BACKGROUND Although recombinant interferon‐α (rIFNα) effectively treats patients with early myelofibrosis, the effect of driver and high molecular risk (HMR) mutations has not been considered. In this phase 2 study, for the first time, the authors correlate response to rIFNα treatment with driver and HMR mutations. METHODS Patients were diagnosed using World Health Organization or International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Only patients who had low or intermediate‐1 Dynamic International Prognostic Scoring System scores with ≥15% hematopoietic bone marrow foci were included. History, symptom assessment, physical examination, and blood and bone marrow studies were performed. Genomic DNA was extracted from frozen cells, and next‐generation targeted sequencing of 45 genes was performed. Either rIFNα‐2b (0.5 million units subcutaneously 3 times weekly) or pegylated rIFNα‐2a (45 μg weekly) with escalation was initiated. All patients were followed at the authors' institution, and regular bone marrow biopsies were encouraged. International Working Group for Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet treatment response criteria were used. RESULTS Of 30 patients (16 women and 14 men; median age, 58 years), 22 were classified as low risk, and 8 were classified as intermediate‐1 risk. Two patients achieved complete remission, 9 achieved partial remission, 4 had clinical improvement, 7 had stable disease; 3 had progressive disease, 1 relapsed, and 4 died. There were 22 patients with JAK mutations, 6 with CALR mutations, and 2 with MPL mutations. Seventy‐three percent of patients improved or remained stable with acceptable toxicity, including 37% who achieved complete or partial remission. There was no correlation between treatment response and baseline driver mutations or Dynamic International Prognostic Scoring System scores. Of 8 poor responders, 3 had ASXL1 or SRSF2 mutations. CONCLUSIONS Early treatment with rIFNα in patients without HMR mutations may prevent the development of marked splenomegaly, anemia, and florid myelofibrosis. Molecular profiling at the time of diagnosis may predict prognosis and treatment response. Cancer 2017;123:2680‐87. © 2017 American Cancer Society.
Introduction Successful treatment of early myelofibrosis (eMF), defined as patients (pts) with low or intermediate-1 (int-1) risk and ≥15% hematopoietic foci in the marrow biopsy, with rIFNα has been reported, but effects of driver and epigenetic mutations on outcomes were not considered. We now report results of our single center phase II study of 30 pts with primary (PM) or secondary (SMF) eMF, correlating the baseline molecular profile with response to rIFNα treatment. Methods We used WHO 2008 and IWG-MRT criteria for the diagnosis of PM and post-polycythemia vera MF (pPV MF) or post-essential thrombocythemia MF (pET MF), respectively. Prognosis was assessed using the Dynamic International Prognostic Scoring System (DIPSS). Response classifications were complete response (CR), partial response (PR), clinical improvement (CI), stable disease (SD), progressive disease (PD). Evaluation included history, examination, spleen size (cm below left costal margin), CBC and differential counts, routine chemistries, liver, renal, and thyroid function tests, marrow biopsy, cytogenetic and molecular genetic evaluations. Marrow specimens were stained routinely for morphology, reticulin, and collagen; fibrosis was graded using the European consensus system. JAK2, CALR and MPL mutations were detected and quantified by amplicon based next generation sequencing (NGS). NGS of 45 genes recurrently mutated in myeloid malignancies was performed on 25 of 30 baseline specimens, including ASXL1, IDH1/2, EZH2 and SRSF2, previously defined