The Emerging Role of Venetoclax for Hematologic Malignancies Beyond Chronic Lymphocytic Leukemia

Jeffrey Baron, PharmD BCOP
Clinical Pharmacy Specialist
Roswell Park Cancer Institute
Buffalo, NY

Eugene Przespolewski, PharmD BCOP
Clinical Pharmacy Specialist
Roswell Park Cancer Institute
Buffalo, NY

Venetoclax is currently approved by the U.S. Food and Drug Administration (FDA) for patients with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) who harbor a 17p deletion, with 71% of such patients responding to therapy and 20% achieving complete response (CR).^1,2 Venetoclax is a B-cell leukemia/lymphoma-2 (BCL-2) inhibitor that, when given, results in activation of pro-apoptotic pathways² to which CLL is exquisitely sensitive, leading to a high incidence of tumor lysis syndrome (TLS) in CLL. To mitigate this risk, the FDA approval information for CLL advises that venetoclax be dosed on a weekly ramp-up schedule with additional supportive care and possible inpatient admission, depending on the disease burden and preexisting hyperuricemia.¹ Overexpression of BCL-2 is not unique to CLL and is found in non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and acute myeloid leukemia (AML), leading to trials exploring the use of venetoclax in treating these malignancies.

Non-Hodgkin Lymphoma and Multiple Myeloma
Overexpression of BCL-2 is observed in many subtypes of NHL. The phase 1 dose-escalation M12-175 trial led to the FDA approval of venetoclax for CLL, but it also included patients with NHL subtypes such as mantle cell lymphoma (MCL); follicular lymphoma (FL); diffuse large B-cell lymphoma (DLBCL), including those with Richter transformation; marginal zone lymphoma (MZL); and Waldenstrom macroglobulinemia (WM).⁴ Venetoclax doses were escalated in a 3+3 design from 200 mg to 1,200 mg. The maximum tolerated dose (MTD) was not reached, and safety expansion proceeded with the 1,200-mg daily dose. Overall response rates (ORR) were 75% in MCL, 38% in FL, 18% in DLBCL, 43% in DLBCL with Richter transformation, 67% in MZL, and 100% in WM. The median progression-free survival (PFS) for the entire population was 6 months but varied among the histologies. These encouraging data led to further studies examining venetoclax in NHL.

Venetoclax in combination with ibrutinib in RR MCL has been studied in a phase 2 trial, given that ibrutinib can decrease MCL-1 levels and possibly prevent venetoclax resistance.⁵ Twenty-four patients received ibrutinib 560 mg daily for 4 weeks followed by venetoclax ramp-up to a target of 400 mg daily (this was a lower dose than the single-agent dose because of potential overlapping toxicities and pharmacokinetic interactions). At 16 weeks, 63% achieved CR. The ongoing phase 3 trial of ibrutinib and venetoclax is based on these encouraging data.⁶ Venetoclax has also been combined with bendamustine and rituximab (BR) in RR FL.^7,8 In a three-arm trial (venetoclax plus rituximab, venetoclax plus BR, and BR alone), the ORR for venetoclax and rituximab was 32% but was 64% in patients not refractory to prior therapy, with 50% achieving CR. Outcomes with venetoclax plus BR versus BR alone were similar, with both showing approximately 65% ORR but greater CRs with the addition of venetoclax (50% vs. 41%).

The efficacy of venetoclax in MM is most promising for patients with t(11;14).⁹ In a phase 1 dose-escalation study, 66 RR MM patients received 21-day cycles of venetoclax at daily doses of 300–1,200 mg without reaching the MTD. Although the ORR was only 21%, 12 out of 14 responders harbored t(11;14), with a median duration of response (DOR) of 10 months. Very good partial responses (VGPRs) were noted in 10 out of 12 t(11;14) patients. Venetoclax has been combined with bortezomib in MM to mitigate venetoclax resistance.¹⁰ In a phase 1b study of venetoclax, bortezomib, and dexamethasone, an ORR of 67% was observed, with greater than 50% of patients achieving at least a VGPR independent of the presence of t(11;14), with a median DOR of 10 months.

Clinical TLS was not observed in trials of venetoclax in MM and was rare in single-agent venetoclax trials in NHL.^9,10 Clinical TLS occurred only in 2 patients with MCL treated in the ibrutinib and venetoclax combination study.⁵ Laboratory TLS occurred in both the single-agent phase 1 venetoclax NHL trial and in combination with BR.^4,7 The most common adverse event (AE) was gastrointestinal distress, and the most severe AE was myelosuppression. Risk of TLS correlates most closely with disease characteristics and patient-associated risk factors.

