Summary
BCL‐2 inhibitor venetoclax demonstrates promising efficacy in paediatric relapsed/refractory acute myeloid leukaemia (r/r AML). This retrospective analysis evaluated 12 patients treated with venetoclax‐based regimens under compassionate use for r/r myeloid malignancies. The overall response rate (ORR) was 41.6%, with complete response (CR) achieved in 33% of patients. Three patients successfully underwent allogeneic haematopoietic scell transplantation (HSCT) after venetoclax bridging therapy. Venetoclax demonstrated a favourable safety profile with manageable side effects. These findings suggest venetoclax's potential as a valuable therapeutic option for paediatric r/r AML, particularly for heavily pretreated patients. Further investigation in larger multicentre trials is warranted to refine treatment strategy.
Keywords: Bcl‐2 inhibitor, paediatric acute leukaemia, refractory or relapsed AML, venetoclax ABT‐199
INTRODUCTION
Combining genomic analysis and minimal residual disease (MRD) assessment in treating acute myeloid leukaemia (AML) has led to better clinical outcomes in first‐line treatment, with 5‐year overall survival (OS) between 65% and 75%, event‐free survival (EFS) between 45% and 60% and only 6% of patients being refractory. 1 , 2 , 3 Unfortunately, relapse remains the major cause of treatment failure, affecting up to 40% of patients. 1 Refractory or relapsed AML (r/r AML) continues to present challenges, with no universal standard of care. In November 2018, the FDA approved venetoclax, a selective BCL‐2 inhibitor, in combination with hypomethylating agents or low‐dose cytarabine for first‐line treatment of newly diagnosed AML in adults. This authorization has sparked interest in exploring venetoclax‐based regimens for paediatric r/r leukaemia. First, robust results are very encouraging, 38 children with r/r AML who received venetoclax at dose of 360 mg/m2 (recommended phase 2 dose) and cytarabine with or without idarubicine. The overall response rate (ORR) and complete response (CR) rate were, respectively, 80% and 70%. 4 Since then, several retrospective series have evaluated a venetoclax‐containing regimen in children with r/r AML. Venetoclax yields better results when combined with other therapeutic agents; it could be used as a bridge to allogeneic haematopoietic cell transplantation (HSCT) and has a favourable safety profile. 5 , 6 , 7 , 8 Here, we report our French monocentric experience with venetoclax‐based therapy in treatment of paediatric patients with r/r AML and myelodysplastic syndrome (MDS).
METHODS
Data were collected from medical records and an institutional review board exemption was obtained to perform retrospective chart review of patients.
Patients received either venetoclax + hypomethylating agent (HMA) or chemotherapy, or venetoclax alone. Treatment was obtained through a compassionate use program and administered orally once daily, either by tablet or a liquid form. Each treatment cycle lasted 28 days, with 14–21 days of active treatment followed by 7‐ to 14‐day window. Patients over 2 years old received dosage adjustments based on weight, and for those under 2 years old, daily dosage was adjusted to age due the immaturity of the CYP3A enzyme, like recommended on the ongoing trial (NCT03236857). Dose escalation of venetoclax at the beginning of the first cycle was performed for all patients. Trough venetoclax plasma concentrations were measured at steady state, that is, 10 days after initiation. No dose adjustments were made based on these measurements, except in case of significantly elevated residual levels due to drug interaction.
Responses were classified as follows: complete response (CR)when blast counts were ≤5% in the bone marrow (BM), with the absence of extramedullary disease and haematological recovery, that is, platelet count >75 G/L and absolute neutrophil count >0.75 G/L; complete response with incomplete recovery (CRi) if no haematological recovery was obtained; partial (PR) when BM blast percentage decreased to 5%–20% or there was a decrease in pretreatment BM blast percentage >50%; and non‐response (NR) when there was an increase or persistence of BM blasts >20% or a reduction of blast percentage <50%.
Overall response rate (ORR) combined patients in CR, CRi and PR. OS and EFS were defined according to international standard. Adverse events (AEs) were reported using the Common Terminology Criteria for Adverse Events version 5.0.
