam metabolik yanıt (TMY) elde edilmiştir. ETP-ALL/LBL’li her iki hasta da derin yanıt (TMY veya ÖKH-negatif TY) almış olup bu durum bu alt tipteki venetoklaks duyarlılığı ile uyumludur. Venetoklaks temelli tedavi sonrası 7 hasta (%53,8) allo-HKNH’ye ilerlemiştir. Medyan genel sağ kalım 7 ay, medyan progresyonsuz sağ kalım 5 ay olup literatürdeki diğer gerçek yaşam serileri ile benzerdir. Toksisiteler yönetilebilir düzeydeydi; her ne kadar ≥ derece 3 sitopeniler yaygın olsa da 7–14 günlük venetoklaks uygulamalarında uzamış sitopeni nadirdi. Enfeksiyöz komplikasyonlar arasında febril nötropeni (%84,6), mukormikoz (%7,7) ve invaziv aspergilloz (%7,7) yer aldı. Hiçbir hasta toksisite nedeniyle tedaviyi bırakmadı.

Sonuç: Venetoklaks temelli rejimler, genç ve yoğun şekilde ön tedavi almış R/R ALL/LBL popülasyonunda yüksek TY/TYi oranları, ÖKH-negatif yanıtlar ve hastaların yarısından fazlasında allo-HKHN’ye geçişi sağlayarak anlamlı bir aktivite göstermiştir. ETP-ALL/LBL alt grubunda gözlenen etkinlik ve daha kısa venetoklaks uygulamalarında izlenen yönetilebilir toksisite profili, gerçek yaşam pratiğinde bireyselleştirilmiş kullanımın uygulanabilirliğini desteklemektedir. Bulgularımız, venetoklaks temelli kombinasyonların R/R ALL/LBL’de umut vadeden bir kurtarma ve köprüleme stratejisi olduğunu göstermekte olup prospektif çalışmalarla doğrulanması gerekmektedir.

Keywords

Venetoklaks , akut lenfoblastik lösemi , lenfoblastik lenfoma , relaps ve refrakter , hematopoietik kök hücre nakli

References

• Ronson A, Tvito A, Rowe JM. Treatment of relapsed/refractory acute lymphoblastic leukemia in adults. Curr Oncol Rep. 2016;18(6):39. doi:10. 1007/s11912-016-0519-8
• Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. New England Journal of Medicine. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866
• Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. New England Journal of Medicine. 2016;375(8):740-753. doi:10.1056/NEJMoa1509277
• Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. New England Journal of Medicine. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783
• DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: cancer and leukemia group b study 19801. Blood. 2007;109(12):5136-5142. doi:10.11 82/blood-2006-11-056754
• Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5): 937-951. doi:10.1182/blood-2009-03-209262
• Short NJ, Jabbour E, Jain N, et al. A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with relapsed/refractory acute lymphoblastic leukemia. Blood Adv. 2024;8(4):909-915. doi:10.1182/bloodadvances.202 3012231
• Pullarkat VA, Lacayo NJ, Jabbour E, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer Discov. 2021;11(6):1440-1453. doi:10.1158/2159-8290.CD-20-1465
• Canaani J, Frisch A, Pollyea DA, et al. Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia. Eur J Haematol. 2023;111(3):365-372. doi:10.1111/ejh.14015
• Richard-Carpentier G, Jabbour E, Short NJ, et al. Clinical experience with venetoclax combined with chemotherapy for relapsed or refractory t-cell acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2020;20(4):212-218. doi:10.1016/j.clml.2019.09.608
• Yiğit Kaya S, Vatani M, Akil R, et al. A complete response with daratumumab, venetoclax, azacitidine and dexamethasone in a heavily pre-treated, chemo-refractory early T-precursor acute lymphoblastic leukemia/lymphoma patient. Ann Hematol. 2025;104(1):829-833. doi:10.1007/s00277-024-06118-8
• Jin X, Liu Z, Wu Y, Ji J. Venetoclax in combination with chidamide and azacitidine for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia with the MLL-AF4 gene: a case report and literature review. Front Immunol. 2024;15. doi:10.3389/fimmu.2024.1475974
• Zhao Y, Jiang S, Tang Y, Zhao L. Venetoclax with CAG regimen for early T-cell precursor acute lymphoblastic leukemia: a case report and literature review. Int J Hematol. 2023;118(4):483-488. doi:10.1007/s121 85-023-03623-w
• Farhadfar N, Li Y, May WS, Adams CB. Venetoclax and decitabine for treatment of relapsed T-cell acute lymphoblastic leukemia: a case report and review of literature. Hematology/ Oncology and Stem Cell Therapy. 2021;14(3):246-251. doi:10.1016/j.hemonc.2019.10.002
• McEwan A, Pitiyarachchi O, Viiala N. Relapsed/Refractory ETP-ALL successfully treated with venetoclax and nelarabine as a bridge to allogeneic stem cell transplant. Hemasphere. 2020;4(3). doi:10.1097/HS 9.0000000000000379
• Zappone E, Cencini E, Defina M, et al. Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. Clin Case Rep. 2020;8(10):2000-2002. doi:10.1002/ccr3.3041
• Luskin MR, Shimony S, Keating J, et al. Venetoclax plus low-intensity chemotherapy for adults with acute lymphoblastic leukemia. Blood Adv. 2025;9(3):617-626. doi:10.1182/bloodadvances.2024014405
• Shi H, Yang F, Cao M, et al. Daratumumab and venetoclax combined with CAGE for late R/R T-ALL/LBL patients: single-arm, open-label, phase I study. Ann Hematol. 2024;103(8):2993-3004. doi:10.1007/s002 77-024-05775-z
• Ravandi F, Senapati J, Jain N, et al. Longitudinal follow up of a phase 2 trial of venetoclax added to hyper-CVAD, nelarabine and pegylated asparaginase in patients with T-cell acute lymphoblastic leukemia and lymphoma. Leukemia. 2024;38(12):2717-2721. doi:10.1038/s41375-024-02414-4
• Cao HY, Chen LL, Wan CL, et al. Venetoclax combined with azacitidine was effective and safe for relapsed/refractory t-cell acute lymphoblastic leukemia/ lymphoblastic lymphoma: preliminary results of a phase 2, multicenter Trial. Blood. 2023;142(1):1501-1501. doi:10.1182/blood- 2023-179733
• Peirs S, Matthijssens F, Goossens S, et al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood. 2014;124(25):3738-3747. doi:10.1182/blood-2014-05-57 4566
• Starza R La, Cambò B, Cambò C, et al. Venetoclax and bortezomib in relapsed/ refractory early t-cell precursor acute lymphoblastic leukemia. JCO Precision Oncology. 2019. doi:10.1200/PO.19
• Yang F, Li Z, Dong C, et al. Daratumumab and venetoclax-containing regimens in the management of relapse after allogeneic hematopoietic stem cell transplantation in hematological malignancies. Blood. 2020;136(1):9-9. doi:10.1182/blood-2020-141766