ALBERT

Description: Background/Objective: Breakthrough hemolysis (BTH) is the return of hemolytic disease activity during treatment with complement C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH). BTH may be associated with inadequate C5 inhibition or complement activating conditions (eg, infection). Despite reports that up to 19% of patients (pts) receiving eculizumab may experience BTH, there is no commonly accepted definition of BTH. The definition of BTH was derived from literature review and expert consensus. BTH was defined as ≥1 new or worsening symptom/sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin

Description: Introduction: We report a life-threatening delayed hemolytic transfusion reaction (DHTR) with hyper-hemolysis syndrome (HHS) in a SCD patient triggered by an anti-IH autoantibody with alloantibody behavior. The intravascular hemolysis was successfully inhibited with Eculizumab therapy. The auto antibody was suppressed with rituximab treatment. Case Report: The patient is a 35 year-old African American female with SCD. She was given two red cell units ABO, Rh matched and negative for antigens to her known alloantibodies, before undergoing a laparoscopic cholecystectomy. She discharged with hemoglobin of 8.2 g/dL. Two weeks later she was admitted with severe fatigue, worsening jaundice, and total body pain. Physical examination was notable for scleral icterus, pale conjunctivae, and a well healed surgical scar on her abdomen. Hemoglobin level was 7.4 g/dL and reticulocyte count was reticulocyte count was 211x103/µl, lactate dehydrogenase (LDH) of 1174 IU/L (nl 5000 IU/L to 1626 IU/L by day 12, 747 IU/L at day 22 and 467 IU/L by day 30. By day 7 of Eculizumab treatment, the patient’s hemoglobin stabilized at 5.4 g/dl without further need for transfusion with normalization of the serum creatinine (0.54 mg/dl). Immunosuppressive therapy with rituximab, 375mg/m2 was given weekly for 4 weeks to suppress the IH antibody. The cold agglutinin titer, initially noted to be 1:512, remained at 1:256 at 6 weeks but dropped to 1:4 by week 12. Discussion: We report a case of delayed hemolytic transfusion reaction with resultant hyperhemolysis triggered by an anti-IH autoantibody with allo-antibody behavior. The anti-IH was reactive at room temperature as well as 37oC, but only weakly reactive with autologous red cells treated with Rituximab to suppress the cold agglutinin and Eculizumab to block the complement mediated hemolysis After initiation of Eculizumab therapy our patient’s LDH levels decreased by 40% within the first week, 70% by day 14, and 90% at four weeks with stabilization of her hemoglobin without further transfusion. Conclusion: We have described the first reported case of HHS triggered by anti-IH formed as a result of red cell transfusion, successfully treated with Eculizumab and Rituximab. The rapid hematologic improvement due to Eculizumabv occurred well before the cold agglutinin titer dropped (7 days vs 84 days). Eculizumab may have utility in the treatment of other cases of severe DHTR, alone or, as in our patient, combined with rituximab. Disclosures Off Label Use: Eculizumab for inhibition of complement mediated hemolysis Rituximab for suppression of cold agglutinin. Liebman:Alexion: married to Dr. Ilene Weitz Other.

Description: Abstract 1033 Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by deficiency of the GPI-anchored complement inhibitory proteins CD55/59. Chronic hemolysis from this deficiency leads to serious clinical morbidities including thromboembolism, chronic kidney disease, and increased mortality. The International Clinical Cytometry Society (ICCS) recommends multiparameter high sensitivity flow cytometry (HSFC) as the method of choice for diagnosing PNH. The ICCS also provides guidance on the clinical indications for testing for PNH, including patients (pts) with bone marrow failure (BMF), unexplained cytopenias, unexplained thrombosis, hemoglobinuria and hemolysis. The aim of this study is to use HSFC with sensitivity up to 0.01% to analyze 6,897 pts who were screened for PNH clones utilizing CD235a/CD59 for RBCs, FLAER/CD24/CD15/CD45 for neutrophils and FLAER/CD14/CD64/CD45 for monocytes. We evaluated the clinical indications for PNH testing with the provided ICD-9 diagnostic (DX) codes and examined the change in PNH clone sizes among pts who had follow-up studies in 3–12 months. Based on a sensitivity of at least 0.01%, 6.1% of all pts (421/6897) were found to be PNH positive. Of those pts, 5,545 pts (80.1%) had ICD-9 DX codes provided. The distribution of PNH clone sizes in these PNH+ pts is shown in Figure 1. Aplastic anemia (AA) and hemolytic anemia comprised the most common reasons for testing. In bone marrow failure syndromes, AA pts had the highest incidence of PNH+ clones, 26.3%, followed by pts with unexplained cytopenia, 5.7%, myelodysplastic syndrome (MDS), 5.5%, and anemia (unspecified or in chronic illness), 3.6% (Table 1). The incidence of PNH+ clones for symptoms such as hemolytic anemia was 22.7%, followed by hemoglobinuria 18.9%, and unspecified hemolysis, 7.9%, unspecified iron deficiency, 2.5%, and thrombosis, 1.4%. Of the 421 PNH positive pts, 89 pts (22%) were identified as having follow-up studies in 3–12 months. These pts were categorized into PNH clone sizes of 0.01% – 0.1% (27 pts, 30%), 0.11% – 1% (7 pts, 8%), 