Venetoclax: A narrative drug review : Cancer Research, Statistics, and Treatment

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Drug Review

Venetoclax: A narrative drug review

Rajendra, Akhil; Sengar, Manju

Author Information
Cancer Research, Statistics, and Treatment: Jul–Sep 2022 - Volume 5 - Issue 3 - p 519-532
doi: 10.4103/crst.crst_179_22
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Abstract

INTRODUCTION

The highly conserved apoptotic pathways rest on the balance of the pro-apoptotic and anti-apoptotic proteins. Activation of the BCL2-associated X protein (BAX) and BCL2 homologue antagonist/killer (BAK) pathways induces apoptosis by triggering mitochondrial outer membrane permeabilization. The BCL2 homology proteins, BCL2L11 (BIM), BH3 interacting domain death agonist (BID), p53-upregulated modulator of apoptosis (PUMA), Noxa, and BCL2-associated agonist of cell death (BAD) antagonize these pro-apoptotic proteins by binding to the BH3 domain present on these proteins. BCL2 is frequently overexpressed in patients with lymphoid and myeloid hematologic malignancies. Early efforts by the scientists at the Walter and Eliza Hall Institute (WEHI) of Medical Research led to the identification of the role of BCL2 in promoting cancer cell survival. The collaboration of WEHI, Genentech, and AbbVie ultimately led to the development of BH3 mimetics. ABT-737 and ABT-263 were the initial BH3 mimetics to be developed. BH3 mimetics are molecules which were developed by reverse engineering to mimic the BH3-binding domains present on the pro-apoptotic molecules. BH3 mimetics bind to BCL2, keeping the BH3-binding domains on the pro-apoptotic molecules free and preventing the BCL2-mediated inhibition of the pro-apoptotic molecules. These pro-apoptotic molecules then create pores on the outer mitochondrial membrane followed by the release of cytochrome c and activation of caspase-9, leading to proteolytic cell death. The initial BH3 mimetics had broad activity against BCL2, BCL-XL, BCL-W, and myeloid cell leukemia-1 (MCL-1), resulting in thrombocytopenia. This led to the development of ABT-199 which is a highly potent and selective BCL2 inhibitor without the dose-limiting thrombocytopenia (due to less inhibition of BCL-XL). This BCL2 inhibitor is now known as venetoclax.[12] The key features of venetoclax are summarized in Table 1.

T1
Table 1:
Key features of venetoclax

METHODS

We searched for data on the websites of the United States Food and Drug Administration (US FDA), European Medicines Agency (EMA) drug manual,[34] PubMed, and UpToDate. We shortlisted the articles that had been published in English between 2012 and 2022. Out of a total of 397 full-text articles identified, we included 57. In addition, we also reviewed the abstracts and conference proceedings of the American Society of Hematology (ASH) 2021 meeting, American Society of Medical Oncology (ASCO) 2021 and 2022 meetings, European Society of Medical Oncology (ESMO) 2021 meeting, and the European Hematology Association (EHA) 2021 and 2022 meetings. Our search terms were “Venetoclax,” “AML,” “CLL,” “Pharmacology,” and “hematolymphoid malignancy.” We also performed an extensive internet search using Google to identify the ongoing trials of venetoclax. A flowchart of our search strategy is presented in Figure 1.

F1
Figure 1:
Flow diagram illustrating the methodology followed to identify the articles for the venetoclax drug review

PHARMACODYNAMIC PROPERTIES

Venetoclax is a selective first in class BCL2 inhibitor with an over 1000-fold affinity for BCL2 than for BCL-XL or BCL-W and no measurable binding to MCL-1. Venetoclax induces apoptosis in a non-TP53 dependent manner. Venetoclax binds directly to the BH3-binding groove of BCL2, rendering the pro-apoptotic molecules free of the inhibitory influence of BCL2, resulting in increased outer membrane permeabilization of the mitochondria followed by caspase-9 activation, leading to apoptosis. In view of the lack of activity on BCL-XL, platelets are spared.[2]