as high molecular risk (HMR) genes. Descriptive statistics were calculated and Fisher's exact test used to explore the relationship between mutations and various results. Pts received either rIFNα-2b or peg-rIFNα-2a starting at a 5x105 to 1x106 units SC 3X wk or 45 to 90 mcg weekly, respectively; dose increase dependent upon tolerance and/or response. Results Of 96 pts with PM or SMF, 30 met study criteria, including 16 women and 14 men (med. dx age 58 yrs). Twenty-one had PM, 7 pPV MF, and 2 pET MF. Twenty-one pts were low risk, 9 int-1. Twenty-two were JAK2V617F(+), 6 CALR(+), and 2 MPL(+). All 7 pPV MF pts were JAK2(+). One pET MF was JAK2(+) and 1 CALR(+). Of PM pts, 14 were JAK2(+), 5 CALR(+), and 2 MPL(+). Med. rx duration has been 5.6 yrs and is ongoing. Clinical toxicity, grade 1 or 2, included mild depression, dry skin, cough, and myalgia. Hem. toxicity included anemia (grade 1-2: 17 pts), leukopenia (grade 1-2: 9 pts), and thrombocytopenia (grade 1-2: 10; grade 3: 2 pts). In these cases, rIFNα dose was temporarily reduced/interrupted until cytopenias resolved. One pt developed hyperthyroidism; treatment was discontinued. Of 30 pts, 2 (7%) had CR, 9 (30%) PR, 4 (13%) CI, 7 (23%) SD. Four (13%) had PD, and 4 (13%) died. Nine of 21 low risk pts had CR or PR, compared with 2 of 9 int-1. A small spleen at baseline was associated with better response in the absence of HMR abnormalities. Of 18 pts with slight or no splenomegaly, 11 had CR or PR, and of the non-responders, 2 had a HMR. Of 12 pts with significant or moderate splenomegaly, none had CR or PR, including 2 with a HMR. Follow up biopsies in 25 pts (83%) a reduction in reticulin fibrosis in 5, increase in 9, and stable in 10. Decrease in cellularity occurred in 12. There was no correlation between decrease in JAK2 allele burden, response, fibrosis, or spleen size. There was no correlation between driver mutations and response (Table). Pts with a HMR had worse responses; of 4 such pts, 0 responded, 1 remained stable, 1 progressed and 2 died. Specifically, pts with ASXL1 mutations seemed to do worse than those without it, although sample size precludes a definitive statement (p=0.19). Conclusion This is the first study considering the effect of baseline mutation status on response to rIFNα treatment in eMF pts. 73% of pts improved or remained stable regardless of initial low or int-1 score or driver mutation, but spleen size and HMR adversely affected treatment response. Although baseline driver mutation status was not prognostically useful, a molecular profile should be obtained initially to identify HMR mutations, which negatively affect response to treatment including rIFNα. In 73% of selected cases, low dose rIFNα in eMF resulted in marrow reversion, regression of splenomegaly or disease stability with tolerable toxicity. Early treatment of MF with rIFNα in pts without HMR may prevent the development of marked splenomegaly, anemia, and florid myelofibrosis. Disclosures Silver: Incyte: Membership on an entity's Board of Directors or advisory committees. Ritchie:Pfizer: Honoraria; Incyte: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Honoraria, Research Funding; Arian: Speakers Bureau. Roboz:Agois: Consultancy; Amgen: Consultancy; Amphivena: Consultancy; Astex: Consultancy; AstraZeneca: Consultancy; Boehringer Ingelheim: Consultancy; Celator: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Genoptix: Consultancy; Janssen Pharamaceuticals: Consultancy; Junno: Consultancy; MedImmune: Consultancy; MEI Pharma: Consultancy; Novartis: Consultancy; Onconova: Consultancy; Pfizer: Consultancy; • Roche Pharmaceuticals: Consultancy; Sunesis: Consultancy; Teva: Consultancy. Orazi:Novartis: Honoraria. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.
