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. 2024 Apr 18;143(16):1616-1627.
doi: 10.1182/blood.2023021959.

Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL

Jennifer A Woyach  1 , Gabriela Perez Burbano  2 , Amy S Ruppert  1   2 , Cecelia Miller  1 , Nyla A Heerema  1 , Weiqiang Zhao  1 , Anna Wall  2 , Wei Ding  3 , Nancy L Bartlett  4 , Danielle M Brander  5 , Paul M Barr  6 , Kerry A Rogers  1 , Sameer A Parikh  3 , Deborah M Stephens  7 , Jennifer R Brown  8 , Gerard Lozanski  1 , James Blachly  1 , Sreenivasa Nattam  9 , Richard A Larson  10 , Harry Erba  5 , Mark Litzow  3 , Selina Luger  11 , Carolyn Owen  12 , Charles Kuzma  13 , Jeremy S Abramson  14 , Richard F Little  15 , Shira Dinner  16 , Richard M Stone  8 , Geoffrey Uy  4 , Wendy Stock  10 , Sumithra J Mandrekar  2   17 , John C Byrd  18
Affiliations

Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL

Jennifer A Woyach et al. Blood. .

Abstract

A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

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Conflict of interest statement

Conflict-of-interest disclosure: J.A.W. received research funding from AbbVie, Janssen, Pharmacyclics, and Schrodinger and consulted for AbbVie, AstraZeneca, BeiGene, Genentech, Loxo/Lilly, Janssen, Merck, Newave, Pharmacyclics, and Schrodinger. A.S.R. is an employee of Eli Lilly but worked at The Ohio State University without conflicts at the time of this work. C.M. received research funding from AbbVie. K.A.R. received research funding from Genentech, AbbVie, Janssen, and Novartis, consulted for AstraZeneca, BeiGene, Janssen, Pharmacyclics, AbbVie, Genentech, LOXO@Lilly, and received travel funding from AstraZeneca. S.A.P. received research funding from Janssen, AstraZeneca, Merck, and Genentech and consults for Pharmacyclics, Merck, AstraZeneca, Janssen, BeiGene, Genentech, Amgen, Mingsight, TG Therapeutics, Novalgen Limited, Kite Pharma, and AbbVie. R.M.S. consults for AbbVie, Actinium, Amgen, Aptevo, Arog, AvenCell, BerGenBio, Bristol Myers Squib, Boston Pharmaceuticals, Cellularity, CTI pharma, Genentech, GlaxoSmithKline, Hermavant, Janssen, Jazz, Kura Onc, Ligand Pharma, Novartis, Rigel, Syros, and Takeda. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
CONSORT diagram. Here, we demonstrate the disposition of all patients screened for A041202 during the current follow-up period.
Figure 2.
Figure 2.
Progression-free survival and OS. Kaplan-Meier curves demonstrating improvement in PFS (A) and OS (B) with ibrutinib and ibrutinib plus rituximab compared with bendamustine plus rituximab.
Figure 3.
Figure 3.
Interaction of treatment groups and specific baseline characteristics. Kaplan-Meier curves showing the interaction of the treatment groups with ZAP-70 methylation (A), TP53 abnormalities (B), and karyotype (C).
Figure 3.
Figure 3.
Interaction of treatment groups and specific baseline characteristics. Kaplan-Meier curves showing the interaction of the treatment groups with ZAP-70 methylation (A), TP53 abnormalities (B), and karyotype (C).
Figure 4.
Figure 4.
Cumulative incidence of AEs. Extended follow-up demonstrates continued incidence of all-grade atrial fibrillation (A), all-grade hypertension (B), and grade 3 or higher hypertension (C) for patients treated with ibrutinib compared with those treated with bendamustine plus rituximab.
Figure 4.
Figure 4.
Cumulative incidence of AEs. Extended follow-up demonstrates continued incidence of all-grade atrial fibrillation (A), all-grade hypertension (B), and grade 3 or higher hypertension (C) for patients treated with ibrutinib compared with those treated with bendamustine plus rituximab.
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References

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