PHARMACOKINETIC PROPERTIES

Following multiple oral administrations, the maximum plasma concentration is reached 5–8 h after the dose. Administration with low-fat food and high-fat food leads to an increase in the venetoclax exposure. Venetoclax is highly bound to the plasma proteins. It is metabolized by cytochrome P450 3A (CYP3A) enzymes. The metabolite, M27, has 58-fold lower inhibitory activity. The elimination half-life (t½) is 26 h. The major route of elimination is via the feces (>99.9%). Asian patients have a 67% higher relative bioavailability in comparison to non-Asians. However, the exposure safety analyses did not show any difference in the toxicity profile between Asian and non-Asian populations.[5] Hence, dose adjustment is not recommended based on the ethnicity.[6]

Chemistry

The International Union of Pure and Applied Chemistry (IUPAC) name for venetoclax is 4-[4-{[2- (4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl] methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4 -ylmethyl) amino] phenyl} sulfonyl)-2-(1H-pyrrolo[2,3-b] pyridin-5-yloxy) benzamide. The chemical structure of venetoclax is depicted in Figure 2. It has a molar mass of 868.4 g/mol.[6]

F2
Figure 2:
Chemical structure of venetoclax

THERAPEUTIC EFFICACY

a. Venetoclax in chronic lymphocytic leukemia (CLL)

CLL cells have high levels of BCL2 expression which contributes to their resistance to apoptosis. Over the past decade, the therapeutic armamentarium of CLL has shifted from chemoimmunotherapy to targeted therapy. Two agents which are at the forefront of this new age therapy are ibrutinib targeting Bruton tyrosine kinase (BTK)[7] and venetoclax targeting BCL2. Venetoclax, by targeting BCL2, helps in causing apoptosis in a p53-independent manner. The role of venetoclax was first established in the M12-175 trial which was a phase I/II trial in patients with relapsed/refractory CLL/small lymphocytic lymphoma (SLL). This trial established that venetoclax is a potent agent in patients with CLL. The dose ramp-up schedule was established through the dose escalation phase of this trial. Venetoclax resulted in an objective response rate (ORR) of 77% (complete response/complete response with incomplete hematologic recovery [CR/Cri] in 30%), median time to first objective response rate of 6 weeks, and median progression-free survival (PFS) of 25 months (95% confidence interval [CI] 17–30 months).[8] The M13-982 trial was performed in a group of patients who had either relapsed/refractory disease or untreated 17p-deleted/TP53-mutated CLL. Venetoclax showed an ORR of 77% (CR/CRi in 20%), 24-month PFS of 54% and 24-month overall survival (OS) of 73%. In 30% patients, minimal residual disease (MRD) status was undetectable, and the median time to MRD negativity was 13.6 months (range, 2.9–27.6 months). Patients who were MRD negative had a superior PFS compared to those who were MRD positive (18 month PFS, 78% vs 51%).[9] After establishing that the combination of rituximab and venetoclax produced a clinically significant response in a phase II trial,[10] this combination was compared to chemoimmunotherapy (bendamustine + rituximab [BR]) in the MURANO trial.[11] The study population included was patients with relapsed/refractory CLL, irrespective of the 17p/TP53 deleted status. The 2-year PFS was significantly prolonged in the patients who received venetoclax–rituximab in comparison with patients who received BR (84.9% vs 36.3%; hazard ratio [HR], 0.17; 95% CI, 0.11–0.25; P < 0.001). Peripheral blood MRD-negativity rate at 9 months was higher in the venetoclax + rituximab arm (62.4% vs 13.3%).[11] The 4-year update of the MURANO trial reported that the PFS benefit persisted in the venetoclax + rituximab arm even after cessation of therapy. There was also a significant OS benefit (4-year OS, 85.3% vs 66.8%; HR, 0.41; 95% CI, 0.26–0.65; P < 0.001).[12]