RESULTS
Twelve patients were included in the analysis; their clinical characteristics and summary of treatments are reported in Table 1 and Figure 1. Median age was 5.5 years (range, 2–12). Diagnoses included r/r AML (n = 11) and myelodysplastic syndrome‐related AML (MDS‐AML) (n = 1). Before being exposed to venetoclax, eight patients had experienced relapse (including 1 patient with 2 prior relapses), five patients received venetoclax after allogeneic HSCT and three patients had refractory AML. One patient received front‐line treatment for an MDS‐AML. Patients had received a median of two previous lines of therapy (range, 1–3). All molecular/cytogenetic alterations included KMT2A rearrangements (n = 3), monosomy 7 with mutation RUNX1 (n = 1), PTPN11 mutation (n = 2), NPM1 mutation (n = 1), ETO2::GLIS2 fusion (n = 1), RUNX1::RUNX1T1 fusion (n = 1), monosomy normal karyotype without classifying molecular abnormalities (n = 2). Patients received a median of two cycles of venetoclax (range: 1–3.5). It was administered with either medium‐ to high‐intensity chemotherapy (5/12), hypomethylating agent (5/12) or in monotherapy (2/12). The median percentage of blasts at venetoclax initiation was 28.5% (range: 15.5%–46%). Extramedullary disease was present in five patients (4 central nervous system (CNS), 1 skin) with AML.
TABLE 1.
Patient characteristics.
| Patients n = 12 | n (%), [range] |
|---|---|
| Age (years) median | 5,5 [2–12] |
| Sex | |
| Male | 7 (58) |
| Female | 5 (42) |
| Diagnosis | |
| Relapsed AML | 8 (66) |
| Refractory AML | 3 (25) |
| MDS‐related AML | 1 (9) |
| Genetics | |
| Inv16 | 1 |
| t(8;21) | 1 |
| NPM1+ | 1 |
| KMT2A t(9;11) | 3 |
| monosomy 7 | 1 |
| PTPN11+ | 2 |
| ETO2::GLIS2 | 1 |
| CNS status | |
| 1 | 8 |
| 2 | 3 |
| 3 | 1 |
| Previous lines of therapies | 2 [1–3] |
| Previous HSCT | |
| No | 8 (66) |
| Yes | 4 (33) |
| BM blasts before the first venetoclax cycle, median (range) % | 28.5% [15.5–46] |
| Number of venetoclax cycles/patient, median | 2 [1–3.5] |
| Venetoclax‐based regimen | |
| Chemotherapy | 5 (42) |
| HMA | 5 (42) |
| Monotherapy | 2 (16) |
| Best response achieved | |
| Complete response (CR + CRi) | 4 (33) |
| Partial response | 1 (8) |
| Overall response rate | 5 (41) |
| Non‐response | 7 (58) |
Abbreviations: AML, acute myeloid leukaemia; BM, bone marrow; CNS, central nervous system; CR, complete response; CRi, complete response with incomplete recovery; HMA, hypomethylating agent; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome.
FIGURE 1.
Responses of patients treated with venetoclax‐based combinations. (A) Swimmer plot of patients receiving venetoclax‐based combinations. (B) Kaplan–Meier estimates of the overall survival and event‐free survival for the entire cohort.
Venetoclax trough plasma concentrations were lower than those typically measured in adults, even for patients under 2 years of age (2/12) suggesting effective drug metabolism. For a patient receiving azacitidine and venetoclax, prophylactic treatment with voriconazole could not be switched, resulting in very high venetoclax residual levels (see Table 4). Reducing the venetoclax dose by 50% lowered the levels, but they remained above the recommended range. The patient developed grade 3/4 cytopenias, which persisted despite dose reduction, with no other notable adverse effects, in a context of disease progression.
TABLE 4.
