Need For Red Cell Transfusion Research Articles

Intravenous iron administration before cardiac surgery reduces red blood cell transfusion in patients without anaemia

BackgroundReducing the need for blood transfusion among patients undergoing cardiac surgery FLA reduce postoperative complications and mortality. Our study aimed to assess the effects of administering preoperative i.v. ferric carboxymaltose on postoperative red cell transfusion requirements in patients without anaemia undergoing on-pump cardiac surgery. MethodsThis double-blind, randomised, placebo-controlled trial was conducted between October 2016 and November 2019, with a follow-up period of up to 6 weeks after surgery. Patients without anaemia who underwent on-pump cardiac surgery were included as participants and administered i.v. iron in the form of ferric carboxymaltose or placebo once, 24–72 h before surgery. The primary outcome was the number of red cell units transfused during the first four postoperative days, and the secondary outcome measures were blood haemoglobin concentrations at 4 days and 6 weeks after surgery. ResultsThe 200 patients included were randomly assigned to the ferric carboxymaltose (n=102) and placebo (n=98) groups. By postoperative Day 4, a significantly lower mean number of red cell units were transfused in the ferric carboxymaltose than in the placebo group, 0.3 (0.8) vs 1.6 (4.4), respectively; P=0.007. The mean haemoglobin concentrations on postoperative Day 4 were 9.7 (1) g dl−1 and 9.3 (1) g dl−1, respectively (P=0.03). Corresponding values at 6 weeks after surgery were 12.6 (1.4) g dl−1 and 11.8 (1.5) g dl−1, respectively (P=0.012). ConclusionsIn patients without anaemia undergoing on-pump cardiac surgery, treatment with a single dose of 1000 mg ferric carboxymaltose i.v. 1–3 days before surgery significantly reduced the need for red cell transfusions and increased the postoperative haemoglobin concentration. Clinical trial registrationNCT02939794.

Predictors of anemia response to momelotinib therapy in myelofibrosis and impact on survival.

We retrospectively reviewed 72 anemic patients with myelofibrosis (MF; median age 68 years), who were JAK2 inhibitor-naïve at the time of study entry to a phase-1/2 momelotinib clinical trial. Driver mutation profile included JAK2 69%, CALR 17%, MPL 8%, and triple-negative 6%; other mutations included ASXL1 39% and SRSF2 17%. Momelotinib was administered at a median dose of 300 mg daily. Anemia response was assessed by formal criteria and documented in 44% of all patients with hemoglobin levels below the sex-adjusted reference range (n =72), 48% of those with hemoglobin <10g/dl (n =54), and 46% of those who were transfusion-dependent at the time of study entry (n =28). Anemia response was more likely with post-essential thrombocythemia MF (83% vs 37%; p=.001), lower serum ferritin (p=.003), and shorter time from diagnosis to momelotinib therapy (p= .001); the first two variables were also predictive in transfusion-dependent patients. Post-momelotinib median survival was 3.2 years; in univariate analysis, survival was superior in anemia responders (median 3.8 vs. 2.8 years; p=.14) and in the presence of type 1/like CALR mutation and inferior in the presence of age > 65 years, ASXL1/SRSF2 mutation, unfavorable karyotype, DIPSS-plus high risk, red cell transfusion need and higher serum ferritin. Multivariable analysis confirmed the favorable impact of anemia response on survival (p=.02; HR 0.5, 3/5/10-year survival; 69%/38%/25%). This survival advantage was also noted in transfusion-dependent patients (3.7 vs. 1.9 years; p=.01; HR 0.3) and appeared to be restricted to patients with an unfavorable genetic profile. The current study suggests a short-term survival benefit associated with anemia response in momelotinib-treated patients with MF.

Nutritional Supplements, Ginseng and Leucine, Increase Erythropoiesis in Diamond Blackfan Anemia Models through Inhibition of Nemo-like Kinase

Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome that is typically associated with mutations in one of at least 20 ribosomal genes and is associated with anemia, congenital abnormalities, and cancer predisposition. The current treatment for DBA is associated with toxicities including iron overload from repeated transfusions, immune suppression from chronic corticosteroid therapy or consequences from stem cell transplantation. Developing new therapies for DBA remains a challenge, since it is a rare disease and the connection between faulty ribosomes and defects in erythropoiesis is still being explored. As such, repurposing existing, approved drugs is one approach to find new ways to treat this disease.We recently identified that Nemo-like Kinase (NLK) is hyper-activated and contributes to disease pathogenesis in the erythroid progenitors of patients with DBA, irrespective of the genetic mutation. NLK is an atypical member of the MAPK family of kinases. Due to a high degree of conservation, kinase inhibitors that specifically target NLK are not currently available, although several small molecules inhibit NLK as an off-target. We are actively pursuing a number of these compounds as potential therapies for DBA. In addition to known kinase inhibitors, we have examined the active components of widely available nutritional supplements. Although rigorous clinical evaluation is required, these supplements are well tolerated and offer an alternative or a complement to conventional drug therapy for DBA.Ginsenoside Rb1, an active component of ginseng, increases erythropoiesis in in vitro models of DBA (2.6-fold) at 50mM (p=0.048) with an EC 50 of 2.3mM. Importantly, ginsenoside Rb1 does not impact healthy erythropoiesis or other hematopoietic lineages and is nontoxic to normal cells. Our results demonstrate that ginsenoside Rb1 does not inhibit NLK kinase activity directly, but rather induces a microRNA (miR-208) that binds to NLK mRNA leading to degradation of transcript by 35.9% (p=0.007) before the protein can be translated.Another nutritional supplement that has been indicated to improve erythropoiesis (in DBA and non-diseased models) and is currently in clinical trials is the amino acid leucine. In DBA progenitors, 5mM leucine increases erythropoiesis from 8.8 to 16.3% of healthy controls. Leucine acts by stimulating the activity of mTORC1 but similar to erythropoiesis, mTORC1 activity is only stimulated from 26.4 to 57.2% of controls in DBA progenitors.Our results demonstrate that leucine does not impact NLK expression or activity directly. Aberrantly activated NLK phosphorylates and inhibits the activation of mTORC1 (target of leucine). The suppression of NLK by 50mM ginsenoside Rb1 restored mTORC1 activity to basal (94.7% of non-diseased control) but also restored leucine sensitivity (from 57.2 to 88.1% of non-diseased controls). Importantly, combining 5mM leucine and 50mM ginsenoside Rb1 increased erythropoiesis from 1.9-fold and 2.6-fold when used alone, to 8.9-fold (or 78.3% of healthy controls) together in our in vitro models of DBA (CI=0.31).Ginseng and leucine offer promising alternatives to steroids and other immunosuppressive drugs for DBA patients. The goal of these studies is to raise the hemoglobin in DBA patients to avoid the need for red cell transfusions. As nutritional supplements are widely available and well tolerated, this class of compounds provides alternatives to currently approved drugs to treat DBA. DisclosuresGlader: Agios: Consultancy.

