Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400-mg daily was based on results of an updated analysis of the pivotal phase III, placebo-controlled JAKARTA trial in patients with JAK-inhibitor-naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first-line fedratinib in patients with myelofibrosis.

A phase III randomized, multicentre, double blind, active controlled trial to compare the efficacy and safety of two different anagrelide formulations in patients with essential thrombocythaemia - the TEAM-ET 2·0 trial.

Anagrelide is an established treatment option for essential thrombocythaemia (ET). A prolonged release formulation was developed with the aim of reducing dosing frequency and improving tolerability, without diminishing efficacy. This multicentre, randomized, double blind, active-controlled, non-inferiority trial investigated the efficacy, safety and tolerability of anagrelide prolonged release (A-PR) over a reference product in high-risk ET patients, either anagrelide-naïve or -experienced. In a 6 to 12-week titration period the individual dose for the consecutive 4-week maintenance period was identified. The primary endpoint was the mean platelet count during the maintenance period (3 consecutive measurements, day 0, 14, 28). Of 112 included patients 106 were randomized. The mean screening platelet counts were 822 × 109 /l (95% confidence interval (CI) 707-936 × 109 /l) and 797 × 109 /l (95% CI 708-883 × 109 /l) for A-PR and the reference product, respectively. Both treatments effectively reduced platelet counts, to mean 281 × 109 /l for A-PR (95% CI 254-311) and 305 × 109 /l (95% CI 276-337) for the reference product (P < 0·0001, for non-inferiority). Safety and tolerability were comparable between both drugs. The novel prolonged-release formulation was equally effective and well tolerated compared to the reference product. A-PR provides a more convenient dosing schedule and will offer an alternative to licensed immediate-release anagrelide formulations.

Chronic myeloid leukemia incidence, survival and accessibility of tyrosine kinase inhibitors: a report from population-based Lithuanian haematological disease registry 2000-2013.

BACKGROUND: Currently available chronic myeloid leukaemia (CML) survival reports have originated from more affluent countries. Herein we report the entire country data on incidence and survival of CML, as well as penetrance of tyrosine kinase inhibitors (TKIs) in Lithuania. METHODS: We analyzed all patients (N = 601) from the national haematological disease monitoring system who were diagnosed with CML between 2000 and 2013. Crude (CR) and age-standardized (weighted) (ASW(R)) incidence and mortality rates, as well as 1-, 5-, and 10-year relative survival rates (RSR) were calculated. Information on TKI penetration is also reported. RESULTS: Throughout the entire 2000-2013 period the median age at diagnosis of CML patients was 62 years. The respective incidence and mortality CRs were 1.28 and 0.78, both characterized by decreasing trends over the observation period. A 5-year RSR increased from 0.33 [95 % CI, 0.27-0.40] in 2000-2004 to 0.55 [95 % CI, 0.47-0.63] in 2005-2009. However, the respective 5-year RSRs for patients aged 65-74 and ≥75 were only 0.33 [95 % CI, 0.24-0.42] and 0.18 [95 % CI 0.07-0.23] during the entire study period. TKI penetrance for CML patients grew from 1.5 % in 2000-2004 to 30.6 % in 2005-2009 and 69.1 % in 2010-2013. TKI penetrance was low in the older age groups (60 % for the 65-74 and 19 % for the ≥75 patient group, in 2010-2013). CONCLUSION: Relative CML survival in Lithuania steadily improved and paralleled the increase in TKI treatment availability. Patients above 64 years rarely received TKIs and their relative survival remained low throughout the observation period. The latency of TKI availability may have influenced the survival trends.

Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.

IMPORTANCE: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials. OBJECTIVE: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles. MAIN OUTCOMES AND MEASURES: The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form). RESULTS: The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was supported by magnetic resonance imaging in 3 cases and suspected clinically in 1 case. CONCLUSIONS AND RELEVANCE: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01437787.

Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia.

This study evaluated the efficacy and safety of dose-dense high-dose methylprednisolone (HDMP) plus rituximab (Rtx) in patients with high-risk CLL. Twenty-nine patients with relapsed or progressive CLL with adverse cytogenetics (17p deletion, TP53 mutation, 11q deletion, and/or trisomy 12) and/or progression within 12 months of fludarabine treatment were included. HDMP (1 g/m(2)) was administered daily for 5 days of each treatment course. Rtx was administered on days 1 (375 mg/m(2)) and 5 (500 mg/m(2)) of the first treatment course, on days 1 (500 mg/m(2)) and 5 (500 mg/m(2)) of the second course, and on day 1 (500 mg/m(2)) of courses 3-6. The cycles were repeated every 21 days. The overall response rate (ORR) was 62%, and 28% of patients had stable disease. In 13 patients with 17p deletion/TP53 mutation, ORR was 69%. After 22 months, the median progression-free and overall survivals were 12 and 31 months, respectively. The most frequent toxicity was hyperglycemia, and three deaths occurred in the study. Dose-dense treatment with HDMP and Rtx is an effective therapy with a favorable safety profile in patients with high-risk CLL, including those with 17p deletion/TP53 mutation.

[Chronic graft-versus-host disease presenting as nephrotic syndrome after allogenic hematopoietic stem cell transplantation]. / Letines ligos 'transplantatas pries seimininka" pasireiskimas nefroziniu sindromu po kraujo kamieniniu lasteliu persodinimo.

Complications of allogenic hematopoietic stem cell transplantation that occur in the first 100 days are considered early and those that begin 100 days after are considered late complications. Chronic graft-versus-host disease is the most common late complication of allogenic hematopoietic cell transplantation, which occurs in 60-80% of long-term survivors and causes significant morbidity and mortality. It is well known that it affects primarily the skin, mucous membranes, cells in the gastrointestinal tract and liver. The kidneys are not considered a target organ for chronic graft-versus-host disease in humans, although renal involvement in patients with chronic graft-versus-host disease, presenting as nephrotic syndrome, has been reported in patients who underwent allogenic transplantation. We present a case of chronic graft-versus-host disease that manifested as nephrotic syndrome after hematopoietic cell transplantation performed 3 years ago. Kidney biopsy revealed membrane nephropathy. Treatment with cyclosporine and methylprednisolone significantly reduced albuminuria.