Venetoclax monitoring.
| Ages (years) | Weight (kg) | Dose (mg) | Trough concentration (ng/mL) | Trough concentration/dose (ng/mL)/mg |
|---|---|---|---|---|
| Aged‐adjusted dose | ||||
| 1.2 | 13 | 150 | 342 | 2.28 |
| 1.7 | 11 | 150 | 163 | 1.08 |
| Weight‐adjusted dose | ||||
| 2.2 | 14 | 250 | 314 | 1.25 |
| 4 | 16 | 250 | 227 | 0.90 |
| 10 | 71 | 400 | 214 | 0.53 |
| 11 | 20 | 200 | 7215 a | 36 |
| 100 | 3681 a | 36 | ||
| 14 | 80 | 800 | 439 | 0.55 |
Drug interaction involving azoles.
The most common AEs, regardless of grade, were haematological and gastrointestinal. Grade 3–4 AE included pancytopenia (n = 1), prolonged neutropenia (n = 4), bacterial infection (n = 3) and diarrhea (n = 1) (see Table 2) No tumour lysis syndrome was observed, and all toxicities were expected and manageable. There were no treatment discontinuations or deaths related to toxicities.
TABLE 2.
Toxicities.
| Adverse event | Venetoclax + HMA | Venectoclax + chemotherapies | Venetoclax | Total |
|---|---|---|---|---|
| All grades/grade ≥ 3 | ||||
| n = 5 | n = 5 | n = 2 | n = 12 | |
| Haematologic AEs | ||||
| Anaemia | 1/0 | 3/1 | 0 | 4 |
| Thrombocytopenia | 1/0 | 3/1 | 0 | 4 |
| Neutropenia | 2/1 | 3/2 | 1/1 | 6 |
| Febrile neutropenia | 0 | 4/2 | 1/0 | 5 |
| Gastrointestinal AEs | ||||
| Nausea | 1/0 | 4/0 | 0 | 5 |
| Diarrhea | 1/1 | 2/0 | 0 | 3 |
| Infectious AEs | ||||
| Sepsis | 0 | 3/3 | 0 | 3 |
| Other AEs | ||||
| Fatigue | 1/0 | 0 | 1/0 | 2 |
| Musculoskeletal pain | 1/0 | 1/0 | 0 | 2 |
| Serious AEs a | 1 | 3 | 0 | 4 |
Abbreviations: AEs, adverse events; HMA, hypomethylating agent.
Serious AEs: One episode of diarrhoea requiring hospitalization for intravenous (IV) hydration; three episodes of sepsis necessitating hospitalization for antibiotic therapy and close monitoring, with a favourable outcome.
Among the patients who received venetoclax combined with cytotoxic agents, three of five patients (60%) achieved CR, while two of five patients did not respond. In the group receiving venetoclax with HMA, one achieved CRi, one had PR and three did not respond. The two patients treated with venetoclax alone did not respond. The ORR in our cohort was 41.6%, best response observed was CR and PR, in 4 (33%) and 1 (8%) patient respectively. Seven patients did not respond, but among them, five experienced stable disease (improved symptoms, decreased blast count) during a median of 3 months (range 2–5). Among the four patients who achieved CR/CRi, all were MRD‐negative, evaluated by flow cytometry. The characterization of these patients is available in Table 3. Three responders received allogeneic HSCT, performed 42, 48 and 90 days after venetoclax initiation, from either haploidentical donor (n = 2) or matched unrelated donor (n = 1). All received myeloablative conditioning prior to HSCT. Among them, two patients died: first from progression of a cutaneous extramedullary relapse 8 months post‐HSCT and the other from invasive fungal infection (mucormycosis) 3 years post‐HSCT, while still in CR. One patient is still alive and in remission 3‐and‐a‐half‐year after HSCT.
TABLE 3.
