Recent clinical trials with JAK or mTOR inhibitors in primary myelofibrosis (PMF) have identified pruritus as one of the most treatment-responsive disease traits. However, little is known about the prevalence of pruritus in PMF or its clinical and laboratory correlates.
The study population was selected among a consecutive series of patients with PMF seen at the Mayo Clinic and in whom bone marrow histologic and cytogenetic information was available for re-review. JAK2, MPL and IDH mutation status and plasma cytokine levels (IL-1b, IL-1RA, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, TNF-α, G-CSF, IFN-α, IFN-γ, MIP-1a, MIP-1b, HGF, IP-10, MIG, MCP-1 and VEGF) were recorded where available. Overall and leukemia-free survival analyses were performed from time of referral to the Mayo Clinic.
Among 566 consecutive patients with PMF (median age 62 years; 368 males), the presence (n=90) or absence (n=146) of pruritus was documented in 236 patients. The prevalence of pruritus was 38% when considering only those patients in whom pruritus history was documented (n=236), and 16% when all study patients (n=566) were considered regardless of whether or not the absence of pruritus was documented in their history. Among the 90 patients with pruritus, it was severe enough to warrant specific therapy in 51 (57%) patients, was aquagenic in 29 (32%), and onset antedated PMF diagnosis in 15 (17%). All 236 patients had information on karyotype: 136 normal, 76 favorable and 24 unfavorable karyotype. Information on JAK2, MPL, and IDH mutations was available in 197 (125 positive), 147 (9 positive), and 131 (2 positive) patients, respectively. In addition, plasma levels of the aforementioned cytokines were available in 63 patients.
Parameters at diagnosis that were significantly associated with presence of pruritus included leukocytosis (p=0.03), absence of leukopenia (p=0.002), and absence of MPLW515 mutation (p=0.02). Borderline significance was noted for JAK2V617F positive status (p=0.08). The incidence of pruritus was 0% (0/9) vs. 41% (56/138) in MPL-mutated vs MPL-unmutated cases and 42% (52/125) vs. 29% (21/72) JAK2 mutated vs unmutated cases, respectively. No significant correlations were noted for age, DIPSS-plus scores, transfusion need, karyotype, or plasma cytokine levels. The association with leukocytosis/leukopenia was subsequently shown to be significant only in JAK2V617F-negative cases. To date, 124 deaths and 19 leukemic transformations have been documented. In JAK2-mutated cases (n=125), pruritus did not affect overall or leukemia-free survival. In JAK2-unmutated cases (n=72), a significant correlation between presence of pruritus and inferior leukemia-free survival was noted (p=0.04), and was independent of leukocytosis, thrombocytopenia or abnormal karyotype.
Pruritus accompanies PMF in a substantial proportion of patients and is more or less likely to occur in the presence of JAK2 or MPL mutations, respectively. In JAK2V617F-negative cases, PMF-associated pruritus clustered with leukocytosis and was independently associated with inferior leukemia-free survival.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.