Validation of the Who-Defined 20% Circulating Blasts Threshold for Diagnosis of Acute Leukemia in Myelofibrosis: A Single Center Study of 144 Patients with Blast or Chronic Phase Disease with Excess Blasts

Background:The World Health Organization (WHO)-defined criteria for acute myeloid leukemia (AML), including blast phase myeloproliferative neoplasms (MPN-BP), includes the presence of ≥20% blasts in the peripheral blood (PB), regardless of blast content in the bone marrow (BM) (Blood 2016;127:2391) . It is currently unclear if this 20% threshold is valid for primary myelofibrosis (PMF), in terms of distinguishing PB-defined MPN-BP from either chronic phase disease with excess blasts (PMF-EB; defined by the presence of 5-19% circulating blasts) or BM-defined MPN-BP.Methods:Diagnoses of MPN, including PMF and MPN-BP, were according to WHO criteria (Blood 2016;127:2391). The study population included chronic phase PMF patients with 5-19% circulating blasts (PMF-EB) and MPN patients with blast phase disease (MPN-BP), defined by the presence of ≥20% blasts in PB only (PB-defined MPN-BP) or BM (BM-defined MPN-BP). Statistical analyses for PMF-EB considered clinical and laboratory data collected at the time of documented PB blast count of ≥5% and for MPN-BP, date of leukemic transformation. Phenotypic and prognostic comparisons considered four distinct categories: i) chronic phase disease with 5-9% circulating blasts (PMF-EB-1), ii) chronic phase disease with 10-19% circulating blasts (PMF-EB-2), iii) MPN-BP defined by ≥20% BM blasts (BM-defined) and iv) MPN-BP defined by ≥20% blasts in PB only (PB-defined).Results:The total number of study patients was144 and included 41 patients with PMF-EB and 103 with MPN-BP; the 41 patients with PMF-EB included 28 with PMF-EB-1 (median age 69 years; 61% males) and 13 with PMF-EB-2 (median age 64 years; 54% males); the 103 patients with MPN-BP included 71 BM-defined (median age 68 years; 69% males) and 32 PB-defined (median age 66 years; 72% males) MPN-BP (p=0.6 for age and 0.6 for gender distribution). The four operational groups were also similar in their need for red cell transfusions (p=0.4), hemoglobin level (p=0.9), leukocyte count (p=0.9) and driver mutational status (p=0.3), including incidence of type 1/like CALR mutations (11% for PMF-EB-1 vs 15% for PMF-EB-2 vs 17% for PB-defined MPN-BP vs 19% for BM-defined MPN-BP). Significant differences were noted for platelet count (lower for both PB and BM defined MPN-BP; p=0.004) and incidence of abnormal karyotype (p=0.02) and unfavorable karyotype (22% for PMF-EB-1, 62% PMF-EB-2, 61% PB-defined MPN-BP and 49% BM-defined MPN-BP; p=0.03). Survival data showed significant difference in favor of PMF-EB, compared to both BM- and PB-defined MPN-BP, while they were similar for PMF-EB-1 vs PMF-EB-2 and for PB- vs BM-defined MPN-BP (Figure 1).Conclusions:The observations from the current study support the prognostic validity of current WHO criteria in distinguishing chronic phase PMF with excess blasts (PMF-EB) from PB-defined MPN-BP. The current study also confirms the validity of using circulating blast percentage to define MPN-BP, regardless of BM blast percentage. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Estimation of risk for major bleeding in native kidney biopsies in patients with multiple risk factors.

Individuals undergoing kidney biopsy are increasingly older and may have concurrent illnesses that cause deranged hematological and renal parameters that are associated with post-biopsy bleeding. We aimed to develop a clinical risk model to quantify bleeding risks in high-risk individuals with multiple risk factors. Single-center retrospective cohort study of consecutive adults with serum creatinine ≥ 2mg/dL (176µmol/L) and had ultrasound-guided percutaneous native kidney biopsies between June 2011 and July 2015 in our tertiary referral center. The primary outcome was major bleeding, defined as need for red cell transfusion, radiological or surgical intervention, or if bleeding led to death within 7days after kidney biopsy. Among 184 native kidney biopsies with serum creatinine ≥ 2mg/dL, median age was 54.1years and eGFR was 18.8ml/min/1.73 m2. Major bleeding occurred in 19 biopsies (10.3%). Multivariate analysis accounting for age, weight, hemoglobin, platelet, prothrombin time and urea found that higher hemoglobin (adjusted OR 0.51, 95% CI 0.33-0.79, p = 0.003) and platelet (adjusted OR 0.99, 95% CI 0.98-0.99, p = 0.01) were independently associated with reduced major bleeding. A risk model that included (1) age ≥ 62years old, (2) hemoglobin < 10g/dL and (3) platelets ≤ 216 × 109/L as categorical variables predicted major bleeding post-biopsy. We developed a risk model that included multiple risk factors to quantify bleeding risks in native kidney biopsies with renal impairment.

