Venetoclax Plus Rituximab: 'Unprecedented' Efficacy in CLL

Alexander M. Castellino, PhD

January 24, 2017

A new chemotherapy-free combination has shown "unprecedented" efficacy in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), say researchers.

The novel drug venetoclax (Venclexta, AbbVie/Genentech Inc) — an oral inhibitor of BCL2, which regulates apoptosis — has already been approved as a single-agent treatment of relapsed or refractory chronic lymphocytic leukemia (r/r CLL) for patients who have the 17p deletion. When used alone, venetoclax produces complete responses (CRs) in about 20% of patients.

Now a CR rate of 50% has been reported from a small, nonrandomized study in which venetoclax was used in combination with rituximab (Rituxan, Genentech, Inc). The responses were deep and long lasting. Additionally, responses were maintained in many patients who came off the drug combination — something never before seen in CLL.

The new findings come from a phase 1b study (study M13-365) published online January 12 in Lancet Oncology..

The combination of venetoclax and rituximab produced a response in 86% of patients, which included CRs in 51% of patients.

Negative marrow minimal residual disease was reported in a substantial number of patients who responded, including 50% of those whose response was partial because of minor residual adenopathy on imaging but whose marrow was histologically clear. Most significant was the observation that after achieving deep responses, a proportion of patients were able to discontinue treatment and still maintain a response, say the researchers.

"[The] results of the current study suggest a novel therapeutic paradigm of time-limited targeted therapy for those patients attaining deep responses, allowing freedom from the burdens and costs of prolonged therapy, while removing the potential clonal selection pressure of continuous drug exposure," the researchers write in their discussion.

"This is the first reported combination data [with venetoclax] in any disease," John F. Seymour, MD, corresponding author of the study, told Medscape Medical News. Dr Seymour is codirector of cancer medicine at the Peter MacCallum Cancer Center and head of the Department of Hematology at the Royal Melbourne Hospital, Australia.

"This study showed that we can safely give venetoclax in combination with rituximab in CLL, using the optimal doses for both drugs," he added.

"[The] findings from this study with venetoclax-rituximab support the concept that a chemo-free regimen might achieve a status of minimal residual disease negativity that remains sustained over time, and at least partly explain the prolonged responses observed in patients even after they ceased all therapy," write Lorenzo De Paoli, MD, and Gianluca Gaidano, MD, from the Division of Hematology at the University of Eastern Piedmont and Maggiore Charity Hospital, Novara, Italy, in an accompanying commentary.

Details of the M13-365 Study

The study enrolled patients with relapsed or refractory CLL or small lymphocytic leukemia (n = 49) sequentially in five dose-escating cohorts. Patients who underwent prior allogeneic or autologous stem cell transplant or who experienced uncontrolled autoimmune cytopenias or other active malignancy within 3 years were excluded from the study.

Venetoclax was given daily with weekly escalations to target doses of 200 to 600 mg. The first cohort started on a 50-mg dose, but following a fatal case of tumor lysis syndrome, this was reduced to 20 mg in subsequent cohorts.

In all patients, rituximab was initiated 1 week after the target venetoclax dose was achieved, with both drugs given together. Patients received six infusions of rituximab, the first on day 1 of month 1 at 375 mg/m2, and subsequent infusions on the first day of months 2 to 6 at 500 mg/m2.

Dr Seymour pointed out that although other sequences of delivering this combination could be considered, safety has been established only for this sequence for this combination. "Other postulated sequences will have to be evaluated in different clinical trials," he said.

After completing combination therapy, patients continued receiving venetoclax as monotherapy until unacceptable toxicity, disease progression, or drug cessation occurred per protocol when patients met the criteria for a complete response or achieved a complete response with incomplete marrow recovery at week 30, independent of whether they had achieved minimal residual disease in the marrow.

