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

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

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