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BackgroundNeoehrlichia mikurensis (N. mikurensis) is a newly discovered tick-borne pathogen that can inflict life-threatening illness in immunocompromised patients. N. mikurensis infection is only detectable by polymerase chain reaction (PCR)-based methodologies. We describe three distinct clinical manifestations of N. mikurensis infection (neoehrlichiosis) in Danish patients receiving B-lymphocyte-depleting therapy, rituximab, for underlying hematological, rheumatological, or neurological disorders. All three patients went through a protracted pre-diagnostic period.MethodsN. mikurensis DNA was detected and confirmed using two methods. Blood was tested by specific real-time PCR targeting the groEL gene and by 16S and 18S profiling followed by sequencing. Bone marrow was analyzed by 16S and 18S profiling.ResultsN. mikurensis was detected in blood samples in all three cases and in bone marrow from one of the three. The severity of the symptoms ranged from prolonged fever lasting more than 6 months to life-threatening hyperinflammation in the form of hemophagocytic lymphohistiocytosis (HLH). Interestingly, all patients presented with splenomegaly and two with hepatomegaly. After starting doxycycline therapy, symptoms were relieved within a few days, and biochemistry and organomegaly quickly normalized.ConclusionWe present three Danish patients recognized by the same clinician over a period of 6 months, strongly suggesting that many cases are going unrecognized. Second, we describe the first case of N. mikurensis-induced HLH and emphasize the potential severity of undetected neoehrlichiosis. Background: Neoehrlichia mikurensis (N. mikurensis) is a newly discovered tick-borne pathogen that can inflict life-threatening illness in immunocompromised patients. N. mikurensis infection is only detectable by polymerase chain reaction (PCR)-based methodologies. We describe three distinct clinical manifestations of N. mikurensis infection (neoehrlichiosis) in Danish patients receiving B-lymphocyte-depleting therapy, rituximab, for underlying hematological, rheumatological, or neurological disorders. All three patients went through a protracted pre-diagnostic period. Methods: N. mikurensis DNA was detected and confirmed using two methods. Blood was tested by specific real-time PCR targeting the groEL gene and by 16S and 18S profiling followed by sequencing. Bone marrow was analyzed by 16S and 18S profiling. Results: N. mikurensis was detected in blood samples in all three cases and in bone marrow from one of the three. The severity of the symptoms ranged from prolonged fever lasting more than 6 months to life-threatening hyperinflammation in the form of hemophagocytic lymphohistiocytosis (HLH). Interestingly, all patients presented with splenomegaly and two with hepatomegaly. After starting doxycycline therapy, symptoms were relieved within a few days, and biochemistry and organomegaly quickly normalized. Conclusion: We present three Danish patients recognized by the same clinician over a period of 6 months, strongly suggesting that many cases are going unrecognized. Second, we describe the first case of N. mikurensis-induced HLH and emphasize the potential severity of undetected neoehrlichiosis.

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]).INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.FUNDING: Sierra Oncology.

Aims: It remains unknown whether the consistently observed increase in haematocrit with sodium–glucose cotransporter 2 inhibitors is caused by diuresis-associated haemoconcentration or increased erythropoiesis. We aimed to investigate the early effect of empagliflozin on erythropoiesis and iron metabolism in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: The Empire HF was a double-blind, randomized, placebo-controlled trial. Patients with a left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NYHA) class I–III symptoms, and on stable guideline-directed HFrEF therapy were randomly assigned (1:1) to empagliflozin or matching placebo once daily for 12 weeks. Exploratory outcomes reflecting changes in erythropoiesis and iron metabolism were analysed. In total, 190 patients were randomized. Baseline characteristics were well-balanced between the groups (age: mean 64 [± 11] years; male: 85%; LVEF: mean 29 [± 8)%; NYHA class II: 78%; type 2 diabetes: 13%; anaemia: 28%; chronic kidney disease: 13%). In this post hoc analysis, erythropoietin was increased with empagliflozin compared to placebo from baseline to 12 weeks (adjusted mean difference 2.6 IU/L, 95% confidence interval [CI] 0.8–4.4; p = 0.0046). Moreover, hepcidin was reduced (adjusted ratio of change 0.76, 95% CI 0.59–0.97; p = 0.031), with no change observed for erythroferrone (adjusted ratio of change 1.17, 95% CI 0.86–1.60; p = 0.31) compared to placebo. No significant treatment-by-subgroup interactions were observed regarding baseline type 2 diabetes, anaemia, or chronic kidney disease (pinteraction >0.05). Conclusion: These findings suggest that empagliflozin increases erythropoiesis and augments early iron utilization in patients with HFrEF. These mechanisms may contribute to the cardioprotective properties of empagliflozin.

