Citations

AbstractMyeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG‐MRT), and AIRC‐Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN‐SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN‐SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient‐years. Vitamin K‐antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN‐SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN‐SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN‐U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to‐date largest, contemporary cohort of MPN‐SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.

LINKED CONTENTThis article is linked to Pai et al and Rowe papers. To view these articles, visit https://doi.org/10.1111/apt.15503 and https://doi.org/10.1111/apt.15537.

Abstract Background Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. Methods Patients with stage I–III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. Results A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). Conclusions We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

Abstract Background Tumor necrosis factor (TNF)-α antagonist therapy has revolutionized the practice of management of inflammatory bowel disease (IBD); however, these medications carry a boxed warning from the Food and Drug Administration for risk of serious infection. We aimed to study the invasive fungal infection, histoplasmosis, in the setting of TNF-α antagonist therapy. Methods We performed a retrospective review of patients with IBD receiving TNF-α antagonist therapy who developed histoplasmosis during the time period January 2001–May 2018 at the Mayo Clinic, Rochester, MN. The medical records of patients were reviewed for demographics, medications, symptoms, diagnosis, treatment, and outcomes including mortality. IBD was diagnosed by biopsy, radiographic, or endoscopic evidence of disease. Results We identified 49 patients (age range 19–74; median 44 years) with a confirmed diagnosis of histoplasmosis while receiving a TNF-α antagonist. 73.5% of cases were classified as disseminated. Median time from starting TNF-α antagonist to histoplasmosis diagnosis was 2.1 years. Liposomal amphotericin B was given in 17 cases as the initial treatment. Itraconazole was given to all 49 patients. Initial treatment was split evenly between inpatient (49%) and outpatient (51%) locations with 6 patients (12%) requiring ICU-level care. Median length of stay was 9.5 days. The total length of treatment for all antifungals was 38.4 weeks, with 20.4% of patients developing documented antifungal side effects. TNF-α antagonist was continued in 9 patients (18.4%) and another 10 patients resumed TNF-α antagonist. Half of those who resumed TNF-α antagonists were on antifungal therapy. There was one histoplasmosis recurrence while off TNF-α antagonist, and three deaths (6%). Conclusion Histoplasmosis outcomes in IBD patients on TNF-α antagonists were mostly favorable; however, approximately half required hospitalization. Many patients were young with few co-morbidities, and over one-third were able to continue or resume TNF-α antagonists without documented recurrence of histoplasmosis. Practitioners should be vigilant for histoplasmosis infections in this patient population who reside in histoplasma-endemic regions. Disclosures All authors: No reported disclosures.

Background and Objectives: The aim of the study was to determine the association between presences of fatty pancreas (FP) with the features of metabolic syndrome (MeS) in patients with non–alcoholic fatty liver disease (NAFLD) and to establish a new noninvasive scoring system for the prediction of FP in patients with NAFLD. Material and Methods: 143 patients with NAFLD were classified according to FP severity grade into the two groups and evaluated for diagnostic criteria of MeS. All patients underwent sonographic examination with adiposity measurements and the liver biopsy. Liver fibrosis was evaluated semi-quantitatively according to the METAVIR scoring system and using non-invasive markers of hepatic fibrosis. Results: Waist circumference (WC) was predictive for increased risk of FP in NAFLD patients. Elevated fasting plasma glucose, total cholesterol, serum amylase and lipase levels were associated with presence of severe FP (p value = 0.052, p value = 0.007, p value = 0.014; p value = 0.024, respectively). Presence of increased amounts of mesenteric fat was associated with severe FP (p value = 0.013). The results of this study demonstrated highly significant association between NAFLD and presence of FP. The model for predicting the presence of FP was designed with probability value above 6.5. Conclusion: Pancreatic fat accumulation leads to worsening of pancreatic function which in turns exacerbates severity of metabolic syndrome associated with both, NAFLD and NAFPD.

