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MURANO trial positions venetoclax as potential chemotherapy replacement in relapsed/refractory CLL

Roshini Claire Anthony
21 Dec 2017
Professor John Seymour

Patients with relapsed/refractory chronic lymphocytic leukaemia (CLL) given a combination of venetoclax and rituximab (VR) demonstrated superior progression-free survival (PFS) over those given bendamustine plus rituximab (BR), a finding which positions VR as a potential new therapeutic option for relapsed/refractory CLL, the phase III MURANO trial shows.

“This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy programme, and it has proved the superiority of the chemotherapy-free approach,” said study lead author Professor John Seymour from the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia, who presented the results at ASH 2017.

Study participants were 389 patients aged ≥18 years who had undergone 1–3 prior lines of therapy (including ≥1 chemotherapy regimen) for relapsed/refractory CLL. They were randomized in a 1:1 ratio to receive monthly intravenous doses of rituximab (375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2–6; each cycle lasting 28 days) plus either oral venetoclax (400 mg QD for up to 2 years or until disease progression or toxicity) or intravenous bendamustine (70 mg/m2 on days 1 and 2 of cycles 1–6).

To reduce the risk of tumour lysis syndrome, the venetoclax dose was gradually increased from 20 to 400 mg over 4–5 weeks.

After a median follow-up period of 23.8 months, 84.9 percent of patients on VR demonstrated no evidence of disease progression compared with 36.3 percent on BR (median PFS, not reached vs 17.0 months; hazard ratio [HR] 0.17, 95 percent confidence interval [CI], 0.11–0.25; p<0.0001). [ASH 2017, abstract LBA-2]

Patients on VR also had superior minimal residual disease clearance compared with those on BR (83.5 percent vs 23.1 percent), as well as a better overall response rate (93.3 percent vs 67.7 percent).

While overall survival (OS) data is yet immature (not reached in either arm), results point to a clinically meaningful improvement in OS with VR compared with BR (91.9 percent vs 86.6 percent at 2 years; HR, 0.48, 95 percent CI, 0.25–0.90; p=0.0186).

Incidence of grade 3–4 adverse events (AEs) was comparable between patients on VR and BR (82 and 72 percent, respectively), with neutropenia being the most commonly reported grade 3–4 AE (58 and 39 percent), followed by anaemia (11 and 14 percent) and thrombocytopenia (6 and 10 percent).

However, it should be noted that the AE reporting period was longer for patients on VR compared with BR, said Seymour. Also, most of the toxicities reported in the VR arm occurred during the combination period compared with the period when venetoclax was administered as a single agent (58 percent vs 11 percent and 11 percent vs 3 percent for neutropenia and anaemia, respectively).

“The current standard of care in many jurisdictions … is chemotherapy together with a monoclonal antibody … [this study] 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,” said Seymour.

Nonetheless, continued follow-up is necessary to assess the duration of benefit following venetoclax treatment cessation, he said. 

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Pearl Toh, 3 days ago
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