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\begin{document}

\title{Venetoclax in combination with chemotherapy as treatment for pediatric
advanced hematologic malignancies: A narrow therapeutic window of
promise and peril}



\author[1]{Amanda E. Marinoff}%
\author[1]{Kathryn Aaronson}%
\author[1]{Anurag Agrawal}%
\author[1]{Benjamin S. Braun}%
\author[1]{Carla Golden}%
\author[1]{Benjamin J. Huang}%
\author[1]{Jennifer Michlitsch}%
\author[1]{Erica Southworth}%
\author[1]{Allyson Thrall}%
\author[1]{Kieuhoa Vo}%
\author[1]{Elliot Stieglitz}%
\affil[1]{University of California San Francisco}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} V \textbf{e}netoclax is frequently used as salvage
treatment in pediatric, adolescent, and young adult (AYA) patients with
advanced hematologic malignancies. However, more robust data are needed
from real-world studies to guide the safe and appropriate use of
venetoclax in this population. \textbf{Procedure:} We retrospectively
reviewed the medical records of all patients diagnosed with hematologic
malignancies less than 30 years of age treated with venetoclax outside
of clinical trials at the University of California San Francisco (UCSF)
Benioff Children's Hospitals from 2016 to 2022. \textbf{Results:} We
identified 13 patients (AML \emph{, n= 8}, B-ALL, \emph{n= 3}, MDS,
\emph{n= 2)} aged 4 months to 27 years. A median of 3 prior lines of
therapy were given (range 0 to 5). All patients received venetoclax in
combination with either a hypomethylating agent or conventional
chemotherapy. Three (23\%) patients achieved a complete remission (CR);
2 (15\%) achieved a partial remission (PR); 3 (23\%) had stable disease
(SD), and 5 (42\%) had progressive disease. Median survival and time to
progression from venetoclax initiation was 9 months (range 2.5 to 52
months), and 3 months (range 2 weeks to 7.5 months), respectively. Five
patients (38\%) developed life-threatening infections while receiving
venetoclax, including bacteremia due to atypical organisms, invasive
pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia,
skin infections, encephalitis with bacterial brain abscesses.
\textbf{Conclusions:} Venetoclax in combination with hypomethylating
agents or cytotoxic chemotherapy was effective in a subset of
pediatric/AYA patients with advanced hematologic malignancies, but was
frequently associated with severe atypical infections, particularly in
combination with cytotoxic chemotherapy.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Therapeutic options for pediatric, adolescent and young adult (AYA)
patients with relapsed/refractory acute myeloid leukemia (AML) are
limited, and outcomes remain dismal; two-year relapse-free rates for
these patients, even with current chemotherapeutic regimens and
hematopoietic stem cell transplant (HSCT), are only
25\%-30\%.\textsuperscript{1-3} Relapsed/refractory acute lymphoblastic
leukemia (ALL) has also remained challenging to treat in children and
AYA, with survival rates lagging significantly behind those observed at
initial diagnosis. Although there have been improvements in outcomes
over the past several decades, only ~50\% of children and AYA with first
relapse of ALL experience long term survival, and outcomes are even
worse with second or later relapses.\textsuperscript{4} Novel
therapeutic strategies are thus needed to improve outcomes in
pediatric/AYA patients with relapsed/refractory (advanced) hematologic
malignancies.

Venetoclax, a potent, highly selective, orally available inhibitor of
the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), has emerged as one
such promising agent. Venetoclax in combination with low-dose cytarabine
or hypomethylating agents is Food and Drug Administration-approved for
adults with newly diagnosed chronic lymphocytic leukemia and AML, based
on results supporting its safety and efficacy in elderly adults deemed
unfit for cytotoxic chemotherapy.\textsuperscript{5-7} Several studies
also suggest these combinations may be effective salvage regimens for
adults with relapsed or refractory AML, even in heavily pre-treated
populations.\textsuperscript{8-10}

Venetoclax is currently the subject of several ongoing phase I/II
clinical trials evaluating its safety and efficacy in pediatric/AYA
patients with relapsed or refractory AML (NCT03194932) and in other
malignancies (NCT03236857). A phase I dose-escalation study of
venetoclax in combination with cytarabine with or without idarubicin in
pediatric patients with relapsed/ refractory AML or ambiguous lineage
leukemia supported the safety and efficacy of venetoclax and
conventional chemotherapy in this population.\textsuperscript{11}Another
phase I dose escalation study demonstrated venetoclax with chemotherapy
and low-dose navitoclax, a~BCL-X\textsubscript{L}/BCL-2 inhibitor, is a
safe and promising combination in pediatric and adult patients with
advanced ALL and lymphoblastic lymphoma.\textsuperscript{12}

Aside from these early-phase trials, the published literature to date
concerning venetoclax in pediatric/AYA patients with hematologic
malignancies consists of a few single-institution reports that support
the safety and efficacy of venetoclax in combination with cytotoxic
chemotherapy in pediatric patients with ALL\textsuperscript{13} and
AML\textsuperscript{14} and in combination therapy with azacitidine in
pediatric patients with MDS or AML unfit for standard
chemotherapy.\textsuperscript{15}

While these reports are encouraging, more robust data are needed to
guide clinicians in the safe and efficacious use of venetoclax
combination therapy across a range of pediatric hematologic
malignancies. We therefore retrospectively reviewed our institutional
experience of venetoclax use in pediatric/AYA patients at the University
of California San Francisco (UCSF) Benioff Children's Hospitals and
report on 13 pediatric and AYA patients with hematologic malignancies
who received venetoclax combination therapy outside of a clinical trial
between 2016 and 2022. We report on exceptional responders and
previously unreported toxicities.

\textbf{Methods}

After IRB approval, a retrospective chart review identified patients
diagnosed with acute leukemia or MDS at age 30 years or younger who
received venetoclax combination therapy at UCSF Benioff Children's
Hospitals. Eligible diagnoses included AML, MDS, and ALL. Patients who
were treated on a clinical trial were excluded from this study.

Complete remission (CR) was defined as disappearance of all clinical
and/or radiologic evidence of disease, plus absolute neutrophil count
(ANC) [?]1.0 \selectlanguage{ngerman}× 10\textsuperscript{3}/L, platelet count \selectlanguage{english}[?]100 x
10\textsuperscript{3}/L, and bone marrow differential with
\textless{}5\% blasts by morphology or flow cytometry of bone marrow.
~Partial response (PR) was defined as no peripheral blasts or peripheral
blood absolute blast count decreased by \selectlanguage{english}[?] 50\% from baseline, bone
marrow with 5 -- 25\% blasts and at least a 50\% decrease in bone marrow
blast percent from baseline, and no evidence of extramedullary disease.
Progressive disease (PD) was defined as \textgreater{} 50\% increase in
absolute peripheral or bone marrow blasts by morphology or flow
cytometry. Stable disease (SD) was defined as the conditions under which
criteria for CR, PR, or PD were not met.

Minimal residual disease (MRD) was defined as multiparameter flow
cytometry of bone marrow with less than 0.01\% blasts. Venetoclax
toxicities were graded per the Common Terminology Criteria for Adverse
Events version 5.0. Overall survival (OS) defined as the time in months
from the start of venetoclax therapy to death, and progression-free
survival (PFS) was defined as the time from the start of venetoclax
administration until disease progression or relapse. Patients alive
without relapse or progression were censored at their date of last
follow-up. Kaplan--Meier curves of OS and PFS were generated.

\emph{\textbf{Next-Generation Sequencing}}

Next generation sequencing was available for 11 patients (14 samples).
An institutional DNA sequencing panel assaying 479 cancer-related genes
was used.\textsuperscript{16} Genomic DNA was extracted from peripheral
blood and tumor tissue microdissected from fresh frozen paraffin
embedded blocks, as previously described.
\textsuperscript{16}Capture-based next-generation sequencing (NGS) was
performed at the UCSF Clinical Cancer Genomics Laboratory, using an
assay targeting the coding regions of these genes,~\emph{TERT}
~promoter, select introns from 40 genes (for detection of gene fusions
and other structural variants), and intergenic regions at regular
intervals along each chromosome (for chromosomal copy number
assessment), altogether with a total sequencing footprint of 2.8 Mb
Sequencing libraries were prepared from genomic DNA with target
enrichment performed by hybrid capture using a custom oligonucleotide
library. Sequencing was performed on an Illumina HiSEquation 2500.
Duplicate sequencing reads were removed computationally to allow for
accurate allele frequency determination and copy number estimates. The
analysis was based on the human reference sequence UCSC build hg19 (NCBI
build 37). Single nucleotide variants and small insertions/deletions
(indels) were visualized and verified using Integrated Genome Viewer.

\textbf{Results}

Patient and Disease Characteristics

Thirteen patients were identified, 8 (62\%) with AML, 3 (23\%) with
B-ALL, and 2 (15\%) with MDS. The median age upon initiation of
venetoclax was 14 years (range: 4 months to 27 years). Six (46\%)
patients were male. Three patients had a history of a prior malignancy:
one patient with T-ALL, one with AML, and one with neuroblastoma. The
median number of lines of therapy was 3 (range 0 to 5). Five (38\%)
patients had received a hematopoietic stem cell transplant prior to
receiving venetoclax therapy. Two patients had a defined predisposition
to developing malignancy: one patient had Schwachman-Diamond Syndrome
(SDS) who developed AML, and one had a germline \emph{GATA2} mutation
who developed MDS. Patient and disease characteristics are summarized in

\textbf{Table 1.}

Treatment and Response

All patients received venetoclax in combination with either a
hypomethylating agent or conventional chemotherapy. Median follow-up
time was 8 months from venetoclax initiation (range 2 to 52 months).
Treatment regimens and responses for each patient are summarized
in\textbf{Table 2 and in Figure 1.} The standard adult AML dosing of 400
mg daily (or adult equivalent weight-based dosing), with a bioequivalent
dose for patients receiving a concurrent CYP3A4 inhibitor, was
given.\textsuperscript{17,18} Three of 8 patients with AML received
venetoclax in combination with decitabine (20
mg/m\textsuperscript{2}daily for 5 days). In two of these three cases,
the patient was a poor candidate for conventional chemotherapy due to
morbidities from prior therapy; in one case, the patient with SDS and
newly-diagnosed AML was deemed ineligible for standard chemotherapy due
to the risk of toxicity.\textsuperscript{19} The remaining 5 patients
with AML received venetoclax in combination with cytarabine (1000
mg/m\textsuperscript{2}/dose every 12 hours for 8 total doses). One
patient with an intracranial myeloid sarcoma received venetoclax and
cytarabine with concomitant focal radiation therapy. Both patients with
MDS received venetoclax in combination with a hypomethylating agent
(decitabine in one case and azacitidine in the other).

Two of the three patients with relapsed B-ALL received venetoclax in
combination with vincristine, dexamethasone, and PEG-asparaginase. One
patient with relapsed B-ALL received venetoclax in combination with
fludarabine, high-dose cytarabine, and G-CSF (FLAG).

The median number of cycles of venetoclax combination therapy patients
received was 1 (range \textless{}1 to 3). The most common reason for
discontinuation of venetoclax was disease progression in 6 patients
(46\%), and in 2 cases it was discontinued due to infections.

Three (23\%) patients achieved a CR; 2 (15\%) achieved a PR; 3 (23\%)
had stable disease, and 5 (42\%) had PD. Of the 3 patients who achieved
a CR, two had a diagnosis of relapsed B-ALL, and one had a diagnosis of
SDS-associated AML. Two of these patients became MRD negative after one
cycle of venetoclax combination therapy. All three patients who achieved
a CR remain alive with no evidence of disease with a median follow-up
time of 48 months.

Nine patients (69\%) experienced disease progression following
venetoclax therapy. Median survival was 9 months from venetoclax
initiation (range 2.5 to 52 months), and median time to progression was
3 months (range 2 weeks to 7.5 months). (\textbf{Fig. 2).}

Toxicities

All patients experienced hematologic toxicity with grade 3-4
thrombocytopenia, anemia, and neutropenia. Non-hematologic Grade 3-4
adverse events (AEs) attributed to venetoclax are summarized
in\textbf{Table 3} . Five patients (38\%) developed grade 3 or higher
infections while receiving venetoclax. Four patients (23\%) developed
bacteremia due to uncommon organisms (Vignettes 1-2), one of whom
developed four distinct episodes of bacteremia in addition to multiple
other infectious complications (Vignette 2). Patient 13 developed Grade
4 encephalitis with multiple rim-enhancing brain lesions thought to be
bacterial abscesses (Vignette 3). Two patients developed invasive
pulmonary infections with Aspergillus. Two patients developed grade 3
skin infections. Patient 6, an infant, developed grade 3 nausea, which
prompted discontinuation of venetoclax. No deaths occurred within 30
days of the start of venetoclax combination therapy, and no grade 5 AEs
were reported as associated with venetoclax. No clinically significant
tumor lysis syndrome was seen.

To demonstrate the wide spectrum of hematologic malignancies treated
with venetoclax and the range of infectious complications that arose in
our experience, we share the following vignettes.

Vignettes

\emph{Vignette 1: Patient 5}

\emph{A 14-year-old male with SDS presented with fever, pancytopenia,
and peripheral blasts. Bone marrow biopsy confirmed a diagnosis of AML
with 17\% blasts, normal cytogenetics, and FISH. Targeted DNA panel
sequencing revealed a somatic pathogenic mutation in IDH1 and a partial
tandem duplication of KMT2A. Bone marrow examination showed a CR by
morphology and negative MRD by flow cytometry after one cycle of
venetoclax and decitabine. His first cycle was complicated by several
episodes of febrile neutropenia and one episode of Rothia mucilaginosa
bacteremia. He received a second cycle of venetoclax and decitabine and
maintained his negative MRD status prior to receiving a matched
unrelated donor HSCT. The patient has remained disease-free after 52
months of follow-up.}

\emph{Vignette 2: Patient 10}

\emph{A 19-year-old male with second relapsed AML, with initial relapse
in the bone marrow and myeloid sarcoma in the cerebellar vermis
requiring a total of 5 lines of therapy including allogeneic HSCT,
presented with a second relapse isolated to the central nervous system
(CNS) as suprasellar myeloid sarcoma two years after initial diagnosis.
He received 2 cycles of venetoclax in combination with cytarabine in
addition to focal radiation to a total of 24Gy. Despite bacterial and
fungal prophylaxis with levofloxacin and micafungin, respectively, his
course was complicated by multiple infections, including pulmonary
infection with Aspergillus, Gram negative rod sepsis secondary to
Klebsiella, additional distinct episodes of bacteremia secondary to
Morganella, Staphylococcus epidermidis, and Actinomyces bacteremia,
cytomegalovirus (CMV) viremia, a pilonidal abscess, and incidentally
discovered appendicitis. Venetoclax was discontinued due to ongoing
infections and was not restarted even after resolution of the infections
due to persistent pancytopenia with severe thrombocytopenia. The patient
developed concern for progressive CNS disease with a new lesion in the
right medulla 7 months after initiation of venetoclax therapy, though
subsequent imaging improved without intervention, raising the
possibility of radiation necrosis or infection. He remains alive with
unclear disease recurrence 9 months following initiation of venetoclax.}

\emph{Vignette 3: Patient 12}

\emph{A 15-year-old with iAMP21-B-ALL presented with early medullary
relapse during cycle 6 of maintenance therapy with bone marrow
evaluation demonstrating 94\% blasts by flow cytometry. She commenced
re-induction with venetoclax in combination with vincristine,
PEG-asparaginase, and dexamethasone. She experienced multiple infectious
complications during treatment with this regimen, including recurrent
and prolonged Enterococcus faecalis bacteremia, invasive Aspergillus
pneumonia, and rim-enhancing brain lesions suspicious for
bacterial~brain abscesses, for which she was treated with a prolonged
course of antibiotics. Bone marrow examination after one cycle showed a
CR by morphology and MRD of 0.26\% by flow cytometry. The patient
achieved MRD negativity after receiving inotuzumab and subsequently
underwent matched sibling HSCT.}

\textbf{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.\textsuperscript{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.\textsuperscript{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
evidence\textsuperscript{11,13-15} 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.\textsuperscript{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. \textsuperscript{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.

\textbf{Conflicts of Interest Statement}

The authors do not have any conflicts of interests to declare.

\textbf{Acknowledgements}

This work was supported by~the Alex's Lemonade Stand Foundation (KTV, E.
Southworth, E. Stieglitz) and~National Institutes of Health (NIH) T32
training grant T32CA128583~(AEM). The contents are solely the
responsibility of the authors and do not necessarily represent the
official views of the NIH.

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\textbf{Legends}

Tables

TABLE 1: Patient and disease characteristics

TABLE 2: Treatment and outcomes

TABLE 3: Non-hematologic adverse events

Figures

1. Swimmer plot showing the clinical course of each patient over time.
Each bar represents one patient treated with venetoclax, color-coded
based on diagnosis (AML, pink; B-ALL, green; MDS, blue). Dates of severe
infection, hematopoietic stem cell transplantation (HSCT), disease
progression, or death are depicted by symbols. Therapy combined with
venetoclax are shown on the left with a white box (hypomethylating
agent, HMA) or black box (chemotherapy). Response to therapy is depicted
in the second column to the left: circles are filled (complete response,
CR), partially filled (partial response, PR), empty (stable disease,
SD), or contain an ``X'' (PD, progressive disease)

2. One-year overall and progression-free survival for 13 patients
treated with venetoclax combination therapy

\textbf{Hosted file}

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