Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia

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Shanafelt TD, et al. "Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia". The New England Journal of Medicine. 2019. 381(5):432-43.
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Clinical Question

In patients 70 years or younger with chronic lymphocytic leukemia (CLL), how does the safety and efficacy of ibrutinib-rituximab compare to the chemoimmunotherapy regimen of fludarabine-cyclophosphamide-rituxmiab?

Bottom Line

Among patients with untreated CLL who are 70 years or younger, treatment with ibrutinib-rituximab (IR) was associated with higher rates of progression-free (PFS) and overall survival (OS) at 3 years compared to chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR).

Major Points

Prior studies established chemoimmunotherapy as the standard-of-care for patients with untreated CLL. This standard was challenged with the introduction of novel agents such as the BTK inhibitor ibrutinib and BCL2 inhibitor venetoclax, which proved to be very active and well tolerated in patients with CLL. A head-to-head study of novel therapy versus chemoimmunotherapy was necessary.

Published in 2019, the ECOG 1912 study randomized 529 patients with CLL under the age of 70 years to receive either ibrutinib-rituximab (IR) or chemoimmunotherapy with FCR. Patients with del17p were appropriately excluded, as prior studies demonstrated the poor efficacy of FCR in this patient group. Groups were balanced with respect to age, sex, Rai stage, ECOG performance status. There was a higher proportion of IGHV unmutated status in the IR group (75% versus 62%). The rate of grade ≥3 adverse events was similar between groups at around 80%; cardiovascular toxicity including grade 3-4 hypertension and atrial fibrillation were more common in the IR group, whereas cytopenias and neutropenic fever were more common in the FCR group. IR treatment was associated with a higher rate of significant bleeding than FCR. The primary endpoint was PFS; OS was a key secondary endpoint to be tested only if the PFS analysis crossed a prespecified threshold. At 3 years, PFS was superior with IR (89.4% vs. 72.9%), and OS was superior as well (98.8% vs. 91.5%). Prespecified subgroup analyses demonstrated wider differences in PFS in patients with del11q and unmutated IGHV.

This study demonstrated the superiority of novel therapy over conventional FCR in patients with untreated CLL without del17p, and importantly showed an overall survival advantage at 3 years to the novel therapy combination. Of note, this study did not address the question of whether ibrutinib needs to be combined with an anti-CD20 antibody such as rituximab, although other studies have demonstrated ibrutinib monotherapy has similar efficacy to ibrutinib plus rituximab.[1][2] Whether FCR should be offered to any patients with non-del17p CLL remains the subject of debate, with experts and key opinion leaders spanning both sides of the argument. However, it seems clear that a non-ibrutinib option may be considered in patients with untreated CLL who desire time-limited therapy since FCR is administered for 6 months, while ibrutinib is given continuously until disease progression. Similarly, patients who are anticipated to have significant toxicity from ibrutinib, such as those patients with pre-existing several cardiovascular disease or at high bleeding risk, may opt for non-ibrutinib based therapy.

Guidelines

NCCN Guidelines for CLL (version 4.2020, adapted):[3]

The following are preferred first-line regimens for CLL/SLL without del17p/TP53 mutation in patients <65 years old without significant comorbidities, frail patients with significant comorbidity, or patients aged >65 years, and younger patients with significant comorbidities:

  • Ibrutinib (category 1)
  • Acalabrutinib +/- obinutuzumab
  • Venetoclax + obinutuzumab

Design

  • Multicenter, open-label, randomized, phase 3 trial
  • N=529 patients with untreated CLL
    • IR (n=354)
    • FCR (n=175)
  • Setting: United States
  • Enrollment: 2014-2016
  • Mean follow-up: 33.6 months
  • Analysis: Intention-to-treat
  • Primary outcome: Progression-free survival

Population

Inclusion Criteria

  • Previously untreated patients with CLL or SLL
  • 18 to 70 years old
  • ECOG status between 0 and 2
  • Life expectancy greater than 12 months

Exclusion Criteria

  • Chromosone 17p13 deletion
  • NYHA class III or IV heart disease or recent MI
  • Positive HBsAg
  • Current use of steroids, warfarin, or CYP3A4 inhibitors/inducers

Baseline Characteristics

  • Mean age: 56 years
  • Female 33%
  • Rai stage 1-2 47%
  • ECOG score 0 63%
  • del11q 22%
  • del13q 34%
  • Unmutated IGHV 71%

Interventions

Randomized to IR or FCR

  • IR group: first cycle consists of ibrutinib alone, followed by 2-7 cycles of ibrutinib with rituximab
    • Ibrutinib 420 mg/day PO
    • Rituximab IV
      • 50 mg/m2 day 1, cycle 2
      • 325 mg/m2 day 2, cycle 2
      • 500 mg/m2 day 1, cycles 3-7
  • FCR group
    • Fludarabine 25 mg/m2 IV
    • Cyclophosphamide 250 mg/m2 IV on days 1 through 3
    • Rituximab IV
      • 50 mg/m2 day 1, cycle 1
      • 325 mg/m2 day 2, cycle 2
      • 500 mg/m2 day 1, cycles 3-6

Outcomes

Comparisons are IR vs. FCR.

Primary Outcomes

Progression-free survival at 3 years
89.4% (95% CI 86-93) vs. 72.9% (95% CI 65.3 to 81.3)

Secondary Outcomes

Overall survival at 3 years
98.9% vs. 91.5% (HR 0.17; 95% CI 0.05-0.54)

Subgroup Analysis

IR was superior to FCR independent of age, sex, Rai stage, and was superior in patients with chromosome 11q22.3 deletion. IR resulted in superior PFS at 3 years among patients with unmutated IGHV (90.7% vs 62.5%; HR 0.26, 95% CI 0.14-0.50) but had no significant difference among patients with IGHV-mutated CLL.

Adverse Events

Incidence of any adverse event grade 3 or higher was similar in both groups. Compared to FCR, IR group had a lower incidence of grade 3 or 4 neutropenia, lower incidence of infectious complications including neutropenic fever, higher incidence of grade 3 or 4 hypertension. There were more cardiac toxic events seen in the IR group.

Criticisms

  • Low percentage of female participants

Funding

National Cancer Institute and Pharmacyclics

Further Reading

  1. Burger JA et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 2019. 133:1011-1019.
  2. Woyach JA et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N. Engl. J. Med. 2018. 379:2517-2528.
  3. NCCN Guidelines for CLL, version 4.2020