Molecular response to imatinib in patients with chronic myeloid leukemia in Tanzania

Imatinib is the mainstay of treatment of patients with chronic myeloid leukemia (CML) in Tanzania. Monitoring molecular response to therapy by real-time polymerase chain reaction at defined milestones is necessary for early detection of treatment failure. However, this assay is not routinely performed in Tanzania; therefore, the depth of molecular response among patients with CML is not known. A total of 158 patients with previously diagnosed CML who received imatinib treatment were recruited from January 2019 and followed up through October 2020 at Ocean Road Cancer Institute. Information was obtained at the time of diagnosis and follow-up. Blood samples were collected in EDTA tubes to measure the BCR/ABL ratio on the Gene Xpert system for molecular response determination. The median age of the 158 adult patients was 45 years (range, 18-86). By reference to established treatment milestones, only 37 (23.4%) achieved optimal molecular response. Signs of advanced-stage disease, in particular the need for red cell transfusions before diagnosis (adjusted odds ratio [AOR], 3.4; 95% CI, 1.32-9.17) and cytopenias (AOR, 2.26; 95% CI, 1.03-4.96) necessitating drug interruptions were statistically validated predictors of treatment failure on multivariate, multinomial logistic regression. Patient survival at the 22-month follow-up was lowest, with 78.6% (95% CI, 69.4-85.4) in the failure-to-respond category and highest in patients achieving optimal response 97.0% (95% CI, 80.9-99.6). In summary, the majority of patients with CML treated with imatinib in Tanzania do not obtain deep molecular response. This outcome can be attributed to late diagnosis, the development of cytopenias requiring multiple drug interruptions, and poor adherence to treatment.

The bleeding risk after endoscopic ultrasound-guided puncture of pancreatic masses

Background Although EUS-fine-needle aspiration (FNA) is considered to be safe, there are limited studies on adverse events of fine-needle biopsy (FNB). Aim To compare the bleeding rate of EUS-FNA and EUS-FNB of solid and cystic pancreatic masses. Methods Our retrospective study included EUS-FNA/FNB of solid and cystic pancreatic masses performed between 02/2017–03/2019 in Klinikum Klagenfurt and 11/2018–03/2019 in University Hospital St. Pölten, Austria. Minor bleeding was defined as an event with a duration of more than 1 min, no need for intervention, large coagulum on the puncture site, or decrease in hemoglobin ≥1.5 g/dL (but <2 g/dL). Major bleeding was defined as a reduction in hemoglobin level ≥2 g/dL, need for red cell transfusions, or interventional hemostasis. Results About 202 patients were biopsied in that period (141 solid, 61cystic pancreatic masses). FNA needle was used in 54.6% of cases with solid pancreatic masses and 73.7% of cysts. Bleeding with hemodynamic instability was not observed in our cohort. In pancreatic cysts, minor bleeding was observed in 8.2% of cases and was associated with the use of FNB needles and lower platelet count. In solid tumors, one major bleeding (0.7%) from a duodenal vessel occurred and was immediately treated with hemoclip. In this group, minor bleeding was observed in 15.6% of cases. Overall, the bleeding rate correlates with the use of FNB needles. Conclusion Use of EUS-FNB needles increases the rate of minor bleeding for both solid and cystic pancreatic tumors, while major bleeding is a rare occurrence, irrespective of the needle type.

Monoclonal Gammopathy with Secondary Atypical Hemolytic-Uremic Syndrome

Monoclonal gammopathy is a clonal plasma cell disorder associated with an increased risk of progression to lymphoproliferative malignancy. In children, monoclonal and oligoclonal gammopathies are rare, and their clinical relevance unrecognized. Atypical hemolytic uremic syndrome (aHUS) is a rare endotheliopathy associated with dysregulated activation of complement, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. We present a case of aHUS that we hypothesize was triggered by monoclonal gammopathy in a child several years after cardiac transplantation. An 11 year old African-American girl with sickle trait was transferred to our cardiac center with a two week history of epigastic pain, emesis, microcytic anemia, hypergammaglobulinemia, and development of renal failure requiring dialysis. She had undergone cardiac transplantation at 7 months of age for dilated cardiomyopathy of unknown etiology and had recovered from acute cardiac rejection requiring ECMO at age 5 years. She had previously experienced at least two episodes of acute kidney injury requiring dialysis with full recovery of function reported. Renal biopsy revealed a severe collapsing glomerulopathy and a thrombotic microangiopathy. Upon transfer to our institution, her labs were notable for microcytic anemia, normal platelet count, haptoglobin, and LDH. A week later, she developed aHUS diagnosed by hemoglobin 9.5 gm/dL, haptoglobin &lt; 30 mg/dL, LDH 314 U/L, platelets 100,000, and a predominance of schistocytes on peripheral blood smear in the setting of acute renal failure. Serum protein electrophoresis (SPEP) revealed a monoclonal spike (1g/dL), identified as IgG kappa by immunoabsorption. A second, smaller monoclonal spike was identified as IgA lambda. aHUS evaluation revealed low C3, normal C4, and 50% CD46 expression by flow cytometry. Bone marrow biopsy with flow cytometry excluded lymphoproliferative disorders. EBV did not amplify with quantitative PCR of peripheral blood, and computed tomography imaging of the body did not detect abnormal mass or lymph nodes. A trial of plasmapheresis did not improve biochemical and hematologic features of aHUS. A trial of eculizumab resulted led to normalization of platelet count and C3, increased haptoglobin, reduced need for red cell transfusion, and less frequent dialysis. Monoclonal gammopathy of unknown significance (MGUS) is rare in children, but may be more common in transplant recipients, especially after cardiac transplants in infants when thymectomy is performed. MGUS associated with secondary aHUS has been rarely reported in adults. The mechanism for aHUS was demonstrated in one case to result from affinity of the paraprotein to a binding site on complement factor H, with subsequent loss of factor H cofactor activity to inhibit alternative complement activation. We hypothesize that immune dysregulation from fluctuating levels of paraproteins during inflammation in our patient with monoclonal gammopathy resulted in recurrent, intermittent episodes of aHUS. We speculate that this was responsible for the patient's collapsing glomerulopathy and dialysis-dependent chronic renal failure. This case highlights the importance of considering monoclonal gammopathy in pediatric patients who develop recurrent kidney failure or atypical hemolytic uremic syndrome in the setting of immune dysregulation. The merit of treating the monoclonal gammopathy with Bortezumib and Rituximab is currently under consideration. Disclosures No relevant conflicts of interest to declare.

