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Venetoclax combination improves PFS in refractory chronic lymphotropic leukemia
ATLANTA — Patients with relapsed or refractory chronic lymphotropic leukemia showed improved PFS 2 years after receiving venetoclax plus rituximab compared with patients treated with bendamustine plus rituximab, according to results from the MURANO clinical trial presented during the late-breaking abstract session of the ASH Annual Meeting and Exposition.
“When we developed this trial, the standard of care in many jurisdictions was chemotherapy together with a monoclonal antibody, the most common being a combination of bendamustine and rituximab [Rituxan; Genentech, Biogen]. Previous studies had shown we would expect approximately a 60% response rate, and the average PFS would be around 15 months,” John Seymour, MD, director of Peter MacCallum Cancer Centre in Melbourne, Australia, and lead investigator of the MURANO trial, said during a press conference. “Venetoclax [Venclexta; AbbVie, Genentech] is an orally administered and very specific and selective inhibitor of BCL-2. As a single agent, it’s shown very high activity, including among patients with poor prognostic factors.”
A previous phase 1 study demonstrated safety and promising efficacy from the addition of rituximab to venetoclax. The study showed improved complete remission rates, with high-quality remissions and no detectable leukemia. Based on those findings, researchers sought to compare that combination with the combination of rituximab and bendamustine.
“These patients have a disease that we, to date, can’t cure, so these patients need therapies repeatedly for their disease,” John Gerecitano, MD, medical oncologist and clinical director of lymphoma outpatient services at Memorial Sloan Kettering Cancer Center, and co-investigator of the study, told HemOnc Today. “Unfortunately, with each subsequent line of therapy, their remissions tend to get shorter. There is an unmet need in having different treatments available, preferably ones that are not toxic and not chemotherapy-based, and that can lead to remissions in a way that does not overlap with mechanisms of action of prior therapies.”
In the study, 389 patients who had received one to three prior therapies, including at least one with chemotherapy, received rituximab with venetoclax (n = 194; median age, 64.5 years) or bendamustine (n = 195; median age, 66 years) for six 28-day cycles.
For patients dosed with the venetoclax combination, researchers used a 4-week or 5-week dose increase of venetoclax from 20 mg to 400 mg daily against potential tumor lysis syndrome. At 6 weeks, patients received IV rituximab monthly for six 28-day cycles (375 mg/m2 at first dose, 500 mg/m2 thereafter). Patients remained on venetoclax for a maximum of 2 years or until disease progression.
Patients assigned the bendamustine combination received 70 mg/m2 IV bendamustine on days 1 and 2 of each of six 28-day cycles in combination with rituximab using the same dosing schedule.
Investigator-assessed PFS at 2 years — determined by standard International Workshop on Chronic Lymphocytic Leukemia guidelines — served as the primary endpoint. Secondary endpoints included independent review committee-assessed PFS, PFS among patients with 17p deletion, best overall response, OS, EFS, duration of response, time to next anti-CLL treatment and achievement of minimal residual disease negativity.
Median follow-up was 23.8 months (range, 0-37.4).
PFS assessed by investigators was 84.9% in the venetoclax combination arm compared with 36.3% in the bendamustine combination arm. Median PFS was not reached in the venetoclax arm, whereas it was 17 months in the bendamustine (HR = 0.17; 95% CI, 0.11–0.25).
“There was a clear difference between venetoclax and bendamustine over 2 years,” Seymour said. “Eighty-five percent of patients remained free from progression or death, compared with a median PFS of 17 months for bendamustine and rituximab, which is slightly better than we may have expected from previous studies with bendamustine and rituximab.”
The review committee confirmed the results, which appeared consistent across all clinical and biological subsets, including among patients with the deletion 17p (HR = 0.14; 95% CI, 0.06-0.33) and without it (HR = 0.18; 95% CI, 0.12-0.28).
Overall response rate was 93.3% in the venetoclax combination arm and 67.7% in the bendamustine combination arm (difference, 25.6%; 95% CI, 17.9-33.3). In addition, 26.8% of patients who received venetoclax achieved complete response compared with 8.2% of patients who received bendamustine.
Researchers also reported a notable improvement in OS (HR = 0.48, 95% CI 0.25-0.9).
No new unexpected adverse events occurred.
The venetoclax combination arm showed neutropenia as the most common grade 3 or 4 adverse event.
“The [incidence] of neutropenia in particular infections [appeared] infrequent, with 5% in the venetoclax and rituximab arm,” Seymour said.
Tumor lysis syndrome also infrequently occurred (3%), and most of the toxicities in the venetoclax arm occurred during the combination period prior to obtaining “profound disease control,” Seymour said.
“There is going to be widespread interest in using [venetoclax plus rituximab] in this patient population, especially since we want to limit the use of chemotherapy due to toxicities,” Gerecitano said.
“This MURANO study ... shows a very clear superiority in [PFS] with consistent effects across all biological subsets regardless of deletion 17p status,” Seymour said. We need longer follow-up to comment on durability after cessation, but this I believe has [the] potential to establish venetoclax and rituximab as one of the standard options for management of patients with relapsed or refractory CLL.” – by Melinda Stevens
Reference:
Seymour JF, et al. Abstract LBA-2. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Seymour reports multiple financial relationships with AbbVie, Celgene, Gilead, Janssen, Morphosys, Roche, Sunesis and Takeda. Gerecitano reports consultant roles with AbbVie, Arantana, Arcus Medica, Bayer, Genentech, Gilead, Incyte, Merck, Mass Medical International, Orexo and Samus Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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This is the registrational study for venetoclax in CLL. I have been involved with the development of venetoclax in CLL since the drug first entered the clinic in 2011. Our early studies suggested that venetoclax is very potent as monotherapy, and a phase 1b study showed that combining venetoclax with rituximab could achieve higher rates of complete remission than venetoclax alone. The phase 1b study also raised the prospect of a time-limited therapy as opposed to continuous indefinite therapy. This phase 3 MURANO study builds on that prior phase 1b study with a large cohort of nearly 400 patients with relapsed or refractory CLL who were randomly assigned to either venetoclax with rituximab or a standard-of-care regimen of bendamustine with rituximab.