Tumor lysis syndrome prophylaxis and management were specified by the study protocol. These included risk categorization and hospitalization based on tumor burden for the first dose of venetoclax and subsequent dose escalations for patients with bulky disease. All patients were hydrated and received a urate-reducing agent.

Safety Results

Safety was the primary endpoint of the study. Three patients discontinued the study before initiation of rituximab — one each for tumor lysis syndrome, progression to Richter's transformation/syndrome, and consent withdrawal.

The most common grade 1/2 treatment-emergent adverse events reported were diarrhea (55%), nausea (51%), and upper respiratory tract infections (57%). Grade 3/4 treatment-emergent adverse events were mostly peripheral blood cytopenias — neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (12%).

The most common serious adverse events were pyrexia (12%), febrile neutropenia (10%), lower respiratory tract infection (6%), and pneumonia (6%).

Grade 3/4 events were managed with supportive care, venetoclax dose reduction or interruption, or rituximab dose interruption, as appropriate.

Fifty-three percent of patients received proplylaxis for infection. Sixteen percent of patients experienced grade 3 infections. Five patients experienced tumor lysis syndrome; two cases (one fatal) were clinical and occurred after the first dose of 50 mg of venetoclax prior to the protocol modification.

The occurrence of tumor lysis syndrome was not different with this combination than with venetoclax monotherapy, Dr Seymour noted.

"This is a powerful drug, and as with any powerful tool, it has to be used with care for it to perform impressively," he said. "If used haphazardly, the drug can cause damage," Dr Seymour added. He stressed that it is important to be attentive to the prophylactic measures that must be instituted when using this drug. These measures include appropriate hydration and administering a urate-reducing agent. "It is also important to monitor the patient and blood biochemistry in the 24 hours after administering the first dose," he added.

Efficacy Results

The study investigators reported rapid and substantial reduction in disease burden in peripheral blood, lymph nodes, and bone marrow.

Of 49 patients, 42 (86%) achieved an overall response, with 25 (51%) experiencing a CR or CR with incomplete bone marrow recovery. Responses were seen across all target doses of venetoclax. The median time to first response was 2.9 months; CRs were seen after a median of 9.2 months.

After completing combination therapy, 11 patients achieved CR; 14 more patients achieved a CR or CR with incomplete marrow recovery after a median of an additional 7 months of venetoclax monotherapy after combination therapy.

Of the 42 patients who responded, 67% (28/42) had no detectable minimal residual disease; this included 20/25 (80%) patients with CR.

At the time of analysis, 82% of patients were progression free; the median time to progression had not been reached at 2 years. Ongoing responses were reported in 89% of patients at 2 years.

"Complete remission rates with venetoclax monotherapy is approximately 20%," Dr Seymour told Medscape Medical News. Although this is a nonrandomized, phase 1 study, the complete response rate of 51% with the combination is substantial, he noted.

"The data for minimal residual disease with this combination is unprecedented," Dr Seymour said. He explained that this level of minimal residual disease eradication has not been reported for other novel agents, such as ibrutinib (Imbruvica, Janssen/Pharmacyclics) and idelalisib (Zydelig, Gilead Sciences). "The same level of scrutiny was not planned and not anticipated within the early venetoclax monotherapy trials, but the rate with the combination appears much higher," he said.

Disease progression was reported in 11 patients, of whom six patients achieved a partial response and five patients progressed with Richter's transformation.

The editorialists point out that evolution to Richter's syndrome occurs in a small proportion of patients and represents transformation to clinically and histologically aggressive diffuse large B-cell lymphoma.

"[In the study,] Richter's syndrome might well have been a pre-existent, albeit unrecognised, condition, possibly consisting of small disease subclones favoured by the selection pressure exerted by previous ineffective lines of chemotherapy," Dr De Paoli and Dr Gaidano write.

Most Patients Off Therapy Maintain Response

Noteworthy was the observation that 13 of 49 patients who achieved a deep response stopped treatment with venetoclax after a median of 10 months on therapy; 12 of these patients had experienced a CR or a CR with incomplete bone marrow recovery.