Intramuscular injections of paraffin oil can cause foreign body granuloma formation and hypercalcemia. Macrophages with the ability to produce high levels of 1,25(OH)2 D3 may induce the mineral disturbance, but no major series of patients have been published to date. Here, medical history, physical evaluation, biochemical, and urinary analysis for calcium homeostasis were obtained from 88 males, who 6 years previously had injected paraffin or synthol oil into skeletal muscle. Moreover, granuloma tissue from three men was cultured for 48 hours ex vivo to determine 1,25(OH)2 D3 production supported by qPCR and immunohistochemistry of vitamin D metabolism and immune cell populations after treatment with 14 different drugs. The 88 men were stratified into men with hypercalcemia (34%), whereas normocalcemic men were separated into men with either normal (42%) or suppressed parathyroid hormone (PTH) (24%). All men had high calcium excretion, and nephrolithiasis was found in 48% of hypercalcemic men, 22% of normocalcemic men with normal PTH, and 47% of normocalcemic men with suppressed PTH. Risk factors for developing hypercalcemia were oil volume injected, injection of heated oil, high serum interleukin-2 receptor levels, and high urine calcium. High 1,25(OH)2 D3 /25OHD ratio, calcium excretion, and low PTH was associated with nephrolithiasis. The vitamin D activating enzyme CYP27B1 was markedly expressed in granuloma tissue, and 1,25(OH)2 D3 was released in concentrations corresponding to 40% to 50% of the production by human kidney specimens. Dexamethasone, ketoconazole, and ciclosporin significantly suppressed granulomatous production of 1,25(OH)2 D3 . In conclusion, this study shows that injection of large oil volumes alters calcium homeostasis and increases the risk of nephrolithiasis. Hypercalciuria is an early sign of disease, and high granulomatous 1,25(OH)2 D3 production is part of the cause. Prospective clinical trials are needed to determine if ciclosporin, ketoconazole, or other drugs can be used as prednisolone-sparing treatment. © 2020 American Society for Bone and Mineral Research (ASBMR).

Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα–treated patients not attaining CHR (P = .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment.

We performed a single-center study of real-world health data to investigate the direct clinical consequence of targeted next-generation sequencing (NGS) results integrated in the clinicopathological evaluation of patients with cytopenia suspected of myelodysplastic syndrome (MDS).The study included 87 newly referred patients, who had a bone marrow examination, which included targeted NGS analysis. NGS was requested at the discretion of either examining pathologist or hematologist. Data were collected retrospectively from patient files including pathology reports with integrated NGS results.The NGS results had a diagnostic impact in 67 cases (77%) when combining both histopathological and final clinical evaluation and provided prognostic value in 19 cases (22%). NGS supported a confident or tentative histopathological diagnosis in 52 cases (60%). Twenty cases (23%) had a final diagnosis of either Clonal Cytopenia of Undetermined Significance (CCUS) or Idiopathic Cytopenia of Undetermined Significance (ICUS). In 4 cases, NGS results affected the choice of principal treatment strategy, including considerations of allotransplantation. Twenty-one patients (24%) could be discharged to primary care physician.In a multidisciplinary clinicopathological real-world setting, NGS analysis of bone marrow samples from selected patients contributed substantially to the diagnostic evaluation and management of patients with cytopenia suspected of MDS. Consequently, we have now included NGS analysis in most routine bone marrow examinations from patients with MDS or unexplained cytopenia.

Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.

The mutational landscape of the Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) displays a high homogeneity as 70% of patients harbor the Januskinase-2 (JAK2)V617F-mutat...

Key Points • We describe a 30-year-old woman who developed thrombocytopenia and multiple thromboses after she received the ChAdOx1 nCoV-19 vaccine. • A maximum 4T HIT score and a positive immunoassay for anti-PF4 antibodies indicated autoimmune HIT as a potential pathogenic mechanism., Recently, reports of severe thromboses, thrombocytopenia, and hemorrhage in persons vaccinated with the chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19, AZD1222, Vaxzevria; Oxford/AstraZeneca) against severe acute respiratory syndrome coronavirus 2 have emerged. We describe an otherwise healthy 30-year-old woman who developed thrombocytopenia, ecchymosis, portal vein thrombosis, and cerebral venous sinus thrombosis the second week after she received the ChAdOx1 nCoV-19 vaccine. Extensive diagnostic workup for thrombosis predispositions showed heterozygosity for the prothrombin mutation, but no evidence of myeloproliferative neoplasia or infectious or autoimmune diseases. Her only temporary risk factor was long-term use of oral contraceptive pills (OCPs). Although both the prothrombin mutation and use of OCPs predispose to portal and cerebral vein thrombosis, the occurrence of multiple thromboses within a short time and the associated pattern of thrombocytopenia and consumption coagulopathy are highly unusual. A maximum 4T heparin-induced thrombocytopenia (HIT) score and a positive immunoassay for anti-platelet factor 4/heparin antibodies identified autoimmune HIT as a potential pathogenic mechanism. Although causality has not been established, our case emphasizes the importance of clinical awareness. Further studies of this potentially new clinical entity have suggested that it should be regarded as a vaccine-induced immune thrombotic thrombocytopenia.

Commercial myeloid next-generation sequencing (NGS) panels may facilitate uniform generation of raw data between laboratories. However, different strategies for data filtering and variant annotation may contribute to differences in variant detection and reporting. Here, we present how custom data filtering or the use of Oncomine extended data filtering improve detection of clinically relevant mutations with the Oncomine Myeloid Research Assay. The study included all patient samples (n = 264) analyzed during the first-year, single-site, clinical use of the Ion Torrent Oncomine Myeloid Research Assay. In data analysis, the default analysis filter was supplemented with our own data filtering algorithm in order to detect additional clinically relevant mutations. In addition, we developed a sensitive supplementary test for the ASXL1 c.1934dupG p.Gly646fs mutation by fragment analysis. Using our custom filter chain, we found 96 different reportable variants that were not detected by the default filter chain. Twenty-six of these were classified as variants of strong or potential clinical significance (tier I/tier II variants), and the custom filtering discovered otherwise undetected tier I/tier II variants in 25 of 132 patients with clinically relevant mutations (19%). The remaining 70 variants not detected by the default filter chain were classified as variants of unknown significance. Among these were several unique variants with possible pathogenic potential judged by bioinformatic predictions. The recently launched Oncomine 5.14 extended filter algorithm detects most but not all of the tier I/tier II variants that were not detected by the default filter. The supplementary fragment analysis for the ASXL1 c.1934dupG p.Gly646fs confidently detected a variant allele frequency of down to 4.8% (SD 0.83%). The assay also detected the ASXL1 c.1900_1922del23 mutation. Detection of clinically relevant variants with the Oncomine Myeloid Research NGS assay can be significantly improved by supplementing the default filter chain with custom data filtering or the recently launched Oncomine 5.14 extended filter algorithm. Our accessory fragment analysis facilitates easy testing for frequent ASXL1 mutations that are poorly or not covered by the NGS assay.

Multicolor flow cytometry is an essential tool for studying the immune system in health and disease, allowing users to extract longitudinal multiparametric data from patient samples. The process is complicated by substantial variation in performance between each flow cytometry instrument, and analytical errors are therefore common. Here, we present an approach to overcome such limitations by applying a systematic workflow for pairing colors to markers optimized for the equipment intended to run the experiments. The workflow is exemplified by the design of four comprehensive flow cytometry panels for patients with hematological cancer. Methods for quality control, titration of antibodies, compensation, and staining of cells for obtaining optimal results are also addressed. Finally, to handle the large amounts of data generated by multicolor flow cytometry, unsupervised clustering techniques are used to identify significant subpopulations not detected by conventional sequential gating.

Standard care for patients with high-risk myelodysplastic syndrome (MDS) is hypomethylating agents such as azacitidine (AZA), which can induce expression of methylated tumor-associated antigens and therefore potentiate immunotherapeutic targeting. In this phase 1 trial, we combined AZA with a therapeutic peptide vaccine targeting antigens encoded from NY-ESO-1, MAGE-A3, PRAME, and WT-1, which have previously been demonstrated to be upregulated by AZA treatment. Five patients who had responded to AZA monotherapy were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. However, no specific immune responses could be detected using intracellular cytokine staining or ELISpot assays. Minor changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were detected. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 5.2 months (range 2.8 to 7.6). Mean survival was 18.1 months (range 10.9 to 30.6) from MDS diagnosis and 11.3 months (range 4.3 to 22.2) from inclusion. Sequencing of bone marrow showed clonal expansion of malignant cells, as well as appearance of novel mutations. The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response. Why the manuscript is especially interesting This study is the first to exploit the potential synergistic effects of combining a multi-peptide cancer vaccine with epigenetic therapy in MDS. Although our results are negative, they emphasize challenges to induce immune reactivity in patients with high-risk MDS.

Background: Standard care for patients with high risk myelodysplastic syndrome (MDS) is hypomethylating agents, such as azacitidine (AZA). AZA can induce expression of silenced genes, including methylated tumor associated antigens. Such tumor associated antigens may be recognized by T cells, and therefore exploited for immunotherapeutic targeting. To our knowledge, this is the first clinical study that combine hypomethylating agents with a multi-peptide therapeutic cancer vaccine in a hematological malignancy. Method: In this open label phase 1 trial (ClinicalTrials.gov NCT02750995), we combine AZA with a peptide vaccine targeting antigens encoded from NY-ESO-1, MAGE-A3, PRAME and WT-1, which have previously been demonstrated to be upregulated by AZA treatment. Four long synthetic peptides containing previously described class I and class II epitopes for a variety HLA types was emulsified in Incomplete Freund's Adjuvant for subcutaneous injection. Patients were included following verified treatment response to six courses of AZA monotherapy. Result: Five patients were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. There was one instance of grade 4 toxicity; a case of neutrophil count decrease, requiring administration of prophylactic antibiotics, and two instances of grade 3 toxicity; platelet count decrease and neutrophil count decrease. No vaccine-specific immune response could be detected using intracellular cytokine staining or ELISpot assays, however changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were identified in individual patients. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 4.9 months (range 2.8 to 7.6). Survival was 17 months (range 10.9 to 30.6) from MDS diagnosis. Sequencing of bone marrow showed clonal evolution of malignant cells, as well as appearance of novel mutations. Conclusion: The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response. Figure 1. (a) Trial design. All participants received six courses of AZA prior to inclusion and were evaluated with bone marrow biopsy for treatment response. Vaccination was given together with the next three courses of AZA. (b) Vaccine composition. Synthetic long peptides from NY-ESO-1, PRAME, MAGE-A3 and WT-1 were emulsified in adjuvant Montanide ISA 51. Figure 1 Disclosures No relevant conflicts of interest to declare.

Introduction: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the three hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of intermediate/high risk MF patients whether JAKi--naïve or previously JAKi-treated as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 was conducted in JAKi-naïve MF patients (n=432) randomized 1:1 to MMB or ruxolitinib (RUX) over a 24-week double-blind dosing period. S2 was conducted in MF patients who experienced hematological toxicity during prior RUX therapy (n=156) randomized 2:1 to MMB or best available therapy (BAT; consisting of RUX in 88% of patients) over a 24-week open-label dosing period. In both trials, following the 24-week randomized treatment (RT) period, patients originally randomized to MMB could continue MMB therapy (MMB→MMB) and those randomized to RUX/BAT were eligible to cross-over to MMB (RUX/BAT→MMB) for additional extended treatment (ET). Over 820 MF patients have received MMB during the compound's clinical development program. Methods: Long term outcome data from S1 and S2 are reported here including survival, response endpoints, and MMB exposure. Overall survival (OS) and leukemia free survival (LFS) were followed for a maximum of approximately 5 years (median of 2.9 years in S1 and 2.3 years in S2). Following participation in S1 and S2, patients were eligible to continue MMB therapy via an extended access protocol (XAP), along with additional Phase 2 MMB subjects. Duration of exposure incorporates XAP data but OS/LFS analyses only include data obtained within S1 and S2. Results: Of the 137 Phase 2 and 3 patients who have enrolled in XAP, 105 remain on MMB with duration on therapy ranging up to 10 years. Across the RT and ET periods of S1 and treatment in XAP, 69% of the 215 JAKi-naïve patients randomized to MMB remained on therapy for ≥ 48 weeks; 44% for ≥ 96 weeks and 30% for ≥ 144 weeks. Of the 104 prior JAKi-exposed subjects randomized to MMB in S2, 47% received MMB (RT, ET and XAP) for ≥ 48 weeks; 25% for ≥ 96 weeks and 17% for ≥ 144 weeks. In both S1 and S2, OS and LFS were similar between treatment groups (stratified HR for OS of 0.99 in S1, 0.96 in S2), demonstrating robust and consistent survival outcomes for patients who commenced JAKi therapy with MMB and those dosed initially with RUX/BAT followed by MMB (Figure 1). In addition, the median OS in S2 (MMB arm of 34.3 months) compares very favorably with previously reported median survival ranging from 13-30 months in patients who have discontinued RUX (Tang, ASH 2019). In S1, splenic response, defined as a reduction in spleen volume of ≥ 35% from baseline at Week 24 was achieved by 26.5% of patients in the MMB group and 29.5% in the RUX group (non-inferiority p The ability to achieve or maintain transfusion independence (TI) represents a substantive clinical benefit in light of the progressive myelosuppression associated with MF. In the RT period of both S1 and S2, a greater proportion of subjects receiving MMB compared with the control arm achieved TI at Week 24, defined as no RBC transfusion and no Hgb level below 8 g/dL in of the prior 12 weeks. The proportion who were TI at Week 24 was approximately 70% for MMB vs 54% for RUX in S1, and 44% for MMB vs 27% for BAT/RUX in S2. For MMB→MMB subjects in S1, the RBC transfusion free rate at Week 48 (ET) was approximately 75% and 67% for RUX→MMB. Similarly, in S2, MMB→MMB subjects had an RBC transfusion free rate of approximately 55% and 40% for BAT/RUX→MMB. For the patients who achieved TI at any time during the study, the median duration of TI response by KM estimate was not reached in S1 and was >1 year in S2. Conclusion: In conclusion, further analyses of data from the 550 JAKi-naïve and previously JAKi-treated patients with MF who received MMB in RT and/or ET show robust long-term survival, sustained efficacy and durability of dosing consistent with MMB's differentiated pharmacological profile. These data demonstrate MMB's potential ability to durably address the unmet needs of patients with intermediate/high risk MF. Disclosures Verstovsek: NS Pharma: Research Funding; Promedior: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Novartis: Consultancy, Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Oh:Constellation: Consultancy; Kartos Therapeutics: Consultancy; Disc Medicine: Consultancy; PharmaEssentia: Consultancy; CTI Biopharma: Consultancy; Incyte Corporation: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy. Harrison:Celgene: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Shire: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau. McLornan:NOVARTIS: Honoraria, Speakers Bureau; JAZZ PHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. McMullin:Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kowalski:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Smith:Sierra Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Mesa:Bristol Myers Squibb: Research Funding; Promedior: Research Funding; AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; Incyte: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy.

