Lynda M Foltz

Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: a snapshot of 1144 patients in the JUMP trial

JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis – a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinib’s mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a ≥50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov.

Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis

Combined Janus kinase 1 (JAK1) and JAK2 inhibition therapy effectively reduces splenomegaly and symptom burden related to myelofibrosis but is associated with dose-dependent anemia and thrombocytopenia. In this open-label phase II study, we evaluated the efficacy and safety of three dose levels of INCB039110, a potent and selective oral JAK1 inhibitor, in patients with intermediate- or high-risk myelofibrosis and a platelet count ≥50×109/L. Of 10, 45, and 32 patients enrolled in the 100 mg twice-daily, 200 mg twice-daily, and 600 mg once-daily cohorts, respectively, 50.0%, 64.4%, and 68.8% completed week 24. A ≥50% reduction in total symptom score was achieved by 35.7% and 28.6% of patients in the 200 mg twice-daily cohort and 32.3% and 35.5% in the 600 mg once-daily cohort at week 12 (primary end point) and 24, respectively. By contrast, two patients (20%) in the 100 mg twice-daily cohort had ≥50% total symptom score reduction at weeks 12 and 24. For the 200 mg twice-daily and 600 mg once-daily cohorts, the median spleen volume reductions at week 12 were 14.2% and 17.4%, respectively. Furthermore, 21/39 (53.8%) patients who required red blood cell transfusions during the 12 weeks preceding treatment initiation achieved a ≥50% reduction in the number of red blood cell units transfused during study weeks 1–24. Only one patient discontinued for grade 3 thrombocytopenia. Non-hematologic adverse events were largely grade 1 or 2; the most common was fatigue. Treatment with INCB039110 resulted in clinically meaningful symptom relief, modest spleen volume reduction, and limited myelosuppression.

Improved survival in red blood cell transfusion dependent patients with primary myelofibrosis (PMF) receiving iron chelation therapy

Many patients with primary myelofibrosis (PMF) become red blood cell (RBC) transfusion dependent (TD), risking iron overload (IOL). Iron chelation therapy (ICT) may decrease the risk of haemosiderosis associated organ dysfunction, though its benefit in PMF is undefined. To assess the effect of TD and ICT on survival in PMF, we retrospectively reviewed 41 patients. Clinical data were collected from the database and by chart review. The median age at PMF diagnosis was 64 (range 43–86) years. Median white blood cell (WBC) count at diagnosis was 7.6 (range 1.2–70.9) × 109/L; haemoglobin 104 (62–145) G/L; platelets 300 (38–2088) × 109/L. Lille, Strasser, Mayo and International Prognostic System (IPS) scores were: low risk, n = 15, 8, 11, 3; intermediate, n = 15, 19, 9, 16; high, n = 5, 11, 5, 7; respectively. Primary PMF treatment was: supportive care, n = 23; hydroxyurea, n = 10; immunomodulatory, n = 4; splenectomy, n = 2. Sixteen patients were RBC transfusion independent (TI) and 25 TD; of these 10 received ICT for a median of 18.3 (0.1–117) months. Pre‐ICT ferritin levels were a median of 2318 (range 263–8400) and at follow up 1571 (1005–3211 µg/L (p = 0.01). In an analysis of TD patients, factors significant for overall survival (OS) were: WBC count at diagnosis (p = 0.002); monocyte count (p = 0.0001); Mayo score (p = 0.05); IPS (p = 0.02); number of RBC units (NRBCU) transfused (p = 0.02) and ICT (p = 0.003). In a multivariate analysis, significant factors were: NRBCU (p = 0.001) and ICT (p = 0.0001). Five year OS for TI, TD‐ICT and TD‐NO ICT were: 100, 89 and 34%, respectively (p = 0.003). The hazard ratio (HR) for receiving >20 RBCU was 7.6 (95% Confidence Intervals [CI] 1.2–49.3) and for ICT was 0.15 (0.03–0.77). In conclusion, 61% of PMF patients developed RBC‐TD which portended inferior OS; however patients receiving ICT had comparatively improved OS, suggesting a clinical benefit. Prospective studies of IOL and the impact of ICT in PMF are warranted. Copyright