Patient achieving CR.
| Sex, age (UPN) | Leukaemia's characteristics | Prior therapies | Venetoclax ‐based regimen | Outcomes |
|---|---|---|---|---|
|
F, 17 years (UPN1) |
Late‐onset bone marrow relapse AML
|
2, including 1 HSCT |
Venetoclax + Cytarabine 4 cycles |
CR Bone marrow relapse right before HSCT (23 days post CR cycle 4) Death of disease at day 393 |
|
M, 3 years (UPN4) |
Early bone marrow relapse AML
|
3 |
Venetoclax + Cytarabine 1 cycle |
CR HSCT at day 42 Relapse at day 240 Death of disease at day 457 |
|
M, 15 years (UPN2) |
Early combined relapse AML
|
1 |
Venetoclax + Cytarabine + Fludarabine 2 cycles |
CR HSCT at day 90 Death due to fungal infection at day 1041 |
|
F, 5 years (UPN3) |
MDS‐related AML
|
1 |
Venetoclax + Azacitidine 1 cycle |
Cri HSCT at day 48 Alive day 1254 |
Abbreviations: AML, acute myeloid leukaemia; HSCT, haematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; UPN, unique patient number.
Median follow‐up of the whole cohort was 11 months (4–42 months). The 1‐year OS was 50% (CI95% 28%–88%), and 1‐year EFS was 25% (CI95% 9.4%–67%). Eleven patients died by the end of follow‐up, with a median time from the start of venetoclax to death of 8 months (range: 3.75–15 months). Causes of death included disease (progression or relapse) in 10 patients and transplantation‐related mortality in one patient (Mucormycosis infection). Analysis of response is shown in Figure 1.
Single‐centre recruitment limits extrapolation of results to the general paediatric population, but these results nonetheless provide valuable insights into the safety and efficacy of venetoclax in clinical practice, where data are scarce. Available trough concentrations and pharmacokinetic profiles in younger patients suggest good drug elimination despite the immaturity of metabolism at this age, more details in Table 4. The efficacy was a secondary outcome measure, but it is noteworthy that four patients achieved CR without the use of anthracyclines, and three of them were able to undergo HSCT in short delay. This regimen could be particularly beneficial for heavily pretreated patients, allowing for less intensive treatment options.
Key questions persist regarding the optimal combination regimen and the number of treatment cycles requested to obtain strong/real remission and to bridge patients to transplant. In our experience, a venetoclax‐cytarabine‐based regimen appears to yield favourable outcomes as a bridging strategy to HSCT and has also been described by Pfeiffer et al. 9 Other studies have reported venetoclax combined with intensive chemotherapy, along with gemtuzomab ozogamicin or CPX‐351, and described promising outcomes in paediatric r/r AML. 10 , 11
In adult AML, NPM1 and IDH2 mutations seems associated with a better response to venetoclax compared to TP53 or FLT3‐ITD mutations. 12 However, the mutational landscape in paediatric AML differs, with a higher prevalence of KMT2A mutations and identifying molecular determinants of long‐term response to venetoclax‐based combination therapy is needed.
Finally, strategies for managing resistance are needed; one possible approach could be to combine anti‐apoptotic molecules targeting both BCL2 and MCL1, thus allowing a synergistic anti‐apoptotic effect. 13 , 14 Another possibility in FLT3‐AML could be to combine FLT3 and BCL2 inhibitors as preclinical data suggest that they may complement each other to enhance efficacy and mitigate resistance, a trend supported by clinical evidence. 15
BCL2‐inhibitors like venetoclax are promising targeted therapy in treating r/r myeloid disorders but significant research efforts and multicentre clinical trials are warranted to refine treatment strategies in these patients.
AUTHOR CONTRIBUTIONS
SC, CC and BB conceived the study, oversaw the project and wrote the manuscript. MED, M Strullu, J‐HD, AB and BB treated patients. SC collected the data, while LG collected the pharmacokinetic data. SC and M Simonin analysed and interpreted the data. All authors approved the final version of the manuscript.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
ETHICS APPROVAL STATEMENT
All clinical investigations were conducted according to the principles of the Declaration of Helsinki.
PATIENT CONSENT STATEMENT
Informed consent was obtained from all legal guardians.
Supporting information
Data S1.
Cousson S, Calvo C, Goldwirt L, Simonin M, Roupret‐Serzec J, Dourthe MÉ, et al. Monocentric experience of venetoclax‐based regimen in paediatric refractory and relapsed AML/MDS . Br J Haematol. 2025;206(1):209–214. 10.1111/bjh.19849
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author.
REFERENCES
- 1. Petit A, Ducassou S, Leblanc T, Pasquet M, Rousseau A, Ragu C, et al. Maintenance therapy with Interleukin‐2 for childhood AML: results of ELAM02 phase III randomized trial. HemaSphere. 2018;2(6):e159. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Zwaan CM, Kolb EA, Reinhardt D, Abrahamsson J, Adachi S, Aplenc R, et al. Collaborative efforts driving Progress in pediatric acute myeloid leukemia. J Clin Oncol. 2015;33(27):2949–2962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Gibson BES, Webb DKH, Howman AJ, De Graaf SSN, Harrison CJ, Wheatley K, et al. Results of a randomized trial in children with acute myeloid Leukaemia: medical research council AML12 trial. Br J Haematol. 2011;155(3):366–376. [DOI] [PubMed] [Google Scholar]
- 4. Karol SE, Alexander TB, Budhraja A, Pounds SB, Canavera K, Wang L, et al. Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose‐escalation study. Lancet Oncol. 2020;21(4):551–560. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Karol SE, Bittencourt H, Morgenstern DA, Macy ME, Khaw SL, Cooper TM, et al. Venetoclax alone or in combination with chemotherapy: responses in pediatric patients with relapsed/refractory acute myeloid leukemia with heterogeneous genomic profiles. Blood. 2020;136:30–31. [Google Scholar]
- 6. Winters AC, Maloney KW, Treece AL, Gore L, Franklin AK. Single‐center pediatric experience with venetoclax and azacitidine as treatment for myelodysplastic syndrome and acute myeloid leukemia. Pediatr Blood Cancer. 2020;67(10):e28398. [DOI] [PubMed] [Google Scholar]
- 7. Trabal A, Gibson A, He J, McCall D, Roth M, Nuñez C, et al. Venetoclax for acute myeloid leukemia in pediatric patients: a Texas medical center experience. Cancer. 2023;15(7):1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Masetti R, Baccelli F, Leardini D, Gottardi F, Vendemini F, Di Gangi A, et al. Venetoclax‐based therapies in pediatric advanced MDS and relapsed/refractory AML: a multicenter retrospective analysis. Blood Adv. 2023;7(16):4366–4370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Pfeiffer T, Li Y, Ashcraft E, Karol SE, Rubnitz JE, Epperly R, et al. Venetoclax‐based therapy as a bridge to allogeneic hematopoietic cell transplantation in children with relapsed/refractory AML. Bone Marrow Transplant. 2023;58(3):328–331. [DOI] [PubMed] [Google Scholar]
- 10. Ishimaru S, Gueguen G, Karol SE, Bautista Sirvent FJ, Ceolin V, Goemans BF, et al. ITCC‐101/APAL2020D: a randomized phase 3 trial of fludarabine/cytarabine/gemtuzumab ozogamycin with or without venetoclax in children with relapsed acute myeloid leukemia. Blood. 2022;140(Supplement 1):3369–3370. [Google Scholar]
- 11. Agresta L, O'Brien MM, O'Brien EJ, Norris RE, Breese EH, Burns KC, et al. V2 trial: a phase I study of venetoclax and CPX‐351 for young patients with relapsed/refractory acute leukemia. J Clin Oncol. 2021;39(15_suppl):TPS7052. [Google Scholar]
- 12. DiNardo CD, Tiong IS, Quaglieri A, MacRaild S, Loghavi S, Brown FC, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135(11):791–803. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Masetti R, Baccelli F, Leardini D, Locatelli F. Venetoclax, a new player in the treatment of children with high‐risk myeloid malignancies? Blood Adv. 2024;8:3583–3595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Roberts AW, Wei AH, Huang DCS. BCL2 and MCL1 inhibitors for hematologic malignancies. Blood. 2021;138(13):1120–1136. [DOI] [PubMed] [Google Scholar]
- 15. Wen X, Wu Y, Huang P, Zheng H. Combined treatment with venetoclax, dasatinib, and FLT3 inhibitors for NUP98‐NSD1+/FLT3‐ITD+ acute myeloid leukemia: a pediatric case report. Pediatr Blood Cancer. 2023;70(7):e30308. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author.