Background Recombinant Interferon Alpha-2a (r-IFNα) is a potent immunomodulating agent, which has been used off-label for the treatment of polycythemia vera (PV) for more than three decades and has been demonstrated to induce high rates of clinical, hematological and molecular responses. Only few studies have compared efficacy and safety of r-IFNα vs. hydroxyurea (HU), which is considered first line therapy for PV patients > 60 years in most parts of the world. However, recent studies have provided encouraging results for the treatment of PV with r-IFNα compared to HU irrespective of age (R. Hoffmann 2016; H. Gisslinger 2018). Aims To examine the difference in efficacy and safety of low-dose r-IFNα in PV patients ≤ 60 or > 60 years of age compared to HU > 60 years of age. Methods Ninety newly diagnosed or previously phlebotomized PV patients only (WHO 2008) were enrolled in the DALIAH trial (NCT01387763). All patients provided written informed consent. Patients ≤ 60 years were randomized (I:I) to r-IFNα-2a (Pegasys®) or to r-IFNα-2b (PegIntron®) whereas patients > 60 years were randomized (I:I:I) to either r-IFNα-2a, r-IFNα-2b or to HU. The starting dose of r-IFNα-2a and r-IFNα-2b was 45 or 35 µg/week, respectively. The HU dose was 500 to 2000 mg/day. Patients randomized to r-IFNα who presented with major thrombosis or platelets > 1500 109/L received HU from inclusion and until normalization of the platelet count. Efficacy assessment consisted of the clinicohematological and the molecular response rates by intention to treat analysis (ITT) using the European Leukemia Net (ELN) 2009 criteria. JAK2V617F analysis was performed by qPCR. Groups were compared by Fisher's Exact Test. Results Three-year analysis was available in all but five patients (n=85) at time of abstract submission (Table 1). The analysis was performed after a median of 36 months (range: 33-39 months). The median treatment dose was 684 mg/day (IQR: 131 - 942) for HU, 51 μg/week (IQR: 30-90 μg/week) and 54 μg/week (IQR: 30-66 μg/week) for r-IFNα-2a age ≤ 60 and > 60, respectively, and 41 μg/week (IQR: 29-45 μg/week) and 36 μg/week (IQR: 31-37 μg/week) for r-IFNα-2b age ≤ 60 and > 60. The overall clinicohematological response rate (ORR) was 68% (13/19) for HU, 42% (14/33) for r-IFNα ≤ 60 years and 39% (13/33) for r-IFNα > 60 years. The partial clinicohematological response rate (PHR) and the complete clinicohematological response rate (CHR) was 53% (10/19) and 16% (3/19) for HU, 9% (3/33) and 33% (11/33) for r-IFNα ≤ 60 years and 9% (3/33) and 30% (10/33) for r-IFNα > 60 years. Neither the ORR, CHR nor the PHR was significantly different between the three groups. Maintenance of CHR from first occurrence to data analysis after 36 months was 11% (2/19) for HU, 21% (7/33) for r-IFNα ≤ 60 years and 18% (6/33) for r-IFNα > 60 years. Forty-seven JAK2V617F positive patients were available for molecular response analysis after 36 months of therapy. A partial molecular response (PMR) was detected in 21% (4/19) of HU treated patients and in 24% (7/29) of r-IFNα treated patients ≤ 60 years and 18% (6/33) of r-IFNα > 60 years. Notably, 7% (2/29) of the r-IFNα treated patients ≤ 60 years obtained a complete molecular response (CMR). The median JAK2V617F reduction from baseline was 38% (IQR: 31-63%) for HU, 79% (IQR: 59-92%) for r-IFNα ≤ 60 years and 73% (IQR: 49-97%) for r-IFNα > 60 years. There was no statistically significant difference in the PMR between groups. Discontinuation of treatment for any reason after 36 months of therapy was 21% (4/19) for HU, 52% (17/33) for r-IFNα ≤ 60 years and 45% (15/33) for r-IFNα > 60 years. Toxicity related discontinuation was 5% (1/19) for HU and 30% (10/33) for both r-IFNα ≤ 60 and > 60 years. Grade 3-4 AEs occurred in 32% (6/19) of HU treated patients, 27% (9/33) in r-IFNα treated patients ≤ 60 years and in 42% (14/33) r-IFNα treated patients > 60 years. SAEs were reported in 21% (4/19) for HU, 9% (3/33) for r-IFNα ≤ 60 years and 24% (8/33) for r-IFNα > 60 years. The numbers of grade 3-4 AEs as well as SAEs were comparable between groups. Conclusion After 36 months of therapy CHR was non-significantly higher in PV patients treated with r-IFNα compared to HU by ITT, irrespective of age. Also, maintenance of CHR was longer for r-IFNα. However, ORR was non-significantly higher for HU. PMR was almost similar between the three groups but the median JAK2V617F reduction was greater for r-IFNα. Toxicity related discontinuation from study therapy was higher for r-IFNα compared to HU. Disclosures Stentoft: Bristol-Myers Squibb: Research Funding; Merck Sharp&Dohme: Research Funding. Hasselbalch:Novartis: Research Funding.

When the number of eosinophil granulocytes in blood increases, the cause is not always easy to disentangle. This review highlights the symptoms of rare clonal and common reactive diagnoses, how to approach the patient clinically, and how to implement the armamentarium of available tests in order to identify the correct diagnosis and offer the proper treatment. Two referral centres for eosinophilia have been established in Denmark to support this activity by a collaboration between all departments of haematology and the relevant specialities, meeting the manifestations of eosinophilia.

Background: To investigate the role of genomics in determining response and resistance to front line treatment in MPN, we performed somatic mutational profiling of the DALIAH trial, a randomized controlled phase III trial of interferon versus hydroxyurea in newly diagnosed MPN patients. Methods: We performed genomic analyses on 202 pre-treatment primary MPN samples obtained from patients enrolled on the DALIAH trial (NCT01387763) and 135 samples obtained after 24 months of treatment. Genomic profiling comprised targeted next generation sequencing (NGS) of 100 genes, selected on the basis of their known or suspected involvement in the pathogenesis of myeloid malignancies, and 1609 informative single nucleotide polymorphisms (SNPs) on chromosome 9p. Clinicohematological response was determined by central review using ELN 2009 (ET, PV and pre-MF) and EUMNET 2005 (PMF) criteria. We evaluated the association of somatic mutations with clinical parameters and with attainment of clinicohematological complete response (CR) at 24 months. Results: Prior to treatment, 191 of 202 (95%) patients had somatic mutations, including 93% with canonical MPN phenotypic drivers: JAK2 (74%), CALR (14%), and MPL (5%). Among those with JAK2 mutations 37% had JAK2 copy-neutral loss of heterozygosity (JAK2 CN-LOH). Patients with PV were more likely to have JAK2 CN-LOH (p = 0.0001) as compared with patients with other MPN subtypes. At baseline, patients with JAK2 CN-LOH had significantly higher hemoglobin (p = 0.0001), higher white blood cell count (WBC, p = 0.002) and lower platelet count (p=0.0001) than patients without JAK2 CN-LOH. Mutations in TET2 (24%), DNMT3A (16%), and ASXL1 (10%) were the most frequent co-occurring non-MPN phenotypic driver mutations and they occurred across all MPN subtypes. In addition, 5% of patients had spliceosome gene mutations, and 6% had mutations in genes involved in RAS/MAPK signaling. Patients with TET2, DNMT3A or ASXL1 mutations were significantly older than patients without these mutations (p= 0.0001) and there was a significant association between the presence of a TET2, DNMT3A or ASXL1 mutation and prior stroke (p = 0.004). There were no other significant associations between somatic mutation status and baseline clinical characteristics. The probability of attaining clinicohematological CR at 24 months was independent of baseline somatic mutations. Among patients with JAK2 mutations who remained on interferon treatment at 24 months, those with CR had a greater reduction in mean variant allele fraction (VAF) (28% to 8%, p Among patients who remained on treatment for 2 years, 44 mutations in 35 patients were newly detected or expanded on serial sampling. DNMT3A mutations were the most frequently acquired, accounting for 41% of new mutations. ASXL1, TET2, PPM1D, TP53, IDH2, and CBL mutations were also recurrently acquired. 97% of patients who acquired new mutations were JAK2-mutant. Among those with acquired DNMT3A mutations, 85% were treated with interferon, and 23% had CR at 24 months. Among those that acquired non-DNMT3A mutations, 38% were treated with interferon and 47% had CR at 24 months. The VAF of newly detected mutations was low (median 1.5%), and half of the patients with newly acquired mutations had at least 50% reduction in JAK2V617F VAF, suggesting that new mutations could either have arisen independently or be subclonal to the dominant JAK2-mutant clone. Conclusions: Using sequential genomic analyses of a phase III clinical trial of interferon versus hydroxyurea in MPN patients, we found mutation-specific and treatment-specific patterns of response. We uncovered distinct patterns of response to interferon in JAK2-mutant MPN as compared with CALR-mutant MPN. We found that DNMT3A mutations were the most frequent acquired mutations at 24 months and that these were enriched in patients treated with interferon. In aggregate, these results provide insights into molecular response and resistance to interferon and inform the clinical use of interferon in MPN patients. Disclosures Hansen: Alexion: Research Funding. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Mullally:Janssen: Research Funding.