Improved survival with iron chelation therapy for red blood cell transfusion dependent lower IPSS risk MDS may be more significant in patients with a non-RARS diagnosis

Retrospective analyses suggest iron overload is associated with inferior survival (OS) in lower risk MDS and iron chelation therapy (ICT) with improvement. However, an analysis of RARS patients found no such association. We analyzed subtypes of lower risk MDS. Median OS for non-RARS without and with ICT was 44 months and not reached (P<0.001), and for RARS 99 and 134.4 months (P=NS); in red blood cell (RBC) transfusion dependent RARS patients not receiving ICT, median OS was 73.8 months (P=0.025). These results suggest a stronger association between ICT and OS in non-RARS MDS than in RARS, with significantly superior OS in transfusion dependent patients receiving ICT.

Clinical Features, Treatment, and Outcome of HIV-Associated Immune Thrombocytopenia in the HAART Era

The characteristics of HIV-associated ITP were documented prior to the HAART era, and the optimal treatment beyond HAART is unknown. We performed a review of patients with HIV-associated ITP and at least one platelet count <20 × 109/L since January 1996. Of 5290 patients in the BC Centre for Excellence in HIV/AIDS database, 31 (0.6%) had an ITP diagnosis and platelet count <20 × 109/L. Initial ITP treatment included IVIG, n = 12; steroids, n = 10; anti-RhD, n = 8; HAART, n = 3. Sixteen patients achieved response and nine patients achieved complete response according to the International Working Group criteria. Median time to response was 14 days. Platelet response was not significantly associated with treatment received, but complete response was lower in patients with a history of injection drug use. Complications of ITP treatment occurred in two patients and there were four unrelated deaths. At a median followup of 48 months, 22 patients (71%) required secondary ITP treatment. This is to our knowledge the largest series of severe HIV-associated ITP reported in the HAART era. Although most patients achieved a safe platelet count with primary ITP treatment, nearly all required retreatment for ITP recurrence. New approaches to the treatment of severe ITP in this population are needed.

Impact of ruxolitinib treatment on the hemoglobin dynamics and the negative prognosis of anemia in patients with myelofibrosis

Ruxolitinib, a Janus kinase 1 and 2 (JAK1/2) inhibitor, is the only approved drug for the treatment of intermediateor high-risk myelofibrosis.[1] In the phase 3 registration trials, ruxolitinib demonstrated rapid and durable reductions in splenomegaly, improvements in symptoms and quality-of-life measures, and prolonged survival in patients with myelofibrosis.[1,2] However, a hematological adverse event profile including anemia and thrombocytopenia has been well characterized. These changes are an extension of ruxolitinib’s pharmacological action that includes inhibition of JAK2-mediated erythropoiesis and megakaryopoiesis.[3] Importantly, this initial decrease in hemoglobin (Hb) seen upon starting ruxolitinib treatment has a characteristic temporal pattern. Typically, Hb levels decrease during the first few weeks of therapy and reach a nadir near week 12. Then, levels gradually increase to a new steady state near baseline by week 24–48 and remain stable for the remainder of treatment.[1,2] A recent predictive modeling analysis using the data from the phase 1/2 study (NCT00509899) and COMFORT studies found that individual patient Hb levels could only be predicted by employing a mechanistic model that established dose–response relationship and accounted for both positive and inhibitory effects of ruxolitinib on erythropoiesis.[4] Anemia is one of the diagnostic criteria for myelofibrosis and a known adverse prognostic factor. In the International and Dynamic International Prognostic Scoring Systems, Hb levels of <100 g/L at the time of diagnosis and during the course of disease, respectively, have been shown to have a significant negative impact on overall survival (OS).[5,6] However, both scoring systems were derived and validated prior to the availability of ruxolitinib. Therefore, here, we characterized the effect of ruxolitinib treatment on the Hb dynamics and assess its impact on OS. We conducted the analysis on a pooled data set from two phase 3 randomized COMFORT studies. Data from a median follow-up of approximately 3 years in each study were used. The design and results from these studies have been described previously.[3,7] Briefly, COMFORT-I is a double-blind, placebo-controlled study, and COMFORT-II is an open-label study comparing ruxolitinib with investigator-determined best available therapy in patients with myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis. For each patient, the starting dose of ruxolitinib was determined based on baseline platelet count (15 or 20 mg, twice daily), and ruxolitinib was individually titrated over the course of treatment to optimize safety and efficacy. Absolute changes in Hb levels from baseline to nadir levels were defined by two predetermined thresholds. An absolute reduction of 3 g/L of Hb from baseline to the lowest value around 12 weeks was considered as a conservative minimal reduction for sensitivity of analysis, whereas an absolute reduction of 30 g/L was considered as a clinically relevant reduction in Hb. Patients were categorized into subgroups based on the thresholds as those having a drop in Hb 3 g/L, drop in Hb> 3 g/L, drop in Hb 30 g/L, and drop in Hb> 30 g/L. Patients who received packed red blood cell transfusions in the first 12 weeks of treatment were considered as drop in Hb> 30 g/L. Baseline characteristics were evaluated against observed patterns of Hb changes. A multivariate Cox proportional hazards regression model was used to assess the

