EDINBURGH – Treatment induction with obinutuzumab and ibrutinib followed by a minimal residual disease (MRD)–driven treatment strategy in patients with chronic lymphocytic leukemia (CLL) yields a high long-term complete response rate and prolonged progression-free and overall survival, according to findings from the phase 2 ICLL-07 trial.
The intent-to-treat (ITT) complete response rate at 16 months in 135 patients who were treated with this strategy was 62%, Anne-Sophie Michallet, MD, reported at the International Workshop on Chronic Lymphocytic Leukemia.
Patients in the multicenter, open-label trial conducted by the French Innovative Leukemia Organization (FILO) were previously untreated, medically fit patients with CLL and no 17p deletion. They were enrolled between November 2015 and May 2017 to receive eight 1,000 mg IV doses of obinutuzumab over six 4-week cycles along with oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib at a dose of 420 mg daily for 9 months.
Ten patients (7.7%) achieved complete response with bone marrow MRD less than 0.01% (undetectable) at 9 months and, by study protocol, continued on only the ibrutinib for 6 additional months. The remaining 120 evaluable patients received four 4-week cycles of fludarabine/cyclophosphamide along with the obinutuzumab and ibrutinib for 6 additional months, explained Dr. Michallet of Centre Léon Bérard, Lyon, France.
The ITT rate at 16 months – the primary endpoint of the study – was achieved with no more than four cycles of fludarabine/cyclophosphamide and obinutuzumab, and exceeded the primary objective of demonstrating a 30% or higher rate of complete response with bone marrow MRD less than 0.01% at the month 16 ITT analysis, she said.
“The ... strategy yielded an overall response rate of 100%, a complete response rate, according to iwCLL [criteria], of 73%, a bone marrow MRD–undetectable rate of 79% [in the ITT population],” she said, adding that the primary objective was achieved with a complete response with a peripheral blood and bone marrow MRD–undetectable rate of 62%.
Response assessments at months 9 and 16 involved whole-body computed tomography scans with tumor measurements and bone marrow trephine biopsy for patients in clinical complete response. MRD testing was performed by eight-color flow cytometry in both peripheral blood and bone marrow.
After month 16, response was clinically assessed every 3 months, and peripheral blood MRD was assessed every 6 months until month 40.
“With a median follow-up of 26.3 months, the 2-year progression-free survival and overall survival were, respectively, 97% and 97.5%,” Dr. Michallet said, noting that the longitudinal follow-up of peripheral blood MRD in the entire cohort showed durability of a deep response. The rate of peripheral blood MRD less than 0.01% at 22 months was 77% in the 10 patients who received only ibrutinib after the 9-month assessment, and 93% in those who received fludarabine/cyclophosphamide after the 9-month assessment.
In patients with immunoglobulin heavy gene variable (IGHV) mutations, the rate of peripheral blood MRD less than 0.01% at month 22 was 96%, and in those without IGHV mutations, the rate was 77%, she noted.
The findings demonstrate that the approach has merit in medically fit, treatment-naive patients with CLL and no 17p deletion, she said, explaining that the fixed-duration, MRD-driven strategy used in this study was developed to “avoid or at least reduce chemotherapy exposure” in the first-line treatment of such patients.
Indeed, the approach was associated with “a high [complete response] rate, a high level of undetectable bone marrow MRD, an acceptable safety profile, and a sustained MRD negativity rate at 12 months after the end of the treatment,” she said.
“This highly effective strategy combining a BTK inhibitor and abbreviated immunochemotherapy deserves further investigation with randomized trials,” she concluded.
ICLL-07 FILO was funded by Roche and Janssen. Dr. Michallet reported having no disclosures.