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https://doi.org/10.1177/2040620719882822
https://doi.org/10.1177/2040620719882822
Ther Adv Hematol
2019, Vol. 10: 1–14
DOI: 10.1177/
2040620719882822
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Introduction
Acute myeloid leukemia (AML) is a hematopoi-
etic stem-cell malignancy characterized by accu-
mulation of clonal myeloblasts in the bone marrow,
peripheral blood and extramedullary tissues.1 The
median age at diagnosis is 68-years old and inci-
dence increases with age.2 The standard curative
treatment of AML consists of intensive
chemotherapy aimed at achieving complete
remission (CR) followed by consolidation with
additional chemotherapy or allogeneic stem-cell
transplantation (HSCT) to prevent relapse.3
However, intensive chemotherapy is not a suita-
ble option for many older patients with significant
comorbidities, baseline organ dysfunction, or
poor performance status, in whom the risk of
Venetoclax for the treatment of newly
diagnosed acute myeloid leukemia in
patients who are ineligible for intensive
chemotherapy
Guillaume Richard-Carpentier and Courtney D. DiNardo
Abstract: Acute myeloid leukemia (AML) is an aggressive hematological malignancy with
a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until
recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the
hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided
only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax,
Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and
Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible
for intensive chemotherapy. Is now approved by the US Food and Drug Administration for
this indication. In the pivotal clinical trials evaluating venetoclax either in combination
with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete
hematological recovery were 54% and 67%, respectively and the median overall survival
(OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes
in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events
with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade
and easily manageable, and myelosuppression, which may require delays between cycles,
granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of
venetoclax administration per cycle. A bone marrow assessment after the first cycle of
treatment is critical to determine dosing and timing of subsequent cycles, as most patients
will achieve their best response after one cycle. Appropriate prophylactic measures can
reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present
clinical data from the pivotal trials evaluating venetoclax-based combinations in older
patients ineligible for intensive chemotherapy, and provide practical recommendations for the
prevention and management of adverse events associated with venetoclax.
Keywords:
acute myeloid leukemia, older patients, treatment, venetoclax
Received: 16 July 2019; revised manuscript accepted: 25 September 2019. Correspondence to:
Courtney D. DiNardo
Department of Leukemia,
The University of Texas MD
Anderson Cancer Center,
1515 Holcombe Boulevard,
Box 428, Houston TX
77030, USA
CDiNardo@mdanderson.
org
Guillaume Richard-
Carpentier
Department of Leukemia,
University of Texas MD
Anderson Cancer Center,
Houston, Texas, USA
882822TAH0010.1177/2040620719882822Therapeutic Advances in HematologyG Richard-Carpentier and CD DiNardo
review-article20192019
Review
Therapeutic Advances in Hematology 10
2 journals.sagepub.com/home/tah
complications and treatment-related mortality is
unacceptably high. In addition, older patients
have a higher frequency of adverse-risk features,
such as secondary AML, complex karyotype and
TP53 mutation, which are associated with
decreased responses to cytarabine-based intensive
chemotherapy approaches. Therefore, older
patients with AML are routinely treated with non-
curative, low-intensity chemotherapy approaches,
aimed at controlling the disease and maintaining
an acceptable quality of life for an extended
period. Low-intensity treatments for AML have
historically included low-dose cytarabine (LDAC)
or hypomethylating agents (HMA) azacitidine or
decitabine (DAC), which prolong survival com-
pared with best supportive care, but prognosis
remains poor, with an expected survival of less
than 12 months.4–6 In the past decade, multiple
attempts with novel agents have failed to provide
significant benefit over LDAC or HMA in older
patients ineligible for intensive chemotherapy.4,7–10
For example, gemtuzumab ozogamicin, an anti-
CD33 antibody–drug conjugate, or clofarabine
added to LDAC, successfully increased the rate of
CR, but these improvements did not translate into
improved survival, and the polo-like kinase inhibi-
tor, volasertib, plus LDAC, provided marginal
improvement in survival at the expense of
increased toxicity.7,8,10 Glasdegib, a hedgehog
pathway inhibitor, is one of the only drugs now
approved by the US Food and Drug Administration
(FDA) in combination with LDAC for older AML
patients ineligible for intensive chemotherapy. In
the BRIGHT phase II randomized trial, the
median overall survival (OS) was 8.8 months
versus 4.9 months in the LDAC plus glasdegib and
LDAC groups, respectively. The CR rate was
17% with LDAC plus glasdegib, and 2% with
LDAC. The combination treatment was well tol-
erated with gastrointestinal symptoms, dysgeusia,
muscle spasms, and fatigue reported as common
nonhematological adverse events.11
Venetoclax is a BH3 mimetic and small molecule
inhibitor of the antiapoptotic protein B-cell lym-
phoma 2 (BCL2). BCL2 is overexpressed in