1.1% – 10% (18 pts, 20%) and 10.1% – 100% (37 pts, 42%). Of the 64 pts who had PNH clone sizes of 0.01% – 0.1% or 10.1 – 100%, one patient (0.02%) had a follow-up study that resulted in a change of category. Of the 25 pts with PNH clones sizes between 0.11% – 1% and 1.1% – 10%, 10 pts (40%) had a follow-up study resulting in an increase in category, 6 pts (24%) had a follow-up study resulting in a decrease in category and 9 pts (36%) had a follow-up study resulting in no change in category.Figure 1.Distribution of PNH Clone Sizes based on 421 PNH+ PatientsFigure 1. Distribution of PNH Clone Sizes based on 421 PNH+ PatientsTable 1:Incidence of PNH Clones in Patients with ICD-9 Diagnostic Code at Dahl-Chase Diagnostic ServicesICD-9 Diagnostic CodeGeneral DescriptionIncidence of PNH Clone284, 284.01, 284.8, 284.81, 284.89, 284.9Aplastic Anemia26.3% (94/357)238.7, 238.72, 238.73, 238.74, 238.75, 238.76Myelodysplastic Syndrome (MDS)5.5% (32/585)287.5Unexplained Cytopenia5.7% (13/230)284.1Pancytopenia6.0% (63/1058)285.2, 285.21, 285.29, 285.9Anemia Unspecified3.6% (40/1122)283, 283.1, 283.10, 283.11, 283.19, 283.2, 283.9Hemolytic Anemia22.7% (147/647)791, 791.2Hemoglobinuria18.9% (14/74)790.6, 790.99, 790.4Hemolysis7.9% (18/227)325, 415.1, 415.11, 434, 434.01, 444.22, 451.11, 451.19, 452, 453, 453.0, 453.2, 453.4, 453.41, 453.89, 453.9, 557, 557.1Thrombosis1.4% (14/967)280.9Unspecified Iron Deficiency2.5% (7/278)Other ICD-9 diagnostic codes2.1% (26/1232)Not Provided4.8% (51/1065)Note: Table reflects patients who had more than one ICD9 code associated with their laboratory tests. In this single-laboratory experience, we evaluated the incidence of PNH in these high risk groups. In this study, 26.3% of pts with the diagnosis of BMF had PNH+ clones detected, underscoring the need to test this group of pts. The study confirmed the utility of testing pts with unexplained hemolytic anemia, hemolysis and hemoglobinuria where the combined rate of positivity was 48%. In addition, this study highlights the need to monitor pts with small PNH clones by HSFC analysis as these pts may show significant variation over time. This examination of ICD-9 DX code association with presence of PNH+ clones confirms the need to actively test high risk populations for PNH based on the ICCS recommendations to ensure accurate diagnosis and early intervention. Disclosures: Weitz: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illingworth:Dahl-Chase: Employment; Alexion: Consultancy, Honoraria, Research Funding.

Description: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal stem cell disorder. Pregnancy in patients with PNH results in an increase in maternal and fetal complications and a consequent increase in maternal and fetal mortality. Maternal complications include thrombosis, cytopenias and infections while fetal complications relate to preterm delivery (de Guibert et al, 2011). Eculizumab is a humanized monoclonal antibody that blocks terminal complement activation, preventing intravascular hemolysis and its consequences. In PNH it reduces the need for transfusions, protects against thrombosis, and may improve long-term survival. We previously showed a benefit in using eculizumab in pregnancy for patients with PNH in a limited number of cases (Kelly et al, BJH 2011). This study was of 70 pregnancies in 57 women. Patients were identified through physician willingness to participate as well as through the Global PNH Registry. A specific questionnaire was sent to physicians. Local IRBs approved the study. Across the 70 pregnancies, 41 women were on eculizumab before conceiving and remained on the drug during pregnancy, 28 women started eculizumab in either the second or third trimester and 1 woman stopped eculizumab at 12 weeks gestation. The median age at PNH diagnosis was 23 years (range 13-36). The median age at the start of each pregnancy was 29 years (range 18-40). Nineteen women (33%) had a prior documented history of aplastic anemia and 8 (14%) had a prior thrombosis. The median PNH granulocyte clone around the start of pregnancy was assessed in 51 cases and was 94.3% (range 24.3-100). There were 62 live births, 2 stillbirths and 6 first trimester miscarriages. There were 3 twin pregnancies. In 1 of these, there was a fetal death due to intrauterine growth retardation (IUGR). Anticoagulation (AC) with low molecular weight heparin (LMWH) was used in 60 pregnancies (86%) and with fondaparinux in 1 case: therapeutic doses were used in 26 pregnancies, prophylactic doses in 28 pregnancies and an intermediate dose in a further 7. Aspirin was used in 4 pregnancies. Folic acid and oral iron supplements were used in 62 (89%) and 26 (41%) pregnancies, respectively. Transfusion requirements increased in pregnancy from a mean of 0.13 units per month in the 6 months before conception to a mean of 0.94 units per month whilst pregnant. This returned to pre-pregnancy levels after delivery. No platelet transfusions were needed in the 6 months before being pregnant compared with 99 platelet transfusions during the pregnancies. Higher doses, or more frequent dosing, of eculizumab was used to treat recurrent intravascular hemolysis in over half the pregnancies (52%) that progressed past the first trimester. Eculizumab was stopped in 10 instances after the postpartum period, 9 due to funding issues and 1 as the patient underwent a bone marrow