Blood cancers

Ibrutinib and venetoclax “impressive” as first line combo in CLL


The combination of ibrutinib and venetoclax has shown “impressive” results in the first-line treatment of chronic lymphocytic leukaemia, an international expert says.

The Phase II study published in the NEJM involving 80 previously untreated high-risk and older patients with CLL found that after 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease.

The authors observed no new safety concerns with combination therapy and the toxicity profile was similar to what has been noted for ibrutinib or venetoclax monotherapy.

“These efficacy results are substantially better than what has been reported with ibrutinib or venetoclax monotherapy for patients with CLL…These results also appear favorable as compared with chemoimmunotherapy,” noted the researchers led by Associate Professor Nitin Jain from the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston.

They noted that a longer follow-up is needed to assess outcomes beyond the 24 cycles of combined therapy.

“The appropriate duration of treatment with targeted agents such as combined ibrutinib and venetoclax in patients with CLL remains uncertain, and this study and several other ongoing trials are exploring this question,” they wrote.

In an accompanying editorial haematologist Adrian Wiestner from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, described the study results as “impressive”.

“Every patient had a response, almost all had a complete response, and in most no residual disease was detected by means of flow cytometry.

Second, there appears to be no added toxicity from combining the two drugs. Third, initiation of venetoclax was facilitated by a period of administration of ibrutinib alone that reduced tumor bulk and the risk of tumor lysis syndrome, ” he wrote.

Professor Wiestner said he was most surprised at the absence of a Kaplan–Meier curve.

“Here, assessment of minimal residual disease (MRD) has replaced the progression-free survival curve of old, indicating a possible shift in focus away from traditional clinical-trial end points and toward even more stringent measures of clinical efficacy that may be central to regulatory decisions,” he observed.

He concluded that extended follow-up of would provide many more insights into targeted therapy of CLL, and potentially help answer important questions such as: Can treatment ever be safely stopped? Are there subgroups with a poor prognosis that require additional therapy? What is the nature and mechanism of ibrutinib and venetoclax resistance? And does substituting a different BTK inhibitor for ibrutinib preserve activity with a lower risk of toxic effects?

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