Systemic Bevacizumab for the Treatment of Chronic Bleeding in Hereditary Hemorrhagic Telangiectasia

▪Introduction: Hereditary hemorrhagic telangiectasia (HHT) is a rare hereditary multisystem vascular disorder causing visceral arteriovenous malformations (AVMs) and mucocutaneous bleeding. Chronic gastrointestinal bleeding and epistaxis frequently produce profound iron deficiency anemia refractory to conventional treatment. Patients with HHT have elevations in vascular endothelial growth factor (VEGF), so the anti-VEGF agent bevacizumab, a recombinant, humanized monoclonal IgG1 antibody that binds to and neutralizes circulating VEGF, is a promising systemic HHT therapy. Currently, data pertaining to the efficacy of bevacizumab for the treatment of HHT is limited to case reports and retrospective studies that do not describe the effect of bevacizumab on objective hematologic parameters (Guilhem et al 2017, Iyer et al 2018). As our institution is an HHT center that has developed a pathway for the use of bevacizumab in HHT patients, we performed a retrospective analysis assessing the efficacy of bevacizumab to alleviate chronic bleeding as measured by improvement in hemoglobin concentration, need for red cell transfusions and iron infusions, and epistaxis control. Management of bleeding in HHT patients is an off-label use of bevacizumab.Methods: All HHT patients treated with systemic bevacizumab for chronic bleeding were selected for retrospective analysis. Data was collected for each patient over a 14-month course, divided into a pretreatment period (six months), induction period (two months), and maintenance period (six months) and included demographics, baseline HHT characteristics, epistaxis grade, surgical interventions, bevacizumab dosing, adverse events, hemoglobin, red cell transfusions, intravenous iron infusions, and other anemia and/or bleeding-directed therapies. Additionally, the peak hemoglobin on bevacizumab over the course of all available follow-up was collected for each patient. Our institution's bevacizumab treatment pathway began with an induction phase (5 mg/kg of IV bevacizumab every two weeks for four treatments) followed by a maintenance phase (5 mg/kg administered monthly thereafter). Statistical tests used in data analysis included the paired t-test, Wilcoxon signed rank test, and Fisher's exact test.Results: 13 HHT patients were treated with bevacizumab for chronic bleeding for a median of 13.9 (range, 4.9-30.1) months. Baseline patient characteristics are shown in Table 1 and hematologic parameters during the pretreatment, induction, and maintenance periods are shown in Table 2. Compared with pretreatment values, bevacizumab treatment increased the mean hemoglobin by 4.0 g/dL (95% CI, 2.6-5.3 g/dL) [mean (95% CI) hemoglobin 8.5 (7.8, 9.9) g/dL versus 12.5 (11.2, 13.7) g/dL, p<0.001)], reduced red cell units transfused by 92% [median of 6 (range, 0-59) units versus 0 (range, 0-15) units, p=0.004], and reduced quantity of iron infused by 73% [mean (95% CI) 462 (257, 668) mg/month versus 126 (75, 178) mg/month, p=0.002]. The peak hemoglobin value measured over the course of all available follow up ranged from 12.1-17.6 mg/dL (Figure 1), with all but two patients (85%) achieving a hemoglobin within the normal range for gender. Twelve of 13 patients did not require red cell transfusions during the entire maintenance period and 11 of 13 patients did not require iron infusions during the latter half of the maintenance period (Figure 2). Epistaxis control (reduction of epistaxis grade to <2) was achieved in 85% with bevacizumab, versus 0% before treatment (p<0.001) and all but one patient experienced improvement in epistaxis grade. No patient required nasal or GI procedures during the maintenance period. Four out of 5 patients receiving antifibrinolytic agents or erythropoiesis-stimulating agents prior to initiation of bevacizumab were able to discontinue these agents during bevacizumab induction and not resume them thereafter. Bevacizumab was well-tolerated, with two patients (15%) developing grade 3 hypertension requiring medical management.Conclusions: Systemic bevacizumab was highly effective to treat chronic bleeding and iron deficiency anemia in HHT. This study is the first to demonstrate the impact of bevacizumab on objective hematologic parameters, such as hemoglobin and iron infusion requirements. Further study is needed to confirm the benefit magnitude and define optimal dosing, treatment duration, and long-term safety. DisclosuresAl-Samkari:Agios: Consultancy. Kuter:Protalex: Research Funding; Rigel: Consultancy, Research Funding; Novartis: Consultancy; Amgen Inc.: Consultancy; Argenx: Consultancy; Bioverativ: Consultancy, Research Funding; BMS: Research Funding; Syntimmune: Consultancy; Pfizer: Consultancy; Dova Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia: Research Funding; ONO: Consultancy.

Risk factors and a prognostic model for postsplenectomy survival in myelofibrosis.

Palliative treatment in myelofibrosis (MF) includes transfusion support, JAK2 inhibitors, involved field radiotherapy and splenectomy. To assist in selecting patients who are likely to benefit from splenectomy, we looked into risk factors for postsplenectomy survival, in 120 consecutive cases (median age 66 years); at the time of splenectomy, 61% displayed red cell transfusion need, 49% platelet count <100 × 10(9)/L, 25% leukocyte count >25 × 10(9)/L, 60% constitutional symptoms and 13% circulating blasts ≥5%; dynamic international prognostic scoring system risk categories were 21% high, 55% intermediate-2, 21% intermediate-1 and 3% low. Among informative cases, karyotype was abnormal in 60% and driver mutational status was JAK2 75%, CALR 15%, MPL 4% and triple-negative 6%. At median follow-up of 1.3 years, from time of splenectomy, 95 (79%) deaths and 30 (25%) leukemic transformations were recorded. Median postsplenectomy survival was 1.5 years; in multivariable analysis, survival was adversely affected by age >65 years, transfusion need, leukocyte count >25 × 10(9)/L and circulating blasts ≥5%; these variables were subsequently used to devise an HR-weighted scoring system with high (3-4 risk factors), intermediate (2 risk factors) and low (0-1 risk factors) risk categories; the corresponding postsplenectomy median survivals were 0.3 (HR 5.9, 95% CI 3.2-11.0), 1.3 (HR 2.9, 95% CI 1.8-4.6) and 2.9 years. Postsplenectomy survival was not affected by driver mutational status or occurrence of leukemic transformation. Leukemia-free survival was predicted by very high risk karyotype. The observations from the current study might help identify appropriate candidates for splenectomy in MF.

