Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis.

Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naïve patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful.

Pegylated interferon alpha - 2a is clinically effective and tolerable in myeloproliferative neoplasm patients treated off clinical trial.

Polycythemia vera, essential thrombocytosis, and myelofibrosis are chronic Philadelphia-negative myeloproliferative neoplasms that are characterized by clonal hematopoiesis, splenomegaly, risk of hemorrhagic and thrombotic sequelae, and profound symptom burden. We review the outcomes of 75 myeloproliferative neoplasm patients treated with pegylated interferon alpha 2a off study at an academic medical center. In the 56 treated polycythemia vera and essential thrombocytosis patients, a complete or partial response was obtained in 78.6% of patients per ELN/IWG-MRT revised criteria, with >80% of polycythemia vera patients becoming phlebotomy independent and 60% of essential thrombocytosis patients having platelet normalization with therapy. In the 19 treated myelofibrosis patients, stable disease was seen in 63.2% of patients. Vascular events occurred in 2/75 (2.6%) of treated patients while on therapy. Grade 3 toxicity was uncommon with leukopenia noted in 1 patient (1.3%). The most common adverse event overall was grade 1 fatigue in 18.7%. This retrospective single center analysis demonstrates pegylated interferon alpha 2a is active and well-tolerated therapy outside the support of a clinical trial. These results substantiate the previously reported efficacy of pegylated interferon alpha 2a in myeloproliferative neoplasms. Further prospective and randomized clinical trial data is required to better delineate pegylated interferon alpha 2a's use in myeloproliferative disease, with emphasis placed on comprehensive molecular characterization, allelic burden quantification, and measurement of histologic response.

Limitations of fibrosis grade as diagnostic criteria for post polycythemia vera and essential thrombocytosis myelofibrosis.

BACKGROUND: The clinical phenotype of patients with myeloproliferative neoplasms (MPNs) including primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET) whom manifest WHO grade 1 marrow fibrosis is poorly defined. Current IWG-MRT criteria require 2+ marrow fibrosis for diagnosis of post PV/ET myelofibrosis (MF). In contrast, the 2008 WHO definition of PMF does not require a minimum fibrosis threshold. METHODS: We retrospectively analyzed the clinical characteristics of 91 MPN patients with 1+ marrow fibrosis. We compared the clinical phenotype of sub threshold fibrosis PV/ET with that manifested by PMF. We applied the IWG-MRT criteria for post-PV/ET MF with the fibrosis component omitted and evaluated for percentage of criteria fulfillment. RESULTS: When IWG-MRT criteria were applied to the PV/ET group, 38/58 (66%) of patients fulfilled criteria for diagnosis of post-PV/ET myelofibrosis except for the 2+ fibrosis requirement. Comparison of sub threshold fibrotic PV/ET clinical phenotype to PMF revealed similar characteristics including heavy symptomatic burden (57% and 52%), presence of splenomegaly (43% and 55%), leukoerythroblastic blood smear (38% and 45%), and median hemoglobin (12.8g/dL and 11.1g/dL). CONCLUSION: MPN progression represents a biological spectrum and definitions of progression in ET/PV may benefit from criteria not restricted by degree of fibrosis.

Diffuse pain syndromes in the elderly.

Diffuse pain syndromes are common in older persons. Fibromyalgia and PMR are the most common but other inflammatory, endocrine and neoplastic diseases may cause diffuse pain as well. A thorough history and physical examination, screening laboratories and response to a trial of low-dose steroids may help to differentiate between syndromes. Fibromyalgia may be a secondary phenomenon associated with some of the other diffuse pain syndromes. This should be kept in mind if a patient fails to respond appropriately to treatments directed at a particular disease.

Acute gouty arthritis is seasonal.

OBJECTIVE: Information regarding effect of weather conditions on gout is sparse. We conducted a study in the USA to examine whether gout is seasonal. METHODS: We reviewed synovial fluid (SF) analyses from our laboratory during 1990-1995 and identified 359 patients who had acute gouty attacks. All fluids of patients with acute gout had intracellular monosodium urate crystals and SF leukocyte counts > 2000/mm3 or more than 10 leukocytes per high power field (HPF). Retrospective chart review of all patients was performed to confirm a clinical picture of acute gout. A control group included 76 patients with acute pseudogout whose SF were analyzed during the same period and who had intracellular calcium pyrophosphate crystals and inflammatory leukocyte counts as in patients with gout. RESULTS: Acute gout was most common during the spring; n = 115 (32%). Ninety (25%) patients had acute gout attacks in the fall; 81 (23%) had acute attacks during the summer; 73 (20%) had acute attacks in the winter. One-way analysis of variance (ANOVA) was used to compare the overall frequency of acute gout during the months and seasons. Using ANOVA, there was no overall statistically significant difference in the incidence of gout per season (p = 0.07), although it approached statistical significance. Acute gouty attacks were more common in the spring compared with winter (p = 0.002) and summer (p = 0.015). There was a trend but no statistically significant difference compared with fall. Winter was the season in which the fewest acute gouty cases were seen, although it was not statistically significant. No seasonal difference was seen in the pseudogout group. There was no correlation between either mean monthly temperature or humidity and the incidence of acute gouty attacks. CONCLUSION: Acute gout attacks are significantly more common in the spring. No seasonal variation was seen in patients with acute pseudogout attacks.

Steroid sparing effect of methotrexate in relapsing polychondritis.

Relapsing polychondritis is a rare inflammatory disorder causing recurrent inflammatory reactions in the cartilaginous structures. It often worsens as prednisone is tapered. We describe 3 biopsy proven patients with relapsing polychondritis in whom methotrexate was useful as a steroid sparing agent in the management of auricular chondritis.