Patients with IBD frequently have hematologic abnormalities suggestive of JAK2 mutated MPNs, but are traditionally classified as reactive processes. Haplotype 46/1 is a well-characterized genetic predisposition, common to both inflammatory bowel disease (IBD) and myeloproliferative neoplasms (MPN). In view of this shared genetic predisposition, we measured the frequency of the JAK2 V617F mutation in IBD patients with thrombocytosis or erythrocytosis, in order to ascertain whether a higher than expected proportion of these patients may in fact have underlying MPNs. 1121 patients were identified with an active diagnosis of Crohn's disease or ulcerative colitis, of which 474 had either thrombocytosis or erythrocytosis. Patients with abnormal counts were tested for the JAK2 V617F mutation during routine follow-up visits. Interim analysis of first 23 patients tested was performed to assess whether the JAK2 V617F positivity rate was statistically significant compared with known expected frequencies in a comparable control population. Of 23 patients, 13 patients had thrombocytosis and 10 had erythrocytosis. Three patients with thrombocytosis (23%), and 1 patient with erythrocytosis (10%), tested positive for JAK2 V617F , exceeding the expected thresholds for statistical significance. In patients with IBD and thrombocytosis or erythrocytosis, a meaningful proportion may harbor an undiagnosed MPN, as indicated by clonal abnormalities such as JAK2 V617F. These findings imply the need for increased testing of these patients for clonal hematologic abnormalities, and importantly, if found, suggest the need for therapeutic strategies with drugs, such as JAK2 inhibitors, in patients with both MPN and IBD.
Introduction Limited effect of JAK2 inhibitors in treating myelofibrosis (MF), either primary (PM) or secondary to polycythemia vera (PV-MF) or essential thrombocythemia (ET-MF), and the limited survival experienced with stem cell transplantation, prompted us to use interferon (rIFNα) in early stage MF (eMF), i.e. low or intermediate-1 disease. rIFNα effects megakaryopoiesis, decreasing megakaryocyte (MK) density and size, inhibiting thrombopoietin-induced signaling, and reducing levels of platelet derived growth factor, which play a major role in the pathogenesis of MF. Moreover, rIFNα affects stem cells in PV. Results we previously reported in eMF showed remission, clinical improvement (CI) or stable disease (SD) in 80% of 17 patients (pts.) with PM (Silver RT et al. Blood. 2011; 117(24):6669-72). Based on this encouraging experience, we expanded our trial with rIFNα to include PV-MF and ET-MF. We now report the results of 32 pts. with eMF. Methods Pts. were seen regularly in our clinic, evaluating symptoms, physical findings, signs of toxicity, routine blood counts and chemistries and JAK2 determinations. Bone marrow biopsies (BMBs) were encouraged annually to evaluate status of disease. The dose of recombinant interferon alpha-2b (rIFNα-2b) treatment was initiated at 500,000 – 1,000,000 units thrice weekly (18) or pegylated interferon alpha-2a (PEG-IFNα-2a), 45 mcg weekly (9). Results 17 women and 15 men, median age 57 years (range: 34-72) were treated. Median duration of disease prior to treatment was 3.4 months. Median values for hematocrit, hemoglobin, and platelet count at baseline were 38.8%, 12.9 g/dL, and 345,000/uL, respectively. 12 pts. (37.5%) met the criteria for PM, 7 (22%) for PV-MF and 11 (34%) for ET-MF. Two (6.3%) PV pts. had continuing phlebotomy requirements and progressive splenomegaly, and marrow fibrosis in the absence of other WHO criteria. Risk categories were assigned based on the IWG-MRT DIPSS-PLUS. Twenty-two pts. were low-risk, 4 intermediate-1, and 6 intermediate-2 (the latter group emerged solely due to incorporation of cytogenetic data; prior to DIPSS-PLUS, the 6 pts. categorized as intermediate-1). The IWG-MRT risk categories were correlated with response (Table). Of 32 pts., 3 (9.4%) had complete remission (CR), 12 (37.5%) partial remission (PR), 3 (9.4%) CI and 7 (22%) SD - an overall response rate of 78%. Three (9.4%) pts. (1: intermediate-1, 2: intermediate-2) died of progressive disease (PD), one of whom was rIFNα non-compliant. Of 32 pts., 10 had no splenomegaly at onset of rIFNα, and 9 remained unchanged during treatment. In 10 pts. initially with slight splenomegaly (< 3 cm below the LCM), the spleen became non-palpable in 