Monocytosis Is a Powerful and Independent Predictor of Shortened Overall and Leukemia-Free Survival in Primary Myelofibrosis

BackgroundThe Dynamic International Prognostic Scoring System (DIPSS)-plus currently provides the most comprehensive prognostic model for primary myelofibrosis (PMF) (JCO 2011;29:392). DIPSS-pluse uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocyte count >25 x 109/L, circulating blasts ³1%, constitutional symptoms, unfavorable karyotype, red cell transfusion need and platelet count <100 x 109/L. More recently, type 1/type 1-like CALR driver mutational status and ASXL1 andSRSF2 mutations were identified as additional DIPSS-plus-independent risk factors for survival in PMF (JAMA Oncol. 2015;1:97). Based on our earlier preliminary observation (Leuk Res. 2007;31:1503), we conducted the current study to fully examine the additional prognostic relevance of monocytosis (absolute monocyte count ≥1 x 10(9)/L) in PMF.MethodsStudy patients fulfilled the 2016 WHO criteria for the diagnosis of PMF, including both pre-PMF and overt PMF (Blood. 2016;127:2391). Additional selection criteria included the availability of absolute monocyte count (AMC) and percentage at time of referral. Targeted next generation sequencing was used to screen for prognostically-relevant mutations (Blood 2015 126:354). Statistical analyses considered clinical and laboratory parameters obtained at time of initial referral to the Mayo Clinic.ResultsPatient characteristics:The study population included 454 patients (median age 64 years; 62% males); 293 (64%) patients harbored JAK2 mutations, 74 (16%) type 1/like CALR, 16 (3%) type 2/like CALR, 24 (5%) MPL and 47 (10%) were "triple-negative". DIPSS-plus risk distribution was 29% high, 38% intermediate-2, 17% intermediate-1 and 15% low; 27% displayed red cell transfusion-dependency, 29% constitutional symptoms, 70% palpable splenomegaly and 36% abnormal karyotype, including 13% with unfavorable karyotype. 301 patients were screened for ASXL1 mutations with 39% mutated, 297 for SRSF2 mutations with 15% mutated, 286 for U2AF1 with 18% mutated, 253 for SF3B1 with 6% mutated, 229 for EZH2 with 5% mutated and 110 for IDH1/2 with 7% mutated.Clinical, cytogenetic and molecular comparisons between PMF patients with and without monocytosis:Among all study patients, 376 (83%) displayed AMC <1 x 10(9)/L; the remaining had either moderate (AMC between 1 and 3 x 10(9)/L; n=65) or marked (AMC >3 x 10(9)/L; n=13) monocytosis. Comparison of these three groups revealed that monocytosis was significantly associated with older age (p=0.0001), higher leukocyte count (p<0.0001), lower platelet count (p=0.01), higher circulating blast percentage (p=0.0002) and higher DIPSS-plus risk distribution (p=0.01). There were no significant differences in the distribution of driver mutations, ASXL1, SRSF2, U2AF, SF3B1, EZH2 or IDH1/2 mutations or incidence of unfavorable karyotype.Survival analysis:After a median follow up of 3.2 years, 265 (58%) deaths and 38 (8%) leukemic transformations were documented. In univariate analysis, all 8 variables included in DIPSS-plus were significantly associated with shortened survival (p<0.001 in all instances). Significant risk factors in univariate analysis also included AMC >3 x 10(9)/L (p<0.0001; HR 5.6, 95% CI 3.1-10.0), AMC 1 to 3 x 10(9)/L (p<0.0001; HR 2.1, 95% CI 1.5-2.9), absence of CALR type 1/type 1-like (p<0.0001) and presence of ASXL1 (p<0.0001) or SRSF2 (p<0.0001) mutations. The significant difference in survival between the three AMC categories (i.e. <1, 1-3 and >3 x 10(9)L) was independent of each one of the eight DIPSS-plus variables, DIPSS-plus, driver mutational status, ASXL1 and SRSF2 mutations (p<0.0001 in all instances). The survival difference between patients with and without monocytosis was evident in both high/intermediate-2 and low/intermediate-1 DIPSS-plus risk groups (Figure). Patients with monocytosis were also more likely to undergo leukemic transformation (HR 3.0, 95% CI 1.4-6.5) and this effect was also independent of karyotype, driver mutational status, ASXL1 or SRSF2 mutations.ConclusionThe current study identifies monocytosis as a powerful risk factor for both overall and leukemia-free survival in PMF and the effect was independent of currently established prognostic models and genetic risk factors. It was particularly noteworthy to document similar distribution of driver mutations among the three monocyte categories. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognosis of Primary Myelofibrosis in the Genomic Era.

Currently, prognostication in primary myelofibrosis (PMF) relies on the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS), and DIPSS-plus, which incorporate age, blood counts, constitutional symptoms, circulating blasts, red cell transfusion need, and karyotype. Although the JAK2 V617F mutation was discovered a decade ago and MPL mutations shortly thereafter, it was the recent discovery of CALR mutations in the vast majority of JAK2/MPL-unmutated patients and recognition of the powerful impact of CALR mutations and triple-negative (JAK2/MPL/CALR-negative) status on outcome that set the stage for revision of traditional prognostic models to include molecular information. Additionally, the advent of next-generation sequencing has identified a host of previously unrecognized somatic mutations across hematologic malignancies. As in the myelodysplastic syndromes, the majority of common and prognostically informative mutations in PMF affect epigenetic regulation and mRNA splicing. Thus, a need has arisen to incorporate mutational information on genes such as ASXL1 and SRSF2 into risk stratification systems. Mutations in yet other genes appear to be important players in leukemic transformation, and new insights into disease pathogenesis are emerging. Finally, the number of prognostically detrimental mutations may affect both survival and response to ruxolitinib, which has significant implications for clinical decision making. In this review, we briefly summarize the prognostic models in use today and discuss in detail the somatic mutations commonly encountered in patients with PMF, along with their prognostic implications and role in leukemic transformation. Emerging prognostic models that incorporate new molecular information into existing systems or exclude clinical variables are also presented.

Hb TAYBE: clinical and morphological findings IN 43 patients.

Hereditary sequence variants in globin genes are usually silent and are rarer in α-globin chains than β-globin chains. Some may lead to an unstable protein with a hemolytic or thalassemic phenotype. Hb Taybe is an unstable α-chain hemoglobin variant caused by the deletion of a threonine residue at codon 38 or 39 of the α1 globin gene. This deletion results in a structural abnormality that affects the α1 β2 contact and the α1 β1 interface, producing a highly unstable Hb. We describe the clinical, laboratory, and morphological characteristics of 43 patients with Hb Taybe, sixteen of whom are heterozygous, eight are homozygous, and nineteen are double heterozygous for Hb Taybe and other α-gene mutations or deletions. The clinical presentation is very variable from a mild hemolytic anemia to the need for red cell transfusion. Morphological characteristics include erythroid hyperplasia, defective hemoglobin production, and dyserythropoietic features. On electron microscopy dyserythropoiesis and cytoplasmic precipitation of globin compatible optical dense material is seen. This is the largest report of Hb Taybe patients. Previous reported cohorts are not related to these cases. We conclude that patients carrying Hb Taybe have a unique hematological and clinical phenotype distinct from other hemoglobinopathies and from congenital dyserythropoietic anemia.

