Myelofibrosis Symptom Research Articles

Ruxolitinib for Myelofibrosis Patients Relapsing after Allogeneic Hematopoietic Transplantation

IntroductionThe Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib is approved for the treatment of symptomatic myelofibrosis (MF) regardless of the JAK2 mutational status. Ruxolitinib can reduce constitutional symptoms and spleen size resulting in an improvement of the performance status and also in a potential prolonged survival. Here we investigated the efficacy and toxicity of ruxolitinib in MF patients who relapsed after allogeneic stem cell transplantation.Patients and methodsBetween the years 2012 and 2016, 10 myelofibrosis patients of our department who relapsed after allogeneic stem cell transplantation received ruxolitinib. Stem cell donor was matched related (MRD) in two patients, matched unrelated (MUD) in six and mismatch unrelated MMUD in two patients. The median age of the patients was 61 years (r: 41-72). The median time from allogeneic transplantation until the start of ruxolitinib treatment was 23.8 months (r: 2.7-85.7). The median treatment duration was 143.5 days (r: 12-369). The median dose of ruxolitinib was 10 mg bid (r: 5-20mg) according to toxicity. Two patients had already received ruxolitinib prior to allogeneic transplantation. All patients had mixed chimerism at start of ruxolitinib. Two patients had already received donor lymphocyte infusions (DLI) prior to ruxolitinib. Two patients started with DLI beginning at day +30 and at day +147 within ruxolitinib treatment. Seven patients were positive for the JAK2V617 mutation and one patient for CALR mutation. Constitutional symptoms were observed in seven patients and splenomegaly in six patients before treatment start. One patient had aGvHD (skin) and three had cGvHD (oral mucosa, skin, liver) at the time of treatment start. In seven patients bone marrow histology was available before and during ruxolitinib treatment.ResultsWe observed an improvement of constitutional symptoms in six patients (86%). The palpable spleen size was reduced in five patients (83%) with splenomegaly (≥50% n=4, <50% n=1). In five of six patients who were dependent on blood and/or thrombocyte transfusions a reduction of the transfusion frequency was seen. Due to thrombocytopenia (CTC grade 3 and 4) dose reduction was necessary in two patients. One patient newly developed leukocytopenia within ruxolitinib treatment (CTC grade 3); before ruxolitinib one patient had grade 1 leukocytopenia and worsened to grade 3. Prior to ruxolitinib the median chimerism was 57% (r: 0-99.7) whereas during ruxolitinib treatment the median chimerism dropped to a median of 0% (r: 0-93.8). The median JAK2-alllele-level before ruxolitinib was 0.87 (r: 0.03-91.3) versus 8.35 (r: 1.83-29.9) during ruxolitinib treatment. The one patient harboring the CALR mutation had an increase of the allelic burden from 0.56 to 1.68. In five of the patients with an available bone marrow biopsy an aggravation of bone marrow fibrosis could be seen whereas no progression could be seen in two patients. The peripheral blast count increased in three patients, in one patient peripheral blasts newly developed. Progressive disease could be seen in all patients (100%) despite of reduction of spleen size, improvement of constitutional symptoms or a prolonged transfusion interval. Three patients transformed to AML. All patients with GvHD had an improvement and or even complete resolution of their GvHD. One patient developed aGvHD of the skin during ruxolitinib treatment but in this patient immunosuppressive therapy had already been stopped at day +30 due to mixed chimerism. No severe infectious complications were seen. None of the patients had to stop ruxolitinib due to side effects.ConclusionThe Janus-Activated Kinase (JAK) 1/2 -inhibitor ruxolitinib can lead to a reduction of spleen size, an improvement of MF-associated constitutional symptoms and a reduction of the blood transfusion-interval in patients with relapse after allogeneic transplantation. However, ruxolitinib does not lead to an increase of donor chimerism. It seems to have little impact on the JAK2V617F-allele level. A further aggravation of bone marrow fibrosis was seen in most of the patients. Despite of clinical improvement all patients experienced further progression of myelofibrosis and three patients even transformed to AML. Furthermore in those patients with GvHD an improvement or even complete resolution of the GvHD was seen. DisclosuresKroeger:Novartis: Honoraria, Research Funding.

Preliminary Results from a Phase I Dose Escalation Trial of Ruxolitinib and the PI3Kδ Inhibitor TGR-1202 in Myelofibrosis

Background: Therapies for myelofibrosis (MF) are limited and most are palliative. The JAK1/2 inhibitor ruxolitinib reduces spleen size and MF-related symptoms and improves survival, but can be limited by dose-dependent anemia and thrombocytopenia. Moreover, nearly half of ruxolitinib responders relapse within 5 years. PI3Kd is highly expressed in MF patient samples, independent of ruxolitinib pre-exposure. In JAK2-mutated cell lines, inhibition of PI3K/AKT signaling reduced proliferation and clonogenic potential. The once daily, next generation PI3Kd inhibitor TGR-1202 inhibited PI3K/AKT signaling and led to apoptosis in leukemia and lymphoma cell lines and was well-tolerated in clinical studies, with a toxicity profile distinct from that of ruxolitinib and other PI3Kd inhibitors. We hypothesized that adding TGR-1202 to ruxolitinib could resensitize or augment the response of MF patients with lost or suboptimal response to single-agent ruxolitinib.Objective: To assess safety of TGR-1202 in combination with ruxolitinib in MF patientsSecondary Objectives: Hematologic response, symptom assessmentMethods: MF patients who had sub-optimal responses to ruxolitinib continued their highest tolerated dose of ruxolitinib without change for ≥ 8 weeks, and were assigned to escalating doses of TGR-1202 in a standard 3+3 algorithm. Adverse events (AEs) were graded by NCI-CTCAE v4.03. Efficacy was assessed according to IWG-MRT consensus response criteria. Symptoms were assessed by the MPN symptom assessment form total symptom score (TSS). All patients received Pneumocystis pneumonia prophylaxis after cycle 1.Results: Eleven MF patients were enrolled and received 400 mg (n=3), 800 mg (n=6), or 600 mg TGR-1202 (n=2) daily. Nine were evaluable for response. Median age was 66y, 73% were male. All had ECOG PS 0-1. Five patients had mutations in JAK2, 4 in CALR, and 3 in MPL; these were mutually exclusive with exception of 1 patient with CALR and MPL mutations (Table 1). Median number of cycles of TGR-1202 + ruxolitinib treatment was 5 (1-13). Grade 2 anemia was the most common AE (Table 2). Two patients had asymptomatic Grade 3 elevations in amylase and lipase that persisted after drug was held, meeting criteria for dose limiting toxicities (DLTs) in 2 separate cohorts (TGR-1202 800mg+ruxolitinib 15mg BID and TGR-1202 800mg+ruxolitinib 10mg BID). Both patients had peak plasma TGR-1202 concentrations 1.5-2x higher than the other patients receiving 800mg TGR-1202, although steady-state levels were equivalent. The maximum tolerated dose (MTD) of TGR-1202 in combination with ruxolitinib was not established. Two patients went off-study due to AEs, and 3 due to progressive disease. One of 9 evaluable patients achieved complete remission and 7 had stable disease. Seven of the 9 evaluable patients had improvement in hematologic parameters and 8 had reduced MF symptoms with a median 33% decrease in TSS (Fig. 1).Conclusions: TGR-1202 + ruxolitinib was well-tolerated. Pharmacokinetic data were consistent with single-agent TGR-1202 (unpublished data), indicating that ruxolitinib does not alter absorption or metabolism of TGR-1202. Grade 3 elevations in amylase and lipase were considered DLTs, per protocol. Although the clinical significance of these asymptomatic laboratory findings is not clear, the protocol was amended to further assay these labs and to exclude concomitant medications with the potential to increase amylase/lipase. Importantly, no grade ≥3 hepatotoxicity, colitis, or thrombocytopenia was seen and no MTD was found. Although only one patient achieved CR, 89% demonstrated clinical benefit with the addition of TGR-1202 to ruxolitinib, supporting further exploration of this combination. [Display omitted] DisclosuresStrickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Miskin:TG Therapeutics, Inc: Employment, Equity Ownership. Cavers:TG Therapeutics: Employment, Equity Ownership. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Mesa:CTI: Research Funding; Promedior: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Savona:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Sunesis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Clinical Outcomes with Ruxolitinib (RUX) in Patients with Myelofibrosis (MF) Stratified By Transfusion Status: A Pooled Analysis of the COMFORT-I and -II Trials

