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.