Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

Abstract

Venetoclax, the best established BH3 mimetic, is a practice-changing proapoptotic drug to treat blood cancers in adults. In paediatrics, the data are less but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the interventions could be potentially molecularly guided as vulnerabilities to BH3 mimetics were reported. Currently, venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated thus far with venetoclax in Poland. We set out to gather this data to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data of November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with haematologic complete remission (CR), was reported in five patients out of ten, whereas five patients did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe that BH3 mimetics have clinical activity in children and should be available to paediatric haemato-oncology practitioners in well-selected applications.

Recent Updates in Venetoclax Combination Therapies in Pediatric Hematological Malignancies

“…Apart from those early-phase trials, the available literature discussing VTX in pediatric/AYA patients with hematologic malignancies contains a couple of single-institution reports [53][54][55][56][57][58][59] (Table 3) or multicenter retrospective analyses [60][61][62][63][64][65][66]. Recent studies support the usage of VTX-containing regimens in myeloid malignancies, especially as a linking therapy for allogeneic hematopoietic stem cell transplantation (HSCT) [60][61][62][63].…”

“…There are favorable (RUNX1-RUNX1T1, CBFB-MYH11, NPM1, and CEBPA bZIP) and unfavorable (MECOM, DEK-NUP214, KMT2A, NUP98, FLT3/ITD, WT1, monosomy 7, monosomy 5, and TP53) pediatric genetic markers that are being used to guide practitioners through patients' management [67,68]. Amongst the available data discussing clinical experience with VTX in children, the most recurrent structural rearrangements or sequence variants observed were KMT2A rearrangements, FLT3 alterations, and NPM1 mutations; many patients who obtained CR had a particular molecular subtype of the malignancy or a cancer predisposition syndrome [51,[60][61][62][63][64][65][66]. It is important to establish which molecular subtypes of pediatric malignancies might display specific VTX vulnerability, despite no evident mechanistic links to BH3 mimetic responses.…”