One limitation with the study is that researchers allowed patients with 17p deletion onto the study, and in the United States we no longer consider bendamustine-rituximab to be a standard of care for these patients. Nonetheless, the efficacy data looked very promising for the venetoclax and rituximab combination. There was very high ORR and a solid complete remission rate in the range of 27%. This complete remission rate is notably lower than what we saw in the phase 1b study, which was closer to 50%. It is possible that the complete remission rate may increase over time with longer follow-up but, even if not, these data are still impressive.
Minimal residual disease negativity rates also appeared high in the blood, and the tolerability of venetoclax with rituximab appeared favorable. There was relatively minimal evidence of tumor lysis syndrome, which had previously been observed in the early development of the drug. Median PFS has not yet been reached for venetoclax and rituximab after 2 years of follow-up in a relapsed/refractory CLL population, which is exciting.
MURANO is potentially a practice-changing study and is likely to lead to the full approval of venetoclax in combination with rituximab across all different risk groups in relapsed/refractory CLL. Because I got involved with the development of this drug early on during the first in-human study, it is exciting for me personally to see it now in this phase 3 trial that has the potential to have a major impact on the care for patients with CLL.
Perspective
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The results of the MURANO study have been highly anticipated. They represent the first phase 3 readout comparing chemoimmunotherapy with targeted immunotherapy for patients with relapsed/refractory CLL.
The results demonstrate the efficacy of a truncated treatment strategy for relapsed/refractory patients, which is a shift in the paradigm of continuous dosing of targeted therapies.
Venetoclax is an oral BCL-2 inhibitor that is approved by FDA to treat patients with relapsed/refractory CLL who harbor 17p deletion. The phase 2 evaluation that led to the FDA approval showed an impressive 80% overall response rate among highly refractory patients. Though a relatively small percentage (7.9%) achieved complete response, this was an impressive finding among patients with refractory CLL who have p53 dysfunction.
The MURANO trial included 389 patients treated with one to three lines of prior therapy. Researchers randomly assigned them 1:1 to venetoclax plus rituximab or bendamustine plus rituximab.
Importantly, patients were stratified according to 17p deletion status and responsiveness to prior therapy.
Investigator-assessed PFS — the primary endpoint — was found to be superior for venetoclax-rituximab (median, not reached vs. 17 months; HR = 0.17; 95% CI, 0.11-0.25). A higher percentage of patients assigned venetoclax-rituximab achieved complete response as assessed by investigators (26.8% vs. 8.2%; P < .0001).
Key toxicities included a low frequency of tumor lysis events, especially in patients treated with venetoclax-rituximab. One clinical tumor lysis event occurred in each treatment arm. Incidence of grade 3 or grade 4 neutropenia was higher in the venetoclax-rituximab arm, alhough there was no increased rate of grade 3 or grade 4 infection. The MURANO trial demonstrated impressive responses in relapsed/refractory CLL, including minimal residual disease negativity, echoing results previously seen in phase 1 and phase 2 studies of single-agent venetoclax.
Expansion of the venetoclax FDA label to include all patients with relapsed/refractory CLL is anticipated in the near future. The role for chemoimmunotherapy in the relapsed/refractory setting is becoming increasingly minimal. 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 retreatment.
Further, p53 derangements would be another predictor of inferior responses to chemoimmunotherapies. Despite this, a significant proportion of patients (48 for venetoclax-rituximab and 51 for bendamustine-rituximab) harbored this poor prognostic feature and were treated with bendamustine-rituximab.
The comparator arm in this study is, therefore, not highly relevant. Nevertheless, the significant degree of minimal residual disease clearance with the venetoclax-rituximab regimen was impressive. The results suggest that the combination of venetoclax with an anti-CD20 antibody is a well-tolerated therapeutic option for some patients with highly refractory CLL.
It is noteworthy that the investigator assessment of complete responses — negative CT and negative bone marrow — vastly differed from the independent review assessments of complete response, with the independent review committee finding much fewer complete responses achieved due to differences in CT scan interpretation.
How significantly the rituximab adds to the effectiveness of venetoclax remains a question. After the initial 6 months of treatment, the PFS curves for the two regimens begin to separate greatly. The PFS among patients assigned venetoclax-rituximab remained above 80% at 24 months.
Truncated therapy with venetoclax is not a standard for patients with relapsed/refractory CLL, although it may be very effective for selected patients. 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.
Because this is an abstract, some very important details regarding complete response and minimal residual disease are not presented, but they will be highly anticipated in the manuscript. The time to minimal residual disease 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 will require ongoing daily venetoclax treatment.
In addition to p53 dysfunction, key disease features — such as complex karyotype and molecular alternations in NOTCH1 and SF3B, among others — may be very important for determining predictors of response to venetoclax-rituximab, and predictors of successful abbreviated therapy.
In current practice, ibrutinib (Imbruvica; Pharmacyclics, Janssen) — an oral Bruton’s tyrosine kinase inhibitor — is used most frequently by U.S. practitioners to treat relapsed/refractory CLL, with venetoclax often considered after ibrutinib failure. The sequencing of therapy may shift toward earlier venetoclax-rituximab usage, with the potential to offer truncated therapy.
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