many myeloid and lymphoid malignancies as a
mechanism of enhanced cell survival. Preclinical
studies have demonstrated that AML cells, espe-
cially leukemic stem cells, are dependent on
BCL2 for survival, and inhibition by venetoclax
can lead to rapid initiation of apoptotic AML cell
death.12,13 Based on this rationale, venetoclax was
first evaluated in relapsed or refractory AML
showing single-agent efficacy with an overall
response rate (ORR) of 19% and a good safety
profile.14 Despite modest results as a single agent
in the relapsed/refractory setting, clear synergy
with venetoclax and both hypomethylating agents
and cytarabine was identified preclinically,15–18
leading to the multicenter phase I/II clinical trials
of venetoclax in combination with either LDAC
or HMA for newly diagnosed untreated AML
patients ineligible for intensive chemotherapy.19,20
In these two pivotal clinical trials, the rates of CR
plus CR with incomplete hematological recovery
(CRi) were 54% and 67% in patients treated
with venetoclax plus LDAC or HMA, respec-
tively, and the median OS was 10.4 months and
17.5 months, representing significant improve-
ment compared with historical cohorts treated
with single-agent LDAC or HMA.4–6 The results
of these nonrandomized clinical trials led to the
accelerated approval of venetoclax by the FDA,
for use in combination with LDAC or HMA for
the treatment of AML in newly diagnosed patients
older than 75 years, or with comorbidities that
preclude intensive chemotherapy. These combi-
nation regimens produce notably different
response kinetics compared with single-agent
LDAC or HMA, as most patients on venetoclax
combinations will achieve their best response
after one cycle. It is also important to be aware
that venetoclax may be associated with aug-
mented or prolonged myelosuppression that can
lead to infections or other cytopenia-related
adverse events. Venetoclax can also cause tumor
lysis syndrome (TLS), and appropriate preven-
tive measures are required to avoid this complica-
tion. In this review, we will summarize the data
from the pivotal clinical trials evaluating the vene-
toclax-based combination therapies in older
patients ineligible for intensive chemotherapy,
and provide practical recommendations to assist
clinicians with the utilization of these regimens in
daily clinical practice.
Venetoclax plus hypomethylating agents
The safety and efficacy of venetoclax in combina-
tion with either azacitidine or DAC was evaluated
in a phase Ib/II clinical trial for patients with
newly diagnosed untreated AML older than
65 years, considered unsuitable candidates for
intensive chemotherapy.19 Patients who had pre-
viously received HMA therapy for an antecedent
hematological disorder were ineligible. Patients
were treated with either standard azacitidine
G Richard-Carpentier and CD DiNardo
journals.sagepub.com/home/tah 3
75 mg/m2 intravenously (IV) or subcutaneously
(SC) for 7 days, or DAC 20 mg/m2 IV for 5 days,
in combination with oral venetoclax at a dose of
400 mg, 800 mg, or 1200 mg daily in the phase Ib
dose-finding period. All patients were hospital-
ized for TLS prophylaxis and monitoring during
a 3–5-day dose ramp-up of the venetoclax in
combination with initiation of the HMA therapy.
All patients required initiation of allopurinol or
other uric-acid-reducing agents prior to initiation
of treatment, TLS biochemistry monitoring prior
to, and 8 h after each new venetoclax dose, and
appropriate oral or IV hydration. A total of 145
patients were enrolled in the dose escalation and
expansion study with a median age of 74 (range
65–86) years and Eastern Cooperative Oncology
Group (ECOG) performance status of 0–1 in
84% of patients. A total of 71 (49%) patients had
adverse-risk cytogenetics, and 36 (25%) patients
had secondary AML.
The most common grade 3 or 4 adverse events
were febrile neutropenia (43%), anemia (25%),
thrombocytopenia (24%), neutropenia (17%),
and pneumonia (13%). Gastrointestinal symp-
toms such as nausea, diarrhea, or constipation
were reported in approximately half of patients;
primarily grade 1 or 2, and typically manageable
without dose interruptions or reductions of vene-
toclax. As expected in patients with AML, infec-
tions were a common adverse event observed in
74% of patients (grade 3 or 4 in 45% of patients),
and 10 patients (7%) died from infectious com-
plications. While no dose-limiting toxicity was
observed, hematological and gastrointestinal
adverse events seemed to be more frequent in
patients receiving venetoclax at 1200 mg daily
compared with the lower doses of 400 mg or
800 mg, and thus the 400 mg and 800 mg dose
levels moved into subsequent expansion cohorts.
Importantly, 68 (47%) patients required a dose
interruption of venetoclax, most often due to per-
sistent cytopenia without residual AML at the
end of the first cycle’s bone marrow aspiration,
requiring subsequent cycle delay to allow for
count recovery.
Among 145 patients, the ORR [comprising CR,
CRi and partial remission (PR)] was 68%, includ-
ing 37% patients achieving CR and 30% patients
achieving CRi (Table 1). Additionally, 21% of
patients achieved a morphologic leukemia-free
state (MLFS) for a total leukemia response rate of
83%, representing all patients who achieved a
bone marrow morphologic remission with less
than 5% blasts, regardless of hematological recov-
ery. The ORR was not significantly different
between a venetoclax dose of 400 mg and 800 mg
(73% versus 68%, respectively), or between azac-
itidine and DAC (76% versus 71%, respectively).
