Venetoclax and Rituximab: New Standard of Care in CLL?

Alexander M. Castellino, PhD

December 12, 2017

ATLANTA — The standard of care for relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL) looks set to change to a combination that does not contain chemotherapy.

The current standard of care is chemoimmunotherapy with bendamustine (Treanda, Teva Oncology) and rituximab (Rituxan, Genentech) (BR), but new results from the MURANO trial show superior results with a new combination of the novel targeted agent venetoclax (Venclexta, AbbVie) with rituximab (VR).

The new data, from a first interim, preplanned analysis of the trial, were presented here in a late-breaking abstract at the American Society of Hematology (ASH) 2017 Annual Meeting.  

They show that VR was associated with a 83% reduced risk for disease progression compared with BR (hazard ratio [HR], 0.17; P < .0001). The superior benefits were observed across all clinical trial endpoints.

"This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach," said lead study author, John Seymour, MBBS, PhD, director of the Haematology Department at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Australia, in an ASH news release.

Dr John Seymour

"It suggests that venetoclax should replace chemotherapy for relapsed/refractory CLL and is suggestive that the combination with rituximab is the preferred manner to use the drug. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting," he added.

John F. Gerecitano, MD, PhD, medical oncologist and clinical director of lymphoma outpatient services at Memorial Sloan Kettering Cancer Center, New York City, who is also a MURANO study investigator, told Medscape Medical News: "This is a trial where the comparator arm is relevant," he said. "The PFS [progression-free survival] with the targeted therapy is superior to a regimen widely used in the real-world setting."

Medscape Medical News approached an expert for outside comments. "Results of MURANO have been highly anticipated and demonstrate the efficacy of a truncated treatment strategy for r/r CLL patients, which is a shift in the paradigm of continuous dosing of targeted therapies," said Nadia Khan, MD, from the Lymphoma & CLL Cancer Translational Research Disease Group at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.   

MURANO Study Details

MURANO is an open-label, randomized, phase 3 study that enrolled 389 patients with r/r CLL who had received 1 to 3 prior lines of therapy. Prior bendamustine use was allowed as long as response duration was at least 24 months.

Patients were randomly assigned equally across the two groups —194 to VR and 195 to BR.  In the VR group, to mitigate the potential for tumor lysis syndrome, venetoclax dose, given orally, was gradually ramped up from 20 to 400 mg daily over 4 to 5 weeks. At week 6, rituximab was given monthly for six 28-day cycles in combination with venetoclax: 375 mg/m2 for the first dose and then 500 mg/m2 for the subsequent doses. Patients continued with venetoclax for a maximum of 2 years or until disease progression.

In the BR group, patients received the drugs at standard doses. Minimum residual disease (MRD) in peripheral blood was determined at screening and at months 4 and 9, and then at 3-month follow-ups.

Dr Gerecitano told Medscape Medical News that a criticism that may be leveled against MURANO is that PFS favored the targeted therapy (VR) because it had maintenance therapy as a built-in advantage. "Having said that, even after the 24-month time point, the PFS curves remain separated in favor of the targeted therapy," he added.

MURANO Results

The first interim analysis occurred at a median follow-up of 23.8 months. Median PFS was not reached for patients in the VR group and was 17 months for patients in the BR group. Estimated 2-year PFS was also superior for VR, at 84.9%, vs 36.3% for BR. These superior treatment effects were seen to be of a similar magnitude across all subgroups analyzed.

Dr Khan noted that p53 mutational status is a predictor of inferior responses to chemoimmunotherapies and that a substantial proportion of patients (about 25% of in each group]) harbored this poor prognostic feature.  

All secondary endpoints also favored VR, including overall survival. With patients receiving VR at a 52% reduced risk for death (HR, 0.48; P = .0186), overall survival (OS) was superior for VR. Two-year OS was 91.9% for VR and 86.6% for BR.

Superior overall response rates (ORRs) were reported for patients receiving VR, at 93.3%, vs 67.7% for BR (P < .0001). Complete remission (CR) or complete remission with incomplete bone marrow recovery (CR/CRi) as determined from bone marrow assessment and computed tomography were more than threefold higher with VR than BR: 26.8% vs 8.2%.

"It is noteworthy that the investigator assessment of complete responses (negative CT [computed tomography] and negative bone marrow) vastly differed from the independent review committee (IRC) assessments of CR/CRi, with the IRC finding much fewer CRs achieved due to differences in CT scan interpretation," Dr Khan said. While ORR for independent review committee was 92.3% for VR and 72.3% for BR, the corresponding CR and CRi rates were 8.2% and 6.2%, respectively.

Notably, MRD clearance was achieved in 83.5% of patients taking VR compared with 23.1% of patients taking bendamustine, and MRD negativity was durable in patients receiving VR.

Most adverse events were similar across the two groups; however, grade 3/4 neutropenia occurred in 58% of patients receiving VR and 39% of patients receiving BR.

VR was superior to BR, Dr Seymour concluded. However, further follow-up is required to evaluate duration of benefit after venetoclax cessation, he added.

Clinical Relevance of New Results

Dr Gerecitano commented that for clinicians who treat CLL, MURANO now offers an attractive option (ie, VR) for patients who are not inclined to receive chemotherapy and even as second-line therapy after chemotherapy, said.

He noted that the good tolerability of the venetoclax combination and the fact that it does not have a cross-resistance mechanism with other treatments that patients are likely to receive make it a very good option for patients.

In the phase 2 evaluation that led to the US Food and Drug Administration (FDA) approval of the venetoclax (for r/r CLL harboring the 17p deletion), an impressive ORR of 80% was achieved in highly refractory patients. Although a relatively small percentage (7.9%) achieved a complete response, this was an impressive finding in patients with refractory CLL who have p53 dysfunction, Dr Khan explained to Medscape Medical News.

"The MURANO trial again demonstrated impressive responses in r/r CLL, including MRD negativity, echoing results previously seen in phase 1 and 2 studies of single-agent venetoclax," Dr Khan said. "Expansion of the venetoclax FDA label to include all r/r CLL patients is anticipated in the near future," she added. 

"The role for chemoimmunotherapy in the relapsed/refractory setting is becoming increasingly minimal," Dr Khan told Medscape Medical News. "Patients treated with chemoimmunotherapy in prior lines should be offered the option of novel targeted therapies either on a clinical trial or as part of standard of care due to vastly inferior outcomes achieved with chemotherapy re-treatment," she added.

According to Dr Gerecitano, this is an attractive option even for the traditional "no go" patients, such as the elderly and those in poor health with accompanying comorbidities, who are not able to tolerate chemotherapy. "Patients over the age of 80 years were included in both arms of the study," he told Medscape Medical News.

Although tumor lysis syndrome with venetoclax was not seen in the MURANO trial, Dr Gerecitano cautioned about using venetoclax in patients with a high tumor bulk and in patients with high levels of tumor circulating cells. "Although it is still perfectly safe, certain precautions need to be taken in these patients, which includes an increase in monitoring during the ramp-up period," he noted.

The significant degree of MRD clearance with the VR regimen was impressive, and this is a well-tolerated therapeutic option for some patients with highly refractory CLL, Dr Khan pointed out.

Dr Gerecitano agreed. "This is of clinical relevance," he said. "We know from prior studies that patients who achieve MRD negativity can maintain durable responses after stopping treatment, and the current study indicates that it is safe to discontinue treatment after 2 years," he added.

"In most studies, it is difficult to determine optimal time for therapy and when it is safe to discontinue. MURANO shows that patients can be comfortable stopping treatment after 2 years and need not be treated indefinitely," Dr Gerecitano said.

Dr Seymour reported that, so far, 65 patients in the MURANO trial had completed 2 years of therapy and as per protocol they were off treatment. The time off treatment is currently less than 3 months for these patients, and so far disease has recurred in 2 patients, he said.

The time to MRD negativity in the experimental arm and the ability of an early deep response to predict sustained control will be highly relevant for understanding which patients may have a planned treatment-free interval and which patients will require ongoing daily venetoclax treatment, Dr Khan commented.

In addition to p53 dysfunction, key disease features, such as complex karyotype and molecular alternations in NOTCH 1 and SF3B, among others, may be important in determining predictors of response to VR and predictors of successful abbreviated therapy, she noted.

"In current practice, ibrutinib, an oral BTK inhibitor, is used most frequently by US practitioners to treat r/r CLL, with venetoclax often considered after ibrutinib failure," Dr Khan told Medscape Medical News. "The sequencing of therapy may shift towards earlier VR usage, with the potential to offer truncated therapy," she added.

However, there is still a question over how much rituximab adds to the effectiveness of venetoclax, according to Dr Khan. She noted that after the initial 6 months of treatment, the PFS curves for the two regimens begin to separate greatly and the PFS for VR-treated patients at 24 months was well over 80%. 

"Truncated therapy with venetoclax is not a standard for r/r CLL patients, though VR may be very effective for selected patients," Dr Khan said. "Once patients stopped venetoclax therapy, there was a sustained benefit reflected in the majority of patients who remained on study, with only a slight decrement from the responses achieved while on treatment," she added.  

MURANO was sponsored by F. Hoffmann-LaRoche. Detailed conflict of interest disclosures are listed at the end of the abstract. Dr Seymour receives honoraria, research funding, speaking fees (one or more) from AbbVie, Celgene, Roche, Janssen, Morphosys, Gilead, Sunesis, and Takeda. Dr Gerecitano is a paid consultant for Merck, Mass Medical International, Incyte, Arcus Medica, Aratana, Bayer, Genentech, Samus Therapeutics, AbbVie, Gilead, and Orexo. Several study authors are employees of AbbVie, Genentech Inc, or F. Hoffmann-La Roche.  Dr Khan reports serving on the advisory board for AbbVie.

American Society of Hematology (ASH) Annual Meeting 2017. Abstract LBA-2.  Presented December 12, 2017.

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