Early postnatal diagnosis of hereditary spherocytosis by combining light microscopy, acidified glycerol lysis test and eosin-5'-maleimide binding assay.

Exact diagnosis of hereditary spherocytosis (HS) is widely considered unreliable around birth. However, early postnatal diagnosis at the beginning of congenital hemolysis may be essential for managing neonatal anemia and hemolytic icterus, identifying those at high risk for severe hyperbilirubinemia, irreversible kernicterus, or sudden need for red cell transfusion. We analyzed 37 blood samples from neonates or infants up to six weeks of life that had been collected in-house or shipped to our laboratory due to suspected red cell membrane disorder. By combining assessment of red cell morphology, acidified glycerol lysis test (AGLT), and eosin-5'-maleimide (EMA) binding assay, we were able to clearly exclude HS in 22 and confirm HS in 10 patients, of which one had undergone red cell transfusion prior to blood sampling. Assessment of red cell morphology and normal test results allowed diagnosis of infantile pyknocytosis or Heinz body anemia in three neonates. Re-evaluation of five patients with inconsistent results of AGLT and EMA binding led to confirmation of HS in two cases. Automated analysis of hematologic parameters revealed elevated proportion of hyperdense cells to be a highly significant indicator for HS in neonatal infants. We showed that assessment of red cell morphology in combination with AGLT and EMA binding assay is a reliable basis for confirming or rejecting suspected diagnosis of HS even in neonates. Our data underline the necessity for blood sampling and laboratory exploration in suspected red cell membrane or enzyme defects at the earliest occasion.

Predictive Factors of Blood Loss and Hospital Stay in Patients With Major Lumbosacral Surgeries: A Multi-Center, Prospective, Cross-Sectional Survey

Background: Blood loss during spinal decompression and fusion is high and at times more than the patient’s total estimated blood. Increased blood loss may increase the risks of morbidity and eventually length of hospital stay (LOS). Objectives: The aim of this study was to identify predictor factors of blood transfusion requirements and the length of hospital stay in adult patients who underwent lumbosacral surgery. Materials and Methods: This was a multicenter cross-sectional study to predict factors of hospital length of stay (LOS) and intraoperative red cell transfusion in patients undergoing major posterior lumbar spinal surgeries. In this study, 298 patients who needed spinal surgery were enrolled. Results: Multiple linear regression results revealed the following information. Among variables that had significant association with the volume of intraoperative blood loss, considerable predictors were the number of level fused (R 2 = 0.42), mean intraoperative SBP (R 2 = 0.22), length of operation (R 2 = 0.31) and increasing age (R 2 = 0.37). Significant predictors for the length of hospital stay were increasing age (R 2 = 0.22), much more comorbid conditions (R 2 = 0.30), operation length (R 2 = 0.27), the number of level fused (R 2 = 0.21) and the volume of intraoperative blood loss (R 2 = O.29). The results of logistic regression revealed that length of operation, preoperative Hb value, number of level fused and mean intraoperative SBP considerably predicted the need for intraoperative blood transfusion. Conclusions: Diminishing intraoperative SBP could decrease intraoperative blood loss and eventually less red cell transfusion and shorter LOS. Besides, correcting preoperative anemia in female patients before elective surgeries could decrease a need for red cell transfusions and ultimately decreased red cell transfusion complication rate and shorter hospital LOS.

Timing of cord clamping in very preterm infants: more evidence is needed

In December 2012, the American College of Obstetricians and Gynecologists published a Committee Opinion entitled "Timing of umbilical cord clamping after birth." It stated that "evidence exists to support delayed cord clamping in preterm infants, when feasible. The single most important benefit for preterm infants is the possibility for a nearly 50% reduction in IVH." However, the Committee Opinion added that the ideal timing of umbilical cord clamping has yet to be determined and recommended that large clinical trials be conducted in the most preterm infants. Published randomized controlled trials include <200 infants of <30 weeks' gestation, with assessments of neurodevelopmental outcome in less than one-half of the children. This is a major gap in the evidence. Without reliable data from randomized controlled trials that optimally include childhood follow-up evaluations, we will not know whether delayed cord clamping may do more overall harm than good. Ongoing trials of delayed cord clamping plan to report childhood outcomes in >2000 additional very preterm infants. Current recommendations may need to change when these results become available. Greater international collaboration could accelerate resolution of whether this promising intervention will improve disability-free survival in about 1 million infants who will be born very preterm globally each year.

Recombinant Human Thrombopoietin Promotes The Recovery Of Megakaryocyte Lineage In Patients With Severe Aplastic Anemia Receiving Immunosuppressive Therapy

