Keywords
Acute myeloid leukemia - B-cell lymphoma-2 inhibitor - chronic lymphocytic leukemia
- venetoclax
Introduction
Hematological malignancies such as lymphoma, acute leukemia, and multiple myeloma
comprise 6.5% of all malignancies.[1] The emergence of various targeted therapies has altered the therapeutic landscape
of these diseases. Chemotherapy, the backbone of hematological malignancies, is now
being gradually replaced by various targeted therapies with a better safety profile.
The discovery of a new class of pro-apoptotic agents has become an important inclusion
in the armamentarium to treat these cancers, irrespective of genetic diversities.[2]
Venetoclax, formerly known as ABT-199, a novel B-cell lymphoma-2 (BCL-2) inhibitor,
has proven its therapeutic safety and efficacy, particularly in chronic lymphocytic
leukemia (CLL) and also in acute myeloid leukemia (AML).[3] Venetoclax is unique for its specificity for BCL-2 protein coupled with minimal
hematological toxicities, making its widespread use in other low-grade BCLs.[4] Combination therapy with this drug has also being tested in acute leukemia such
as acute lymphoblastic leukemia (ALL) and aggressive lymphomas.[5]
Discovery
Professor Andrew Roberts, a hematologist from the Walter and Eliza Hall Institute
of Australia, in 1988, found that BCL-2 protein had a role in cancer progression.[6] His team then noticed that venetoclax had shown a remarkable response in the killing
of leukemic cells in animal models. This led to the development of venetoclax as a
potential cure for CLL and other hematological malignancies.
Mechanism of Action
Venetoclax is a BH-3 mimetic group of oral agents. It is a BCL-2 and BCL-XL inhibitor
which promotes apoptosis.[7] After binding with BCL-2 protein, it activates caspase with displacement of apoptotic
inducers such as BIM and BAX, thereby leading to initiation of apoptotic pathway and
cell killing. It has a greater affinity with BCL-2 with significantly reduced activity
against BCL-XL protein which is responsible for thrombocytopenia.[8]
Approved Indications With Food and Drug Administration Approval Status
Approved Indications With Food and Drug Administration Approval Status
-
17p deleted CLL post first-line failure – Food and Drug Administration (FDA) approval
in 2016
-
CLL irrespective of the p53 status post first-line failure in 2018 gained FDA approval
-
Elderly AML in combination with hypomethylating agents – FDA approval in 2018
-
All patients with CLL in first line – FDA approval in 2019.
Pharmacokinetics
-
Distribution: Volume of distribution – 256–321 L
-
Protein binding: Highly bound to plasma protein
-
Metabolism: Hepatic, predominantly via CYP3A
-
Half-life (elimination): 26 h (approximately)
-
Time to peak: 5–8 h
-
Excretion: Predominantly via feces (>99.9%).
Dosage and Administration Instructions
Dosage and Administration Instructions
Tablets are available in three strengths (10 mg, 50 mg, and 100 mg), and it should
be taken with meal and water. The dosing depends as per disease site. In CLL, an escalating
dose schedule over the first 5 weeks [Table 1]a] and 400 mg once daily until unacceptable toxicity or disease progression thereafter
is recommended, whereas in AML, the dose is escalated in the first 4 days along with
azacitidine or decitabine or low-dose cytarabine [Table 1]b]. Such kind of dose escalation strategy is adopted to debulk the tumor burden, reduce
the chance of developing tumor lysis syndrome (TLS), and to check the tolerance of
the drug. Venetoclax has significant drug interactions with concomitant use of CYP3A
inhibitors such as imatinib, crizotinib, aprepitant, spironolactone, and various azoles
(except posaconazole). Drug interactions have also been seen with P-glycoprotein inhibitors
such as amiodarone, statins, and proton-pump inhibitors. The dose of venetoclax needs
to be reduced by 50% when used concomitantly with these agents.
Table 1a
Escalating dose schedule in first 5 weeks in chronic lymphocytic leukemia
|
Week
|
Recommended daily dose level (mg)
|
|
1
|
20
|
|
2
|
50
|
|
3
|
100
|
|
4
|
200
|
|
5
|
400
|
Table 1b
Escalating dose schedule in first 4 days in acute myeloid leukemia
|
Day
|
Recommended daily dose (mg)
|
|
1
|
100
|
|
2
|
200
|
|
3
|
400
|
|
4 and beyond
|
400 (with azacitidine or decitabine)
|
|
4 and beyond
|
600 (with low-dose cytarabine)
|
Common Side Effects
Hematologic side effects
-
Neutropenia – In patients with AML with Grade 4 neutropenia occurring upfront, the
drug is not withheld. However, in patients who have post remission, then the next
dose is delayed till the recovery of counts
-
Febrile neutropenia – For the first occurrence with Grade ≥3 neutropenia with fever
and or infection, interrupt venetoclax till the recovery of counts and then it may
be restarted at the same dose level. For second and subsequent episodes, dose reduction
should be done [Table 2]. Consider discontinuing venetoclax for patients who require dose reductions to <100
mg for more than 2 weeks
-
Anemia
-
Thrombocytopenia.