The venetoclax + obinutuzumab combination was assessed in preclinical studies and found to produce greater B cell depletion than the venetoclax + rituximab combination or venetoclax alone.[13] Based on this, in the CLL14 trial, venetoclax + obinutuzumab was compared to chlorambucil + obinutuzumab (which was the then standard of care from the CLL11 trial).[14] Patients recruited had CLL and comorbidities (Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance (CrCl) <70 ml/min). The combination of venetoclax + obinutuzumab resulted in a significantly longer PFS (24-month PFS, 88.2% vs 64.1%; HR, 0.35; 95% CI, 0.23–0.53; P < 0.001). The MRD-negativity rate was higher in the venetoclax + obinutuzumab arm (peripheral blood 75.5% vs 35.2%, bone marrow 56.9% vs 17.1%) at 3 months after treatment completion.[15] There are no head-to-head comparative trials with BTK inhibitors in the treatment naïve or the relapsed setting. However, as suggested in the MURANO trial and the CLL14 trial, with the use of venetoclax, we could go back to a fixed-duration therapy. In the MURANO trial, venetoclax was administered for 24 months, whereas in the CLL14 trial, it was administered for 12 months. This underlines the fact that venetoclax leads to a deeper response, as evidenced by the superior MRD-negativity rate in the venetoclax arm across all the above-mentioned trials. On the other hand, ibrutinib needs to be administered continuously till disease progression/poor tolerance. The combination of venetoclax and ibrutinib was found to have a synergistic effect with non-overlapping toxic effects in preclinical studies.[16] This combination was used in a phase II study from the MD Anderson Cancer Center (Texas, USA). Ibrutinib was administered as monotherapy for three cycles. Venetoclax was added from the fourth cycle onwards. The combination was administered for a total of 24 cycles. Patients who became MRD negative at the end of 24 cycles were kept on observation. Patients, who remained MRD positive at the end of 24 cycles, were continued on ibrutinib until disease progression or the development of unacceptable toxic effects. At the end of 12 cycles, the rate of CR/CRi was 88% with 61% attaining MRD negativity. The estimated 1-year PFS and OS were 98% (95% CI, 94–100) and 99% (95% CI, 96–100), respectively.[17] The GLOW trial compared this combination (ibrutinib + venetoclax) with the combination of chlorambucil + obinutuzumab. Patients with TP53 mutation and 17p deletion were excluded. At a median follow-up of 27.7 months, ibrutinib + venetoclax resulted in a longer PFS (24-month PFS, 84.4% vs 44.1%; HR, 0.216; 95% CI, 0.131–0.357; P < 0.001). The MRD-negativity rate was significantly higher in the ibrutinib + venetoclax arm (55.7% vs 21%; P < 0.001).[12]

In conclusion, fixed-duration therapy with venetoclax in combination with obinutuzumab is a recommended first-line treatment for patients with CLL. This combination can be used in patients with or without 17p-deleted/TP53 mutation. Venetoclax in combination with ibrutinib has shown efficacy in comparison with chlorambucil + obinutuzumab. However, its efficacy needs to be compared to that of venetoclax + obinutuzumab. Venetoclax in combination with rituximab is a recommended second-line treatment. Single-agent venetoclax is a recommended agent for 17p-deleted CLL patients who have received one prior line of treatment.

b. Venetoclax in acute myeloid leukemia (AML)

Preclinical studies have confirmed that AML cell lines also express BCL2 and are dependent on BCL2 for their survival.[18] The first clinical trial of venetoclax was a phase II single-arm study in patients with relapsed/refractory AML. Venetoclax (800 mg daily) resulted in an ORR of 19% (CR in 6% and CRi in 13%). Antileukemic activity (not meeting the International Working Group [IWG] response criteria) was seen in an additional 19% patients. The 6-month leukemia-free survival was 10%, and the 6-month OS was 36%. Responses were more frequent in patients with isocitrate dehydrogenase (IDH) mutations.[19] The synergistic activity of venetoclax with a number of agents has been documented including chemotherapeutic agents like daunorubicin and cytarabine, epigenetic regulators like azacytidine and panobinostat, and targeted agents like quizartinib, enasidenib, and alvocidib.[20] The combination of venetoclax with hypomethylating agents was first studied in a phase Ib trial in which venetoclax was combined with either azacytidine or decitabine. Patients included in this trial had newly diagnosed AML, were 65 years or older, and were unfit for standard induction chemotherapy. In the dose escalation arm of the study, venetoclax was ramped up to either 400 mg, 800 mg, or 1200 mg. During the dose escalation phase of the study, the 1200 mg dose was found to be associated with a high rate of grade 3 gastrointestinal and hematological side effects, leading to the use of the 400 mg and 800 mg doses in the dose expansion cohort. At a median follow-up of 15 months, the CR + CRi rate was 67%, the median duration of CR + CRi was 11.3 months (95% CI, 8.9—NR) and the median OS was 17.5 months (95% CI, 12.5—NR). The median time to first response was 1.2 months (range, 0.8–13.5 months). Among the patients with CR + CRi, the MRD-negativity rate was 29%. In the subgroup analysis, patients with nucleophosmin 1 (NPM1) mutation and IDH mutation had a superior survival compared to patients with poor-risk cytogenetics and TP53 mutation.[21] These results were superior to those in the historical cohort treated with hypomethylating agents alone (CR + CRi rate 30% and median OS, 7.7–10.4 months).[222324] The confirmatory phase III trial (VIALE-A) compared the combination of azacytidine + venetoclax with azacytidine alone in patients over 65 years old who were unfit for intensive chemotherapy. The median OS in the overall population was significantly better for the combination therapy (14.7 months vs 9.6 months; HR, 0.66; 95% CI: 0.52–0.85; P < 0.001). Both the CR + CRi rate and the median duration of response (DOR) were also improved from 28.3 to 66.4% (P < 0.001), and 13.9 months to 17.8 months, respectively.[25] Similarly, after the excellent results obtained from the combination of low-dose cytarabine and venetoclax in a phase Ib/II trial,[26] the combination was compared to single-agent low-dose cytarabine in a randomized phase III trial, VIALE-C. At the primary analysis, the study did not meet its primary objective of improvement in OS (7.2 months vs 4.1 months; HR, 0.75; 95% CI, 0.52–1.07).[27] However, after an additional unplanned 6-month follow-up, the median OS in the patients treated with the venetoclax + low-dose cytarabine combination was 8.4 months versus 4.1 months for the patients who received low-dose cytarabine (HR, 0.70; 95% CI, 0.50–0.99; P = 0.04).[28]

Based on these results, the FDA granted approval for the combined use of venetoclax with azacytidine or decitabine or low-dose cytarabine in older patients with newly diagnosed AML who were unfit for intensive therapy.[29] The use of venetoclax in combination with intensive therapy has been studied in a non-randomized fashion which has resulted in encouraging results in the form of CR rate of 91% (95% CI, 76–98%), MRD negativity of 97% (95% CI, 83–100%), estimated 1-year EFS of 72% (95% CI, 56–94%), and estimated 1-year OS of 97% (95% CI, 91–100%). Venetoclax was administered during induction on day 4 (100 mg), day 5 (200 mg), and days 6–11 (400 mg).[30] Additional randomized trials are needed to establish the efficacy of venetoclax in combination with intensive therapy.

Off-label indications for venetoclax

i. Relapsed/Refractory mantle cell lymphoma

In a phase I study of venetoclax in 106 patients with relapsed/refractory non-Hodgkin’s lymphoma, there were 28 patients with mantle cell lymphoma. This study noted that patients with mantle cell lymphoma had the best ORR of 75%, with a CR rate of 21% and a median PFS of 14 months.[31] In view of the preclinical evidence of synergism between ibrutinib and venetoclax in mantle cell lymphoma,[323334] a phase II trial was conducted (AIM trial).[35] This was an investigator-initiated single-arm study using a combination of ibrutinib and venetoclax in patients with relapsed/refractory mantle cell lymphoma and those with untreated mantle cell lymphoma who were unfit for standard cytotoxic therapy. Patients received ibrutinib at 560 mg once daily for the first 4 weeks followed by a ramp-up schedule of venetoclax. The steady-state dose was 400 mg once daily. Following an amendment in the study protocol, the dose of venetoclax was increased to 800 mg in the patients who did not achieve a CR. The study included 24 patients (23 had relapsed/refractory and one had untreated mantle cell lymphoma); the median follow-up was 15.9 months. At week 16, the CR rate was 42% (non-positron emission tomography [PET] assessment) which was significantly superior to the results obtained with ibrutinib in a historical cohort (9%; P < 0.001).[36] When PET responses were also included, the CR rate at week 16 was 62%. MRD negativity (as per flow cytometry) was attained in 67% patients. The median PFS and OS were not reached, PFS and OS at 12 months were 75% (95% CI, 60–94%) and 79% (95% CI, 64–97%), respectively, and at 18 months were 57% (95% CI, 40–82%) and 74% (95% CI, 57–95%), respectively.[35]

In conclusion, there is enough evidence to establish the activity of venetoclax in mantle cell lymphoma. Single-agent venetoclax can be used in patients with relapsed/refractory mantle cell lymphoma. The combination of venetoclax + ibrutinib can be used in patients who have failed one prior line of therapy. However, its efficacy over ibrutinib monotherapy in this setting has not been established in a randomized controlled trial.

ii. Relapsed/refractory multiple myeloma

Preclinical data have shown increased sensitivity of myeloma cell lines to venetoclax. This increased sensitivity was particularly seen in myeloma cells which were positive for t (11;14).[37] A phase I trial in patients with relapsed/refractory multiple myeloma evaluated the use of venetoclax as single-agent therapy. At the end of the dose escalation phase of the study, the 400 mg and 1200 mg doses were planned as the starting dose and maximum planned doses, respectively. In this cohort of 66 patients, the ORR was 21%, very good partial response (VGPR) was achieved in 15%, and the median DOR was 9.7 months (95% CI, 7—not reached). Responses were predominantly seen in patients with t (11;14) translocation. In the subset of patients with t (11;14), the ORR was 40% and the VGPR was 27%.[38] The use of dexamethasone and bortezomib along with venetoclax in preclinical models was found to be synergistic.[3940] Subsequently, a phase I trial using this combination reported an ORR of 67%. The recommended phase 2 dose (RP2D) of venetoclax was 800 mg once daily.[41] A phase III double-blind randomized trial, BELLINI, was conducted using either venetoclax or placebo in combination with bortezomib and dexamethasone for relapsed/refractory multiple myeloma. At a median follow-up of 18.7 months, the ORR and VGPR rates were significantly higher in the venetoclax combination arm, with a doubling of the median PFS (22.4 months vs 11.5 months; HR, 0.63; 95% CI, 0.44–0.9; P < 0.01). MRD negativity was achieved in 13% patients. This trial had 114 patients with either t (11;14) translocation or high BCL2 expression (as assessed using the polymerase chain reaction [PCR]). In this cohort of 114 patients, the median PFS was not reached in the venetoclax combination arm (NR vs 9.9 months in the placebo combination arm; HR 0.21; 95% CI, 0.11–0.41; P < 0.0001), the ORR was 85% (vs 70% in the placebo combination arm), and MRD negativity was 19% (vs 0 in the placebo combination arm). In contrast, in patients without t (11;14) translocation and with low BCL2 expression, there was no difference in the median PFS between the venetoclax and placebo combination arms. In addition, there were early signals in this study to suggest a higher infection-related mortality in the first 30 days in patients whose disease was negative for the t (11;14) translocation, had low BCL2 expression, and who received the venetoclax combination. Thus based on these reports, venetoclax (in combination with bortezomib and dexamethasone) can be used in patients with relapsed/refractory multiple myeloma with t (11;14) translocation and/or high BCL2 expression.[42]

iii. DLBCL

Attempts to improve upon the outcomes of standard chemoimmunotherapy in patients with DLBCL have been made over the last decade with the use of lenalidomide, ibrutinib, and bortezomib along with conventional chemoimmunotherapy. But these combinations have not resulted in statistically significant improvements in survival in the phase III studies.[434445] Overexpression of BCL2 and rearrangements involving BCL2 have been associated with inferior outcomes. Hence, attempts were made to target BCL2 in these patients. The phase IB CAVALLI study established the potential of venetoclax as a rational targeted agent with chemotherapy-sensitizing capability when used along with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP), albeit with increased grade 3 and 4 hematological toxicities. The RP2D of venetoclax was 800 mg once daily on days 4 to 10 in cycle 1, and days 1 to 10 in cycles 2 to 8.[46] The single-arm CAVALLI phase II study combined venetoclax with R-CHOP and was compared with the historic GOYA study.[47] After a median follow-up of 32 months, the venetoclax + R-CHOP combination produced a significantly prolonged PFS (80% vs 67%; HR, 0.61; 95% CI, 0.43–0.87). However, in the overall population there was no significant difference in OS as compared to the historical cohort (86% vs 81%; HR, 0.72; 95% CI, 0.48–1.1). There was a trend toward improvement in survival in the subgroup of patients with BCL2 overexpressed DLBCL (83% vs 75%; HR, 0.67; 95% CI, 0.38–1.19).[48]

