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Ibrutinib-Rituximab Wins Out in Waldenstrom's Macroglobulinemia

— Risk of disease progression or death reduced by 75% versus rituximab alone

MedpageToday
A vial of Rituxan (Rituximab) and bottle of Imbruvica (ibrutinib) capsules over a blurred microscopy of b-cell lymphoma.

The combination of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) and rituximab was superior to rituximab alone across all clinical outcomes for patients with Waldenstrom's macroglobulinemia, a rare B-cell lymphoma, according to the final analysis of the randomized phase III iNNOVATE study.

Over a median follow-up of 50 months, median progression-free survival (PFS) was not reached with ibrutinib-rituximab compared with 20.3 months for rituximab plus placebo (HR 0.25, 95% CI 0.15-0.42, P<0.0001), demonstrating a 75% reduction in the risk of disease progression or death, reported Christian Buske, MD, of University Hospital of Ulm in Germany, and colleagues in the .

"Long-term follow-up showed that ibrutinib plus rituximab had ongoing superiority across clinical outcomes compared to rituximab alone in patients with WM [Waldenstrom's macroglobulinemia] regardless of prior treatment status or MYD88/CXCR4 genotype, confirming its role as a standard of care for WM," wrote JCO associate editor Suzanne Lentzsch, MD, PhD, of NewYork-Presbyterian Hospital/Columbia University Medical Center in New York City, commenting on the relevance of the study.

For example, in patients with the MYD88WT/CXCR4WT genotype, the 54-month PFS rate was 70% with ibrutinib-rituximab versus 30% with placebo-rituximab. In patients with the MYD88 L265P/CXCR4WT genotype, these rates were 72% versus 25%, respectively, and in patients with the MYD88 L265P/CXCR4WHIM genotype, they were 63% and 21%, respectively. Estimated 48-month PFS rates were similar.

Additionally, in previously untreated patients, the 54-month PFS rate was not evaluable in either the ibrutinib-rituximab arm or the placebo-rituximab arm, while the 48-month PFS rates were 70% and 32%, respectively. In previously treated patients, the 54-month PFS rates were 68% versus 20%, and the 48-month PFS rates were 71% and 20%.

Buske and colleagues randomized 150 patients with symptomatic Waldenstrom's macroglobulinemia 1:1 to the ibrutinib plus rituximab arm (median age 70, 60% men) or the placebo plus rituximab arm (median age 68, 72% men). Eligible patients who had been treated with a rituximab-containing regimen were required to have had a response that lasted for at least 12 months.

The primary endpoint was PFS, while secondary endpoints included overall response rate (ORR), hematologic improvement per change in serum hemoglobin levels, time to next treatment (TTNT), overall survival (OS), and safety.

Patients receiving ibrutinib-rituximab demonstrated higher overall response rates: 92% vs 44% with placebo-rituximab. Major response rates (partial response or better) were also significantly higher with the combination (76% vs 31%), with the depth of response increasing over time.

Fewer patients in the combination arm received subsequent treatment (12% vs 63%), with median TTNT not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab.

More patients receiving ibrutinib-rituximab had sustained hemoglobin improvement (77% vs 43%, respectively). OS was not reached in either arm.

As for safety, the most common grade ≥3 treatment-emergent adverse events (AEs) of clinical interest with the combination were atrial fibrillation and hypertension; 25% of patients experienced any grade hypertension (15% experiencing grade 3 or 4), and 19% experienced any grade atrial fibrillation (16% experiencing grade 3 or 4). The authors reported that these events stabilized after the first 2 years of treatment, and became infrequent in succeeding years.

They also noted that 10 of the 75 patients in the placebo-rituximab arm discontinued treatment because of an AE (most due to infusion-related reactions).

"Most AEs leading to an ibrutinib dose reduction resolved following dose reduction, suggesting that AEs can be managed effectively with dose modification, allowing patients to stay on therapy and maintain disease control," Buske and colleagues observed.

"Ibrutinib-rituximab remains an efficacious and well-tolerated chemotherapy-free regimen for patients with WM regardless of prior treatment or MYD88 and CXCR4 mutational status," they concluded.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was supported by Pharmacyclics LLC, an AbbVie company.

Buske reported relationships with Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Celltrion, MorphoSys, and Regeneron, Merck Sharp & Dohme, and Amgen.

Other co-authors also reported multiple relationships with industry.

Primary Source

Journal of Clinical Oncology

Buske C, et al "Ibrutinib plus rituximab versus placebo plus rituximab for Waldenström's macroglobulinemia: final analysis from the randomized phase III iNNOVATE study" J Clin Oncol 2021; DOI: 10.1200/JCO.21.00838.