Conference Coverage

Ibrutinib response in CLL/SLL less affected by select risk factors


 

AT THE IWCLL MEETING

– Risk factors associated with poor outcomes in chronic lymphocytic leukemia/small lymphocytic leukemia patients treated with standard therapies appear to have less relevance with ibrutinib treatment, according to an integrated analysis of data from the randomized, phase III RESONATE, RESONATE 2, and HELIOS trials.

In the combined analysis, at a median follow-up of 21 months, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and complete response rate (CRR) were better in ibrutinib-treated patients than in comparator-treated patients – and, in the ibrutinib-treated patients, the outcomes did not differ based on the adverse genomic factors examined, Thomas J. Kipps, MD, PhD, said at the annual International Workshop on Chronic Lymphocytic Leukemia.

Sharon Worcester/Frontline Medical News

Dr. Thomas J. Kipps

The three-study analysis pooled data from 1,210 patients, including 620 ibrutinib-treated patients, and compared outcomes for the presence or absence of immunoglobulin heavy-chain variable region gene (IGHV) mutation status, chromosome 11q deletion (del[11q]), trisomy 12, and complex karyotype.

The trials compared well with each other, but differed in terms of number of prior therapies received by patients, he said. Furthermore, the analysis did not examine the effect of del(17p); patients with that deletion were included only in the RESONATE trial.

In RESONATE, ibrutinib was superior to ofatumumab in relapsed/refractory CLL/SLL. In RESONATE 2, ibrutinib was superior to chlorambucil in treatment-naive patients with CLL/SLL. In HELIOS, ibrutinib with bendamustine/rituximab was superior to placebo with bendamustine/rituximab in patients with relapsed/refractory CLL/SLL.

In the new multivariate analysis of the pooled data from these trials – adjusting for the four genomic risk factors and age, sex, ECOG performance status, cytopenia, lactate dehydrogenase (LDH), bulky disease, and number of prior therapies – only having had one or more vs. no prior therapies, and having two or more vs. one prior therapies was associated with shorter PFS and OS in ibrutinib-treated patients, with a trend toward significance.

In comparator-treated patients, however, unmutated IGHV, del(11q), complex karyotype, male sex, two or more prior therapies, and bulky disease all were associated with significantly shorter PFS. Complex karyotype, male sex, bulky disease, ECOG performance status greater than 1, and elevated LDH were associated with significantly shorter OS.

“We need to debate on what the significance of this is and how that can be incorporated into our idea about first-line therapies,” said Dr. Kipps, who was an investigator in both RESONATE trials and is a professor of medicine at the University of California, San Diego.

In univariate analysis of data from ibrutinib-treated patients, unmutated IGHV, del(11q), trisomy 12, and complex karyotype were generally not associated with shorter PFS, OS, or lower ORR or CRR.

Overall survival with and without unmutated IGHV was 78% and 84%, respectively; with and without trisomy 12 was 82% and 80%, respectively; and with and without complex karyotype was 77% and 78%, respectively.

ORR, for example, was comparable in the presence (90%) and absence (89%) of unmutated IGHV in ibrutinib-treated patients, as was CRR, at 29% and 26%, respectively.

In the presence and absence of trisomy 12, ORR was 85% and 91%, respectively; CRR was 33% and 22%.

In the presence and absence of complex karyotype, ORR was 88% and 89%, respectively, and CRR was 18% and 24%.

In the presence and absence of del(11q), ORR was 91% and 90%, respectively, and CRR was 22% and 27%.

The only difference that reached statistical significance was the complete response rate with trisomy 12, which favored the presence of trisomy 12.

Interestingly, the ibrutinib-treated patients with del(11q) had a trend toward longer PFS and OS, compared with those without del(11q), said Dr. Kipps.

At 36 months, PFS was 74% with the presence of del(11q) and 68% with the absence of del(11q) (hazard ratio, 0.73 vs. 1.88 in comparator-treated patients), and overall survival at 42 months was 80% in patients with del(11q) and 78% in those without del(11q) (HR, 0.73), Dr. Kipps said.

“The [finding in the] patients with the complex karyotype was a bit surprising, and I think this requires further analysis,” he said, explaining that complex karyotype actually was associated with a shorter PFS in patients treated on the comparator arm, and that this finding conflicts with earlier data.

The findings suggest ibrutinib-treated patients with trisomy 12, for reasons that are unclear, had a significantly higher complete response rate, but not greater PFS or OS vs. those without trisomy 12, Dr. Kipps said.

“It’s also interesting that ... unmutated antibody genes or del(11q) or complex karyotype were adverse prognostic factors in patients treated with comparator treatments, but not necessarily in patients treated with ibrutinib-based therapy,” he said.

Furthermore, although a prior phase II study involving heavily pretreated patients suggested that del(11q) may have adverse prognostic influence on PFS, that finding may not be borne out in patients with fewer lines of prior therapy.

The findings suggest that genomic risk factors associated with poor outcomes with initial chemoimmunotherapy may be less apparent in patients treated with ibrutinib.

“I think this is important, because it may then turn a prognostic factor into a predictive factor, meaning, a predictor of adverse outcomes for a given type of therapy as opposed to adverse prognostic value overall,” he concluded.

Ibrutinib (Imbruvica, Pharmacyclics) was approved by the Food and Drug Administration in January 2015 for the treatment of CLL after previous therapy. Dr. Kipps has received research funding from and/or served as a consultant or advisor for AbbVie, Genentech, Gilead, and Pharmacyclics, an AbbVie company.

sworcester@frontlinemedcom.com

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