Responses were rapid with a median time to initial
response of 1.2 months. With a median follow up
of 15.1 months, the median OS was 17.5 months
[95% confidence interval (CI), 12 months to not
reached (NR)] and the median duration of
response (DOR) was 11.3 months (95% CI,
8.9 months to NR). Measurable residual disease
(MRD) negativity was assessed longitudinally in
bone marrow aspirates by multiparameter flow
cytometry detecting leukemia-associated immu-
nophenotypes with a sensitivity of 10−3. MRD
negativity was achieved in 28/97 (29%) patients in
CR or CRi and median OS and DOR were NR in
these patients. In return, patients in CR or CRi
who did not achieve MRD negativity had a median
DOR of 11.3 months and median OS was NR.
Certain genomic features were confirmed to be of
prognostic significance with HMA plus veneto-
clax therapy (Table 1). In patients with interme-
diate-risk and adverse-risk cytogenetics, the CR/
CRi rates were 74% and 60% and the median OS
were 12.9 months and 6.7 months, respectively.
Patients with a TP53 mutation had lower CR/CRi
rates of 47% and median OS of 7.2 months (95%
CI 3.7 months to NR), whereas patients with
IDH1/2 and NPM1 mutations had higher CR/
CRi rates of 71% and 92% with a median OS of
24.4 months (95% CI, 12.3 months to NR) and
not reached (95% CI, 11.0 months to NR),
respectively.
The combination of venetoclax plus 10-day DAC
was evaluated in an ongoing phase II clinical trial
at the MD Anderson Cancer Center, enrolling
newly diagnosed patients older than 60 years
ineli gible for intensive chemotherapy as well as
relapsed/refractory AML.21 DAC was adminis-
tered for 10 days per cycle until ORR was
achieved, then was administered for 5 days on
subsequent cycles. With the 10-day DAC regi-
men, venetoclax was administered for 21 days in
cycle 1 then a bone marrow aspiration was per-
formed on day 21 to guide the additional dura-
tion of venetoclax therapy. In patients with
clearance of blasts (<5%), venetoclax was with-
held, beginning on day 21, to allow count recov-
ery, whereas in patients with persistent disease,
Therapeutic Advances in Hematology 10
4 journals.sagepub.com/home/tah
Table 1. Summary of the clinical data for venetoclax in combination with low-dose cytarabine or
hypomethylating agents.
CR + CRi rate,
n (%)
Median DOR, months
(95% CI)
Median OS, months
(95% CI)
Venetoclax + LDAC
All patients 44/82 (54) 8.1 (5.3–14.9) 10.1 (5.7–14.2)
Cytogenetic risk
Intermediate 31/49 (63) NA 15.7 (7.0–NR)
Adverse 11/26 (42) NA 4.8 (2.9–11.7)
AML
De novo 30/42 (71) NA 16.9 (11.7–NR)
Secondary 14/40 (35) NA 4.0 (3.0–6.5)
Mutations
FLT3 7/16 (44) NA 5.6 (3.0–14.3)
IDH1/2 13/18 (72) NA 19.4 (5.1–NR)
NPM1 8/9 (89) NA NR (0.5–NR)
TP53 3/10 (30) NA 3.7 (0.3–10.1)
Venetoclax + HMA
All patients 97/145 (67) 11.3 (8.9–NR) 17.5 (12.3–NR)
Cytogenetic risk
Intermediate 55/74 (74) 12.9 (11.0–NR) NR (17.5–NR)
Adverse 42/71 (60) 6.7 (4.1–9.4) 9.6 (7.2–12.4)
AML
De novo 73/109 (67) 9.4 (7.2–11.7) 12.5 (10.3–24.4)
Secondary 24/36 (67) NR (12.5–NR) NR (14.6–NR)
Mutations
FLT3 13/18 (72) 11.0 (6.5–NR) NR (8.0–NR)
IDH1/2 25/35 (71) NR (6.8–NR) 24.4 (12.3–NR)
NPM1 21/23 (91) NR (6.8–NR) NR (11.0–NR)
TP53 17/36 (47) 5.6 (1.2–9.4) 7.2 (3.7–NR)
CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete hematological recovery; DOR,
duration of response (CR + CRi); HMA, hypomethylating agent; LDAC, low-dose cytarabine; NA, not available; NR, not
reached; OS, overall survival.
G Richard-Carpentier and CD DiNardo
journals.sagepub.com/home/tah 5
the venetoclax was continued until day 28. Once
in remission, the administration of venetoclax was
kept at 21 days or reduced to 14 days for subse-
quent cycles, depending on hematological recov-
ery. Data presented at the American Society of
Hematology (ASH) 2018 annual meeting reviewed
the first 24 newly diagnosed AML patients
enrolled in the trial, including 6 patients (25%)
with complex cytogenetics and 4 patients (17%)
with TP53 mutations. The CR/CRi rate in these
newly diagnosed patients was 92% (22/24), and
among 21 evaluable responders, 11 patients
(52%) achieved MRD negativity. Importantly, all
four patients with TP53 mutation achieved CR.
Although the adverse events were similar to DAC
for 5 days plus venetoclax, myelosuppression was
significant with the 10-day DAC induction with
median time to neutrophil recovery above
0.5 × 109/l of 56 days and median time to platelet
recovery above 50 × 109/l of 32 days, leading to
the study modification to do a bone marrow aspi-
ration and stop venetoclax on day 21. The poten-
tial for prolonged cytopenia observed with this
regimen during induction underscores the critical
importance of performing a bone marrow aspira-
tion at day 21 to withhold venetoclax in early-
responding patients and reduce the risk of
cytopenia-related adverse events. Additional fol-
low up from this cohort is anticipated later this
year.
