According to a letter published in Leukemia, researchers found no significant difference in progression-free survival (PFS) based on depth of response at 1 year in patients with chronic lymphocytic leukemia (CLL) on treatment with the Bruton’s tyrosine kinase inhibitor ibrutinib. However, they found that patients with multiple enlarged lymph nodes after 1 year of therapy had an inferior PFS.
“While depth of remission has been shown to be a predictor of longer PFS with time-limited therapies such as chemoimmunotherapy and venetoclax-based regimens, its utility in the setting of BTKi monotherapy has previously been unclear,” the researchers wrote in their letter.
To identify patients who could potentially trial discontinuation of ibrutinib in the future, the investigators assessed whether response at 1 year could predict long-term PFS in CLL patients on treatment with ibrutinib.
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They performed a retrospective analysis of CLL patients enrolled in 4 sequential clinical trials of ibrutinib as monotherapy or in combination with ofatumumab at the Ohio State University in Columbus, Ohio.
Response was evaluated at approximately 12 months using the overall 6 largest lymph nodes for each patient from computed tomography (CT) of the neck, abdomen/pelvis, and chest or clinical assessment when CT was not available.
The researchers categorized responses by clinical response criteria, International Workshop on CLL (IWCLL) 2018 guidelines, and IWCLL 2018 response with clinical complete responses (cCRs). Response groups included complete response (CR), CR with incomplete marrow recovery (CR-i), partial response (PR), PR with lymphocytosis (PR-L), stable disease (SD), and progressive disease (PD). The team calculated PFS from response assessment at the time point closest to 12 months to progression or death, whichever occurred first.
A total of 237 patients, with a median age of 65 years (range, 27-89), were included in the study. Most patients were male (70%), were on treatment with ibrutinib monotherapy (76%; 24% with ibrutinib in combination with ofatumumab), and had high-risk disease features, including 64% with Rai stage III/IV disease, 58% bulky adenopathy at baseline, 82% IGHV unmutated, 54% with complex karyotype, and 36% with del(17p).
According to 12-month assessment based on IWCLL 2018 response with clinical CRs, 4% of patients achieved a CR; 3% achieved CR-I; 1% achieved cCR; 77% achieved PR; 12% achieved PR-L; and 3% had SD. With a median follow-up duration of 72.7 months (range 0.9-101.1), the median PFS was 49.7 months (95% CI, 42.3-59.5), and the researchers found no significant difference among response groups (P =.28).
In a multivariable analysis accounting for significant individual prognostic factors from a univariable analysis, the team found that age (hazard ratio [HR] for 5-year increase, 0.90; 95% CI, 0.82-0.99; P =.04), MYC abnormality after 24 months (HR, 2.34; 95% CI, 1.48-3.70; P =.0003), unmutated IGHV after 24 months (HR, 2.09; 95% CI, 1.0-4.34; P=.05), National Heart, Lung, and Blood Institute (NHLBI) score (HR, 1.47; 95% CI, 1.22-1.76; P <.0001), and number of enlarged lymph nodes at 12 months (HR, 1.13; 95% CI, 1.01-1.26; P =.04) remained significantly associated with PFS.
“Our findings have significant implications for future therapies and direction of research,” the researchers wrote. “Currently, studies are underway that focus on adding additional therapies to ibrutinib in an attempt to deepen response. Our data suggest that approaches like these might be best targeted to patients with multiple residual nodes at the end of therapy.”
Limitations of the study included the retrospective design, a small percentage of patients who achieved CR, a patient population that included predominately patients with high-risk features and multiple prior therapies, limited to no MYC status assessment at most centers, and an inability to assess treatment adherence.
Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Sigmund AM, Huang Y, Ruppert AS, et al. Depth of response and progression-free survival in chronic lymphocytic leukemia patients treated with ibrutinib. Published online July 16, 2022. Leukemia. doi:10.1038/s41375-022-01640-y
