Biomarker Incorporated Into Novel CLL Outcome Prediction Model

Italian researchers continue the quest to better manage patients with chronic lymphocytic leukemia (CLL), tweaking a comprehensive scoring system to identify patients at high risk of treatment failure. As described in HemaSphere, among the innovations emerging from their recent work is to include in their system a biomarker called CD49d that, currently, is not routinely considered for this purpose.^1,2

Many signs point to CD49d—a VLA-4 integrin alpha chain—being able to improve prognostic stratification of patients for both progression-free survival (PFS) and overall survival (OS), declared the authors.

The retrospective, multicenter study analyzed data from 401 patients with CLL who were treated with ibrutinib between December 2013 and March 2022; about 75% were 65 years or older when starting the agent. After a median follow-up of 29.9 months and 26.5 months from ibrutinib start, 112 patients had died and 169 had disease progression, respectively.

The investigators found that high expression of CD49d (≥ 30% positive cells) or expression of CD49d according to a bimodal pattern—concurrent CD49d-positive and CD49d-negative subpopulations, irrespective of the 30% cutoff)—could identify CLL cases treated with ibrutinib that were associated with shorter PFS.

CD49d may be a better predictor of CLL-related outcomes compared with lactate deyhdrogenase, the researchers of this study believe | Image Credit: laufer-stock.adobe.com

Further, the team looked closely at TP53, a tumor suppressor. Their evidence suggested that only the patients with concurrent TP53 mutation and deletion—not just one or the other—would not typically respond maximally to ibrutinib. And then they put the two together.

Consistently, they said, “the concomitant presence ofTP53disruption and high CD49d expression selected a subgroup of patients with a particularly high risk of progression, even when compared with cases withTP53disruption or CD49d expression alone.”

Updated 4-Part Model

Based on their work, the researchers made modifications to the standard 4-part point-based model that has been used to calculate relative risk of poor outcomes:

• β2-microglobulin ≥ 5 mg/L, 1 point (unchanged from original scale)
• lactate dehydrogenase (LDH) serum concentration > 250 U/L, 1 point (unchanged from original scale)
• concomitantTP53deletion and mutation, 1 point (but 0 points for only a deletion or only a mutation, a change from the original)
• treated with more than 1 prior therapy, 1 point (the original assigned this point even if the patient had just a single prior therapy)

Then, using novel multivariable analyses, they scrutinized the individual parameters of the modified 4-factor score together with CD49d expression. Consequently, they wrote, LDH was excluded as an independent predictor in favor of CD49d expression (PFS, P = .0068; OS, P = .0015).

Excluding LDH data in favor of CD49d expression data, the patient scores were as follows: 45 scored 0, 137 scored 1, 141 scored 2, 65 scored 3, and 13 scored 4.

In terms of PFS, patients with scores of 0 and 1, the relative best outcomes, were not significantly different (P = .7328), nor were those with scores 3 and 4, with the relative worst outcomes (P = .7877). However, cases with a score 2, showing intermediate outcomes, differed significantly from all other scores.

Including CD49d in the model improved its PFS and OS prediction capabilities (both P < .0001) vs previous models. Focusing, for instance, only on patients with 0 or 1 prior therapy lines, high-risk patients (n = 14) presented significantly shorter PFS than intermediate-risk (n = 55; P = .0083) and low-risk (n = 143; P < .0001) cases.

Because this scoring model was generated from patients treated with ibrutinib, its efficacy should be confirmed in the context of second-generation Bruton tyrosine kinase inhibitors, concluded the team. Still, based on their current results, they suggest that patients who fall into the high-risk category should be the top candidates considered for combination therapies and/or enrollment in clinical trials.

References

1. Bomben R, Zucchetto A, Laureana R, et al. CD49d expression is included in a revised 4‐factor model predicting outcome in patients with chronic lymphocytic leukemia treated with ibrutinib: a multicenter real‐world experience. HemaSphere.2024;8(7):e128.doi:10.1002/hem3.128

2. Tissino E, Pozzo F, Benedetti D, et al. CD49d promotes disease progression in chronic lymphocytic leukemia: new insights from CD49d bimodal expression. Blood. 2020;135(15):1244-1254. doi:10.1182/blood.2019003179