Acute Myeloid Leukemia
Older patients with AML who are unable to tolerate induction are commonly managed with low-intensity therapy such as hypomethylating agents (HMAs; azacitidine and decitabine) or low-dose cytarabine (LDAC), limited by low response rates and short overall survival (OS). However, the activity of HMAs, which act via epigenetic modification of p53 and the anti-apoptotic pathway, provides a compelling rationale for BCL-2 inhibition with venetoclax as a single agent and in combination with chemotherapy.

The safety and efficacy of venetoclax in high-risk RR AML or newly diagnosed (ND) patients deemed unfit for induction was established via a phase 2 single-arm study.¹¹ Thirty-two patients received single-agent venetoclax 800 mg daily, with a 19% ORR, enriched for patients with isocitrate dehydrogenase (IDH) mutations, which showed 33% CR or CR with incomplete count recovery (CRi) rate. Following these encouraging results, venetoclax was evaluated in combination with LDAC in a phase 1b/2 study for ND AML in patients 65 years and older who were considered unfit for induction.¹² Venetoclax was given as a 5-day dose escalation starting at 50 mg daily up to a target dose of 600 mg daily with LDAC on days 1–10 of a 28-day cycle. Seventy percent achieved a CR or CRi, with 1 year OS estimated to be 75%. Notably, median time to response was 30 days, a shorter period than that of the 2–4 cycles often required for HMAs. A long-term update has been presented by 71 patients enrolled with a 62% CR or CRi and median DOR of 15 months. Venetoclax 600 mg daily plus LDAC is being evaluated.

Venetoclax has also been combined with HMAs in the treatment of elderly patients who have ND AML and intermediate- or poor-risk cytogenetics in a phase 1b study.¹³ Patients were enrolled in one of three groups: (A) venetoclax plus decitabine 20 mg/m² on days 1–5, (B) venetoclax plus azacitidine 75 mg/m² on days 1–7, and (C) venetoclax plus decitabine (dosed as above) with posaconazole (to assess venetoclax pharmacokinetics). Venetoclax dose escalation followed a standard 3+3 design up to 1,200 mg daily. Fifty-seven patients were enrolled: 23 in group A, 22 in group B, and 12 in group C. Overall, 61% achieved CR or CRi. An updated report described results for 145 patients enrolled; 60 received venetoclax 400 mg, 74 received venetoclax 800 mg, and 11 received venetoclax 1,200 mg, with an ORR of 83%, including 66% CR or CRi and a median OS of 17.5 months. Venetoclax 400 mg daily was determined to be the optimal dose and is currently being evaluated in a phase 3 study with HMAs.

The efficacy of venetoclax in combination with LDAC or HMAs in AML is encouraging. It is important to note that no new safety signals were identified. The most common AEs were gastrointestinal distress and myelosuppression. One patient who received venetoclax plus LDAC developed tumor lysis. This low TLS incidence may be due to lesser tumor burden compared to CLL patients with leukocytosis and lymphadenopathy. However, in all the AML trials discussed above, the first cycle was administered on an inpatient basis with a dose-escalation phase, which may complicate interpretation of the true risk if the therapy had been given on an outpatient basis.

Conclusion
Venetoclax is the first FDA-approved BCL-2 inhibitor, and data are rapidly emerging on its use in treating numerous hematologic malignancies that are sensitive to BCL-2 inhibition, including NHL, MM, and AML. As oncology pharmacists, we are in an ideal position to assist in identifying patients who may benefit from this agent and to assist in toxicity management. Across the studies discussed above, laboratory TLS appears to be uncommon, and clinical TLS even less common. Risk for TLS appears to be tied to the disease and the patient; those with high tumor burden, aggressive disease characteristics, and patient-related risk factors seem to be at highest risk. For AML patients starting venetoclax at our institution, the first cycle is administered on an inpatient basis for TLS monitoring. Patients with NHL and MM are monitored in an observation status for the first few days of each early dose escalation.

We can also assist with drug acquisition and insurance coverage. NHL, MM, and AML are currently off-label indications, so insurance coverage is highly variable, but this situation may improve with the emergence of phase 3 data in these indications. We must also be prudent about screening for drug interactions. Concomitant use of strong (e.g., voriconazole, posaconazole) or moderate (e.g., isavuconazole, fluconazole) CYP3A4 inhibitors may be necessary in treating these hematologic malignancies. Venetoclax should be dose reduced 50% with a moderate CYP3A4 inhibitor and 75% with a strong CYP3A4 inhibitor.¹ Venetoclax is an exciting addition to the therapeutic armamentarium for several hematologic malignancies.

References

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