Udgivelsesdato: 2008-Oct-27 Treatment of Graves' disease (GD) with the B-lymphocyte depleting agent rituximab in addition to standard methimazole-therapy prolongs remission. Paradoxically, it does not mediate a reduction in thyrotropin receptor antibody (TRAb) levels over that of methimazole monotherapy. Using a bioassay involving Chinese hamster ovary cells transfected with the human thyrotropin receptor, we found that the stimulatory capacity of TRAbs was reduced markedly, by 66+/-22%, upon treatment with rituximab and methimazole for 21 days (p

Background Treatment of Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPNs) with recombinant pegylated interferon alpha2a/b (rIFN-alpha) has proven effective. It is well known that prolonged therapy with recombinant type 1 interferons (IFN-alpha and IFN-beta) may induce neutralizing antibodies (nAbs) against the drug leading to treatment failure. Most data on type 1 IFN immunogenicity are available from studies of patients with multiple sclerosis treated with rIFN-beta, and patients with hepatitis C treated with rIFN-alpha. A few reports have demonstrated nAbs in MPN patients not responding adequately to rIFN-alpha treatment, but the phenomenon has not been thoroughly investigated in MPNs. Patients and Methods Newly diagnosed patients with MPNs enrolled in the Danish multicenter trial - DALIAH (Low-dose rIFN-alpha versus Hydroxyurea in The Treatment of Ph-Negative MPNs) were included. Patients were randomized to treatment with either rIFN-alpha 2a or 2b at a starting dose of 45 and 35 mikrograms once weekly, respectively. The occurrence of neutralizing Abs (nAbs) against rIFN-alpha was investigated at baseline, month 12 and month 24 by reporter gene assays (iLiteTM alphabeta and iLiteTM antialpha, Biomonitor A/S, Copenhagen, Denmark). JAK2 V617F quantitative mutation analyses were performed as previously described (Larsen TS, BJH 2007). Statistical analyses were performed using STATA version 9.0. Results Ninety-two patients on sustained treatment with rIFN-alpha2a (n=48) and rIFN-alpha2b (n=44) for 12 months were analyzed for this study. Forty-five patients had ET, 39 patients had PV and 8 patients had proliferative PMF. Thirty-six out of 39 (92%) PV patients, 22 out of 45 (49%) ET patients and 4 out of 8 (50%) PMF patients were JAK2V617F mutated. Hematological responses at 12 months: ET: 67% CR, 29 % PR; PV: 64% CR, 31% PR (ELN 2009 criteria); PMF: 50% had at least a minor response (EUMNET). The median serum concentration of bioactive IFN-alpha at 12 months was 12,4 (range Conclusions Development of nAbs in MPN patients completing treatment for 12 months with rIFN-alpha seems exceedingly rare as no patients, neither complete responders nor patients not meeting criteria for complete hematological remission developed nAbs after 12 (24) months of therapy. Its apparent rarity does not justify a routine investigation of nAbs in patients not responding to rIFN-alpha treatment. There was no significant correlation between serum concentration of rIFN-alpha 2a and -2b and clinical or molecular responses. The intriguing finding that one of 24 patients had pre-existing cross reacting nAbs against rIFN-alpha 2a and 2b before commencing rIFN-alpha treatment is interesting and was associated with an insufficient response. Disclosures Off Label Use: Recombinant interferon-alpha 2a and -2b in the treatment of chronic Philadelphia-negative myeloproliferative neoplasms.. El Fassi:Novartis Denmark: Honoraria, Other: Have conducted an educational session for Novartis Denmark, regarding MPNs and ruxolitinib, for this a honorarium was received.. Bjerrum:Bristoll Myers Squibb, Novartis and Pfizer: Other: educational activities. Hasselbalch:Novartis: Research Funding. Bendtzen:Pfizer: Honoraria; Eurodiagnostica AB: Equity Ownership; Novo-Nordisk: Equity Ownership.