Background: The phase 3 COMFORT trials demonstrated that the Janus kinase (JAK)1/JAK2 inhibitor RUX reduces spleen volume, prolongs overall survival (OS), and improves MF−related symptoms and measures of quality of life in patients with intermediate-2 or high-risk MF, compared with either placebo (COMFORT-I) or best available treatment (BAT; COMFORT-II). Many patients with MF are anemic or transfusion-dependent; the impact of these features on clinical outcomes is unknown. We evaluated the relationship between transfusion requirement and clinical outcomes in patients treated with RUX in the COMFORT studies. Methods: Analyses of data pooled from COMFORT-I and -II were stratified by baseline anemia status (defined as receiving ≥2 units of red blood cells [RBCs] within the 12 weeks before baseline or baseline hemoglobin [Hb] Results: Overall, 301 patients were randomized to RUX (baseline anemia, n=138 [45.8%]) and 227 to the control group (placebo or BAT; baseline anemia, n=113 [49.8%]). In the RUX group, a greater proportion of patients who were nonanemic at baseline (range, 73.4%-73.8%) achieved transfusion independence compared with those who had anemia at baseline (range, 15.5%-22.4%). Week 24 transfusion independence vs nonindependence status did not significantly affect OS in the RUX group (P=0.1322; Figure A), whereas it was significant (P=0.0004; Figure B) in the control group. Similarly, Week 24 transfusion dependence vs nondependence status did not significantly affect OS in the RUX group (P=0.4547; Figure C), whereas it was significant (P=0.0323; Figure D) in the control group. Median OS was significantly longer in the RUX vs control group for patients who were not transfusion independent (baseline anemia, 200 vs 137 weeks; nonanemic, 271 vs 166 weeks; overall P=0.002) or became transfusion dependent (baseline anemia, 210 vs 127 weeks; nonanemic, 292 vs 90 weeks; overall P=0.0323). Changes from baseline in spleen volume, body weight, and TSS at Week 24 were not affected by transfusion or anemia status in the RUX group; however, TSS worsened in the control group among patients who did not achieve transfusion independence vs those who did. Risk of transfusion dependence decreased after Week 24 in the RUX group. The probability of becoming transfusion independent after 1 year of treatment was similar in both treatment groups (approximately 0.75); median time to transfusion independence for the RUX and control groups was 16.6 and 12.0 weeks, respectively. For patients in the RUX group who became transfusion dependent, the mean monthly units of RBCs peaked at Week 20 (2.82 units), decreasing thereafter to 0.52 units at Week 240. Transfusion dependence did not affect RUX discontinuation rates or dosage. Conclusion: Transfusion requirement had little impact on clinical outcomes or treatment discontinuation within the RUX group but was associated with reduced OS and worsened TSS in the control group. The risk of becoming transfusion dependent, units of RBCs administered, and the monthly proportion of patients requiring transfusions decreased rapidly after 24 weeks of RUX treatment. Disclosures Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Verstovsek:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Geron: Research Funding; Lilly Oncology: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Incyte Corporation: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Paquette:Bristol-Myers Squibb: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity9s Board of Directors or advisory committees; Baxalta: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Langmuir:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau.

Selective Inhibition of Nuclear Cytoplasmic Transport As a New Treatment Paradigm in Myelofibrosis

▪Myelofibrosis (MF) is a hematopoietic stem cell neoplasm characterized by constitutive activation of JAK/STAT signaling due to mutations in JAK2, calreticulin or MPL. Many MF patients suffer from severe constitutional symptoms and have reduced life expectancy due to cytopenias, progression to acute myeloid leukemia and thromboembolic events. JAK kinase inhibitors such as ruxolitinib (RUX) reduce MF symptoms, but like all other drugs used in MF, are not curative, with persistence of mutant cells and prompt symptom rebound upon discontinuation. This defines a clinical need to identify strategies capable of inducing more profound and durable responses in MF.To identify previously unrecognized molecular vulnerabilities in MF, we infected HEL cells (homozygous for JAK2V617F) with a barcoded lentiviral shRNA library targeting ~5,000 human signal transduction genes, with 5-6 shRNAs/gene (Cellecta Human Module 1). Conditions were optimized to achieve a multitude of infection (MOI) of ~1. Barcode abundance was compared between days 0 and 9 after infection by next generation sequencing. Candidates were selected based on ≥ 15-fold reduction of abundance by ≥ 2 shRNAs targeting the same gene, similar to Khorashad et al. [Blood. 2015;125(11):1772-81]. Amongst the genes meeting these criteria, nuclear cytoplasmic transport (NCT) was significantly enriched, with RAN and RANBP2 amongst the top genes, suggesting that HEL cells may be highly dependent on NCT. For confirmation, HEL cells were stably transduced with doxycycline (DOX)-inducible shRAN. After 72 hours DOX-induced knockdown of RAN reduced viable cells by 77.3±5.5% and colony formation by 82.8±1.3% and dramatically increased apoptosis (uninduced: ~10% vs. induced: ~50%). Similar results were observed in SET-2 cells (heterozygous for JAK2V617F). We next cultured HEL and SET-2 cells with graded concentrations of the KPT-330 (selinexor, Karyopharm), an inhibitor of CRM-1, the core component of NCT, or RUX as a comparison. Selinexor was five-fold more potent than RUX against HEL cells (IC50: 98nM for KPT vs. 536 nM for RUX) and as potent as RUX in SET-2 cells (IC50:~100 nM). Importantly, RUX-resistant HEL cells (IC50:24µM) were highly sensitive to inhibition of NCT by knockdown of RAN or selinexor (IC50:160nM). Selinexor also selectively inhibited colony formation by primary MF vs. cord blood (CB) CD34+ cells (IC50:93nM for MF vs. 203nM for CB). Lastly, selinexor enhanced RUX-induced growth inhibition and apoptosis in primary MF CD34+cells cultured ex vivo for 72h (including both JAK2 mutation positive and negative MF samples, n=3 for each, and RUX resistant patient samples, n=6). Nuclear:cytoplasmic fractionation of HEL cells revealed that the expression and nuclear localization of the tumor suppressors FoxO3A and APC, but not of PP2A and nucleophosmin (NPM) were significantly increased upon knockdown of RAN, which may contribute to the increased apoptosis following NCT inhibition.To determine the in vivo effects of selinexor in MF, we induced MPN in Balb/c mice by transplanting donor marrow infected with JAK2V617F for three weeks, and then treated mice (n=13/group) with vehicle, selinexor (initial dose 20 mg/kg, 3x weekly, orally) or RUX (initial dose 50 mg/kg twice daily, orally) or the combination of RUX plus selinexor for up to 4 weeks. Combination treatment significantly reduced white blood cell counts and normalized spleen size. Compared to vehicle, selinexor alone significantly reduced GFP+cells in the spleen, and this effect was further enhanced with the combination treatment. Histopathology revealed that combination treatment restored splenic architecture, while bone marrow fibrosis was not significantly altered by selinexor or the combination. Mice in all groups, including the combined vehicle controls, experienced considerable weight loss, suggesting that toxicity may be partially due to high dose and frequent drug administration. Experiments with the next generation NCT inhibitor KPT-8602 [Etchin et al., Leukemia, 2016 Jun 24] are underway.In summary, our results suggest that MF cells are exquisitely dependent on NCT, and that NCT inhibition alone or in combination with RUX may reduce JAK2V617F allelic burden. This identifies NCT as a prime therapeutic target in MF. A phase I clinical trial of selinexor in refractory MF is in preparation. DisclosuresBaloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Deininger:BMS: Consultancy, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Pharmacologic management of myelofibrosis.

Myelofibrosis is a BCR-ABL-negative myeloproliferative neoplasm characterized by abnormal hematopoiesis. Alterations to the Janus kinase-signal transducer and activator of transcription pathway result in dysregulation of gene transcription and cell proliferation. Patients with symptomatic myelofibrosis present with a variety of signs and symptoms including, but not limited to myelosuppression, marked splenomegaly, abdominal discomfort, fatigue, and blood transfusion-dependence. Traditional myelosuppressive therapies including hydroxyurea, azacitidine, and cladribine aim to reduce constitutional symptoms and control the burden of disease. Immunomodulators can potentially reverse anemia associated with myelofibrosis, but are poorly tolerated by most patients. The novel Janus kinase 2 (JAK2) inhibitor, ruxolitinib, has demonstrated marked improvements to constitutional symptoms and splenomegaly. While survival benefit has not yet been demonstrated, continued research into pharmacologic management of myelofibrosis offers the promise of altering the course of disease progression.

Evolution of Myelofibrosis Treatment

Myelofibrosis (MF) is a classical Philadelphia chromosome-negative myeloproliferative neoplasm characterized by clonal proliferation of pluripotent stem cells, dysfunctional kinase signaling, and abnormal cytokine release. MF is a heterogeneous disease, ranging from asymptomatic to being associated with one or more of the following problems: profound anemia, splenomegaly, constitutional issues, and even rapid progression to overt leukemia. Recently, important progress has been made. A Janus kinase (JAK) 2 mutation affects both pathogenesis and prognosis. Conventional treatment is primarily palliative and has only limited effects on the natural course of the disease. Allogeneic stem cell transplantation is the only curative treatment, but is presently limited to eligible intermediate-2 and high-risk patients. Ruxolitinib, the first drug approved by the Food and Drug Administration for treatment of intermediate-2 and high-risk patients, is currently the best available therapy for symptomatic MF patients. Additional JAK inhibitors are under investigation. Emerging therapies include immunomodulators and inhibitors of histone deacetylase (HDAC), mammalian target of rapamycin (mTOR), and telomerase. A better understanding of disease pathogenesis will lead to the development of better treatments modifying the disease course and, ultimately, curing the condition. Keywords: Myelofibrosis; Treatment; JAK 중심 단어: ê³¨ìˆ˜ì„¬ìœ ì¦; 치료; JAK

JAK1/2 Inhibitor Ruxolitinib Controls a Case of Chilblain Lupus Erythematosus

JAK1/2 Inhibitor Ruxolitinib Controls a Case of Chilblain Lupus Erythematosus

Efficacy and Safety of Single-Agent Ruxolitinib Therapy for Myelofibrosis and Polycythemia Vera: A Meta-Analysis

Background: Ruxolitinib, a potent JAK1/JAK2 inhibitor, was approved by the FDA for the treatment of myelofibrosis (MF) and polycythemia vera (PV) in 2011 and 2014, respectively. The aim of this study was to evaluate the efficacy and safety data of single-agent ruxolitinib in patients with MF or PV through meta-analysis of reported clinical trials.Methods: PubMed and Web of Science databases were searched for clinical trials of ruxolitinib for the treatment of MF or PV through June 30th, 2015. Only clinical trials in which ruxolitinib was used as single-agent therapy for MF or PV were included in this meta-analysis. Pooled odds ratios (ORs) for proportion of patients with >= 35% reduction in spleen volume (primary outcome) and risk ratios (RRs) for dichotomous data with 95% confidence interval (CI) were analyzed using OpenMeta[Analyst] with a random effect model. Pooled ratios of adverse events of ruxolitinib therapy were also calculated.Results: Six clinical trials including 3 randomized controlled trials (RCTs) of 987 patients were identified and included in the analysis. Four studies were conducted in MF patients, and 2 studies in PV patients. Pooled data from the 3 RCTs (2 for MF and 1 for PV) showed that ruxolitinib, compared to placebo or standard therapy/best available therapy (BAT), significantly increased the proportion of patients with a reduction in spleen volume of 35% or more (OR = 79.55, 95% CI = 22.51-281.11, p < 0.001). Ruxolitinib improved the symptoms associated with MF or PV. Only the 2 RCTs for MF analyzed overall survival (OS), one of which showed OS benefit with ruxolitinib. Pooled data from all 6 trials showed that the most common hematologic adverse events were all grades anemia (71.8%) and thrombocytopenia (54.1%), regardless of whether or not they were deemed related to ruxolitinib therapy. Incidence of grades 3/4 anemia and thrombocytopenia was 30.2% and 15.3%, respectively, but rarely led to discontinuation of the drug. The most common non-hematologic adverse events were diarrhea (all grades = 18.1%, grades 3/4 = 1.1%), fatigue (all grades = 14.0%, grades 3/4 = 2.0%), peripheral edema (all grades = 12.0%, grades 3/4 = 0%), and dyspnea (all grades = 10.0%, grades 3/4 = 0.9%). Further analysis was conducted to evaluate the attributable risks of the adverse events using data from the 3 RCTs. Compared to placebo or standard therapy/BAT, ruxolitinib significantly increased the risk of developing all grades anemia (RR = 1.10, 95% CI = 1.03-1.17, p = 0.005), grades 3/4 anemia (RR = 1.87, 95% CI = 1.20-2.93, p = 0.006), all grades thrombocytopenia (RR = 2.04, 95% CI = 1.47-2.83, p < 0.001), but not grades 3/4 thrombocytopenia (RR = 2.04, 95% CI = 0.72-7.98, p = 0.153), all grades diarrhea (RR = 1.45, 95% CI = 0.96-2.20, p = 0.079), fatigue (RR = 0.865, 95% CI = 0.62-1.20, p = 0.382), peripheral edema (RR = 0.85, 95% CI = 0.61-1.18, p = 0.337), and dyspnea (RR = 1.25, 95% CI = 0.63-2.49, p = 0.520).Conclusions: Single-agent ruxolitinib therapy results in improvement of symptoms in MF or PV and significant reduction in spleen size compared to placebo or standard therapy/BAT. Anemia and thrombocytopenia were the most common hematologic adverse events, but rarely led to the discontinuation of therapy. Diarrhea, fatigue, peripheral edema and dyspnea were the most common non-hematologic adverse events, but not significant compared to placebo or standard therapy/BAT. DisclosuresChang:Johnson & Johnson: Other: Stock.

A Phase-Ib/II Study of Ruxolitinib Plus Pomalidomide in Myelofibrosis

Background: Myelofibrosis (MF) patients (pts) frequently suffer from constitutional symptoms, splenomegaly, and cytopenia. While ruxolitinib (RUX) is available for the treatment of symptomatic splenomegaly and constitutional symptoms in MF, therapeutic options for the treatment of cytopenia are limited. Recent data indicate that the immunomodulatory drug pomalidomide (POM) may improve anemia and thrombocytopenia in a subset of MF pts (e.g. Tefferi et al., J Clin Oncol 2009). We designed a single arm, multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212 trial, NCT01644110) to evaluate potential synergistic effects of both drugs in MF.Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and achievement of red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality of life, progression-free survival, and overall survival. Main inclusion criterion is pre-treated or untreated primary or secondary (post-ET / post-PV) MF with anemia (Hb <10 g/dL and/or RBC transfusion dependency). Key exclusion criteria are suitability for allotransplant, low platelet count (<100 /nL), and severe neutropenia (ANC <0.5 /nL). While POM is given at the fixed dosage of 0.5 mg QD, RUX is started at 10 mg BID with dose modifications being allowed to optimize efficacy and to manage myelosuppression. According to a Simon´s two-stage design, recruitment will be extended to a total number of 72 pts if response is achieved in a minimum of 12/37 pts tested initially.Results: Safety of the combination therapy was evaluated favorably by an independent safety monitoring committee after treatment of the first 6 pts as reported previously (Stegelmann et al, ASH 2014). Here, we present follow-up data from 25 pts. Median age of the study population was 75 years (range 51-82). Ten of 25 pts (40%) had one or more previous therapies. The most frequent previous drugs were hydroxyurea (n=6), ruxolitinib (n=3), EPO (n=2), pomalidomide (n=2), and steroids (n=2). Median Hb at study entry was 8.6 g/dL (range 6.8-10.6); 6 pts (24%) were RBC transfusion dependent. Median spleen size measured by ultrasound was 18 cm (range 13-28). Eight pts (32%) were intermediate-1, 10 pts (40%) intermediate-2, and 7 pts (28%) high-risk according to the dynamic international prognostic scoring system (DIPSS). Mutation frequencies of JAK2 V617F, MPL W515L, and CALR exon 9 were 72%, 12%, and 16%, respectively. ASXL1 was mutated in 5 pts (20%). Regarding safety, 287 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Among these, worsening of anemia (°3/°4) was the most frequent AE (n=35 in 9 pts), followed by musculoskeletal pain (n=25 in 6 pts; °1-°3), and constitutional symptoms (n=13 in 2 pts; °1-°3). In total, 11 serious AE (SAE) CTCAE °2-5 were recorded. While 9 SAE (pneumonia °3, n=3; cardiac decompensation °5, malignant melanoma °2, septic shock °5, syncope °3, and TIA °2, worsening of general condition °3, n=1 each) were considered non-related to the study drugs, 2 SAE (hemoglobin °4, neuropathy °3) were considered related. Of note, neuropathy resolved after end of study. Treatment interruptions and dose reductions of RUX were uncommon. RUX could be step-wise increased to 15 or 20 mg BID in 10 pts (40%). Median time on treatment was 8 28-days cycles (range 1-13) in 24 pts, while one patient has not yet started therapy; 14 pts (56%) are still on study treatment. A total of 10 pts (40%) discontinued, due to death (n=2), no response after 12 cycles (n=5), or withdrawal of informed consent (n=3). Within this short observation time, 3 pts experienced ´clinical improvement´ (CI) according to IWG-MRT criteria in the following categories: i) spleen reduction, ii) spleen reduction + increase of Hb, and iii) increase of both Hb and ANC. RBC transfusion independency criteria have not yet been fulfilled in transfusion dependent pts. None of the study pts progressed during treatment.Conclusions: Taking into account that the majority of study pts were pre-treated and at advanced risk, the combination therapy of RUX and POM was well tolerated and is feasible. First efficacy evaluation shows that clinical improvement regarding reduction of splenomegaly and improvement of cytopenia is achieved in a subset of MF pts. Recruitment of the study continues. An update on safety and efficacy will be presented at the meeting. DisclosuresHochhaus:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schlenk:Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

A Phase 2 Study to Evaluate the Efficacy and Safety of Simtuzumab in Adult Subjects with Primary, Post Polycythemia Vera (PV) or Post Essential Thrombocythemia (ET) Myelofibrosis

Background: Simtuzumab (SIM) is a humanized monoclonal antibody that inhibits lysyl oxidase-like molecule 2 (LOXL2), an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across many fibrotic diseases. In pre-clinical models, inhibition of LOXL2 blocks fibroblast activation, which plays an important role in the development of organ fibrosis. In Phase 1 studies, SIM was well-tolerated in patients (pts) with advanced solid tumors, liver fibrosis, and idiopathic pulmonary fibrosis (IPF). A Phase 2, open-label study to determine the efficacy of SIM alone (Stage 1) and combined with ruxolitinib (rux) (Stage 2) in pts with primary myelofibrosis (PMF) and post-ET/PV MF was initiated.Methods: Eligible pts had intermediate-1, intermediate-2, or high risk disease and Eastern Cooperative Oncology Group performance status of <2. The primary endpoint was rate of clinical response as defined by a reduction in bone marrow fibrosis score following 24 weeks of treatment with SIM. Patients were randomized in a 1:1 ratio to receive 200 mg or 700 mg SIM by intravenous infusion every 2 weeks as monotherapy (Stage 1, n=24) or combined with rux (Stage 2, n=30). Patients received SIM for up to 24 weeks. Bone marrow biopsies and aspirates were performed approximately every 3 months. Bone marrow fibrosis scoring was performed and quantified at local investigator sites using the European Consensus on Grading Bone Marrow Fibrosis. Myelofibrosis symptoms were evaluated using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and changes in hematologic parameters and splenomegaly were assessed.Results: Between 7/14/11 and 9/22/14, 54 pts were randomized and treated (200 mg SIM [n=12], 700 mg SIM [n=12], 200 mg SIM/rux [n=15], and 700 mg SIM/rux [n=15]). In Stage 1, 0 subjects (0%) in the SIM 200 mg group and 2 subjects (16.7%; 90% CI 3.0%, 43.8%) in the SIM 700 mg group showed a reduction in bone marrow fibrosis score from Baseline to Week 24. In Stage 2, 1 subject (6.7%; 90% CI 0.3%, 27.9%) in the SIM 200 mg/rux group and 2 subjects (13.3%, 90% CI 2.4%, 36.3%) in the SIM 700 mg/rux group showed a reduction in bone marrow fibrosis score from Baseline to Week 24. In an exploratory analysis, similar numbers of subjects showed increases in bone marrow fibrosis scores. SIM treatment was not associated with meaningful improvements in hematologic parameters or reductions in MPN-SAF score or spleen size. The most frequent adverse events were those commonly associated with MF, including constitutional symptoms and reductions in hematological parameters.Conclusions: SIM treatment alone or in combination with rux is safe but does not reliably reduce bone marrow fibrosis in pts with MF. The reason for reduction of marrow fibrosis in some patients and increase in others is unclear and may be sampling variability. Clinical studies of SIM in IPF and liver fibrosis are ongoing. DisclosuresSavona:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mesa:Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding; Promedior: Research Funding; Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Oh:CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Dong:Gilead Sciences: Consultancy, Equity Ownership. Thai:Gilead Sciences: Employment, Equity Ownership. Gotlib:Allakos, Inc.: Consultancy.

Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis

AbstractPacritinib (SB1518) is a Janus kinase 2 (JAK2), JAK2(V617F), and Fms-like tyrosine kinase 3 inhibitor that does not inhibit JAK1. It demonstrated a favorable safety profile with promising efficacy in phase 1 studies in patients with primary and secondary myelofibrosis (MF). This multicenter phase 2 study further characterized the safety and efficacy of pacritinib in the treatment of patients with MF. Eligible patients had clinical splenomegaly poorly controlled with standard therapies or were newly diagnosed with intermediate- or high-risk Lille score. Patients with any degree of cytopenia were eligible. Thirty-five patients were enrolled. At entry, 40% had hemoglobin <10 g/dL and 43% had platelets <100 000× 109/L. Up to week 24, 8 of 26 evaluable patients (31%) achieved a ≥35% decrease in spleen volume determined by magnetic resonance imaging and 14 of 33 (42%) attained a ≥50% reduction in spleen size by physical examination. Median MF symptom improvement was ≥50% for all symptoms except fatigue. Grade 1 or 2 diarrhea (69%) and nausea (49%) were the most common treatment-emergent adverse events. The study drug was discontinued in 9 patients (26%) due to adverse events (4 severe). Pacritinib is an active agent in patients with MF, offering a potential treatment option for patients with preexisting anemia and thrombocytopenia. This trial was registered at www.clinicaltrials.gov as #NCT00745550.

JAK-STAT pathway activation in malignant and nonmalignant cells contributes to MPN pathogenesis and therapeutic response.

The identification of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) has led to the clinical development of JAK kinase inhibitors, including ruxolitinib. Ruxolitinib reduces splenomegaly and systemic symptoms in myelofibrosis and improves overall survival; however, the mechanism by which JAK inhibitors achieve efficacy has not been delineated. Patients with MPN present with increased levels of circulating proinflammatory cytokines, which are mitigated by JAK inhibitor therapy. We sought to elucidate mechanisms by which JAK inhibitors attenuate cytokine-mediated pathophysiology. Single-cell profiling demonstrated that hematopoietic cells from myelofibrosis models and patient samples aberrantly secrete inflammatory cytokines. Pan-hematopoietic Stat3 deletion reduced disease severity and attenuated cytokine secretion, with similar efficacy as observed with ruxolitinib therapy. In contrast, Stat3 deletion restricted to MPN cells did not reduce disease severity or cytokine production. Consistent with these observations, we found that malignant and nonmalignant cells aberrantly secrete cytokines and JAK inhibition reduces cytokine production from both populations. Our results demonstrate that JAK-STAT3-mediated cytokine production from malignant and nonmalignant cells contributes to MPN pathogenesis and that JAK inhibition in both populations is required for therapeutic efficacy. These findings provide novel insight into the mechanisms by which JAK kinase inhibition achieves therapeutic efficacy in MPNs.

HARMONY: An Open-Label, Multicenter, 2-Arm, Dose-Finding, Phase 1b Study of the Combination of Ruxolitinib and Buparlisib (BKM120) in Patients with Myelofibrosis (MF)

BACKGROUND: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that has demonstrated improvements in splenomegaly, MF-related symptoms, and quality of life measures and prolonged survival in 2 phase 3 studies. JAK signaling can activate the PI3K/mTOR pathway, and constitutive PI3K activation has been implicated in numerous cancers. Preclinical and early clinical results indicate benefit with inhibition of PI3K in MF. Buparlisib is a pan-PI3K inhibitor with specific and potent activity against class I PI3Ks. The aims of HARMONY are to evaluate the safety of co-administration of RUX and buparlisib in patients (pts) with MF and determine a recommended phase 2 dose (RP2D).METHODS: This is a dose-finding, phase 1b study (NCT01730248) of RUX plus buparlisib in intermediate- or high-risk MF pts. Pts must have palpable splenomegaly ≥ 5 cm below the costal margin and MF symptoms. There are 2 treatment groups (JAK inhibitor–naive pts [arm A] and pts not benefiting from prior JAK inhibition [arm B]) and 2 study phases (dose escalation and expansion). Dose escalation is guided by a Bayesian logistic regression model with overdose control and depends on dose-limiting toxicities in cycle 1 and other safety findings. Each dose level consists of ≥ 3 evaluable pts; the 5 dose levels are (RUX [mg bid]/buparlisib [mg qd]) 10/60, 15/60, 15/80, 20/80, 20/100. 9 evaluable pts are required at the final dose level to determine an RP2D and proceed to the expansion phase; 10 additional pts per arm will be treated at the RP2D. PK of RUX was assessed by LC-MS/MS on day 1 after the first dose of RUX and on days 2 and 8 when administered in combination with buparlisib.RESULTS: To date, 33 pts (arm A, n = 20; arm B, n = 13) have been treated in the dose-escalation phase. Baseline characteristics were (arm A and arm B) median age, 64 y (range, 48-79 y; 45% ≥ 65 y) and 61 y (53-74 y; 31% ≥ 65 y); male, 50% and 62%. RP2D was selected based on tolerability in the investigated dose levels, with additional confirmation from dose-selection recommendations derived through a Bayesian model.Currently, RUX 15 mg bid/buparlisib 60 mg qd was determined as the RP2D in both arms; the study is proceeding into the expansion phase.At data cutoff (April 1, 2014), 15 (75%) and 8 (62%) pts were ongoing in arm A and arm B with a median exposure of 11.3 wk (range, 2.3-48.4 wk) and 19.0 wk (range, 0.6-50.9 wk), respectively. The primary reasons for discontinuation included lack of efficacy (10%) in arm A and AEs (15%) in arm B; all other reasons were in 1 pt each. There was 1 death (arm A) from duodenal ulcers/perforation, assessed as not related to study drugs by the investigator.Despite the short follow-up, a ≥ 50% reduction from baseline in palpable spleen length was achieved by 70% and 54% of pts in arms A and B; 7 pts had a resolution of splenomegaly (6 in arm A; 1 in arm B). All pts with prior JAK inhibitor treatment, including 5 who had no previous spleen length reductions, had reductions with the combination.Hematologic AEs included anemia (all grade [grade 3/4]: arm A, 30% [15%]; arm B, 31% [23%]) and thrombocytopenia (40% [10%]; 62% [39%]). Nonhematologic AEs were primarily grade 1/2 (Table). Overall, 20% and 23% of pts experienced serious AEs; these occurred in 1 pt each, with the exception of pyrexia (n = 2).PK parameters of RUX were comparable when administered alone or in combination with buparlisib, suggesting a lack of impact of buparlisib on RUX PK.CONCLUSIONS: The combination of RUX and buparlisib was well tolerated, with early signs indicating promising efficacy even in pts who have previously failed JAKi; preliminary RP2D was assessed as RUX 15 mg bid/buparlisib 60 mg qd for both arms. Updated efficacy and safety for the dose-escalation phase will be presented (July 1, 2014 data cutoff).TableNonhematologic AEs in ≥ 2 Pts in Either ArmPts, %Arm A n = 20Arm B n = 13All GradeGrade 3/4All GradeGrade 3/4Abdominal distension15080Abdominal pain100150Abdominal pain lower00150Abdominal pain upper50150Diarrhea100468Dyspepsia10000Nausea100310Stomatitis15588Vomiting50150Asthenia00310Fatigue100230General health deterioration00150Edema peripheral10000Pyrexia1502315Nasopharyngitis150150Decreased appetite50468Hyperglycemia15500Hyperkalemia55150Arthralgia20580Pain in extremity10080Dizziness50230Anxiety205150Confusional state10080Depressed mood00158Depression00158Insomnia50150Epistaxis50150Hyperhidrosis00310Night sweats00230Hypertension10500 DisclosuresDurrant:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Yes; Ruxolitinib is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Buparlisib is an investigational agent. Koren-Michowitz:Novartis: Honoraria, Research Funding. Lavie:Novartis: Membership on an entity’s Board of Directors or advisory committees. Martinez-Lopez:Novartis: Research Funding; BMS: Honoraria; Celgene: Honoraria. Vannucchi:Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding. Stalbovskaya:Novartis: Employment, Equity Ownership. Atienza:Novartis: Employment. Iommazzo:Novartis: Employment. Gopalakrishna:Novartis: Employment. Gisslinger:AOP ORPHA: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy.

Effective Very Long Term (6+ Years) Lenalidomide Therapy for Myelofibrosis

BackgroundLong term treatment options for symptomatic myelofibrosis (MF) are limited despite of rapid expansion in the knowledge of deranged pathways in myeloproliferative neoplasm (MPN) since the discovery of JAK2V617F mutation in 2005. MF is a biologically heterogeneous disorder ushering individualized intervention.AimTo describe the characteristics of patients who showed very long term response to lenalidomide therapy for MF.Patients and MethodsFrom 40 patients who were treated with lenalidomide (21 days of 28 days cycle) and prednisone (in initial 3 cycles only) for MF, in a clinical study conducted at our center (Quintas-Cardama A. et al. J Clin Oncol 2009 Oct 1;27(28):4760-6), patients with continued response for more than 72 months on lenalidomide were reviewed retrospectively.ResultsFive patients (12.5%) showed clinical response for 72 months and longer on lenalidomide. The median treatment duration was 94 months. Median age was 55 (Table 1.).Initial dose was 10mg/day and dose was reduced for toxicity or escalated to optimal response. Diarrhea (grade 1 and 2), neutropenia (grade 3) and peripheral neuropathy (grade 2) were reported as therapy-related toxicity and resolved with lowered dose level. Patient 1 died of sudden infection without neutropenia in 72 months of treatment. Patient 3 had increasing blasts with sudden splenomegaly and switched to other clinical trial at 83 months.Major symptoms before therapy included fatigue, wasting and abdominal discomfort from splenomegaly; all improved on therapy. Including 2 patients who had required erythropoietin injection before lenalidomide therapy, all 4 patients with anemia had > 2g/dL improvement in hemoglobin. Splenomegaly started to improve as early as the completion of Cycle 1 and continued to improve as late as Cycle 20. Spleen size reduction at best response includes complete or near complete disappearance of palpable organomegaly (Patient 4 and 5). JAK2V617F mutation was present in 3 patients; Patient 3 had mutated myeloproliferative leukemia (MPL) gene. Bone marrow (BM) reticulin fibrosis has improved at its best response in all patients (Figure 1).ConclusionLenalidomide has been used in MF with potential effect on tumor microenvironment, NK/T cell function and cell cycle with proapoptotic property. Retrospective review of the patients on lenalidomide single agent maintenance for longer than 6 years revealed a small group of patients with very durable response and low toxicity, with benefits on anemia, splenomegaly, symptoms and bone marrow fibrosis.LEN, lenalidomide; NP, neuropathy; TKI, tyrosine kinase inhibitor; CI and PR, clinical improvement and partial remission by IWG-MRT 2013, a Not assessed by a questionnaire; b MPL mutation positive, c At progression, d requiring phlebotomy [Display omitted] [Display omitted] DisclosuresRavandi:Incyte Corporation: Research Funding. Verstovsek:Celgene: Research Funding.

A Multicenter Phase-Ib/II Study of Ruxolitinib/Pomalidomide Combination Therapy in Patients with Primary and Secondary Myelofibrosis: Safety Data from the Mpnsg-0212 Trial (NCT01644110)

Background: Myelofibrosis (MF) is characterized by poor prognosis, and patients (pts) frequently present with constitutional symptoms, splenomegaly, and anemia. Although ruxolitinib (RUX) is available for the treatment of constitutional symptoms and splenomegaly, therapeutic options for the treatment of anemia are limited. Recent data indicate that immunmodulatory drugs such as lenalidomide or pomalidomide (POM) can improve anemia and/or thrombocytopenia. We designed a multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212) to evaluate potential synergistic effects in MF.Aims: Based on data from the first 6 pts,we performed a safety assessment to evaluate feasibility and toxicity of combination therapy. Primary study-endpoint is response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, response duration, quality of life, progression-free survival and overall survival.Study Design: Key inclusion criteria are primary or secondary (post-ET / post-PV) MF, anemia with hemoglobin level <10 g/dL, and splenomegaly. Key exclusion criteria are MF pts suitable for allotransplant, platelets <100x10E+9/L, and neutrophils <0.5x10E+9/L. POM is given at a fixed dosage of 0.5 mg QD. RUX was started at 10 mg BID. Dose modifications of RUX were allowed to increase efficacy and to manage myelosuppression. Safety assessment is done after treatment of the first 6 pts for ≥1 cycle. The safety profile is defined favourable if ≤1 of the first 6 pts had a treatment limiting toxicity associated with one of the study drugs (non-hematological toxicity CTCAE ≥°3 and/or hematological toxicity CTCAE ≥°4).Results: Between August 2013 and March 2014, 6 pts were registered. Database lock for the safety analysis was April 22, 2014. Median time on treatment was 4.3 months (range, 1.0-9.4 months). RUX dose was maintained at 10 mg BID in 5 pts, and increased stepwise to 20 mg BID until cycle 6 in 1 pt (ID001). POM was administered continuously. In total, 8 hematological toxicities CTCAE °3 (anemia) were recorded in the 6 pts over the total period of 26 cycles; 3 events already pre-existed before study entry and affected the same pt (ID005). In contrast, anemia increased in 5 pts and made RBC transfusions necessary. However, no CTCAE °4 anemia, no CTCAE °3/4 thrombocytopenia, and no CTCAE °3/4 neutropenia occurred.Study treatment was stopped in 2/6 pts, in ID003 at cycle 3 (cardiac decompensation) and in ID002 at cycle 6 (withdrawal). The following events of non-hematological toxicities CTCAE °3 (n=2) and °5 (n=1) were observed in these 2 pts: 2 SAEs (neuropathy and pneumonia) in ID002 and 1 SUSAR (cardiac decompensation) in ID003 who died during an in-hospital stay. No causal relationship with the study drugs was seen for pneumonia, whereas neuropathy was considered POM-associated. After discontinuation of POM, neuropathy resolved. ID003 was hospitalized for cardiac decompensation with immediate stop of study drugs and died 13 days later. Therefore, causal relationship between study treatment and the SUSAR is unlikely. Three additional unrelated non-hematological adverse events CTCAE °3 occurred in the remaining pts: 1 was pre-existing without aggravation (muscle cramps) and 2 represented MF symptoms not meeting seriousness criteria (musculoskeletal pain, reduced general condition).Conclusion: Based on our safety analysis, the combination therapy was well tolerated. The observed toxicities were within the expected range according to the reported toxicity profiles for the respective single agents and with regard to the general condition of the pts. Therefore, the safety profile of 6 pts treated within the MPNSG-0212 trial was favourably evaluated by the investigators and by an independent data safety monitoring committee. Recruitment of the study continues. An update on safety and first efficacy data will be presented. DisclosuresNo relevant conflicts of interest to declare.

How we manage JAK inhibition in allogeneic transplantation for myelofibrosis.

Hematopoietic stem cell transplantation (HCT) is currently the only curative treatment for myelofibrosis (MF), but this option is complicated by high incidences of associated morbidity and mortality. Ruxolitinib, a janus-activated kinase (JAK) 1/2 inhibitor, has proven to be beneficial in reduction of splenomegaly, improvement of constitutional symptoms, and possibly in overall survival. However, use of JAK inhibitors in the peritransplant period has been complicated by unpredictable response, return of MF symptoms or cytokine storm reaction upon discontinuation, and lack of long-term response data. This review considers the current limited available data on JAK inhibitor use prior to HCT, including common side effects and possible impact of severe adverse events on discontinuation of the drug. We provide our experience and recommendations regarding use of JAK inhibition in patients undergoing HCT. Additional studies are needed to determine the optimal schedule of JAK inhibitors in the transplant protocols and their impact on engraftment, graft-versus-host disease, and survival.

Significant Improvement In Quality Of Life (QoL) In Patients With Chronic Myeloproliferative Neoplasms and Myelofibrosis Treated With JAK-1 and JAK-2 Inhibitor Ruxolitinib. A Single Institution Experience In Mexico

IntroductionMyeloproliferative Neoplasms can shorten the life of patients and affect severely their quality of life as a result of constitutional symptoms mediated by cytokines and from massive splenomegaly characteristic of these diseases. The objective measurement of symptoms in Myelofibrosis is essential for the presence of general constitutional symptoms as fatigue and is considered adverse prognostic value for survival. The systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with JAK-2 inhibitors. Material and MethodsTo assess the impact on quality of life in patients with Myeloproliferative Neoplasms treated with the inhibitor Ruxolitinib, there was applied the questionnaire Myelofibrosis Symptom Assessment Form (Mesa et al. Leukemia Research. 2009: 33; 1199-1203) to 16 patients included in the Compassionate Use of Ruxolitinib Program: 8 men and 8 women were included with a median age of 63 years; 4 patients with primary Myelofibrosis, 3 with Myelofibrosis post Polycitemia vera and 9 with Myelofibrosis post essential Thrombocythemia. The median patient follow-up was 9 months. The patients started with a dose of 20 mg Ruxolitinib orally every 12 hours. ResultsThe questionnaire was administered to all patients at each visit and the results of the ratings of the patients were presented as median of each answer at baseline, 3, 6 and 12 months of follow-up (table 1). By comparing the differences of each parameter measured between the start and at 3, 6 and 12 months were statistically significant for all variables (P <0.001, CI: 95%). The most significant changes were observed when comparing data at baseline and follow-up to the maximum time, however were obvious from the first quarter of observation on fatigue and symptoms dependent splenomegaly in most general symptoms, which actually disappeared completely after 3 months of treatment and not relapsed during the track and in the perception of the quality of life of patients. The variables with lower proportional change recorded were general activity, mood, walking tolerance and everyday work. [Display omitted] Discussion and conclusionsThe treatment of Myeloproliferative Neoplasms with Ruxolitinib represents a major advance in the management of malignant Myeloproliferative and achieved excellent improvement in overall constitutional symptom control, splenomegaly and the general perception of the quality of life of these patients. The objective measurement of symptoms of Myelofibrosis is essential, since the presence of general constitutional symptoms as fatigue is considered adverse prognostic value for survival and systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with inhibitors JAK-2. Disclosures:No relevant conflicts of interest to declare.

Cytokine Profile Changes In 309 Myelofibrosis Patients: Comparison Of JAK1/JAK2 Inhibitor Therapy Vs. Placebo – Correlative Analysis From The Comfort-I Trial

BackgroundInflammatory deregulation may be a major factor in cancer related symptoms (Dantzer Nature Rev Clin Oncol 2012). Improved symptoms in myelofibrosis (MF) patients treated with single arm ruxolitinib (JAK1/JAK2 inhibitor) studies has been correlated with normalization of selected cytokines increased pre-therapy (c-reactive protein, IL-1ra, MIP-1b, TNF-a, and IL-6; Verstovsek NEJM 2010). We sought to assess the impact of JAK1/JAK2 inhibitor therapy on cytokine levels and the relationship between cytokine levels and symptoms prior to and during JAK1/JAK2 inhibitor therapy in the phase III placebo controlled COMFORT-I trial (Verstovsek NEJM 2012). MethodsCytokine levels (89 cytokines measured at baseline and at weeks 4 and 24) and MF symptoms (assessed by MFSAF 2.0 – Mesa JCO 2013) were collected during the blinded phase of COMFORT-I. Patients were randomized to ruxolitinib vs. placebo. Plasma was used for the measurement of cytokines using Rules-Based Medicine, Inc. (Austin, TX) Human MAP panel. Associations between the MFSAF total symptom score (TSS) and log2-transformed cytokine data were investigated at baseline using Spearman correlations and linear regression. Mixed models were used to assess cytokine and TSS changes over time within each arm and overall. Logistic regression was used to assess the relationship between baseline cytokines and TSS response (>/=50% reduction from baseline) at week 24, and between week 4 cytokine changes and TSS response (>/=50% reduction from baseline) at week 24 within each arm and overall. Mixed and logistic regression models combining data across arms also included terms for visit, arm, and visit-by-arm interaction. All models also included age, gender, and body mass index (BMI). Given the large number of cytokines being investigated, p<0.001 was considered statistically significant. Cytokine values below the limit of detection were set at the lowest limit of detection and 25 cytokines were excluded from statistical analysis due to having more than 30% of data missing or below the limit of detection. ResultsPatients: 309 subjects were randomized in COMFORT-I with median age 68 (range 40-91), 46% female, 50% primary myelofibrosis, and 61% high risk. All 309 subjects had cytokines measured at one or more of the three visits included in this analysis, with 308 having cytokine values paired with a TSS score at the same visit.Cytokines at Baseline: At baseline, the highest Spearman correlations with symptomatic burden (as assessed by the TSS) were observed for APOA1 (rho=-.21) and FERRITIN (rho=-.20), followed by INTLK5, MIP1A, MMP3, INTLK2, MGB, INTLK1A, and INTLK7 with correlations between -.15 and -.17 (all p<0.01). After adjusting for age, sex, and BMI, VCAM1 and APOA1 were significantly associated with TSS at baseline.Cytokine and Symptom changes during trial: Changing levels of 5 cytokines were significantly associated with change of TSS over time beyond the change due to visit, arm, visit-by-arm interaction, age, sex and BMI including VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII. Within the placebo arm, only 5 cytokines significantly changed over time compared to 46 cytokines in the ruxolitinib arm (visit-by-arm interaction was significant for 43 in the overall models). VCAM1, B2MICG, and TNFRII were among the 5 cytokines which changed in the placebo arm, and VCAM1, LEPTIN, TIMP1, B2MICG, and TNFRII were among the 46 cytokines which changed in the ruxolitinib arm. No baseline cytokines and no changes in cytokines at week 4 univariately predicted week 24 TSS response within either arm at the p<0.001 level. ConclusionsIn the first serial assessment of MF symptoms and plasma cytokine levels in the conduct of a placebo controlled trial we found 5 cytokines in which improved levels correlated with decreased MF symptom burden in ruxolitinib treated patients. Development of a multivariate model for predicting symptom response, correlations with splenic response and impact on survival benefit of therapy is ongoing. Disclosures:No relevant conflicts of interest to declare.

