Atlanta (FRONTLINE MEDICAL NEWS) – The potential of two- and three-drug combinations to induce deep, minimal residual disease (MRD)–negative responses in patients with chronic lymphocytic leukemia (CLL) was demonstrated in multiple studies presented at the annual meeting of the American Society of Hematology.

Previous studies have suggested that, in contrast to single-agent kinase inhibitor treatment, combinations of treatments, namely kinase or B-cell lyphoma 2 inhibitors combined with anti-CD20 antibodies, can induce MRD negativity at a high rate. For example, in a report on the CLL14 trial, 11 of 12 previously untreated patients were MRD negative after treatment with the BCL-2 inhibitor venetoclax and anti-CD20 antibody obinutuzumab (Blood. 2017;129:2702-5. doi:10.1182/blood-2017-01-761973).

This new batch of studies presented at ASH 2017 provided additional evidence for the venetoclax and obinutuzumab combination, as well as other combinations that appear to provide favorable rates of MRD-negative CLL, including obinutuzumab and venetoclax plus ibrutinib and, notably, a combination that included venetoclax and ibrutinib but no anti-CD20 antibody.

A phase II trial presented by Nitin Jain, MD, of MD Anderson Cancer Center, Houston, looked at the combination of venetoclax and ibrutinib for patients with previously untreated high-risk CLL or relapsed/refractory CLL. The regimen under evaluation starts with daily ibrutinib monotherapy for 3 months before venetoclax is added.

For the first line cohort of 36 patients, the bone marrow MRD-negativity proportion was 0% after 3 months of ibrutinib and 21% after 3 months of ibrutinib plus venetoclax, then 45%, 80%, and 100%, respectively, after 6, 9, and 12 months of combination therapy, Dr. Jain reported. In the relapsed/refractory cohort, MRD negativity was 8% after 3 months of combination therapy and 40% after 12 months. “Responses continue to improve with time, with many patients achieving bone marrow MRD-negative remission,” Dr. Jain said.

The study showed “very impressive MRD rates,” commented Ian W. Flinn, MD , of Sarah Cannon Research Institute, Nashville, Tenn. “I think it’s still up for further discussion and research to find which is the best combination.”

Dr. Flinn presented results from a phase Ib GP28331 study of venetoclax and obinutuzumab in patients with previously untreated CLL in which MRD was assessed in peripheral blood and bone marrow.

All 32 patients achieved peripheral blood negativity at some point on study, Dr. Flinn said, and 75% achieved bone marrow negativity. The complete response rate was 72% (23/32), but notably, high rates of undetectable bone marrow MRD were seen irrespective of response status, Dr. Flinn said.

All patients had at least one adverse event, with grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia reported most commonly.

Preliminary progression-free survival data (PFS) suggested “durable clinical outcomes” for the combination, with an estimated 18-month PFS of 90.5%, he said.

A third study assessed the combination of obinutuzumab, ibrutinib, and venetoclax, finding that the combination induced MRD negativity in 14 of 24 (58%) treatment-naive CLL patients, according to Kerry A. Rogers, MD , of Ohio State University, Columbus.

The combination had a 96% response rate and is “extremely effective at eliminating detectable CLL,” Dr. Rogers noted.

Most adverse events were hematologic, and high-grade adverse events were rare, she said.

Results for the study’s primary endpoint, rate of MRD-negative complete remission, are expected by May 2018, Dr. Rogers said, adding that further follow-up will be needed to determine PFS for the combination.

Session attendees asked presenters whether they felt there was scientific justification for inclusion of the anti-CD20 antibody rituximab in future trials designed in part to assess MRD negativity.

“I think that obinutuzumab has greater efficacy in patients with CLL, compared to rituximab, and so our hypothesis is that it is a superior antibody to combine with venetoclax,” Dr. Flinn said.

AbbVie provided funding for the study on venetoclax and ibrutinib. Dr. Jain reported disclosures from venetoclax makers AbbVie and Genentech, ibrutinib makers Janssen and Pharmacyclics, and others.

Genentech and AbbVie provided support for the study on venetoclax and obinutuzumab. Dr. Flinn reported disclosures related to both companies and others.

Dr. Rogers reported no conflicts related to the study on obinutuzumab, ibrutinib, and venetoclax. One of her associates reported disclosures related to ibrutinib makers Novartis and Pharmacylics, among others.

SOURCE: Jain N et al. ASH 2017 Abstract 429 ; Flinn I et al. ASH 2017 Abstract 430 ; Rogers K et al. ASH 2017 Abstract 431 .


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