Venetoclax plus low-dose cytarabine
The combination of venetoclax with LDAC was
evaluated in a phase Ib/II clinical trial in patients
60 years or older with previously untreated AML
ineligible for intensive chemotherapy.20 Study eli-
gibility was overall similar to the previous study
with the notable exception that HMAs were
allowed for the previous treatment of an anteced-
ent hematologic disorder such as myelodysplastic
syndrome. Patients were treated with LDAC at a
dose of 20 mg/m2 by daily SC injection on days
1–10 per 28-day cycle, in addition to daily admi-
nistration of oral venetoclax, which was initiated
at a dose of 50 or 100 mg daily, and increased
over 4–5 days up to the target dose. Hospitalization
and TLS prophylaxis were mandated in the same
manner as with the HMA-combination study
during the initial ramp-up portion. During the
phase Ib period of the study, no maximum toler-
ated dose was identified, but many patients
receiving 800 mg daily of venetoclax experienced
prolonged myelosuppression, requiring cycle
interruptions to allow count recovery. Therefore,
venetoclax 600 mg was selected as the phase II
recommended dose and a total of 82 patients
were enrolled at this dose. The median age of
patients was 74 (range, 63–90) years, and 49% of
patients had an antecedent hematological disor-
der, including 29% who had previously been
treated with HMA. Most patients had a reasona-
ble performance status (ECOG 0–1 in 71%) and
32% of patients had adverse-risk cytogenetics.
Similar to the experience with HMA plus veneto-
clax, the most common grade 3 or 4 adverse events
were cytopenia, febrile neutropenia, and infec-
tions. Nausea, diarrhea, hypokalemia, and fatigue
were common nonhematological adverse events.
With the combination of LDAC and venetoclax
600 mg daily, the CR/CRi rate was 54% (95% CI,
42–65%) including CR and CRi in 26% and 28%
patients, respectively (Table 1). Patients with
de novo AML had a CR/CRi rate of 71%, com-
pared with a CR/CRi rate of only 35% in patients
with secondary AML. The CR/CRi rate was 62%
in patients who never received HMA therapy and
33% in patients with prior receipt of HMA.
Cytogenetic risk was again prognostic, with CR/
CRi rates of 63% and 42% in patients with inter-
mediate-risk and adverse-risk karyotype, respec-
tively. Patients with mutations in NPM1 or IDH1/2
had particularly good responses to the venetoclax
plus LDAC combination with CR/CRi rates of
89% and 72%, respectively, whereas patients with
mutations in TP53 or FLT3 had lower responses
with CR/CRi rates of 30% and 44%, respectively.
The median DOR was 8.1 months (95% CI 5.3–
14.9 months) among patients achieving CR/CRi,
and the median OS was 10.1 months (95% CI,
5.7–14.2 months) in the global population
(Table1). In patients who were never exposed to
HMA, the median OS was 13.5 months (95% CI,
7.0–18.4 months) compared to 4.1 months (95%
CI, 2.9–10.1 months) in patients who had previ-
ously been treated with HMA.
Management of venetoclax-related adverse
events
Management of cytopenia with venetoclax-
based regimens
Cytopenia and infections are the most frequent
grade 3 or 4 adverse events observed with the vene-
toclax-based low-intensity regimens. In the pivotal
clinical trials evaluating venetoclax plus LDAC or
Therapeutic Advances in Hematology 10
6 journals.sagepub.com/home/tah
HMA chemotherapy, treatment-emergent grade 3
or 4 neutropenia (<1.0 × 109/l) occurred in 17–
27% of patients and grade 3 or 4 thrombocytopenia
(<50 × 109/l) occurred in 24–38% of patients.19,20
Febrile neutropenia was reported in 42–43% of
patients and infection of any grade occurred in
74% of patients treated with HMA plus veneto-
clax.19,20 In order to reduce the risk of infections
and other cytopenia-related adverse events with the
venetoclax-based combinations, delays between
cycles, granulocyte colony-stimulating factor
(G-CSF) administration, or shorter duration of
venetoclax administration per cycle may be
required. We provide herein some recommenda-
tions and an algorithm to assist clinicians in the
management of cytopenia occurring in older
patients treated with venetoclax-based low-inten-
sity regimens (Figure 1).