54-year-old man with childhood-onset type I diabetes mellitus who had preserved renal function but blindness secondary to his diabetes mellitus presented with a 5-day his-tory of malaise and diarrhea.On admission, he was dehydrated, hypotensive, and hypo-thermic (96.1oF/35.6oC). Initial laboratory values showed a potassium level of 9.2 (N, 3.6–5.0) mmol/L, and a sodium level of 122 (N, 137–145) mmol/L. The potassium level was confirmed on arterial samples.The initial ECG showed a regular idioventricular rhythm with bizarre, broad QRS complexes, and a frequency of 32 beats per minute (Figure A). Over a 5-hour period, on correc-tion of the hyperkalemia, he converted to sinus rhythm (Figure B and C) initially with a first-degree atrioventricular block (Figure B). Furthermore, the characteristic peaking of the T waves related to the hyperkalemia normalized (Figure C).On follow-up, an increased level of adrenocorticotropic hormone, the absence of response to synthetic adrenocorti-cotropic hormone, and strongly positive adrenal antibodies revealed that the patient had developed autoimmune adrenal insufficiency (Addison disease).Thomas Addison recognized the potential effects of adrenal insufficiency on the heart, and he described one of the marked features of the condition as “a remarkable feebleness of the hearts action” in his original monograph from 1855.

Metformin-associated lactate acidosis is rare but serious and characterized by metabolic acidosis and elevated lactate. We describe a single-institution experience of four cases in one year. Despite pH levels of 6.85 to 7.12 and lactate levels of 11-28 mmol/l three of the patients survived. Two of the patients had normal kidney function previous to hospitalization. Treatment includes fluid replacement, IV sodium bicarbonate and haemodialysis.

Udgivelsesdato: 2009-Nov

Most current approaches for treating Graves' disease are based essentially upon regimes developed nearly 50 years ago. Moreover, therapeutic approaches for complications such as thyroid-associated ophthalmopathy (TAO) and dermopathy are singularly dependent on conventional approaches of nonspecific immunosuppression. The recent development of an induced model of experimental Graves' disease, although incomplete as it lacks the extrathyroidal manifestations, provided opportunities to investigate immune intervention strategies, including influence upon the autoreactive B and T cell players in the autoimmune process. These major advances are generating new possibilities for therapeutic interventions for patients with Graves' disease and TAO.

Graves' disease (GD) is caused by autoantibodies to the thyrotropin receptor (TRAb). In a controlled study using the B-lymphocyte depleting agent rituximab (RTX), an RTX-specific effect was found on long-term remission following methimazole (MMI) therapy. However, benefits were limited to patients with low baseline TRAb levels, and the decrease in TRAb levels observed after treatment with RTX in combination with MMI was no greater than that observed after treatment with MMI alone. Considering its price and adverse effect profile, RTX therapy does not seem to be a relevant treatment option in uncomplicated GD. The potential use of other immunomodulatory agents in GD is discussed.

The current medical treatment options for Graves' ophthalmopathy (GO) are unsatisfactory. Recent treatment of GO patients with the B-lymphocyte depleting monoclonal antibody rituximab or with the anti-tumor necrosis factor-alpha agents etanercept and infliximab has shown promising results. We discuss the use of these and other biological agents targeting B lymphocytes, T-lymphocyte interaction with antigen-presenting cells, or cytokines in the future treatment of GO.

Departments of Endocrinology and Metabolism (D.E.F., L.H.) and Clinical Pathology (O.C.), Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Immunology Section 7631 (C.H.N.), Rigshospitalet, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark; and Division of Ophthalmic Plastic, Reconstructive and Orbital Surgery (R.Z.S.), California Pacific Medical Center, San Francisco, California 94115

Udgivelsesdato: 2007-May CONTEXT: Graves' disease (GD) is a common TSH receptor autoantibody (TRAb)-mediated disorder. Because B lymphocytes are important self-antigen presenting cells and precursors for antibody-secreting plasma cells, temporary B-lymphocyte depletion with the monoclonal antibody rituximab (RTX) might be of benefit in GD. OBJECTIVE/DESIGN: The objective of this prospective, controlled, nonrandomized study was to investigate the effect of RTX in GD. SETTING/PATIENTS: We studied 20 outpatients referred to a university clinic with newly diagnosed (four with relapse) untreated GD. Ten received RTX (+RTX), whereas 10 did not (-RTX). INTERVENTION: The patients received methimazole (MMI) for a median of 102 d (+RTX) and 110 d (-RTX) before the study. Patients in the +RTX group received 375 mg RTX/m(2) iv on d 1, 8, 15, and 22, and all patients were withdrawn from methimazole (MMI) at d 22. MAIN OUTCOME MEASURES: We measured time to relapse of hyperthyroidism and changes in autoantibody levels. RESULTS: Four patients in the +RTX group remained in remission with a median follow-up of 705 d (range, 435-904 d), whereas all the patients in the -RTX group had relapsed by d 393 (P < 0.05). All of the patients in remission had initial TRAb levels below 5 IU/liter (normal