Abstract Background: The myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) can be characterized by heterogeneous symptoms, disease features, and prognosis. Timely monitoring of blood counts and if needed, referral for discussion of stem cell transplant (SCT), are critical to optimizing survival and quality of life. In connection with the MPN SCT Transplantation Timing Taskforce's (MS3T's) work in developing the DIPPS-based Stem Cell Spectrum Timing Tool, the survey was deployed to explore factors contributing to delayed entry to SCT. National Comprehensive Cancer Network (NCCN) guidelines for MPNs strongly recommend referral to specialized centers with expertise in the management of MPNs (Mesa et. al. 2017). To date, efforts to assess the timing and quality of MPN patient care from the patient's perspective have been minimal. Methods: Patients were recruited from MPN-related Facebook pages, subscribers of MPNforum Magazine and E-mail support groups including the MPN-NET, MPDchat, and the MPN Research Foundation. Hematologists, MPN patients, and advocates constructed the 11-item survey questions and content. The survey was available for patient response between July 4-11th2018. Patients were queried on MPN type, time of diagnosis, and details regarding knowledge of their MPN disease features and care. Data: Demographics.Overall 2382 MPN patients responded to the online survey. Of these, 901 (38%) patients had ET, 865 (36%) had PV, 561 (24%) had MF, 41 (2%) had MPN-unclassifiable or MPN/MDS overlap and 15 (1%) did not respond. Among MF patients, 56% reported having primary MF, 42% secondary MF, 1% prefibrotic MF, and 1% reported having already undergone SCT (1% did not specify type of MF or transplant). The majority of patients were diagnosed with their MPN by a hematology/oncology (77.8%) or family practice (15 %) physician. MPN Care provider and monitoring: Out of all respondents, 35% reported being cared for by an MPN specialist, 36% were not cared for by an MPN specialist and 27% were unsure if their provider was an MPN specialist. Overall less than half (42%) of patients reported having sought a second opinion from an MPN specialist. The majority (87%) of participants knew their mutational status relating to the highly publicized and widely tested JAK2 V617F mutation (73.8%) and CALR (10.2%). However, a statistically insignificant number of patients had any idea of other driving and secondary mutations including MPL, EZH2, SRSF2, IDH1/2 or ASLX-1. Blood counts were reviewed by a hematologist for the majority of patients (93% responded "yes", 4% responded "sometimes", 3% responded "no"). SCT Referral: Among ET and PV, <1% of patients reported being referred to SCT. For MF, 34% of participants reported having been referred for SCT discussion (30% for primary MF and 28% for secondary MF). Conclusions: MPN patients often report receiving care outside of the care of an MPN specialist. Additionally, despite the poor outcomes and higher likelihood of progression to AML, less than a third of patients with secondary MF report being referred for SCT discussion. Independent validation of patient responses, particularly in regards to MPN specialized care and timing of transplant discussion should be investigated further. However, these patient responses suggest many patients may be receiving less than optimal MPN care. These results demonstrate the importance of community hematology/oncology physician and patient education regarding optimal MPN care. Disclosures Mesa: UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Palmer:Novartis: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Scherber:Gilead: Honoraria.