In conclusion, there is evidence to suggest the activity of venetoclax in patients with DLBCL; however, randomized trials will be needed to determine its place in the treatment landscape of DLBCL.

VENETOCLAX IN THE INDIAN SCENARIO

Venetoclax has not yet been approved for use in India.[49] However, patients can procure venetoclax after completing the appropriate import procedures. Indian patients with AML are a decade younger that those in the West, with 63% of them presenting with infection and 55% having multi-drug resistant (MDR) infection, precluding them from the use of intensive chemotherapy.[50] A case series from India included seven patients who were unfit for intensive chemotherapy and were treated with the combination of venetoclax and azacytidine. All seven patients attained early hematological recovery with a median time to complete recovery of 35 days (range, 22–60) and six patients attained morphological remission. At a median follow-up of 8 months, four patients were alive and in remission. Consolidation with high-dose and intermediate-dose cytarabine was given in three patients after the attainment of complete remission.[51] A single-center prospective observational study from India included 26 AML patients with clinicoradiologic evidence of infection, Eastern cooperative oncology group performance status ≥2, or comorbidities. Therapy was individualized based on the performance status, comorbidities, and the nature of infection. Cohort A received azacytidine and venetoclax till progression. This treatment was preferred in patients who were unfit for the 7 + 3 (cytarabine 100–200 mg/m2 continuous infusion daily for 7 days + daunorubicin 60–90 mg/m2 daily for 3 days) regimen. Cohort B received venetoclax along with the modified 7 + 3 regimen. Cytarabine infusion 100 mg/m2 was administered to all patients. The dose of daunorubicin was based on the severity of the infection. Patients who achieved a complete remission and had cleared the previous infection were consolidated with high-dose cytarabine. At 1 year, the RFS was 66.7% in cohort A and 100% in cohort B. At 1 year, the OS was 76.2% in cohort A and 74% in cohort B.[52] Thus, in young patients who are unfit for 7 + 3 induction, azacytidine + venetoclax or venetoclax induction with individualized dosing of daunorubicin and cytarabine can be considered.

TOLERABILITY

Venetoclax had an acceptable tolerability profile in patients with CLL and AML. The most common adverse events, grade 3/4 adverse events, and serious adverse events are summarized in Table 2.