Background: The Philadelphia-negative, chronic myeloproliferative neoplasms (MPN) include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (MF) (PMF). Chronic inflammation and a deregulated immune system are considered important for clonal evolution and disease progression. Ruxolitinib is a potent anti-inflammatory agent and has shown great benefit in MPN patients (pts), reducing spleen size and inflammation-mediated symptoms, thereby improving quality of life (QoL). Interferon-alpha2 (IFNa2) has been used successfully for decades in the treatment of MPN. However, 10-20% of pts are intolerant to IFNa2, yet others show limited response. Since concurrent inflammation might attenuate the efficacy of IFNa2 therapy, a combination therapy (CT) with the two agents may be more efficacious than monotherapy, likely reducing the inflammation-mediated adverse effects of IFNa2 as well. The purpose of this COMBI-trial is to evaluate the safety and efficacy of CT with IFNa2 and ruxolitinib. Patients and Methods: At the time of data cutoff, a total of 30 pts ≥18 years with prefibrotic or hyperproliferative PMF (n=7), PV (n=20) or post-PV MF (PPV-MF) (n=3) with or without prior treatment with IFNa2 and without serious comorbidity were enrolled. Evidence of active disease was required. Initial therapy was IFNa2 45 μg x 1 sc/week (Pegasys®) or 35 μg x 1 sc/week (PegIntron®) + ruxolitinib (Jakavi®) 20 mg x 2/day. Efficacy was evaluated by internationally accepted clinicohematological response criteria, with the modification that splenomegaly was assessed by palpation instead of imaging, by week 2 and 1, 3, 6 and 9 months. In addition, JAK2V617F-allele burden was monitored. Adverse events (AE) including serious AE (SAE) were recorded. Results: Median treatment duration was 24.4 weeks (range, 3.4 weeks-43.3 weeks). Twenty-seven pts were previously treated with IFNa2 (n=18 intolerant, n=5 unresponsive, n=4 both). Three pts were treatment-naïve. Twenty-seven pts (90%) remained on CT; 3 pts discontinued treatment due to an AE. One patient died from transformation to AML shortly after initiation of CT and was not included in this interim analysis. Marked improvements in pruritus, night sweats, and fatigue were recorded within the first 2-3 days in the large majority of pts and in all within 4 weeks. Palpable splenomegaly in 7 pts at baseline was significantly reduced by week 2. Hct control without phlebotomy was achieved by week 4 in 78 % of pts (7 of 9), who at baseline had an elevated hct. Only 3 pts required a total of 3 phlebotomies after initiation of CT. In Figure 1 median hct levels at 0, 1, 3, 6 months are shown. Overall, complete response (CR) was achieved as best response in 19 pts (63.3%) and partial response (PR) or major response in 8 pts (26.7%). Only 3 pts (10%) had no response (NR) to treatment. Among PV pts, 15 (75%) achieved CR (week 2, n=6; 1 month, n=6; 3 months, n=3). The other 5 PV pts achieved PR (week 2, n=3; 1 month, n=2). In PMF pts, CR (n=2) or major response (n=2) was achieved in 4 pts (57.1%) by week 2 or 1 month, and NR in 3 pts (42.8%). Among PPV-MF pts, 2 pts (66.7%) achieved CR and 1 patient (33,3%) PR by week 2. Furthermore, JAK2V617F% declined significantly as depicted in Figure 2 (JAK2V617F% over time for each patient) and 3 (median JAK2V617F% at 0, 3, 6 months). Anemia (n=15, 2 grade 3), granulocytopenia (n=13, 2 grade 3) or thrombocytopenia (n=6, 1 grade 3) were the most common AEs and were managed by dose reduction. One patient with PPV-MF (leuko- and thrombocytosis) developed pancytopenia within the first 2 weeks on CT, necessitating pausing medication for > 2 weeks. Eleven SAEs requiring hospitalization were recorded in 9 pts: pneumonia (n=3), fever (n=2), lipotymia, hematemesis, phlebitis, herpes zoster, angina pectoris and arterial hypertension, 1 patient each. Conclusion: CT with IFNa2 and ruxolitinib is highly efficacious and safein pts with PV or hyperproliferative MF,who were unresponsive or intolerant to monotherapy with IFNa2. Complete clinicohematological responses were achieved in the majority of pts in concert with a reduction in the JAK2V617F-allele burden. In general, the treatment was well tolerated. The preliminary results from this study are highly promising, encouraging a prospective study with CT in newly diagnosed pts. Additional follow-up data will be presented including QoL assessment and the impact of concurrent treatment with statins. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Off Label Use: The combination therapy with ruxolitinib (JAK1-2 inhibitor) and interferon-alpha is off-label in MPNs. The concept is dual myelosuppressive action and dual clonal suppression in addition to the anti-inflammatory properties of ruxolitinib.. Bjørn:Novartis Oncology: Research Funding. Bjerrum:Bristoll Myers Squibb, Novartis and Pfizer: Other: educational activities. El Fassi:Novartis Denmark: Honoraria, Other: Have conducted an educational session for Novartis Denmark, regarding MPNs and ruxolitinib, for this a honorarium was received.. Nielsen:Novartis: Research Funding. Pallisgaard:Roche: Other: travel grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Speakers Bureau; Novartis: Other: travel grant, Research Funding, Speakers Bureau; Qiagen: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Speakers Bureau. Hasselbalch:Novartis: Research Funding.

Rituximab (RTX) is a murine/human monoclonal antibody to CD20, a protein expressed almost exclusively on human B-lymphocytes. RTX induces rapid and marked B-cell depletion with beneficial clinical effects in 1/3 to 1/2 of rheumatoid arthritis patients. Treatment is given as two iv. infusions with a two-week interval and in combination with methotrexate. Mild to moderate side-effects are frequent, particularly during the first infusion, but long-term side-effects are generally rare, although pulmonary events and reactivation of viral infections of the liver is of concern.

Udgivelsesdato: 2006-Jul

The possible adverse consequences of biological therapies in inflammatory bowel diseases (IBDs) were recently highlighted in this journal by D’Haens ( Gut 2007; 56 :725–32). We here describe a hitherto unappreciated adverse effect to treatment with the B lymphocyte (B cell) depleting agent rituximab (RTX),1 namely the occurrence of ulcerative colitis and arthritis shortly after treatment with RTX. Our patient, a 45-year-old Caucasian female, had had mild irritable bowel symptoms since 1992 at which time rigid sigmoidoscopy and bowel x ray were normal. She had never received any therapy, had never previously had joint pain, and was not predisposed to IBD. In April 2005 she was diagnosed with Graves’ disease, and after uncomplicated standard methimazole therapy she received four weekly doses of 375 mg/m2 RTX from day 1 to 22 as part of a clinical trial.2 The trial was approved by the local ethics committee …

Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.