Abstract Background: Patients (pts) with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from difficult MPN associated symptoms which impact quality of life (QoL). The impact of initial cytoreduction on ET/PV symptoms, resulting toxicity and QoL have not been prospectively studied. Methods: MPD-RC 112 trial (NCT01258856) randomized 168 therapy-naive (hydroxyurea [HU] <3 mo) high risk ET/PV pts (<5 years of disease) to response adjusted pegylated interferon alpha 2a (PEG) or HU. MPN symptoms, in depth toxicity assessment, and QoL were measured by two symptom instruments (MPN-SAF, EORTC QLQ-C30: baseline,3, 6, 9, and 12 mo) and toxicity questions. Blinded response review by European Leukemia Net (ELN) hematological responses (HR) was conducted at 12 months. Individual time point and longitudinal group comparisons were based on mixed models adjusting for age. Results: Patients: Of 168 randomized pts (86 HU, 82 PEG), 164 (98%) completed the survey package at baseline and 151 (HU 83%; PEG 98%) completed at least 1 survey during treatment. Median age was 61 (range 18-87) with 70 (42%) females; 81 (48%) / 87 (52%) with ET / PV; 46 (27%) had a history of a thrombosis. 119 (71%) received prior HU (up to 3 months). Baseline characteristics were balanced between arms with the exception of age (median HU 63 vs. PEG 60 yrs; p=0.02). Baseline Symptom Burden /QoL: Mean MPN-SAF Total Symptom Score (TSS), scale 0 [absent]-100 [worst imaginable] was 15.8 (SD 12.6; range 0-62.0) with means of 15.1 (SD 12.6) / 16.5 (SD 12.6) for ET / PV which were slightly lower than reported means of a previous cohort receiving any line of treatment (Scherber RM, JCO 2012). Median number of moderate (defined as score >=3) symptoms in ET patients was 3.0 and PV 4.0. Most common moderate symptoms were fatigue (65.9%), insomnia (37.2%), numbness (33.5%) , itching (29.9%), dizziness (27.4%), early satiety (26.8%) , headache (23.2%), sad mood (23.2%), inactivity (22%), concentration (20.7%). 50.6% of patients had one or more symptom with a score >=6. Mean QLQ-C30 global health status/QoL (GHS/QoL) was 70.8 (SD 21.9) - comparable to a general population (mean 71.2, SD 22.4) and better than a general cancer population (mean 61.3, SD 24.2; QLQ-C30 Reference Manual 2008). At baseline, TSS, symptoms, and QoL were similar between treatment arms. In patients with TSS >20 at baseline (highly symptomatic, n=50; ET:20, PV:30), median TSS was 28.0 (range 20.0 to 62.0); the highest scored symptom was fatigue (median=7.0), itching (median=4.5) and insomnia (median=4.0). Impact of Therapy on Symptom Burden/QoL: On HU, pts experienced worsening QoL (physical, cognitive functioning, HRQoL) and some persistent or transient worsened symptoms (inactivity, concentration (p<0.05) (Table 1)). On PEG, pts experienced worsening of fever, dyspnea, appetite loss and PEG-related symptoms including flu-like symptoms, injection site irritation, blurry vision, and visual changes (all p<0.05), but not sad mood (not corrected for antidepressants). In comparing arms, change in TSS significantly differed (p=0.01) between arms with increasing symptoms on HU vs PEG at 3 and 6 mo, but lower symptom burden at 9 and 12 mos (Figure 1). In highly symptomatic pts (with a baseline TSS > 20, n=50), improvements in weight loss, abdominal discomfort, fatigue, itching, fever, early satiety (12 m.) were observed in pts on HU. For PEG, in highly symptomatic pts, improvements were observed for overall TSS score, fatigue, inactivity, night sweats, and itching (with similar toxicities to all PEG patients). ELN Response and Symptom Burden/QoL: Among the 133 pts with 12-mo symptom data, complete hematologic response (CHR) rate was 43%. Inactivity and sad mood were worse in those patient achieving a CHR (inactivity: CHR worsening 0.68 vs PHR/NR better 0.26; p=0.03; sad mood: CHR worsening 0.67 vs PHR/NR better 0.67, p=0.002)). These latter changes were not related to higher doses utilized (in either arm), suggesting obtaining CHR may have negative effects on patient symptoms. Conclusions:In pts with a significant baseline MPN symptom burden, cytoreductive therapy has both a beneficial impact on baseline MPN symptom burden but also leads to therapy associated toxicity, although different patterns of efficacy and toxicity between HU and PEG. Achievement of a CHR in PV/ET may be associated with higher rates of drug related toxicities, and the value of achieving CHR may need further validation. Disclosures Mesa: Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Genentech: Research Funding; Pfizer: Research Funding. Mascarenhas:Merck: Research Funding; CTI Biopharma: 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; Roche: Research Funding; Promedior: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Research Funding. Rambaldi:Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Amgen Inc.: Consultancy. Yacoub:Novartis: Honoraria, Speakers Bureau; Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Harrison:Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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. Mead:Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy. Kessler:Sangamo: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Biomarin: Research Funding. Kremyanskaya:Incyte: Research Funding. Rampal:Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Stemline: Research Funding; Celgene: Honoraria. Hoffman:Incyte: Research Funding; Janssen: Research Funding; Merus: Research Funding; Formation Biologics: Research Funding; Summer Road: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment.

Abstract We describe the features of 24 cases of atypical CD5+ small B-cell leukaemia unclassifiable by current methods. The male/female ratio was 3 (18M/6F), with a median age at diagnosis of 58 years (range 39–84 years). All cases were CD5 positive, but with an immunophenotype and morphology atypical for CLL. All cases were negative for t(11;14) and other B cell malignancies were excluded. FISH analysis was carried out using probes for IGH break apart, t(14;19) involving BCL3, trisomy 12, 13q14, 11q22–23 (ATM) and 17p13 (p53 locus). IgVH somatic mutations were analysed using direct sequencing (2% cut off). FISH using IgH break apart probe showed 8 (32%) cases with a split at 14q32. These 8 cases were further investigated using a FISH probe for t(14;19). Four cases (16%) exhibited t(14;19) ie. showed the IgH/BCL3 rearrangement in >70% of cells. Further characterisation of the 24 cases, at additional loci showed that 4 (16%) patients had 17p deletion, 3 (12%) 11q deletion, 3 (12%) 13q deletion, and 14 cases (56%) trisomy 12. The 8 cases showing a split IgH signal did not show deletions of 17p, 11q, or 13q but trisomy 12 was present in 7/8 (88%) patients. Sixteen out of 24 (67%) cases had unmutated IgVH genes with VH3 and VH4 families being used in 91% (22/24). Interestingly, unlike in chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL), the VH1 family was not used in this group of patients. All 4 cases with t(14;19) showed unmutated IgVH genes. Of the sixteen patients without involvement of 14q32, only 2 patients have died with a median follow up of 5.5 years. Of the 4 cases with the t(14;19) (IgH/BCL3 rearrangement), 3 required treatment within 2.5 years of diagnosis and two out of four patients died 5 years after diagnosis, following Richter’s transformation suggesting that this rearrangement is a poor prognostic factor and defines a group with a distinct clinical outcome. Our findings show a high frequency of 14q abnormalities in atypical CD5+ small B-cell leukaemia. BCL3 rearrangement is seen in a significant subset of these cases. The BCL3 gene encodes a nuclear protein that belongs to the IkB family of inhibitors of NFkB. It is involved in the regulation of a variety of transcription factors and it is able to stimulate the expression of cyclin D1. The dysregulation of BCL3 via its juxtaposition to the regulatory element of the IgH locus in our cases suggests a pathogenic role for BCL3 in these B cell disorders and may define a group of patients with a more aggressive clinical course. Further, we have examined these cases for signatures, defined in myeloma, characteristic of NFkB deregulation. We suggest that in cases of CD5 positive B-cell disorders with an immunophenotype and morphology atypical for CLL, and negative for t(11;14), rearrangements involving the IgH locus are frequent and have allowed us to identify cases with poor prognosis and with a pathogenesis that involves deregulation of NFkB.

Abstract Background Thrombotic microangiopathy (TMA) is a clinicopathologic diagnosis that can be characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and end-organ damage. Though most patients will present with the hematologic abnormalities of MAHA and thrombocytopenia, there are some that never demonstrate those features and only present with acute renal injury. Here we describe the clinical presentation, laboratory assessment, management, and outcomes of patients with renal-limited TMA (rTMA). Methods After IRB approval, the electronic medical record was searched from 2008-March 2017 for patients managed at our institution with a clinical diagnosis of rTMA supported by renal biopsy. Inclusion criteria were as follows: 1) Presence of TMA on renal biopsy, 2) Absence of MAHA 3) No history of renal transplant prior to diagnosis of TMA. Clinical notes were reviewed to document the physician-determined cause of TMA. If no cause was listed, cause of TMA was based off of labs and clinical observation. Results Thirty-five patients (18 female) met clinical criteria for a diagnosis of rTMA. Median age at time of biopsy was 59 years (range 9 to 87). Creatinine at time of biopsy was 2.4 mg/dL (range 0.55 to 6.4). Evidence of chronic TMA was noted on 17 specimens and an additional 3 had findings of chronic and acute TMA. Ten patients had ADAMTS13 activity performed and all were >10% with negative inhibitor screen (median 66%(26-100)). 24 patients (68.6%) had complement serology assessed. Three patients (12.5%) had low C3 while C4 was normal in 19 patients (79%). One patient in our cohort had complement mutational testing performed with no evidence of a pathogenic variant. Most common etiology of rTMA was medications (28.5%) and underlying rheumatologic disorder (20%)(Table 1). In 6 patients (17%), an identifiable cause was not elucidated. Management of TMA was dependent on underlying etiology of rTMA. Discontinuation or dose adjustment of TMA-causative medications was recommended in 4 patients and 25% of patients had normalization of Cr. Four patients received therapeutic plasma exchange (TPE) for median 5 (2-5) days. Causes of rTMA for those receiving TPE were gemcitabine, bevacizumab, unspecified connective tissue disease, and rTMA due to an unknown cause. 50% of patients were noted to have improvement in Cr with TPE. Antihypertensive medications were used for rTMA secondary to uncontrolled hypertension (n=4) and scleroderma (n=4). 11 patients (31%) were observed or treatment for causative underlying etiology was pursued, while 7 patients were treated with glucocorticoids. Of 6 patients, with no identifiable underlying cause, 4 were treated with observation, 1 was treated with GC, and one was treated with TPE Fourteen patients (38.9%) required dialysis; 6 of these patients were able to discontinue dialysis less than two months after initiation. Three patients (8.3%) with rTMA, respectively due to tacrolimus toxicity, longstanding hypertension, and systemic lupus erythematosus, received a renal transplant, and one additional pt (2.8%) with rTMA due to scleroderma remained on the renal transplant waiting list at time of death. In a median follow-up time of 8.73 months (range 0 to 47.9), 16 patients (44.4%) died. Median time from diagnosis of TMA to death was 12.1 months (range 1.47 to 58.2). No deaths were directly attributable to underlying TMA. Conclusion Renal-limited TMA is a pathologic diagnosis that in our cohort was most likely to medications or underlying rheumatologic conditions. rTMA was managed by treating the underlying disorder or removing the causative medication. Though cause of rTMA was evident in the majority of patients, 17% had no identifiable precipitating factor predisposing to rTMA. Larger studies are required to delineate optimal management and surveillance strategies for these patients. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction HU is the treatment of choice for patients (pts) with high risk ET/PV, however, PEG has been proposed as an alternative option due to its proposed potential to modify disease course. An interim analysis of MPN-RC 112 (Blood 2016 128:479;) did not reveal a difference in PR/CR rates between HU and PEG therapy after 12 months in the first evaluable 75 pts treated. Here we present the results and long-term follow-up of all pts participating in this pivotal study [NCT01259856]. Methods MPN-RC 112 was a randomized, open label, phase 3 clinical trial comparing HU and PEG in pts with high risk ET/PV. Pts were treated for up to 12 months to achieve PR or CR (ELN/IWG-MRT response criteria). Pts who achieved a PR/CR continued therapy for up to a maximum of 6 years. Minimum follow up was 1 year from the time the last pt was randomized. The primary objective was to compare the CR rate following HU vs. PEG at 12 months with 3 month confirmation. Secondary