Patient-Reported Outcomes in Myeloproliferative Neoplasms: A Systematic Review

Background: Myeloproliferative neoplasms (MPNs) are a class of clonal myeloid malignancies categorized into three distinct subtypes based on clinical, histopathologic and laboratory markers. Consequently, the treatment goal of MPNs is their long-term management, preventing sequelae like thrombosis, progression to myelofibrosis or leukemia, and symptom control. The advent of targeted therapies in the form of JAK-2 inhibitors and pegylated interferons have changed the treatment landscape of MPNs, particularly regarding quality of life, hence the assessment of patient-reported outcomes (PROs) has gained importance in the long-term management of MPNs.

Objectives: This systematic review aims to summarize PROMs used in MPN trials, assess their reporting consistency, and explore their validity and interpretability.

Methods: We conducted a systematic search of the MEDLINE and CENTRAL databases for RCTs in MPN on July 17th, 2023, updating a previous search from January 1st, 2015, to August 20th, 2021. RCTs were eligible for inclusion irrespective of participant or disease characteristics, interventions or publication status. The primary objective was to identify PROMs utilized in MPN trials and assess their reporting consistency by cross-examining trial publications with their registry entries and study protocols, where available. Additionally, we gathered information on trial, disease, patient, and treatment characteristics. Data extraction was conducted using a predefined extraction template.

Based on the PROMs referenced in included MPN trials, we conducted a secondary search to find corresponding validation studies. Following trial selection, we extracted study population characteristics, tool details, measurement properties, and interpretability information. Results were synthesized narratively.

Results: The search update yielded 1,434 records. Following screening, we identified 21 reports of nine new studies, bringing the total to 308 reports of 87 studies, including our previous search. Two newly identified studies were completed, with one available as a full text. The other studies were still ongoing. Across all studies, PRO assessment was planned in 72 trials (83%). In 12 of 72 studies (18%), PRO was a primary outcome, while others listed PROs as secondary or exploratory endpoints. Among these, five explored MPN-directed treatments (three trials of JAK inhibitors, one of telomerase inhibitors, and one interferon trial). One trial investigated pruritus interventions, and one targeted the prevention of thromboembolic sequela. The remaining five trials examined diet, exercise, lifestyle, or traditional medicine interventions.

Across RCTs, 27 different PROMs were reported. The most frequently referenced global PROMs included the EORTC QLQ-C30 in 19 trials (26 %) and the EQ-5D in 16 trials (22 %). MPN-SAF-based (32 trials, 44%) and MF-SAF-based tools (28 trials, 39 %) were among the most cited disease-specific PROMs. The reported symptoms-specific outcome measures were mainly directed at assessing fatigue or pruritus.

Our second database search identified validation studies for 10 tools that included target population participants. Apart from the generic cancer questionnaire EORTC-QLQ C30 and the non-disease-specific EQ-5D, the majority of studies pertained to the development and refinement of various MF-SAF and MPN-SAF tool iterations (MF-SAF, MPN-SAF, MPN-SAF TSS, MF-SAF v2.0, MF-SAF v4.0, MPN-SD). Three reports addressed the PROMs' development and content validity. When compared to tools assessing similar constructs, construct validity and responsiveness of different tool modifications generally showed correlations above 0.50, and assessment of the correlation between different MF-/MPN-SAF tools showed high convergent validity. Only one study investigated the interpretability for the MF-SAF v4.0, reporting a minimal clinically important difference through anchor-based analysis.

Conclusion: This review emphasizes the integral role of PRO assessment in MPN clinical trials. Given their use as primary endpoints and their growing importance in patient management, it is crucial to select tools that have undergone rigorous development and validation. Moreover, the interpretability of PROMs is essential for their suitability for both research and routine clinical practice.

Registration: PROSPERO, CRD42023447408

Oliva:Daiichi Sankyo: Consultancy, Honoraria; Janssen: Speakers Bureau; Ryvu: Consultancy, Honoraria, Patents & Royalties; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Halia Therapeutics: Patents & Royalties; Amgen: Consultancy, Honoraria, Speakers Bureau; Grande Ospedale Metropolitano Bianchi Melacrino Morelli: Current Employment; Sobi: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Ionova:Sobi, Novartis: Research Funding.