Evaluating the serial use of the Myelofibrosis Symptom Assessment Form for measuring symptomatic improvement: performance in 87 myelofibrosis patients on a JAK1 and JAK2 inhibitor (INCB018424) clinical trial.

Myelofibrosis (MF) is a myeloproliferative neoplasm that is characterized by a series of consequences from the clonal disease.1 Included among the consequences of MF are the development of ineffective hematopoiesis (and thus potentially anemia and other cytopenias), leukoerythroblastosis, splenomegaly through perhaps a variety of mechanisms including (but not limited to) ineffective hematopoiesis and splenic sequestration of immature myeloid cells, significant constitutional symptoms (night sweats, fevers, weight loss), pruritus, risk of blastic transformation, and premature death.2 We have previously demonstrated that the symptomatic burden among patients with MF is significant both from directly observable effects of disease (ie, from anemia and/or splenomegaly) and by self-reported outcomes from MF patients for less quantifiable symptoms such as fatigue, night sweats, and pruritus.3 We have also reported that the prevalence of these symptoms is relatively uniform across the 3 main subtypes of MF (namely, primary MF, post-polycythemia vera MF [post-PV MF], and post-essential thrombocythemia MF [post-ET MF]).4 In addition, the presence of significant constitutional symptoms is not only bothersome for the individual patient, but has been found to be prognostically detrimental and is included as an adverse prognostic factor in the International Working Group for Myelofibrosis Research and Treatment prognostic score for MF.5 Historically, therapies for MF have been largely palliative, with very limited ability to significantly impact the symptomatic burden of patients afflicted with the disease. However, the discovery of the JAK2-V617F mutation in 20056 (and subsequent discovery of related myeloproliferative neoplasm-associated mutations7,8) has ushered in an era of targeted therapeutic approaches for MF including JAK inhibitors,9 which down-modulate the dysregulated activity of JAKs that is characteristic in the myeloproliferative neoplasms. Initial results of these targeted trials demonstrated a profound ability of these medications to decrease MF-associated splenomegaly and symptoms.10,11 The difficulty was that no current instrument of patient-reported outcomes adequately and concisely assessed the spectrum of MF-associated symptoms. Therefore, we developed, and validated in a single time point validation study, the Myelofibrosis Symptom Assessment Form.4 This instrument captured the spectrum of MF-associated constitutional symptoms (fatigue, night sweats, fevers, pruritus, weight loss) and splenomegaly-associated symptoms (abdominal pain, early satiety, mechanical effects from the spleen). This prior validation of the Myelofibrosis Symptom Assessment Form used a series of established instruments of patient-reported outcomes to validate the questions and results obtained from the Myelofibrosis Symptom Assessment Form. In addition, a separate question is asked relating to an overall assessment of quality of life. We sought to evaluate the use of the Myelofibrosis Symptom Assessment Form for measurement of baseline symptoms and sensitivity to detect changes when used serially in clinical trials. Therefore, we used the Myelofibrosis Symptom Assessment Form in serial administrations in conjunction with the largest phase 2 trial ever conducted for that disorder, the open label phase 2 trial of the selective JAK1 and JAK2 inhibitor INCB018424 (Trial 251).10