Treatment with the norepinephrine-dopamine reuptake inhibitor methylphenidate significantly reduced cancer-related fatigue in patients with hematologic malignancies compared with placebo, according to findings from the randomized, double-blind, crossover MICRO trial reported by Frederiksen et al in the Journal of Clinical Oncology. The improvement exceeded the prespecified threshold for clinical relevance, and treatment was generally well tolerated.
Study Details
The investigator-initiated, multicenter trial enrolled 152 adults with hematologic malignancies and persistent fatigue at eight hematology departments in Denmark between June 2018 and October 2024. Eligible patients had a fatigue score of ≥ 4 on a 10-point visual analog scale for at least 14 days and a hemoglobin concentration of at least 8.0 g/dL. Patients who had received chemotherapy or venetoclax within the preceding 8 weeks or were receiving concomitant psychopharmacologic treatment were excluded.
Patients were randomly assigned to receive methylphenidate or placebo for 6 weeks, followed by a 1-week washout period and crossover to the alternative treatment for another 6 weeks. Methylphenidate was administered at 5 mg twice-daily during week 1; 10 mg twice-daily during week 2; and 20 mg twice-daily during weeks 3 through 6. The primary endpoint was change in the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) score, with higher scores indicating less fatigue.
The median patient age was 59 years, and 44% were women. Lymphomas and myeloproliferative neoplasms were the most common malignancies. At enrollment, 55% of patients were in posttreatment follow-up, 25% were receiving ongoing cancer treatment, and 20% were untreated. Overall, 130 patients (85.5%) completed both treatment periods.
Key Results
FACIT-F scores improved by a mean of 8.9 points (95% confidence interval [CI] = 7.3–10.4) during methylphenidate treatment compared with 3.9 points (95% CI = 2.3–5.4) during placebo treatment. The between-treatment difference was 5.0 points (95% CI = 2.8–7.2; P < .01), exceeding the prespecified 4.25-point threshold for a clinically meaningful improvement.
Other fatigue assessments supported the primary findings. The between-treatment differences favored methylphenidate on the EORTC QLQ-C15-PAL fatigue domain (–13.0 points, 95% CI = –19.6 to –6.4) and fatigue visual analog scale (–1.2 points, 95% CI = –1.7 to –0.6). Patients also reported an additional 0.7 hours awake per day (95% CI = 0.1–1.2; P = .02) with methylphenidate.
Following methylphenidate treatment, 57.6% of patients reported some improvement in fatigue, compared with 29.2% following placebo. At study completion, 52.3% reported feeling best during the methylphenidate period, compared with 23.1% during the placebo period.
Adverse events were generally mild but occurred more frequently during methylphenidate treatment than during placebo treatment (57% vs 40%; P = .01). Reported events included headache, dizziness, tremor, and palpitations. Grade 3 or 4 adverse events were reported in 2% of patients during each treatment period.
The investigators concluded: "[Methylphenidate] treatment alleviated fatigue and may be considered as a pharmacologic fatigue intervention in patients with hematologic cancer."
Henrik Frederiksen, MD, PhD, of the Department of Hematology, Odense University Hospital, Odense, Denmark; the Department of Clinical Research, University of Southern Denmark, Odense, Denmark; and the Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by the Danish Cancer Society, the Danish Comprehensive Cancer Center, and others. For full disclosures of the study authors, visit ascopubs.org.
