Patient-Reported Outcomes May Help Predict CLL/SLL Outcomes

Patient-reported outcomes (PROs) may offer a useful way to identify patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who are at higher risk for poor survival and serious treatment-related adverse events, according to a pooled analysis of 3 randomized clinical trials.¹ The study, published in Therapeutic Advances in Hematology, evaluated baseline PRO data from 1238 patients receiving ibrutinib-based therapy in the RRESONATE (NCT01578707), RESONATE-2 (NCT01722487), and HELIOS (NCT01611090) trials.

Investigators applied European Organisation for Research and Treatment of Cancer (EORTC) thresholds for clinical importance to scores from the EORTC QLQ-C30, a standardized questionnaire assessing symptoms, functioning, and quality of life. Their analysis found that clinically important PRO impairments were common before treatment.^1,2

What Were the Patients Reporting?

Overall, 920 patients (74%) reported at least 1 clinically important PRO domain, while 395 (32%) reported impairments in 5 or more domains.¹ The most frequently affected areas were physical function (46%), dyspnea (44%), social function (33%), fatigue (31%), and financial difficulty (30%). In addition, the number of impaired PRO domains was associated with progressively worse clinical outcomes. After adjustment for baseline clinical factors, each additional clinically important PRO domain was associated with a 7% increase in risk of death, a 3% increase in the risk of disease progression or death, and a 3% increase in the risk of grade 3 or higher adverse events.

Patients with the highest PRO burden appeared to face substantially greater risks. Compared with patients reporting no clinically important PRO impairments, those with 5 or more had more than twice the risk of death (adjusted HR, 2.04; 95% CI, 1.42-2.94; P < .001) and a 47% higher risk of grade 3 or higher adverse events (HR, 1.47; 95% CI, 1.17-1.85; P = .003). The group with 5 or more impaired domains also had a 31% higher risk of progression or death (HR, 1.31; 95% CI, 1.01-1.69; P = .043).

Physical functioning emerged as the strongest individual prognostic domain. Patients with clinically important impairment in physical function had a 73% higher risk of death (HR, 1.73; 95% CI, 1.38-2.18; P < .001) and a 36% higher risk of grade 3 or higher adverse events (HR, 1.36; 955 CI, 1.17-1.58; P < .001). The investigators reported that physical function provided the greatest improvement in model discrimination for overall survival, with a C-index of 0.63.

The findings suggest that PROs may capture aspects of patient health that are not fully reflected in conventional clinical assessments. PRO measures have been incorporated into recommendations for cancer care across active treatment and follow-up, reflecting their potential value in informing clinical management.³

“Clinically important PRO domains were common among patients with CLL/SLL initiating ibrutinib-based therapy and were independently associated with survival and toxicity outcomes,” the authors wrote.

The investigators also found differences according to treatment setting. The associations between cumulative PRO burden and survival, progression-free survival, and adverse events were observed primarily among patients with relapsed or refractory disease in RESONATE and HELIOS. No significant associations were observed in the treatment-naive RESONATE-2 cohort, although the authors cautioned that the subgroup was smaller and had fewer outcome events.

The Impact on Future Care

These results could have implications for risk stratification and supportive care in CLL/SLL. The authors suggested that routinely collecting PROs could help clinicians recognize patients with substantial symptoms of functional burden and potentially provide earlier supportive interventions. They concluded that cumulative PRO impairment could support “earlier identification of high-risk patients, individualized treatment planning, and better alignment between therapeutic goals and patients’ functional and symptom burden.”

However, the study does not establish that PRO impairment causes worse outcomes. The analysis was retrospective, and the original trials predominantly enrolled patients with an Eastern Cooperative Oncology Group performance status of 0 or 1, limiting generalizability to patients with poorer functional status. Molecular prognostic factors such as IGHV and TP53 mutation status were also unavailable for adjustment. The authors called for prospective validation before PRO burden is incorporated into broader risk-stratification approaches.

References

1. Abuhelwa AY, Almansour SA, Al-Shamsi HO, et al. Prognostic value of patient-reported outcome thresholds on survival and adverse events in CLL/SLL: a pooled analysis of ibrutinib trials. Ther Adv Hematol. 2026:17: 20406207261480380. doi:10.1177/20406207261480380
2. Giesinger JM, Loth FLC, Aaronson NK, et al; EORTC Quality of Life Group. Thresholds for clinical importance were established to improve interpretation of the EORTC QLQ-C30 in clinical practice and research. J Clin Epidemiol. 2020;118:1-8. doi:10.1016/j.jclinepi.2019.10.003
3. Di Maio M, Basch E, Denis F, et al; ESMO Guidelines Committee. The roles of patient-reported outcome measures in the continuum of clinical care: ESMO Clinical Practice Guideline. Ann Oncol. 2022;33(9):878-892. doi:10.1016/j.annonc.2022.04.007