objectives included a comparison of toxicity and tolerability; PR rates; incidence of specific pre-defined toxicities and tolerance to therapy; impact of therapy on key biomarkers; survival and incidence of myelodysplastic syndrome, myelofibrosis, or leukemic transformation; and incidence of major cardiovascular events. Bone marrow pathologic responses were evaluated by central blinded expert review at baseline, 12, 24 months and end of study. Results The study accrued 168 pts; 86 were randomized to HU and 82 to PEG. A summary of pt baseline characteristics by treatment arm is shown in Table 1 and were well balanced between the treatment arms except for median age which was higher in the HU arm (p=0.02). Median duration of follow up was 89.9 weeks (range, 0 to 292.3) and the median treatment duration was 86.0 weeks (range, 0 to 287.3). At 12 months, the overall response rate (ORR= PR+CR) was 69.8% and 78% for HU and PEG, respectively (p=0.22). Figure 1 shows the distribution of responses stratified by disease type. At 24 months, 59 pts were on treatment with an ORR of 22/25 (88%) for HU and 31/34 (91%) for PEG. When considering all 106 pts who were eligible to receive treatment for 24 months (due to study closure), the ORR was 22/54 (40.7%, PR: 11 (20.4%), CR: 11 (20.4%)) for HU and 31/52 (59.6%, (PR: 15 (28.9%), CR: 16 (30.8%)) for PEG, p=0.04. Best ORR at any time on study was seen in 70.9% and 81.7% of HU and PEG treated pts, respectively, p=0.10. The median maximum change from baseline spleen volume was -6% (-100.0 - +53.8) in 112 evaluable pts and was similar between arms, p=0.99. Bone marrow morphologic responses are shown in Table 2 and the best response (CR) seen at any time on study for ET treated with HU was 52% (12/23) vs PEG 32% (8/25) and for PV treated with HU 19% (6/31) vs PEG 6% (2/34). Cytogenetic analyses at diagnosis were available in 86% (144/168). An abnormal karyotype was seen in 15% (22/144). Five PV and one ET pt lost their chromosomal abnormalities: 3 after one year (HU=1, PEG=2) and three after two years of therapy (HU=2, PEG=1). AE information is available for 162 pts (HU: 80; PEG: 82) (Table 3). Six pts randomized to HU never received treatment due to study withdrawal prior to initiation of treatment. Sixty pts had a grade 3 or higher event [HU: 22 (27.5%) and PEG: 38 (46.3%)]. 28 PV pts had a grade 3/4 [HU: 10 (24.4%) and PEG: 18 (41.9%)]. Four pts had a grade 4/5 event [HU: 3 (7.3%) and PEG: 1 (2.3%)]. 32 ET pts had a grade 3/4 [HU:12 (30.8%) and PEG:20 (51.3%)]. Two pts had a grade 4/5 event [HU:1 (2.6%), PEG:1 (2.6%)]. Additional outcomes of interest on study include one death attributed to new diagnosis of lung cancer (HU:1), progression to myelofibrosis (HU:1), vertebral artery occlusion (HU:1), and cerebral vascular accident (PEG:1). Reasons for study discontinuation are shown in Table 4. The effect of therapy on symptom burden and quality of life will be presented in a companion abstract (Mesa et al). The impact of mutation status on therapeutic outcome as well as the molecular responses will be presented at the meeting. Conclusion The final analysis of MPN-RC 112 revealed that the CR rates in pts with high risk ET/PV treated with PEG and HU at 12 and 24 months were similar. PEG was associated with a higher rate of grade 3/4 toxicity. Each drug appeared equally capable of modifying the natural history of high risk ET/PV based upon their effects on spleen size, karyotypic abnormalities, histopathological parameters and the low incidence of thrombotic complications and disease evolution in both arms. Disclosures Mascarenhas: Novartis: Research Funding; Promedior: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Merck: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rambaldi:Amgen Inc.: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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. Mead:Bristol-Myers Squibb: Consultancy; Elstar: Research Funding; Celgene: Research Funding; ARIAD: Consultancy; Evotek: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Cell Therapeutics: Consultancy. Kessler:Genentech: Research Funding; Sangamo: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin: Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; DSMB: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees. Kremyanskaya:Incyte: Research Funding. Rampal:Stemline: Research Funding; Incyte: Honoraria, Research Funding; Constellation: Research Funding; Jazz: Consultancy, Honoraria; Celgene: Honoraria. Mesa:CTI Biopharma: Research Funding; Novartis: Consultancy; Genentech: Research Funding; Promedior: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding. Dueck:Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Hoffman:Incyte: Research Funding; Formation Biologics: Research Funding; Merus: Research Funding; Janssen: Research Funding; Summer Road: Research Funding.