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Ibrutinib/Rituximab Improves Outcomes vs Standard Chemoimmunotherapy in Previously Untreated CLL


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In an interim analysis of a U.S. phase III trial (E1912) reported in The New England Journal of Medicine,1 Tait D. Shanafelt, MD, of Stanford University School of Medicine, and colleagues found that ibrutinib/rituximab improved progression-free and overall survival vs standard chemoimmunotherapy in patients up to age 70 with previously untreated chronic lymphocytic leukemia (CLL) without chromosome 17p13 deletion. This trial was designed and coordinated by the Eastern Cooperative Oncology Group (ECOG)–American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group in collaboration with other National Clinical Trials Network Cooperative Groups.

Tait D. Shanafelt, MD

Tait D. Shanafelt, MD

Study Details

In the multicenter trial, 529 patients were randomly assigned 2:1 between March 2014 and June 2016 to receive ibrutinib and rituximab for 6 cycles, after a single cycle of ibrutinib alone, followed by ibrutinib until disease progression (n = 354) or standard chemoimmunotherapy (n = 175). The primary endpoint was progression-free survival in the intent-to-treat population.

Patients in the ibrutinib/rituximab group received ibrutinib at 420 mg/d until disease progression or unacceptable toxicity and rituximab at 50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and 500 mg/m2 on day 1 of cycles 3 through 7 in 28-day cycles. Standard chemoimmunotherapy consisted of 6 cycles of fludarabine at 25 mg/m2 and cyclophosphamide at 250 mg/m2 on days 1 through 3 with rituximab (FCR) at 50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and 500 mg/m2 on day 1 of cycles 2 through 6 in 28-day cycles.

For the ibrutinib/rituximab vs chemoimmunotherapy groups: the mean age was 56.7 years (41.0% ≥ 60 years) vs 56.7 years (40.0% ≥ 60 years); 66.7% vs 68.6% were male; Rai stage risk was low (0) in 3.1% vs 5.1%, intermediate (I or II) in 52.8% vs 53.7%, and high (III or IV) in 44.1% vs 41.1%; ECOG performance status was 0 for 63.8% vs 62.3%, 1 for 33.6% vs 36.0%, and 2 for 2.5% vs 1.7%; Dohner classification included chromosome 11q22.3 deletion in 22.0% vs 22.3%, trisomy 12 in 19.8% vs 15.4%, normal in 19.5% vs 21.1%, chromosome 13q deletion in 34.2% vs 33.1%, and other in 4.0% vs 8.0%; and IgHV mutation status was mutated (favorable) in 25.0% vs 38.3% and nonmutated (unfavorable) in 75.0% vs 61.7%.

Progression-Free and Overall Survival

The first interim analysis was performed in September 2018. The median follow-up was 33.6 months. Progression-free survival at 3 years was 89.4% in the ibrutinib/rituximab group vs 72.9% in the control group (hazard ratio [HR] = 0.35, P < .001), with the results meeting the protocol-defined efficacy threshold for the interim analysis. Overall survival rate at 3 years was 98.8% vs 91.5% (HR = 0.17, P < .001).

Subgroup analyses of progression-free survival showed that hazard ratios significantly favored ibrutinib/rituximab independent of age (HR = 0.32, 95% confidence interval [CI] = 0.18–0.56 for < 60 years; HR = 0.44, 95% CI = 0.20–0.97 for ≥ 60 years), sex (HR = 0.30, 95% CI = 0.12–0.77, for women; HR = 0.40, 95% CI = 0.23–0.67, for men), and Rai stage (HR = 0.35, 95% CI = 0.18–0.65, for 0 to II; HR = 0.38, 95% CI = 0.19–0.74, for III to IV). Hazard ratios were 0.24 (95% CI = 0.10–0.62) for patients with chromosome 11q22.3 deletion, 0.73 (95% CI = 0.19–2.89) for those with trisomy 12, 0.78 (95% CI = 0.29–2.04) for those with normal classification, and 0.22 (95% CI = 0.08–0.60) for those with chromosome 13q deletion.

IBRUTINIB/RITUXIMAB VS CHEMOTHERAPY AND IMMUNOTHERAPY

  • Progression-free survival was 89.4% vs 72.9% at 3 years in patients with previously untreated CLL who received ibrutinib/rituximab vs chemoimmunotherapy.
  • Overall survival was 98.8% vs 91.5 at 3 years.

Progression-free survival at 3 years was significantly better with ibrutinib/rituximab among 281 patients without IgHV mutation (3-year rate = 90.7% vs 62.5%, HR = 0.26, 95% CI = 0.14–0.50) but not among the 114 patients with IgHV mutation (87.7% vs 88.0%, HR = 0.44, 95% CI = 0.14–1.36).

Assessment of minimal residual disease in peripheral blood at 12-month response assessment in 276 patients (78.0%) in the ibrutinib/rituximab group and 103 patients (58.9%) in the standard chemoimmunotherapy group showed higher levels of residual disease (ie, a lower minimal residual disease–negativity rate) at cycle 12 in the ibrutinib/rituximab group (8.3% vs 59.2%).

Adverse Events

Grade ≥ 3 adverse events occurred in 80.1% of the ibrutinib/rituximab group vs 79.7% of the chemoimmunotherapy group, with the most common adverse events in the ibrutinib/rituximab group including neutropenia (26% vs 45% in FCR group), increased lymphocytes (22% vs 8%), hypertension (19% vs 8%), and leukocytosis (18% vs 8%). Infectious complications of grade ≥ 3 occurred in 10.5% vs 20.3% of ibrutinib/rituximab and FCR-treated patients, respectively. Other grade ≥ 3 adverse events included hemorrhagic events in 1.1% vs 0% of patients and cardiac toxicity in 6.5% vs 1.8%. Atrial fibrillation of any grade was observed in 7.4% vs 3.2%. The rate of second primary cancers was similar between the groups, with the most common second primary cancers in the ibrutinib/rituximab group being nonmelanoma skin cancer (n = 11) and melanoma (n = 6).

The investigators concluded: “[A]mong patients 70 years of age or younger with previously untreated CLL, the combination of 6 cycles of ibrutinib/rituximab therapy followed by ibrutinib given continuously until relapse resulted in progression-free survival and overall survival that were superior to those with 6 months of chemoimmunotherapy with fludarabine/cyclophosphamide/rituximab. However, indefinite use of ibrutinib therapy has been associated with substantial expense…and the potential for long-term toxic effects and may increase the risk of clonal selection leading to drug resistance.” 

DISCLOSURE: The study was funded by the National Cancer Institute and Pharmacyclics. For full disclosures of the study authors, visit www.nejm.org.

REFERENCE

1. Shanafelt TD, Wang XV, Kay NE, et al: Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 381:432-443, 2019.

 


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