Autoimmune syndromes presenting as a paraneoplastic manifestation of myelodysplastic syndromes: clinical features, course, treatment and outcome

Autoimmune manifestations (AIM) are reported in up to 10-30% of myelodysplastic syndromes (MDS) patients; this association is not well defined. We present herein a retrospective chart review of single center MDS patients for AIM, a case discussion and a literature review. Of 252 MDS patients examined, 11 (4.4%) had AIM around MDS diagnosis. International Prognostic Scoring System scores were: low or intermediate (int)-1 (n=7); int-2 or high (n=4). AIM were: culture negative sepsis (n=7); inflammatory arthritis (n=3); vasculitis (n=4); sweats; pericarditis; polymyalgia rheumatica (n=2 each); mouth ulcers; pulmonary infiltrates; suspicion for Behcet’s; polychondritis and undifferentiated (n=1 each). AIM treatment and outcome were: prednisone +/- steroid sparing agents, n=8, ongoing symptoms in 5; azacitidine (n=3), 2 resolved; and observation, n=1, ongoing symptoms. At a median follow up of 13 months, seven patients are alive. In summary, 4.4% of MDS patients presented with concomitant AIM. MDS should remain on the differential diagnosis of patients with inflammatory symptoms.

Published guidelines versus real-life practice in the diagnosis and treatment of essential thrombocythemia.

intensity [RIC]), primary disease, and status at transplant. Thrombocytopenia was distinguished as persistent or transient in the presence of a or <30 day duration of platelet count reduction, respectively. Clinical conditions related or associated with the development of thrombocytopenia (i.e. cGVHD, infectious complications, relapse, microangiopathy, or other) were evaluated. Quantitative variables were tested for normal distribution using the Shapiro-Wilk test. Comparisons between groups were performed with t test or U-Mann Whitney test, depending on Shapiro-Wilk test results. g tests were used to analyze categorical values; when assumptions for g test were not verified, Fisher’s exact test was used. Survival curves were estimated using the Kaplan-Meier method. Overall survival (OS) was analyzed using log-rank tests and Cox proportional hazard models, after the proportional hazards assumption had been verified.

Evolving Therapeutic Options for Polycythemia Vera: Perspectives of the Canadian Myeloproliferative Neoplasms Group

Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis and acute myeloid leukemia. The discovery of the JAK2 V617 mutation marked a significant milestone in understanding the pathophysiology of the disease and subsequently the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin level and presence of the JAK2 V617 mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potential prolongation of survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapy and is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging, with molecular responses occurring in some patients. Ongoing phase 3 studies of HU versus pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of the JAK1/2 inhibitor ruxolitinib in comparison to best available treatment in HU-intolerant or -resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice.