Discussion
We report on our real-world experience using venetoclax in pediatric and AYA patients with hematologic malignancies. Our experience builds on emerging data demonstrating the efficacy of venetoclax across a range of diagnoses and underscores the risk of life-threatening infections that may be associated with venetoclax-based regimens in this population.
To date, published reports have concluded venetoclax is well-tolerated in combination with a variety of cytotoxic agents in pediatric/AYA patients with hematologic malignancies.11-14 Our experience calls attention to the severity and range of atypical infections patients experienced during treatment with venetoclax. Five patients (38%) experienced at least one opportunistic infection, including bacteremia caused by multiple uncommon organisms, invasive pulmonary fungal disease, CMV viremia, and Grade 4 encephalitis with bacterial brain abscesses in one case. (Table 3, Vignettes 1-3). Infections occurred in an equal proportion of patients who received venetoclax combined with a hypomethylating agent and with cytotoxic chemotherapy, but they were generally more severe and prolonged with the latter combination. All patients who experienced serious infections notably received prophylactic antibiotics and antifungals at the start of venetoclax treatment with dose adjustments for concomitant azole use.18
Oncology providers should therefore be aware of the potential risk of life-threatening infections associated with venetoclax, particularly in combination with cytotoxic chemotherapy, and should consider dose modifications where appropriate as well as supportive therapies, including growth factor and infection prophylaxis. These interventions should also be investigated in a clinical trial setting.
Our experience also adds to the growing evidence11,13-15 that venetoclax may be effective in combination with multiple regimens across a range of hematologic malignancies, even in the relapsed/refractory setting. We found a subset of responders, even among those who received multiple lines of prior therapy. Three patients achieved a CR: one patient with SDS-associated AML who received venetoclax and decitabine and achieved a CR after 1 cycle, and two patients with relapsed B-ALL who received venetoclax with a 3-drug induction chemotherapy backbone (vincristine, dexamethasone, and PEG-asparaginase) each achieved a CR after receiving one cycle of therapy. Both patients with B-ALL were subsequently treated with bispecific T-cell engagers as bridging therapy to HSCT. Two patients who had received 3 or more prior lines of chemotherapy achieved a PR: one patient with treatment related-AML who received venetoclax and decitabine and one patient with refractory AML who received venetoclax with cytarabine; neither patient had significant venetoclax-related toxicities.
Our experience is also in agreement with prior studies suggesting patients unfit for conventional chemotherapy may benefit from venetoclax in combination with a hypomethylating agent.6,14 This combination was generally well-tolerated, and in two cases of patients with refractory AML, it afforded excellent quality of life in the palliative setting.
Venetoclax was not effective in our two cases of infant AML, both with GLIS fusions, which are associated with a highly refractory phenotype across pediatric AML subtypes. 20,21 Alternative therapies remain desperately needed in this population.
The ability to draw conclusions about specific subgroups of patients from this experience is limited by the small sample size and heterogeneous group of patients, disease biologies, and treatment regimens. Our cohort was predominantly comprised of patients with relapsed and refractory disease, 70% of whom had received 3 or more prior lines of therapy; thus, our findings may not be generalizable to other populations, including those receiving upfront therapy for newly diagnosed hematologic malignancies. Nevertheless, our experience highlights the potential promise and risks associated with venetoclax across a diverse set of pediatric and AYA patients with hematologic malignancies, providing real-world evidence complementary to randomized clinical trial data for guiding decision-making in routine clinical practice. Our findings suggest incorporation of venetoclax into a variety of anti-leukemia regimens may be effective in a subset of pediatric and AYA patients with relapsed/refractory AML, ALL, and MDS, but this strategy may be associated with an increased risk of life-threatening infections. Future studies should focus on identifying subgroups of patients most likely to benefit from venetoclax and on mitigating previously underrecognized infectious complications.