T2
Table 2:
Safety profile of venetoclax

DOSAGE AND ADMINISTRATION

  1. General considerations
  2. In view of the risk of development of tumor lysis syndrome (TLS), venetoclax is administered in a ramp-up fashion in both AML and CLL. In AML, the ramp-up is done over 3–4 days, whereas in CLL, the ramp-up is done over a period of 5 weeks. The ramp-up schedule is summarized in Table 3.
  3. Special considerations:
    1. TLS prophylaxis for CLL
    2. In view of the high risk of TLS, especially in patients with CLL, the ramp-up schedule is performed over a period of 5 weeks. Prior to initiation of therapy with venetoclax, the risk of TLS should be assessed. The risk of development of TLS in CLL is determined by the tumor burden and the absolute lymphocyte count.[11] The risk stratification used in CLL is summarized in Table 4. It must be noted that the risk stratification used here is different from that proposed by Jones et al.[53]
      Pre-treatment TLS prophylaxis to be used based on the risk stratification is summarized in Figure 3.[3] After the appropriate TLS measures have been instituted, venetoclax is started at a dose of 20 mg once daily. Following the first dose, the TLS parameters should be checked 6–8 h after administration, as this is when the earliest change of TLS can occur. The subsequent day’s dose should be administered only after the TLS parameters have been assessed. Before and after each dose ramp-up, the TLS parameters should be checked. A summary of the monitoring for the dose ramp-up is provided in Figure 4.[54] The extended ramp-up schedule used in CLL ensures that the cell kill observed is gradual, reducing the risk of tumor lysis.
    3. TLS prophylaxis for AML
    4. The dose ramp of venetoclax in patients with AML is over 3–4 days. Patients who are at high risk for tumor lysis (elevated white blood cell count, baseline abnormal TLS parameters) may need hospitalization prior to the initiation of therapy. This is summarized in Figure 5.
    5. Venetoclax in special populations
      1. Pediatric population
      2. The safety and efficacy of venetoclax in children and adolescents has not been studied; hence, it is not recommended for pediatric use.
      3. Pregnancy
      4. Venetoclax should not be used during pregnancy. Its use in pregnant mice during the period of organogenesis resulted in post-implantation loss, intrauterine growth retardation (IUGR), and an increase in the early termination of pregnancy.[5556]
      5. Lactating women
      6. Data regarding excretion of venetoclax via milk is not available. It is recommended to discontinue breastfeeding during treatment with venetoclax.[5556]
      7. Renal insufficiency
      8. No dose adjustment is recommended for mild, moderate, or severe renal impairment.[57]
      9. Hepatic insufficiency
      10. No dose adjustment is recommended for mild (normal total bilirubin and aspartate transaminase > upper limit of normal (ULN) or total bilirubin 1–1.5 × ULN) or moderate hepatic impairment (total bilirubin >1.5–3 × ULN). A 50% dose reduction is recommended during the initiation, ramp-up phase and during the steady-state period for severe hepatic impairment (total bilirubin >3 × ULN).[57]
  4. Drug Interactions and Dose modifications
  5. Interactions of venetoclax are primarily centered around the following enzymatic reactions—
    • Venetoclax is metabolized by CYP3A4
    • Venetoclax is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)
    • Venetoclax is a P-gp and BCRP inhibitor and a weak inhibitor of organic anion transporting polypeptide 1B1 (OATP1B1).
    The important interactions of venetoclax are summarized in Table 5.
    The dose modifications of venetoclax for potential interactions are summarized in Table 6.
  6. The approved indications and dosing of venetoclax are summarized in Table 7.
  7. Dose modifications are summarized in Tables 8-10.

F3
Figure 3:
Risk-based tumor lysis syndrome prophylaxis for venetoclax in chronic lymphocytic leukemia
F4
Figure 4:
Dose ramp-up schedule with tumor lysis syndrome (TLS) monitoring in chronic lymphocytic leukemia
F5
Figure 5:
Dose ramp-up schedule with tumor lysis syndrome monitoring in acute myeloid leukemia (WBC = white blood cell; TLS = tumor lysis syndrome)
T4
Table 4:
CLL Risk stratification for tumor lysis syndrome (pre-treatment)
T3
Table 3:
Ramp-up schedule of venetoclax
T5
Table 5:
Important interactions of venetoclax
T6
Table 6:
Management of potential venetoclax interactions with CYP3A inhibitors and P-gp inhibitors
T7
Table 7:
Approved indications and dose
T8
Table 8:
Dose modification in CLL
T9
Table 9:
Dose reduction for toxicity during venetoclax treatment for chronic lymphocytic leukemia
T10
Table 10:
Dose modification in acute myeloid leukemia (AML)

Important ongoing clinical trials investigating the use of venetoclax are summarized in Table 11.

T11
Table 11:
Ongoing clinical trials of venetoclax

CONCLUSIONS

Selective BCL2 inhibition which has been in preclinical development over the past two decades has finally achieved fruition with the development of venetoclax. With the introduction of venetoclax into the therapeutic armamentarium of CLL, we now have a non-chemotherapy fixed-duration regimen with long-term remissions. In patients with AML, the use of venetoclax has resulted in long-term remissions in older patients who were previously treated with regimens that produced dismal outcomes. The understanding of the dependence of BCL2 in the biology of other B cell malignancies is pushing venetoclax into the other hematological malignancies as evidenced by the excellent results seen in relapsed/refractory mantle cell lymphoma and relapsed/refractory multiple myeloma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

Apoptosis; BCL2; targeted therapy; venetoclax

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