Although the protocol provided the opportunity to get off therapy, it was not mandated, Dr Seymour explained. In the study, 57% (28/49) of patients had the opportunity to come off study drug, but not all patients/physicians chose this option, he noted.

"Initially based on differing philosophies between patients and physicians, there may be some hesitancy in coming off study drug," Dr Seymour said. "As experience with venetoclax accumulates and data on the durability of ongoing disease control off therapy matures, the 'risk appetite' of individual patients will likely change," he added.

Patients with deep responses who ceased therapy have remained in remission for a median of 10 months, with remission being sustained for as long as 3 years in one patient, Dr Seymour noted.

"With all other novel agents tested to date, control of leukemia is only achieved in the context of continuing therapy," Dr Seymour explained. "With ongoing monitoring, this is the only combination for which it has been shown that therapy can be safely discontinued," he said. This approach to clinical management of CLL may alleviate the logistic, financial, and toxicity burdens of continuous therapy, Dr Seymour explained.

"Remarkably, the maintenance of a response to venetoclax without the need for continuous exposure is a peculiar feature of this drug among the new small-molecule treatments available for chronic lymphocytic leukaemia, and represents an important added value for patients as well as for health-care systems," Dr De Paoli and Dr Gaidano note.

Two patients who stopped treatment experienced asymptomatic clinical CLL progression after 24 months off therapy. Venetoclax was reinitiated in both patients. Both subsequently achieved a partial response and are continuing therapy.

"It is reassuring to know that if disease progresses after stopping therapy, we can reestablish control," Dr Seymour told Medscape Medical News.

However, Dr Seymour and colleagues note that although "deep responses attained with the combination of venetoclax and rituximab were durable and the high number of patients with negative minimal residual disease are promising," longer follow-up is required to determine whether this translates into prolonged survival. "Patients in this study continue to be followed," Dr Seymour said.

The Changing Treatment Landscape of CLL

Dr DePaoli and Dr Gaidano indicate that with "little understanding of its molecular pathogenesis, scant innovation in treatment options, and little hope of eradication," CLL had been the "Cinderalla" of hematologic malignancies for many decades.

They note that the past few years have seen a dramatic change in the treatment landscape of CLL, and treatment continues to change at a sustained pace.

Currently, immunochemotherapy treatment options for r/r CLL include B-cell receptor targeting with Bruton's tyrosone kinase and PI3k-delta inhibitors — ibrutinib (Imbruvica, Pharmacyclics/Jannsen) and idelalisib (Zydelig, Gilead), respectively — and the anti-CD20 antibodies rituximab and ofatumumab (Arzerra, Novartis).

"The obvious question in this era of precision medicine is which patient benefits the most from which specific treatment," the editorialists write.

"Notably, because combining venetoclax with rituximab is feasible without compromising the venetoclax dose, and because newer and more potent anti-CD20 antibodies are now available, the outcome achieved by targeting BCL2 and CD20 has the potential to be further enhanced by combining venetoclax with novel anti-CD20 drugs," Dr De Paoli and Dr Gaidano write.

Dr Seymour said that venetoclax is being evaluated with other anti-CD20 antibodies.

But he added that in this study, venetoclax and rituximab were used at their optimal doses.

"Bringing this optimal combination to the frontline setting with curative intent is the desired endgame of this journey," Dr Seymour told Medscape Medical News.

The study was funded by AbbVie Inc and Genentech Inc. Dr Seymour has received research funding from AbbVie and is a consultant and advisory board member for AbbVie, Roche, and Genentech. The disclosures of other study authors are available in the original article. Dr Gaidano has received personal fees from Roche, Janssen, Gilead, AbbVie, Amgen, Morphosys, and Karyopharm. Dr De Paoli has received personal fees from Celgene and Amgen.

Lancet Oncol. Published online January 12, 2017. Abstract, Editorial


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