▪ ObjectiveTo assess the effectiveness of recombinant human thrombopoietin (rhTPO) in severe aplastic anemia (SAA) patients receiving immunosuppressive therapy (IST). MethodsEighty SAA patients receiving IST during a period from January 2007 to December 2011 were included in this retrospective analysis. Thirty-two subjects also received rhTPO treatment (15,000 U, three times a week, subcutaneously). The remaining 48 patients did not receive rhTPO treatment. The choice of using (or not using) rhTPO was based on physician discretion, and more importantly, patient will (partly based on financial capability to afford the medication). rhTPO was discontinued when platelet count returned to normal range. Hematologic response, bone marrow recovery, transfusion interval (platelet or red-cells), and the time to transfusion-free status were compared. ResultAt 6th months after the treatment, hematologic response along at least one lineage was achieved in 65.6% of the subjects receiving rhTPO vs. 41.7% in those who did not receive rhTPO (p=0.04). Response rate of megakaryocyte and erythroid lineage at 3rd months was also higher in subjects receiving rhTPO than in those who did not (43.8% vs. 10.4%, p=0.001; 50.0% vs. 20.8%, p=0.006). The mean number of megakaryocyte per bone marrow slide was higher in subjects receiving rhTPO than those who did not (9.7±3.1 vs. 2.6±4.2, p=0.002) after three months. The percentage of nucleated erythroid cells in bone marrow was also higher in subjects receiving rhTPO after three months (22.2±13.2% vs. 13.6±13.9% in those who did not receive rhTPO; p=0.007). The percentage of reticulocytes in peripheral blood was higher in subjects receiving rhTPO (1.9±1.4% vs. 0.7±0.4% in those who did not receive rhTPO; p=0.001) after three months. Myeloid percentage in bone marrow did not differ at any time points (3, 6, or 9 months). The need for platelet transfusion was lower in subjects receiving rhTPO (transfusion interval: 13.8±14.3 vs. 6.9±5.2 and 26.3±28.9 vs. 15.7±13.1 days in those who did not receive rhTPO during the first three and six months, respectively; P=0.004, P=0.03). The need for red cell transfusion was also lower in subjects receiving rhTPO (interval: 32.5±22.0 vs. 11.9±7.2 days and 50.4±27.9 vs. 23.9±20.1 days during the first three and six months, respectively; p=0.001 P=0.009). Time to independence from platelet transfusion was significantly shorter in subjects receiving rhTPO (99.9±49.9 vs. 156.3±14.5 days in those who did not receive rhTPO; p=0.01). ConclusionrhTPO improves hematologic response and promotes bone marrow recovery in SAA patients receiving IST. Disclosures:No relevant conflicts of interest to declare.

Normal Karyotype Primary Myelofibrosis (NK-PMF): Clinical and Molecular Prognostication In 690 Patients

BackgroundThe Dynamic International Prognostic Scoring System-plus (DIPSS-plus) uses eight adverse factors to predict survival in primary myelofibrosis (PMF): age >65 years, hemoglobin <10 g/dL, leukocytes >25 x 109/L, circulating blasts 31%, constitutional symptoms, red cell transfusion need, platelets <100 x 109/L and unfavorable karyotype (J Clin Oncol. 2011;29:392). The latter two also predicted leukemic transformation. Most recently, an international study of 879 PMF patients identified ASXL1, SRSF2, EZH2 and IDH1/2 mutations as inter-independent predictors of shortened overall or leukemia-free survival (Leukemia 2013Apr 26 doi: 101038/leu2013119. 2013). Molecular prognostication is now well established for acute myeloid leukemia with normal karyotype (NK). There is currently little information on clinical or molecular prognostication in NK-PMF. MethodsDiagnosis of PMF was according to WHO criteria. The study population included all referrals to the Mayo Clinic, Rochester, MN, USA or the University of Florence, Florence, Italy. Information on clinical and laboratory parameters and karyotype was available in all study patients, at time of referral, which coincided with time of sample collection for mutation screening. The current study considered only those patients with NK-PMF. ASXL1, EZH2, SRSF2, IDH1/2 and JAK2 mutations were performed on variable number of patients depending on bone marrow or granulocyte DNA availability. Clinical parameters examined for prognostic relevance included those listed for DIPSS-plus, less unfavorable karyotype. ResultsA total of 690 patients with NK-PMF patients were studied. Median age was 65 years (14-89). The percentage of patients with age >65 years was 48%, red cell transfusion dependent 35%, hemoglobin <10 g/dL 49%, platelets <100 x 10(9)/L 19%, leukocyte count >25 x 10(9)/L 15%, circulating blasts ≥1% 49% and constitutional symptoms 33%. At a median follow-up of 29 months, 351 (51%) deaths and 39 (6%) leukemic transformations were recorded. Mutational frequencies and clinical correlatesThe respective frequencies (mutated/number of patients studied) of JAK2V617F, ASXL1, EZH2, SRSF2 and IDH1/2 mutations were 60% (284/473), 34% (72/214), 8% (14/179), 15% (37/249) and 5% (14/262). There was no significant association between JAK2V617F and any one of the aforementioned mutations. Inter-mutation association was evident only between SRSF2 and IDH1/2 (p=0.0005). Each one of the DIPSS-plus risk parameters was examined for correlation with a specific mutation: ASXL1 was associated with leukocyte count >25 x 10(9)/L (p<0.0001) and circulating blasts ≥1% (p=0.0005); EZH2 with leukocyte count >25 x 10(9)/L (p=0.008); and SRSF2 with age >65 years (p=0.0007), transfusion need (p=0.04) and hemoglobin <10 g/dL (p=0.03). JAK2V617F was associated with age>65 years (p=0.003) and leukocyte count >25 x 10(9)/L (p=0.02). Predictors of overall and leukemia-free survivalIn univariate analysis, all 7 DIPSS-plus parameters, as well as ASXL1, EZH2, SRSF2 and IDH1/2 mutations showed significant association with shortened survival: When each of these analyses was adjusted for age, all except constitutional symptoms and SRSF2 mutations retained their significance. Multivariable analysis of the six age-independent DIPSS-plus variables identified all but transfusion-need as independent predictors of inferior survival. A similar analysis restricted to mutations identified ASXL1 and EZH2 as being independently adverse. When both mutations and DIPSS-plus variables were included in the multivariable model, only four parameters remained significant: age >65 years (HR 4.2; p<0.0001), platelets <100 x 10(9)/L (HR 3.4; p<0.0001), ASXL1 mutations (HR 2.2; p=0.0001) and EZH2 mutations (HR 2.7; p=0.001). A similar analysis identified SRSF2 mutations (HR 5.9; p=0.0003) and platelets <100 x 10(9)/L (HR 4.3; p=0.005) as the only predictors of leukemia-free survival. ConclusionsIn NK-PMF, molecular markers might be prognostically more useful than conventional models that rely on clinical features. In the current study, thrombocytopenia was the only clinical variable, other than age, with additional value to molecular prediction of survival and leukemic transformation. Disclosures:No relevant conflicts of interest to declare.

Decreased Levels of Total or HDL Cholesterol in Primary Myelofibrosis Are Associated with Shortened Survival: DIPSS-Plus Independent Prognostic Value.