8. Of 3 pts. with moderate (>3 – 9 cm BLCM) spleens, and 9 (> 9 cm BLCM) with marked splenomegaly, there was a more variable response (1 – 16 cm decrease). Follow-up BMBs were possible in 22 pts.; in 12, reduction in cellularity occurred after a median treatment period of 2 years. Of 15 pts. with reduction in splenomegaly and evaluable BMBs, 7 had reduction in cellularity, 3 showed significantly improved MK morphology, marrow architecture, and striking reduction of reticulin and collagen fibrosis (grade 3 to 1); 3 showed no change in morphology, but nevertheless, experienced reduction in spleen size. Of the 32 pts., 23 (71.8%) were JAK2V617F (+). Of 19 follow-up specimens, 7 had a median allelic burden decrease of 44%., the remainder were unchanged Abnormal cytogenetics did not influence response. All pts. initially experienced the usual side effects of rIFNα which were mild in degree (grade 1-2) and subsided with time or dose adjustment; including mild depression, dry skin, cough, myalgia, fatigue and asthenia. Seventeen pts. developed increasing anemia (13: grade 1; 4: grade 2); one had grade 3 thrombocytopenia. In these cases, the dose was temporarily reduced or interrupted until cytopenias resolved. One pt. developed hyperthyroidism and treatment was discontinued. Conclusions In this eMF, single-arm study, we conclude that rIFNα prevents disease progression and can induce remission with acceptable toxicity, improving marrow morphology which usually, but not always, correlates with reduction in splenomegaly, warranting an expanded phase 3 trial, currently underway. IWG-MRT treatment response stratified by DIPSS-PLUS risk at baseline. Disclosures: Silver: Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Off Label Use: The use of recombinant and pegylated interferon alpha in the treatment of myelofibrosis. Feldman:Tragara Pharmaceuticals: Consultancy.
Rationale-Previous studies indicate that the rewarding effect of D-1 dopamine (DA) receptor stimulation in nucleus accumbens (NAc) shell is greater in food-restricted (FR) than in ad libitum fed (AL) rats. The D-1 receptor is positively coupled to adenylyl cyclase and activates protein kinase A (PKA).Objectives-The purpose of this study was to determine whether PKA is involved in the rewarding effect of D-1 receptor stimulation and, if so, whether it is involved in the enhanced response of FR rats.Materials and methods-Rats were stereotaxically implanted with microinjection cannulae in NAc shell and a stimulating electrode in lateral hypothalamus. Rewarding effects of SKF-82958 (1.5 or 3.0 µg, bilaterally) in the presence and absence of PKA inhibitor, Rp-cAMPS (8.9 µg), and PKA activator, Sp-cAMPS (8.9 µg), were assessed using the curve-shift method of selfstimulation (ICSS). Basal NAc levels of DARPP-32 phosphorylated on Thr34 and Thr75 were measured.Results-Rp-cAMPS increased the rewarding effect of SKF-82958 in AL but not FR rats, doubling the ICSS threshold-lowering effect of the 3.0 µg dose. Sp-cAMPS decreased the rewarding effect of SKF-82958 in FR but not AL rats. Levels of phospho-DARPP-32 (Thr75), which inhibits PKA, were higher in FR than AL rats. Conclusions-Resultsindicate that inhibition of PKA enhances the unconditioned rewarding effect of D-1 receptor stimulation and that decreased PKA may be involved in the effect of FR on drug reward. Evidence for involvement of D-2 receptor-expressing neurons in the enhancing effect of PKA inhibition is discussed. Keywordsfood restriction; nucleus accumbens; reward; self-stimulation; D-1 receptor; protein kinase A; SKF-82958; Rp-cAMPS; Sp-cAMPS; DARPP-32 * corresponding author, kc16@nyu.edu, tel: 212-263-5749, fax: 212-263-5591.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2013 June 01. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMore than 90% of neurons in the nucleus accumbens (NAc) dopamine (DA) terminal field are medium spiny neurons (MSN) (O'Donnell and Grace 1993), and less than 1% coexpress D-1-and D-2-like DA receptors (Shuen et al. 2008). Recent evidence suggests that excitation of D-1 DA receptor-expressing MSNs mediates reward-related behavior including cocaine-conditioned place preference and locomotor sensitization (Lobo et al. 2010 Chronic food restriction (FR) increases the reward magnitude of drugs whose primary rewarding effects are mediated by DA in NAc medial shell (...
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