Table 2
Dose de-escalation strategy for toxicity during venetoclax therapy
|
Dose at interruption (mg)
|
Restart dose (mg)*
|
|
*During the ramp-up phase, continue the reduced dose for 1 week before increasing
the dose
|
|
400
|
300
|
|
300
|
200
|
|
200
|
100
|
|
100
|
50
|
|
50
|
20
|
|
20
|
10
|
Nonhematologic side effects
-
TLS – In patients with laboratory TLS or clinical TLS post initiation of venetoclax,
the drug for the next day is withheld. If the TLS requires more than 48 h to resolve,
then the drug is restarted at a reduced dose [Table 2]. Blood biochemistry (uric acid, creatinine, potassium, phosphorus, and calcium)
should be done periodically during therapy to monitor TLS parameters
-
Diarrhea
-
Edema
-
Upper respiratory tract infection.
Landmark Trials
Phase I and II trial
A Phase I trial was conducted to optimize the dose of venetoclax in relapsed CLL.
Among the two different subgroups, the dose-escalation group was treated with dose
schedules from 20 mg weekly to 1200 mg daily, whereas the expansion cohort group was
treated with 20 mg daily followed by a stepwise increase up to 400 mg weekly. The
overall response of the entire cohort was 79%, with TLS reported as a dose-limiting
toxicity.[9] Its role in relapsed multiple myeloma and B-cell non-Hodgkin lymphoma (NHL) is ongoing.
A Phase II study by Jain et al. among treatment naïve high risk elderly CLL populations treated with ibrutinib monotherapy
(420 mg daily) for three cycles followed by adding venetoclax (weekly dose escalation
to a target dose of 400 mg daily) from cycle four onwards. This combination therapy
was given for two years' duration (total 24 cycles). At 1 year, 88% of patients were
in complete remission and 61% achieved undetectable minimal residual disease (MRD)
in the bone marrow.[10]
MURANO trial
The Phase III randomized trial (MURANO) established the role of venetoclax with rituximab
in comparison to bendamustine with rituximab with a superior overall survival and
progression-free survival (PFS) benefit in patients with relapsed CLL irrespective
of p53 status.[11] The 2-year PFS rate was significantly higher (84% vs. 36%) in the venetoclax arm.
Although the rate of Grade 3 and Grade 4 neutropenia was higher in the venetoclax
and rituximab group, the rate of febrile neutropenia and infection was less in comparison
with the bendamustine arm.[11]
VIALE trial
Venetoclax received accelerated approval for the treatment of elderly AML who are
unfit for intensive chemotherapy based on the Phase 1 and 2 VIALE trials which compared
venetoclax with low-dose azacytidine (LDAC) versus LDAC alone.[12] This showed to have improved PFS in the venetoclax arm with superior complete remission
rates.
Cost-Effectiveness
The cost-effectiveness of venetoclax was measured in a cost-effective model which
showed to have a lower cost than bendamustine plus rituximab- and ibrutinib-based
combinations in the treatment of CLL over a 12-month duration.[13]
Newer Uses in the Pipeline
Newer Uses in the Pipeline
There have been recent evidences on the use of venetoclax in certain aggressive NHL
such as refractory mantle cell lymphoma,[14] relapsed diffuse large B-cell lymphoma,[15] and relapsed follicular lymphoma.[16] Recent clinical trials have also suggested the use of venetoclax in refractory ALL,
especially T-ALL and relapsed multiple myeloma with (11:14) translocation.[17]
Take-Home Points
-
Venetoclax is the first selective BCL-2 inhibitor
-
It is approved by FDA in CLL and AML
-
Its role in other B-cell NHLs, multiple myeloma, and ALL is now being tested either
in monotherapy or in combination in several clinical trials
-
It is used in escalating doses in CLL and AML.
-
TLS and neutropenia are the most common adverse reactions.
Conclusion
Venetoclax might become an important therapeutic agent against several hematological
malignancies in the near future considering the acceptable toxicity profile. It is
effective after failure of ibrutinib in CLL, but reverse is not true. In relapse/refractory
CLL, this drug attained higher rates of MRD negativity in peripheral blood and bone
marrow. We can predict that in the future, venetoclax either in monotherapy or in
combination will achieve landmark milestones in the treatment of different hematological
malignancies.