After the first cycle of therapy with a venetoclax-
based combination, a bone marrow aspirate and
biopsy should be performed to assess the response
to treatment, including blast percentage and cel-
lularity of the bone marrow. This should be per-
formed between day 21 and 28 from the start of
combination therapy and is particularly impor-
tant for guiding the timing of the second cycle of
therapy and inform on any appropriate dose
adjustments. In patients with persistent disease
after the first cycle of treatment, venetoclax
should be continued without interruption, and
the next cycle should start as scheduled, as any
persisting cytopenias are related to the active
AML and will not resolve until remission is
achieved. In patients without morphologic evi-
dence of leukemia (i.e. <5% blasts, or a therapy-
induced aplastic marrow), persistent cytopenia is
most likely secondary to combination therapy. In
such cases, we recommend to withhold veneto-
clax and delay the start of the next cycle for up to
14 days to allow neutrophils to recover above
0.5 × 109/l and platelets to recover at least above
25 × 109/l (ideally above 50 × 109/l) before start-
ing the next cycle of therapy. When more than
1 week is necessary for counts to recover prior to
the second cycle of therapy, we recommend
decreasing the duration of venetoclax administra-
tion to 21 days for the subsequent cycle. A repeat
bone marrow aspiration may be required after
2–3 weeks if cytopenia persists with an empty or
MLFS marrow at the end of cycle 1, to evaluate
the status of disease. In subsequent cycles, if
prolonged cytopenias reoccur and patients
remain in remission, the duration of venetoclax
administration can be further shortened to 14 days
per cycle (or 21 days if the patient was still receiv-
ing 28 days per cycle), and G-CSF may also be
given to help with the recovery of neutrophils. If
patients tolerate G-CSF well with improvement
in their neutrophil counts, then pegylated-G-CSF
may be considered for subsequent cycles. G-CSF
is often utilized at our institution for patients with
venetoclax-related neutropenia, particularly once
they have achieved MRD negativity in order to
avoid any stimulation of blasts, which could bias
the interpretation of later bone marrow aspirates.
Additionally, in the setting of a hypocellular bone
marrow and ongoing cytopenias without evidence
of persistent disease, the dose of HMA may also
be reduced or shortened according to standard
practice. In these circumstances, we often recom-
mend reducing the azacitidine to 5 days per cycle
(instead of 7) and DAC to 3 or 4 days per cycle
(instead of 5), which conveniently decreases the
number of hospital visits for patients. Alternatively,
the dose of azacitidine may be decreased to 50 mg/
m2 (and further to 37.5 mg/m2 or 25 mg/m2) or
DAC to 15 mg/m2 (and further to 10 mg/m2).
Venetoclax doses adjustments and drug
interactions
Venetoclax is approved by the FDA at a dose of
600 mg in combination with LDAC and 400 mg,
in combination with HMA. Higher doses of vene-
toclax in combination with LDAC or HMA are
associated with a higher frequency of prolonged
cytopenia and do not add clinical benefit.
Importantly, because venetoclax is metabolized
by the CYP3A4 cytochrome system, venetoclax
dosing must be adjusted in the setting of concom-
itant administration of CYP3A4 inhibitors.
Common CYP3A4 inhibitors utilized in AML
patients include the strong inhibitors posacona-
zole and voriconazole and the moderate inhibi-
tors fluconazole, isavuconazole, and ciprofloxacin
(Table 2). Based on pharmacokinetic studies, the
dose of venetoclax should be reduced by 50%
with administration of a moderate CYP3A4
inhibitor (i.e. 200 mg of venetoclax + HMA), and
should be reduced by 75% of the target dose with
administration of a strong CYP3A4 inhibitor (i.e.
100 mg of venetoclax + HMA).22 Patients taking
venetoclax should avoid intake of grapefruit prod-
ucts, as they contain CYP3A inhibitors, and
moderate or strong CYP3A4 inducers should be
avoided, as they may decrease the levels of vene-
toclax and impact its efficacy (Table 2).
G Richard-Carpentier and CD DiNardo
journals.sagepub.com/home/tah 7
Prevention of tumor lysis syndrome
TLS may occur after initiation of venetoclax
therapy due to the rapid initiation of apoptosis in
leukemic cells caused by BCL2 inhibition. The risk
of TLS is elevated in patients with certain risk fac-
tors such as elevated lactate dehydrogenase, white
blood cell counts (WBC) above 25 × 109/l, uric
acid above 7.5 mg/dl (446 µmol/l) and pre-existing
Day 28 bone
marrow aspiration
ANC < 0.5 x 109/L or Plt < 25 x 109/L after
frist cycle of venetoclax + LDAC or HMA
Persistent disease
(Blasts ≥ 5%)
Start next cycle
without delay or dose
modification
Marrow remission
(Blasts < 5%)
Hold venetoclax and
delay next cycle
Blood count recovery
≤ 1 week
Blood count recovery
> 1 week or severe cytopenias
Start next cycle
without dose modification
Reduce venetoclax to
21 days per cycle*
G-CSF
administration
if needed
(especially if MRD-)
Recurrent/Persistent cytopenias
on subsequent cycles
Bone marrow
aspiration
AML Relapse
(Blasts ≥ 5%)
Marrow remission
(Blasts < 5%)
Consider alternative
treatment
HMA dose reduction according
to standard practice
if hypocellular
Figure 1. Algorithm for the management of cytopenia with venetoclax-based combination regimens.
AML, acute myeloid leukemia; ANC, absolute neutrophil count; G-CSF, granulocyte colony-stimulating factor; HMA,
hypomethylating agents; LDAC, low-dose cytarabine; MRD−, minimal residual disease negative; Plt, platelets.
*Venetoclax can be reduced further to 14 days per cycle for persistent and/or recurrent cytopenias in subsequent cycles.
Therapeutic Advances in Hematology 10
8 journals.sagepub.com/home/tah
renal insufficiency, such as a creatinine above
1.4 mg/dl (124 µmol/l).23 Careful monitoring and
appropriate preventive measures with the initia-
tion of venetoclax can minimize the risk of TLS,
which appears to be much less in AML than what
has been observed in chronic lymphocytic leuke-
mia (CLL).24 Initiating venetoclax at a lower dose
followed by a short daily ramp-up is recommended
for achieving the target dose while reducing the
risk of TLS in sensitive patients (Figure 2).
Patients can start venetoclax at a dose of 100 mg
on the first day of the cycle, in combination with
LDAC or HMA, and the dose can thereafter be
doubled every day until achieving the target dose
(i.e. 100–200–400 mg with HMA and 100–200–
400–600 mg with LDAC; Figure 2). In patients
on CYP3A4 inhibitors, an adjusted daily ramp-up
(e.g. 50–100–200 mg, with moderate CYP3A4
inhibitors and 20–50–100 mg with strong CYP3A4
inhibitors) is reasonable and appropriate. During
the venetoclax dose ramp-up, patients should
remain well hydrated with oral or IV fluids and
they should receive uric-acid-lowering agents
(allopurinol or rasburicase). Laboratory parame-
ters of TLS should be monitored at least daily
prior to each new dose of venetoclax and in
patients at higher risk, we also recommend moni-
toring TLS biochemistry 6–8 h after administra-
tion of each new dose. Furthermore, it is
recommended to lower WBC below 25 × 109/l
with hydroxyurea before starting treatment with
venetoclax, to decrease risk of TLS. With these
preventive measures, no clinically significant TLS
was reported in the clinical trials of venetoclax
plus HMA and only two cases of laboratory (not
clinical) TLS were reported with LDAC plus
venetoclax. With these reassuring data, it is fore-
seeable that selected patients with no risk factors
for TLS could start venetoclax combination
therapy in an appropriate outpatient setting in
which the above preventive measures and monitor-
ing can be applied. In addition to standard risk fac-
tors for TLS, NPM1 and IDH1/2 mutations might
be AML-specific risk factors, given the greater sen-
sitivity of AML with these mutations to BCL2
inhibition, and anecdotal experience of clinically
significant TLS has been observed in such cases.21
Future directions
Based on the two independent nonrandomized
studies showing safety and high efficacy of veneto-
clax in combination with LDAC or HMA for the
treatment older patients with newly diagnosed
AML ineligible for intensive chemotherapy, vene-
toclax-based regimens are now established treat-
ment options for the treatment of newly diagnosed
older or unfit patients.19,20 Ongoing phase III ran-
domized clinical trials evaluating venetoclax versus
placebo in combination with either LDAC or HMA
Table 2. Drug interactions and venetoclax dose adjustments.
CYP3A4 inhibitors*
Moderate CYP3A4 inhibitors:
Azole antifungals: fluconazole, isavuconazole
Protease inhibitors: amprenavir, atazanavir, darunavir/ritonavir
Calcium-channel blockers: diltiazem, verapamil
Others: aprepitant, ciprofloxacin, erythromycin
Reduce dose of venetoclax by 50%
Strong CYP3A4 inhibitors:
Azole antifungals: posaconazole, voriconazole
Protease inhibitors: indinavir, lopinavir/ritonavir, telaprevir
Others: clarithromycin, conivaptan, telithromycin
Reduce dose of venetoclax by 75%
CYP3A4 inducers*
Moderate CYP3A4 inducers:
Bosentan, efavirenz, etravirine, modafinil, nafcillin
Avoid concomitant administration
Consider changing to alternative drugs
Strong CYP3A4 inducers:
Avasimibe, carbamazepine, phenytoin, phenobarbital, rifampin,
St. John’s wort
*These lists are not exhaustive and caution should be exercised when prescribing new medications to patients receiving
venetoclax-based regimens with regards to potential drug–drug interactions.
G Richard-Carpentier and CD DiNardo
journals.sagepub.com/home/tah 9
have now completed accrual, and results are eagerly
anticipated to confirm the added benefit of veneto-
clax to low-intensity therapy in older patients with
AML ineligible for intensive chemotherapy
[ClinicialTrials.gov identifiers: NCT02993523,
NCT03069352].
To continue improving the outcome of older
AML patients ineligible for intensive chemothe-
rapy, several therapeutic avenues trying to cir-
cumvent mechanisms of primary or secondary
resistance to venetoclax-based regimens are cur-
rently under investigation (Table 3). The most
recognized and studied mechanism of resistance
to venetoclax is overexpression of MCL1 or
BCL-XL, two other antiapoptotic proteins from
the BCL2 family, which may compensate BCL2
inhibition to promote leukemic-cell survival.25
Inhibition of MCL1 represents a more promising
avenue than inhibition of BCL-XL, since severe
thrombocytopenia was a dose-limiting toxicity
with navitoclax, a nonselective BCL2 inhibitor
also targeting BCL-XL, in patients with relapsed/
refractory CLL.26 In preclinical models, down-
regulation of MCL1 by genetic knockdown or
pharmacological inhibition was shown to over-
come the resistance of AML cells to BCL2 inhi-
bition, providing rationale for potential synergistic
combination therapies of MCL1 inhibitors with
venetoclax.27–30 Direct MCL1 inhibitors are
therefore currently being evaluated in combina-
tion with venetoclax for patients with relapsed/
refractory AML (Table 3). Downregulation of
MCL1 can also be achieved indirectly by inter-
fering with the MAPK, p53 and CDK9 path-
ways, which regulate the expression of MCL1.
Cobimetinib, a mitogen-activated protein kinase
(MEK) inhibitor suppressing the MAPK signal-
ing pathway, downregulates MCL1 and acts syn-
ergistically with venetoclax in preclinical models
of AML.31 Similarly, p53 activation with MDM2
inhibition promotes degradation of MCL1 and
may overcome resistance to venetoclax in wild-
type TP53 AML samples.32 These combination
strategies are being tested in an ongoing phase Ib
clinical trial evaluating combinations of veneto-
clax with idasanutlin (an MDM2 inhibitor) or
cobimetinib (MEK inhibitor) in relapsed or
refractory AML (Table 3). In preliminary results
of this study presented at ASH 2017, the overall
response rate (including CR, CRi and CRp) was
18% (4/22) and 20% (4/20) with venetoclax in
combination with cobimetinib and idasanutlin,
respectively.33 The most common adverse events
were febrile neutropenia, and diarrhea that was
specifically associated with the cobimetinib
arm.33 Additionally, cyclin-dependent kinase 9
(CDK9) also regulates MCL1 protein levels and
the CDK9 inhibitors dinaciclib and alvocidib
have preclinical efficacy either alone or in
Figure 2. Venetoclax dose ramp-up and tumor lysis syndrome preventive measures.
HMA, hypomethylating agents; IV, intravenously; LDAC, low-dose cytarabine; SC, subcutaneously; TLS, tumor lysis
syndrome; VEN, venetoclax; WBC, white blood cell count.
Therapeutic Advances in Hematology 10
10 journals.sagepub.com/home/tah
combination with venetoclax.34,35 Clinical trials
evaluating the combination of venetoclax with
alvocidib or dinaciclib are currently recruiting
patients (Table 3).
Based on the established efficacy of FLT3 and
IDH1/2 inhibitors in the treatment of AML, the
addition of targeted agents to venetoclax-based
regimens represent an additional promising
Table 3. Ongoing clinical trials with venetoclax-based combinations for older patients with AML.
Treatment Trial phase Clinical.Trials.gov identifier
Untreated AML
Azacitidine + venetoclax versus placebo Phase III NCT02993523
Low-dose cytarabine + venetoclax versus placebo Phase III NCT03069352
Azacitidine + venetoclax Phase II NCT03466294
Decitabine 10 days + venetoclax Phase II NCT03404193
LDAC + cladribine + venetoclax and
azacitidine + venetoclax
Phase II NCT03586609
Azacitidine + venetoclax + pevonedistat (NEDD8-
activating enzyme)
Phase I/II NCT03862157
Venetoclax + ivosidenib ± azacitidine Phase I/II NCT03471260
Azacitidine + venetoclax + avelumab (PD-L1 inhibitor) Phase I/II NCT03390296
Azacitidine + venetoclax + gemtuzumab ozogamicin Phase I/II NCT03390296
Relapsed or refractory AML
Venetoclax + dinaciclib (CDK9 inhibitor) Phase Ib NCT03484520
Venetoclax + alvocidib (CDK9 inhibitor) Phase Ib NCT03441555
Venetoclax + ruxolitinib (JAK2 inhibitor) Phase I NCT03874052
Venetoclax + gilteritinib (FLT3 inhibitor) Phase I NCT03625505
Venetoclax + quizartinib (FLT3 inhibitor) Phase Ib/II NCT03735875
Venetoclax + AMG-176 (MCL1 inhibitor) Phase Ib NCT03797261
Venetoclax + S64315 (MCL1 inhibitor) Phase I NCT03672695
Venetoclax + cobimetinib (MEK inhibitor) or
Venetoclax + idasanutlin (MDM2 inhibitor)
Phase Ib/II NCT02670044
Venetoclax + lintuzumab-Ac225 (anti-CD33 monoclonal
antibody)
Phase I/II NCT03867682
Azacitidine + venetoclax + Lintuzumab-Ac225 Phase I/II NCT03932318
Venetoclax + HDM201 (MDM2 inhibitor) Phase I NCT03940352
Venetoclax + selinexor (XPO1 inhibitor) Phase I NCT03955783
AML, acute myeloid leukemia; LDAC, low-dose cytarabine.
G Richard-Carpentier and CD DiNardo
journals.sagepub.com/home/tah 11
therapeutic avenue to further improve outcomes
in older patients with FLT3- or IDH1/2-mutated
AML (Table 3). FLT3 mutation is the most fre-
quent molecular alteration in AML occurring in
25–30% of cases and is associated with a higher
risk of death and relapse.36–38 In the study evaluat-
ing venetoclax plus LDAC, patients with FLT3
mutations had a lower CR/CRi of 44% and shorter
median OS of 5.6 months, whereas responses and
survival were similar to the global population in
the study evaluating venetoclax plus HMA
(Table 1).19,20 Addition of FLT3 inhibitors to
these venetoclax-based regimens may increase the
remission rates and survival, especially consider-
ing the added benefit of sorafenib to azacitidine
demonstrated in patients with untreated or
relapsed/refractory AML with FLT3-ITD muta-
tion.39,40 In the ongoing study at MD Anderson
evaluating 10-day DAC plus venetoclax in older
AML patients ineligible for intensive chemothe-
rapy, patients with FLT3 mutations may also
receive a targeted FLT3 inhibitor [ClinicalTrials.
gov identifier: NCT03404193]. Additional
research is warranted to determine the benefit of
the addition of FLT3 inhibitor to venetoclax-
based combinations in untreated AML patients.
In patients with relapsed/refractory FLT3-mutated
AML, clinical trials evaluating venetoclax plus
gilteritinib and venetoclax plus quizartinib are
currently enrolling patients to improve upon the
efficacy of single-agent FLT3 inhibitors and test
the synergy of these combinations [ClinicalTrials.
gov identifiers: NCT03625505, NCT03735875].
Recurrent mutations in IDH1 or IDH2 occur in
15–25% of AML. Ivosidenib (IDH1 inhibitor)
and enasidenib (IDH2 inhibitor) can successfully
achieve remission in ~40% of patients with
relapsed or refractory AML harboring these
mutations.36–38,41,42 Both preclinical and clinical
studies have demonstrated that IDH1/2-mutated
AML has an increased sensitivity to veneto-
clax.19,20,43 In patients with IDH1/2-mutated
AML enrolled in the pivotal trials of venetoclax-
based combinations, the median OS was
19.4 months and 24.4 months, with LDAC and
HMA, respectively, which is longer than in the
global population of each study (Table 1).19,20
Based on the efficacy of IDH inhibitors and vene-
toclax in IDH1/2-mutated AML, it is likely that
combinations of these drugs will act synergisti-
cally in patients harboring these mutations. This
concept is currently being tested in a clinical trial
at the MD Anderson Cancer Center with a
combination of venetoclax and ivosidenib, with
or without azacitidine in patients with IDH1-
mutated AML [ClinicalTrials.gov identifier:
NCT03471260]. In preliminary results available
for 12 evaluable patients treated with ivosidenib
and venetoclax, the remission rate (including CR,
CR with partial hematologic recovery [CRh] or
CRi) was 75% comparing favorably with response
rates of ~40% with single-agent ivosidenib in
relapsed/refractory IDH1-mutated AML.44 So far,
no signal of significant added toxicity has been
observed with this regimen, suggesting that tri-
plet-drug combinations are likely to have a favora-
ble risk–benefit profile. However, longer follow up
with a higher number of patients is required to
confirm this statement, which may also be depend-
ent on which agents are combined together.
Other approaches currently under investigation
to improve venetoclax-based combinations in
older, untreated AML patients ineligible for
intensive chemotherapy include the combination
of azacitidine plus venetoclax with either gemtu-
zumab ozogamicin, an anti-CD33 antibody–drug
conjugate, avelumab, a programmed-cell-death-
ligand-1 inhibitor, or pevonedistat, a NEDD8-
activating enzyme inhibitor, based on results from
previous clinical trials evaluating these agents (or
other agents of the same family) in combination
with HMA. In relapsed/refractory AML, clinical
trials are evaluating the safety and efficacy of
venetoclax in combination with other experimen-
tal agents including, but not limited to, lintu-
zumab-Ac225, a CD33 monoclonal antibody,
selinexor, a selective inhibitor of nuclear export
specifically blocking XPO1, and HDM201, a
MDM2 inhibitor activating p53 in AML with
wild-type TP53 status (Table 3). Lastly, combi-
nation of venetoclax with panobinostat, a histone
deacetylase inhibitor, showed promising TP53-
independent activity in preclinical models of
AML.45 A clinical trial evaluating the combina-
tion of venetoclax plus HDAC inhibitor is planned
to open. This combination could be beneficial for
patients with TP53-mutated AML who continue
to have an adverse prognosis with venetoclax-
based combination therapies.
Conclusion
The prognosis of older AML patients ineligible
for intensive chemotherapy has been dismal for
decades. The addition of venetoclax to LDAC
and HMA therapies represent promising
Therapeutic Advances in Hematology 10
12 journals.sagepub.com/home/tah
combination therapies with impressive remission
rates and favorable OS, now FDA approved for
the treatment of newly diagnosed and older or
unfit AML patients. To reduce the risk of pro-
longed cytopenia and cytopenia-related compli-
cations such as febrile neutropenia and infections,
while maintaining optimal antileukemic activity,
proposed management guidelines are described
in this review and encouraged for patients treated
with venetoclax-based combinations. Awareness
of venetoclax dose reductions in the setting of
CYP3A4 inhibitors are essential to prevent toxic-
ity, and preventive measures and appropriate
monitoring for TLS are fundamental during the
first week of treatment during the venetoclax dose
ramp-up. Many clinical trials are currently ongo-
ing evaluating how to further improve upon com-
binations of venetoclax plus LDAC or HMA in
older AML patients ineligible for intensive
chemotherapy.
Funding
The authors received no financial support for the
research, authorship, and/or publication of this
article.
Conflict of interest statement
GR-C has no relevant conflict of interest to dis-
close. CDD discloses honoraria from Daiichi
Sankyo, Jazz Pharmaceuticals and Syros, and
consultant and advisory roles for Abbvie, Agios,
Celgene and Notable Labs.
ORCID iD
Courtney D. DiNardo https://orcid.org/0000-
0001-9003-0390
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