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Highlights from

American Society of Hematology

Annual meeting 2018

San Diego 1-4 December 2018

Alliance: Ibrutinib demonstrates superior PFS to standard CIT in treatment-naive patients aged ≥65 with CLL

Take-home messages
  • Older patients with CLL are underrepresented in clinical trials
  • The study was the first of its kind to compare ibrutinib with an aggressive CIT regimen of bendamustine and rituximab
  • Estimated 2-year PFS data demonstrate that ibrutinib is superior to CIT in this setting
“The successful completion of this trial showed us that clinical trials in this patient population is of great clinical interest.”

Dr Jennifer Woyach, Oncologist, Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, US

A unique study was presented at this year’s American Society of Hematology (ASH) 60th Annual Meeting, comparing progression-free survival (PFS) with ibrutinib versus chemoimmunotherapy (CIT) for the first time in treatment-naive patients aged ≥65 with chronic lymphocytic leukaemia (CLL).

The combination of chemotherapy with an anti-CD20 antibody, or CIT, is the current gold standard for older patients with CLL. Though it is efficacious in prolonging survival, it is associated with toxic side effects, the risk of which increases with age.

“Despite now widespread use in the front-line setting following FDA approval for this indication in 2016, the efficacy of ibrutinib versus standard CIT has not previously been investigated,” explained Dr Jennifer Woyach, Oncologist, Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, US, who presented the trial results at ASH 2018.

Ibrutinib is a targeted small-molecule therapy that inhibits Bruton’s tyrosine kinase (BTK), a key signalling molecule in the B-cell antigen receptor and cytokine receptor pathways. It has previously been compared with chlorambucil but has not been trialled against a more aggressive CIT regimen.

Alliance A041202, a multicentre phase III trial, set to examine the use of ibrutinib in treatment-naive patients aged ≥65 with CLL, comparing three treatment arms: bendamustine + rituximab (BR; n=183), ibrutinib only (n=182) and ibrutinib + rituximab (IR; n=182). Patients in the BR arm were permitted to cross over to the ibrutinib-only arm at time of progression.

Median age was 71 years, 67% of patients were male, and patients had CrCl ≥40 mL/min, bilirubin ≤1.5x ULN. Patients were excluded if they had a significant life-limiting intercurrent illness or need for warfarin treatment.

“In the eligible patient population, PFS was significantly higher in the ibrutinib-containing arms than in the BR arm,” observed Dr Woyach. The estimated PFS at 2 years was 87% in the ibrutinib-only arm versus 74% in the BR arm (hazard ratio: 0.39; 95% CI: 0.26-0.58; p<0.001). Estimated PFS was 88% in the IR arm (hazard ratio vs BR: 0.38; 95% CI: 0.25-0.59; p<0.001).

Although this was the first time ibrutinib was observed in combination with rituximab in a prospective phase III setting, there was no significant difference in between the IR and ibrutinib-only arms of the study (hazard ratio: 1.00; 95% CI: 0.62-1.62; p=0.49).

Patients were stratified by risk factors for CLL, such as absence/ presence of del(17p13.1) or del(11q22.3), TP53 mutation, karyotype, ZAP-70 methylation status, IgVH mutation and Rai stage. In these prespecified subgroups, PFS was longer in the ibrutinib-containing regimens than the BR regimens, with no significant difference among patients with ZAP-70 methylation. For patients with del(17p13.1), the 2-year PFS estimate was 0% in the BR arm, 75% in the ibrutinib arm (95% CI: 31-93), and 73% in the IR arm (95% CI: 37-90; intention-to-treat population).

At the median follow-up of 38 months, there was no difference between groups in terms of the secondary analysis, overall survival (OS). Median OS has not been reached in any arm.

Grade 3-5 haematologic adverse events (AEs) were more common in the BR arm (61%) versus the ibrutinib-only and IR arms (41% and 39%, respectively). Dr Woyach noted, “Importantly though, BTK inhibition is not without toxicity, including serious toxicity in this patient population, so close monitoring remains important”. Grade 3-5 non-haematologic AEs were less common in the BR arm (63% versus 74% for both ibrutinib only and IR).

“In conclusion, ibrutinib and IR result in superior PFS compared with BR in the front-line setting for older patients with CLL,” explained Dr Woyach, noting that this was a significant therapeutic advance in this setting. She concluded that the associated toxicities and cost justify its use, and that it could reduce the need for long-term continuous treatment. The findings have now been published in the New England Journal of Medicine.

Dr Woyach added, “I would like to mention that the next phase III cooperative group studies, A041702 and EA9161, which will both open this month, will address the question of whether ibrutinib combined with venetoclax and obinutuzumab as a strategy for discontinuation is superior to standard therapy. Please look out for these studies if you see patients with CLL.”

Based on: Woyach J A, Ruppert A S et al. Ibrutinib alone or in combination with rituximab produces superior progression (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American intergroup study A041202 (abstract 6). Presented on Sunday 2 December 2018.

Woyach J A, Ruppert A S et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 2018; DOI:10.1056/NEJMoa1812836

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