Decrease Of T Regulatory Cells In Patients With Myelofibrosis Receiving Ruxolitinib

Ruxolitinib, a JAK1/JAK2 inhibitor, is considered effective and safe in the relief of splenomegaly and symptoms in Myelofibrosis (MF), and it is now approved for this use in US and EU. Since 2009, we have treated 47 patients with MF enrolled in two consecutive clinical trials with ruxolitinib (Clinicaltrials.gov Identifiers: NCT00463385 and NCT00669578) or under an individual patient therapeutic use. Among these patients, one developed tuberculosis, two herpes zoster infections, three herpex simplex reactivation, and one non-bacterial pneumonia of suspected viral origin. This incidence of infectious adverse effects is in agreement with the Novartis reported high incidence of urinary tract infections (12.3%), herpes zoster (4.3%), and tuberculosis (1%) (JAKAVI, Summary of product characteristics. Basel, CH: Novartis Pharma AG; 2012). Accordingly, a case of Cryptococcus neoformans pneumonia in a patient receiving ruxolitinib has been recently described (Wysham NG et al, Chest 2013;143(5):1478-9). Considering that a protective role for regulatory T-cells (Tregs) against specific viral pathogens, some parasites, and fungal pathogens has been documented (Rowe JH et al, Immunology 2012;136:1-10), we have investigated the possible role of ruxolitinib in modulating immune surveillance, by asseessing the frequency of circulating Tregs in patients affected by MF receiving ruxolitinib. In particular, we evaluated by cytofluorimetric analysis both total peripheral blood (PB) CD4+ T cells and the CD25+CD127low/-FOXP3+ Tregs subset in 11 patients (JAK2V617F: n=9) with MF (disease duration: median 60 months, range 6-360) who never received JAK2 inhibitors and were out of chemotherapy since at least three months. The evaluations were performed before they received ruxolitinib (full approved dose) (T0) and at defined time points for 1 year. Results are expressed as % of CD4+ cells. We found that the PB CD4+ T cell frequency was stable during the study (data not shown), whereas a significant reduction of the Treg frequency was evident in all patients since 30 days after the first dose of ruxolitinib (Figure, panel A) as well as at the subsequent time points, with values that were below our lower limit of normality (dotted line). One of these patients experienced ruxolitinib withdrawal after 120 days of therapy: the frequency of Tregs on day 150 increased up to normal levels, speaking in favour of a direct effect of the drug on Treg ferquency (Figure, panel B). Based on our results, we argue that the severe reduction in circulating Tregs may count as a major cause of immunosurveillance disruption during ruxolitinib therapy. This observation is in agreement with previous evidence that inhibition of the JAK2 pathways reduces in vitro FOXP3 expression blocking STAT5 signalling (Murawski MR et al Ann.N.Y.Acad.Sci 2006; Barrio S et al Br J Hematol 2013). [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Relationship Between Cytokine Levels and Symptoms in Patients (Pts) With Myelofibrosis (MF) From COMFORT-II, a Phase 3 Study of Ruxolitinib (RUX) Vs Best Available Therapy (BAT)

BackgroundRUX is a JAK1/ JAK 2 inhibitor that has demonstrated improvements in splenomegaly, MF-related symptoms, and quality of life measures in the 2 phase 3 COMFORT studies. We recently demonstrated possible prognostic/predictive relationships between baseline (BL) cytokine levels and changes in spleen volume. Here, we evaluated the associations between cytokine levels and symptoms in COMFORT-II. MethodsTen symptoms, (fever, weight loss, easily tired, loss of appetite, pain, itching, sleeping well, lack of energy, night sweats, and trouble sleeping) were assessed at BL and weeks 8, 24, and 48 using the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) instrument (0 to 4 scale). In this exploratory analysis, reverse coding of symptoms (except sleeping well) was performed. A high score reflects low symptom burden, and a positive change indicates improvement. Plasma samples were analyzed using Rules-Based Medicine's HumanMAP v1.6, measuring 89 cytokines at weeks 4, 24 and 48. Cytokines with ≥ 30% of values below lower limit of quantification were excluded. Two binary (0/1) variables were defined; Symptom Present = 1 when symptom score ² 2 and Improvement = 1 when change from BL symptom score > 0.Associations between Symptom Present and BL cytokine level were evaluated using univariate logistic regression (adjusted for IPSS risk and JAK2 mutation status), and for those associated at BL, the relationship between the fold-change in cytokine level (log2) and the Improvement over time was evaluated. Improvement and fold-change in a cytokine were considered as a bivariate response vector, and if the components of the response vector correlated it implied that the change in symptom score and change in cytokine were correlated over time. ResultsOf the 10 symptoms analyzed, 9 had BL associations with cytokines (Figure). Table shows cytokines and symptoms for which changes from BL were associated over time.At BL, lower ferritin levels were associated with itching and night sweats, lower leptin levels with weight loss, higher IL 1 receptor-α (IL1RA) levels with loss of appetite and higher CD40L, Pal1, and RANTES levels with not sleeping well. RUX-treated pts were more likely to have improvements in itching and night sweats than BAT-treated pts and had larger increases in ferritin levels over time. Larger changes in leptin levels with RUX treatment positively correlated with improvements in weight loss. IL1RA decreased significantly with time in the RUX arm and negatively correlated with loss of appetite, which improved over time. ConclusionsBoth BL levels and changes over time of various cytokines significantly correlated with MF-related symptoms. Ferritin levels appeared to be an important component of itching and night sweats. Additional analyses are required to explore the relationships between changes in cytokine levels and quality of life measures. These observations suggest a link between individual cytokines and symptoms in MF enhancing our understanding of the disease and providing a potential basis for future patient management tools. [Display omitted] [Display omitted] Disclosures:Squires:Novartis Phama AG: Employment. Harrison:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gisslinger:AOP Orphan Pharmaceuticals: Advisory Board Other, Honoraria; Novartis: Advisory Board, Advisory Board Other, Research Funding; Sanofi-Aventis: Advisory Board, Advisory Board Other, Honoraria; Shire: Advisory Board, Advisory Board Other, Honoraria; Celgene: Advisory Board Other, Honoraria; Janseen: Advisory Board, Advisory Board Other, Honoraria. Passamonti:Sanofi: Honoraria; Novartis: Honoraria. Al-Ali:Novartis: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Kiladjian:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marker:Novartis: Employment. Mendelson:Novartis: Employment. Stalbovskaya:Novartis: Employment, Equity Ownership. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Knoops:Novartis: Consultancy; BMS: Consultancy.