Elsevier

Leukemia Research

Volume 59, August 2017, Pages 26-31
Leukemia Research

Research paper
Development of a harmonized patient-reported outcome questionnaire to assess myelofibrosis symptoms in clinical trials

https://doi.org/10.1016/j.leukres.2017.05.012Get rights and content

Highlights

  • Myelofibrosis is a highly symptomatic myeloproliferative neoplasm

  • Myelofibrosis causes both splenomegaly-related and constitutional symptoms

  • The MFSAF v4.0 assesses the severity of seven core symptoms of myelofibrosis

  • The MFSAF v4.0′s 24-h and 7-day recall formats are available for use in trials

  • Research is needed to confirm the measurement characteristics of the MFSAF v4.0

Abstract

Along with reducing spleen size, relieving symptom severity is a key objective of the treatment of myelofibrosis (MF). Several questionnaires have been developed for patient self-report of MF symptoms in clinical trials and each includes unique instructions, items, and/or response scales. This variability in questionnaire content increases uncertainty; it is unclear which questionnaire is the most appropriate for assessing MF symptoms and it makes comparisons across trials difficult. The Patient-Reported Outcome (PRO) Consortium’s MF Working Group (WG) was established to review existing MF symptom questionnaires and to develop a harmonized, consensus-based PRO questionnaire for use in future MF trials. The WG focused on the seven core symptoms of MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety, and bone pain. The resulting Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) asks respondents to report symptom severity at its worst for each of the seven items on a 0 (Absent) to 10 (Worst Imaginable) numeric rating scale. The MFSAF v4.0, for which there are 24-h and 7-day recall formats, will be maintained and licensed by the Critical Path Institute and made publicly available for use in future clinical trials.

Introduction

Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm that primarily affects older individuals and is characterized by progressive bone marrow fibrosis and ineffective hematopoiesis. Dysregulation of the Janus kinase (JAK) −STAT pathway resulting from mutations that lead to constitutively active JAK2 [1], [2] or increased proinflammatory cytokines that signal through JAK1 and JAK2 [3] are believed to underlie splenomegaly and symptoms associated with MF. This understanding of the underlying pathophysiology of MF has led to the development of new treatments; Ruxolitinib is approved for the treatment of MF, and other JAK inhibitors [4], [5], [6], [7] and non-JAK inhibitor compounds [8] are under investigation.

MF is associated with significant, debilitating symptoms including early satiety, abdominal discomfort, and pain under the ribs on the left side of the body due to splenomegaly and fatigue, night sweats, bone pain, fever, and weight loss due to inflammation and hypercatabolic state [9], [10], [11], [12], [13], [14], [15]. Although some of these symptoms, such as fatigue, are not specific to MF, their prevalence and severity are substantially higher among patients with myeloproliferative neoplasms than in matched controls [16]. Demonstrating an improvement in MF symptoms is an important goal in clinical trials. This improvement may be manifested as a reduction in symptom burden from baseline, a delay in worsening of symptoms, or both. Ruxolitinib substantially reduced symptoms in the COMFORT-I trial; a reduction in symptoms of 50% or more was observed in 45.9% of patients assigned to ruxolitinib compared to 5.3% of patients assigned to placebo [14]. Symptom reductions were also observed in an open-label, dose-ranging study of fedratinib [17] and in a randomized clinical trial of pacritinib [18].

Several questionnaire variants for patient self-report of MF symptoms have been used in clinical trials and observational research. These variants include different symptoms, recall periods, descriptions of symptoms, and/or response scales. This variability increases uncertainty associated with assessing symptoms in trials. In the drug development context, lack of a harmonized questionnaire may lead to regulatory uncertainty as well as unnecessary expenditure of substantial time and money to develop new questionnaires, which further compounds the problem. Stakeholders reviewing MF trials, including regulatory bodies, are required to evaluate each MF symptom questionnaire variant, which increases complexity and may make it difficult to interpret observed effects on symptoms. Additionally, the use of multiple MF symptom questionnaires makes it difficult to compare the efficacy of different treatments across trials. The development of a harmonized MF symptom questionnaire that can be used across clinical trials is needed to address these limitations.

The MF Working Group was established by the Critical Path Institute’s Patient-Reported Outcome (PRO) Consortium [19] to create a publicly available, consensus-based, harmonized version of an MF symptom questionnaire that can be used across MF treatment trials. Another goal of the Working Group is to facilitate adoption of the harmonized MF symptom questionnaire by the biopharmaceutical industry and academic investigators. The Working Group focused on seven symptoms of MF identified through existing patient- and clinician-based evidence to be the most relevant: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side of the body, early satiety, and bone pain. After a significant amount of preparatory work was completed and the existing evidence was assembled, the MF Working Group held a meeting on March 2, 2016, to gain consensus around a harmonized MF symptom questionnaire. The harmonization panel included an MF patient, representatives from the Critical Path Institute, US Food and Drug Administration (FDA), and pharmaceutical companies, as well as clinical experts and individuals with expertise in the development of PRO questionnaires for use in clinical trials. This article describes the efforts of the MF Working Group and the outcome of the harmonization meeting.

Section snippets

Review of existing measures

The MF Working Group conducted a comprehensive review of existing MF symptom questionnaires, in order to identify items that had been used to assess the seven core MF symptoms in previous studies. The questionnaires were identified through a review of the published literature and by soliciting information from questionnaire developers. Eight MF symptom questionnaires were identified (Table 1; see also supplemental materials) along with several individual items that were designed to address

Harmonization meeting

The Working Group’s harmonization panel meeting was held on March 2, 2016. The panel used the findings from the literature review and the listing of individual items included in the supplemental materials to this article as a foundation in developing the harmonized items. General administration considerations, including recall interval and mode of administration, were discussed. Each symptom item was then considered sequentially and the group considered different wording options for the

Conclusions

The MF Working Group recommends that the MFSAF v4.0 be used in future clinical trials to assess MF symptom severity. The MFSAF v4.0 will be publicly available via a licensing agreement with the Critical Path Institute. Researchers who utilize the instruments will be asked to share any results regarding the performance of the MFSAF v4.0 with the Working Group. This will enable continued evaluation and refinement of the items. Additionally, submitting the instrument to FDA’s Drug Development Tool

Funding

Funding for this research was provided by the following PRO Consortium member firms: CTI BioPharma and Janssen Pharmaceuticals. In addition, Critical Path Institute’s PRO Consortium is supported, in part, by Critical Path Public-Private Partnerships Grant Number <gn1 > 1U18FD005320</gn1> from the U.S. Food and Drug Administration.

Authorship contributions

All authors participated in the Myelofibrosis Working Group Consensus Development Meeting and were involved in the drafting of the manuscript.

Acknowledgments

The PRO Consortium gratefully acknowledges the following individuals for their participation at the Myelofibrosis Working Group Consensus Development Meeting: Developing a Harmonized Version of a Daily Symptom Diary for Myelofibrosis Clinical Trials, held on March 2, 2016 in Silver Spring, Maryland: Michelle Campbell, PhD (FDA); Wen-Hung Chen, PhD (FDA); Chiun-Fang Chiou, PhD (Janssen); Amylou Dueck, PhD (Mayo Clinic); Joseph Feliciano, PharmD (employed by CTI BioPharma at the time the

References (30)

  • R. Kralovics et al.

    A gain-of-function mutation of JAK2 in myeloprolifera-tive disorders

    N. Engl. J. Med.

    (2005)
  • A. Tefferi

    Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1

    Leukemia

    (2010)
  • A. Pardanani et al.

    A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis

    Blood Cancer J.

    (2015)
  • A. Pardanani et al.

    Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis

    Leukemia

    (2013)
  • A.W. Roberts et al.

    BMS-911543, a selective JAK2 inhibitor: a multicenter phase 1/2a study in myelofibrosis

    Blood

    (2013)
  • Cited by (13)

    • Anemia in myelofibrosis: Current and emerging treatment options

      2022, Critical Reviews in Oncology/Hematology
    • Addressing symptom burden in myeloproliferative neoplasms

      2022, Best Practice and Research: Clinical Haematology
      Citation Excerpt :

      The MPN-SAF Total Symptom Score (TSS), which is calculated as the total score from these questions rated from 0 to 10, has demonstrated strong correlation with overall quality of life and has excellent internal consistency [9]. Additional iterations of the MPN-SAF TSS have been made to include a fatigue item [10,11], modified to include only six elements [12], and clustered into splenomegaly, hypervelocity, and cytokine-related symptoms [13]. The evolution of MPN-specific PROs is shown in Fig. 1.

    • Advancing Effective Clinical Trial Designs for Myelofibrosis

      2021, Hematology/Oncology Clinics of North America
      Citation Excerpt :

      Recently, to harmonize MF symptom burden questionnaires across academic and industry partners, the MF-SAF version 4.0 was developed and includes 7 items: fatigue, night sweats, pruritus, abdominal discomfort, pain, early satiety, and bone pain. The MF-SAF version 4.0 is recommended for use in MF trials and is available as a 7-day diary (24-hour recall) or 1-time (1-day recall) assessment.41 Graphical display of TSS data appears in Fig. 2 and follows recommendations for optimal visualization of PROs by Snyder and colleagues.42

    • Quality of Life in Myeloproliferative Neoplasms: Symptoms and Management Implications

      2021, Hematology/Oncology Clinics of North America
      Citation Excerpt :

      Ruxolitinib-treated patients who achieved a 35% or greater decrease in spleen volume experienced the greatest improvements in these patient-reported outcomes. Further refinements in language, collaboration with the PRO Institute and members of the Study Endpoints and Labeling Development team at the US Food and Drug Administration led to the final version of the MFSAF 4.0 (Table 2).5 With a total of 7 items, the MFSAF 4.0 had a total possible score range of 0 to 70.

    • Beyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies

      2018, The Lancet Haematology
      Citation Excerpt :

      Incorporation of health-related quality of life and other PRO measures to inform the patient experience while exposed to a cancer therapy can add value to our understanding of the effect of a new intervention. Efforts are underway to standardise how PRO measures can be analysed and presented.82,83 There is now growing interest in using item libraries such as the PRO-CTCAE to provide the needed flexibility to select the relevant emergent symptomatic adverse events for the trial context that can inform drug safety and tolerability in addition to measuring health-related quality of life.

    View all citing articles on Scopus
    1

    This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

    View full text