AbstractAbstract 2851 Background:It is widely appreciated that total cholesterol (TC) and triglyceride (TG) levels are decreased in patients with primary myelofibrosis (PMF). However, a systematic study looking into the serum lipid profile in PMF and its phenotypic and prognostic relevance is lacking. Methods:An updated Mayo Clinic database of 1008 karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify study patients in whom serum lipid and lipoprotein levels were available at time of referral. Overall (OS) and leukemia-free (LFS) survivals were calculated from the time of referral, which was also the time of serum lipid analysis. Results:A total of 207 patients met the above stipulated criteria and had measurement of TC (n=207), TG (n=204), HDL cholesterol (HDL-C) (n=187), LDL cholesterol (LDL-C) (n=176) and non-HDL cholesterol (N-HDL-C) (n=184). The corresponding median (range) values (mg/dL) were 132 (57–296), 147 (42–742), 31 (8–96), 67 (11–186) and 104 (7–249). TC was significantly (P<0.05) lower in the presence of male sex, older age, red cell transfusion need, hemoglobin <10 g/dL, marked splenomegaly, circulating blasts, constitutional symptoms, JAK2 V617F, and ASXL1 mutations. TG was significantly (p<0.05) lower in the presence of JAK2 V617F, red cell transfusion need, hemoglobin <10 g/dL and thrombocytosis. DIPSS-plus risk categories showed significant differences in their TC (p<0.0001), HDL-C (p=0.004), LDL-C (p=0.004), and N-HDL-C (p=0.009) profiles with higher levels seen in lower risk patients; there were no correlations with TG levels.In univariate analysis, lower levels of TC, HDL-C, LDL-C and N-HDL-C were all associated with shortened survival (P<0.01 for each association) whereas survival was not affected by TG level (p=0.42). Multivariable analysis in the context of DIPSS-plus confirmed the independent prognostic relevance of both TC (p=0.05) and HDL-C (p=0.02) for OS. A similar analysis disclosed no correlation with LFS. Exclusion of patients receiving statin or other anti-lipid treatment did not affect the overall results. Patients in the lower quartiles for either TC (approximately <100 mg/dL) or HDL-C (approximately <25 mg/L) compared to those with higher levels displayed significantly shorter survival (Figure; RR 2.4, 95% CI 1.6–3.7; p<0.0001) that was not accounted for by DIPSS-plus (RR 1.6, 95% CI 1.1–2.5; p=0.03). Conclusions:Decreased levels of total or HDL cholesterol in PMF cluster with adverse disease features and carry a DIPSS-plus independent adverse prognostic value. Measurement of TC and HDL-C in PMF might be useful in monitoring disease progression and treatment response. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Associations and Prognostic Interactions Between Circulating Levels of Hepcidin, Ferritin, and Inflammatory Cytokines in Primary Myelofibrosis.

AbstractAbstract 2831 Background and Aims:Primary myelofibrosis (PMF) is characterized by ineffective erythropoiesis, an underlying inflammatory state and potentially, iron overload in the setting of red cell transfusions. The potential interaction between these clinical variables and assessment of their independent prognostic contribution, if any, is of interest within the context of well established prognostic parameters including the DIPSS-plus model and increased circulating levels of inflammatory cytokines (J Clin Oncol. 2011 Apr 1;29(10):1356–63). Consequently, we studied the relationship between circulating levels of hepcidin (a surrogate for inflammation, iron stores and ineffective erythropoiesis), ferritin (iron stores and inflammation), red cell transfusion need (ineffective erythropoiesis) and soluble inflammatory cytokine levels in PMF patients. Methods:The diagnosis of PMF was according to WHO criteria. Inclusion in this study required availability of archived plasma, bone marrow biopsy, and cytogenetic information at the time of first referral. Plasma total hepcidin levels were measured by ELISA (USCN Life Sciences, Wuhan, China). Serum ferritin was measured as part of routine clinical assessment (normal range: males: 24–336 mcg/L; females: 11–307 mcg/L). Concentrations of plasma cytokines were analyzed in duplicate by using Multiplex Bead-Based Luminex technology (Invitrogen, Carlsbad, CA). Results:Two hundred and three PMF patients met the above stipulated criteria; 136 (67%) were males and the median age at referral was 63 years (range 17–83). Their dynamic international prognostic scoring system (DIPSS)-plus risk categorization was: low-risk 22 (11%), intermediate-1 26 (13%), intermediate-2 85 (42%) and high-risk 70 (34%).Hepcidin levels (median 156279 pg/mL; range 8082–2088002) were strongly correlated with serum ferritin (n=146; median 207 mcg/L; range 14–5367) (r2=0.43, p <0.0001). Both were directly correlated with red cell transfusion need and age, and inversely with hemoglobin level (all p <0.05); however, there was no correlation with increased levels of inflammatory cytokines (>3 standard deviation above mean of normal controls for IL-2 and/ or IL-8) (p>0.05).At a median follow up of 35 months, 104 (51%) deaths and 18 (9%) leukemic transformations were recorded. In univariate analysis, increased levels of hepcidin (HR=2.0; p=0.0006) and ferritin (HR=2.7; p<0.0001) were predictive of inferior overall survival and this significance was sustained during multivariable analysis that included either increased inflammatory cytokine levels (HR=3.2 and 2.7, respectively) or transfusion need (HR=1.7 and 2.2, respectively) as covariates. When all 4 variables (i.e. increased levels of hepcidin, ferritin, inflammatory cytokines and transfusion need) were considered together in the Cox model, only increased inflammatory cytokine levels retained their prognostic significance (HR=2.7; p=0.0046). Furthermore, neither increased ferritin nor increased hepcidin levels were prognostically significant for overall survival when tested either individually or together against the DIPSS-plus model (p>0.05).In univariate analysis, increased hepcidin level, but not increased ferritin or transfusion need, was predictive for inferior leukemia-free survival (HR=2.8; p=0.04) and this significance was sustained in multivariable analysis that included either cytogenetic risk categories (very-high risk versus high-risk versus other) (HR=2.7; p=0.046) or thrombocytopenia (platelet count <100 × 109/L) (HR=2.7; p=0.047) as covariates. Conclusions:Circulating levels of hepcidin and ferritin are highly correlated variables in PMF and appear to provide redundant prognostic information for overall survival in this setting. The lack of correlation with inflammatory cytokines suggests that ineffective erythropoiesis may be the common link for their apparent prognostic value noted during univariate analysis. In contrast to inflammatory cytokines, neither hepcidin or ferritin levels were useful as a complement to the DIPSS-plus prognostic model in the current analysis. The relationship between hepcidin and leukemia-free survival is intriguing however the pathogenetic mechanism remains obscure and needs confirmation in additional patients. Disclosures:No relevant conflicts of interest to declare.