transplant. Two patients who stopped eculizumab 12 weeks after delivery experienced a thrombosis. The first experienced a mesenteric thrombosis 4 weeks after stopping eculizumab whilst on therapeutic dose of LMWH and the second suffered a Budd-Chiari 8 weeks after stopping eculizumab. Both were recommenced on eculizumab immediately. The mean reduction in platelet count from the start of pregnancy to delivery was 37 x 109/l. There were 10 significant bleeding episodes: 1 recurrent epistaxis, 1 antepartum bleed and 8 postpartum bleeds. Two patients experienced a postpartum thrombosis whilst on eculizumab, 1 a deep vein thrombosis and the other a mesenteric thrombosis, likely precipitated by a plasma infusion. Nineteen births were premature (31%), mainly due to pre-eclampsia (6 cases) and IUGR (5 cases). Four babies had complications due to prematurity: 1 had toxic megacolon and required a temporary ileostomy, and the other 3 had initial growth retardation due to prematurity. Twenty-five babies were breast fed and in 10 cases, breast milk was tested for eculizumab but no drug was detected. Eculizumab was not detected in 13 cord blood samples and was found at very low levels in a further 7 samples (11.8-21.2µg/ml). In conclusion, eculizumab appears safe to use in pregnancy in PNH and does not appear to cross the placenta in significant quantities to block complement or to be excreted in breast milk. Higher doses may be required later in pregnancy to prevent hemolysis. Overall pregnancy outcomes in this group are better than historical controls with supportive therapies alone without eculizumab. Disclosures Kelly: Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Höchsmann:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals: Speakers Bureau. Röth:Alexion Pharmaceuticals: Speakers Bureau. Weitz:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hill:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Risitano:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Patriquin:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Muus:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Turner:ICON Clinical Research: Employment. Schrezenmeier:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peffault de Latour:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Description: Background/Objective: Ravulizumab (ALXN1210) is an innovative C5 inhibitor with high C5 affinity and a half-life approximately 4 times longer than eculizumab. In the largest interventional clinical study of C5 inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH) to date, ravulizumab administered every 8 weeks (q8w) was shown to be noninferior to eculizumab (every 2 weeks [q2w]) across 2 coprimary endpoints and 4 key secondary endpoints, due to its ability to provide immediate, complete, and sustained inhibition of complement C5 (Lee et al, EHA-2018). Because PNH is a rare disease, prospective evaluation of new agents for the treatment of this disease, with the exception of ravulizumab, has been limited to small populations. As a result, assessing the effect of treatment in patients with unique disease characteristics and gaining a full understanding of the benefit-to-risk profile of new therapies, has been challenging. The objective of this protocol-specified analysis was to evaluate the relative efficacy of ravulizumab and eculizumab in adult patients with PNH based upon baseline hemolysis level, transfusion history, and demographics. Methods: In this phase 3, randomized, open-label, noninferiority, multicenter study (NCT02946463), patients ≥18 years of age with confirmed diagnosis of PNH, naive to complement inhibitor therapy, with lactate dehydrogenase (LDH) level ≥1.5 times upper limit of normal (xULN), and ≥1 PNH-related sign/symptom at screening received ravulizumab or eculizumab over a 183 day study period. Coprimary efficacy endpoints were transfusion avoidance and LDH normalization. Secondary endpoints were percent change in LDH, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, and proportion with stabilized hemoglobin levels. Subgroup analyses were performed on each of these endpoints, based on transfusion history (0, 1-14, or 〉14 units of packed red blood cells [pRBCs] in the year prior to the first dose of study drug), screening LDH levels (1.5-14 pRBCs in the 12 months before randomization, both baseline LDH subgroups, and most of the demographic subgroups (Panel B). No sensitive subgroups were identified for either of the coprimary endpoints. Similarly, point estimates favored ravulizumab in the majority of patient subgroups across each of the key secondary endpoints, including: 8/17 of the subgroups on the assessment of percent change in LDH; 12/17 subgroups on the assessment of change in FACIT-Fatigue score; 13/17 subgroups on the assessment of breakthrough hemolysis; and 13/17 subgroups on the assessment of hemoglobin stabilization. Conclusions: Results of this prespecified analysis revealed point estimates favoring ravulizumab for the majority of the diverse subgroups of PNH patients analyzed. The consistency of these data across subgroups confirms the robustness of the results of this study. The benefit of ravulizumab in terms of transfusion avoidance and LDH normalization was retained across all subgroups. These results provide evidence supporting the use of ravulizumab for the treatment of complement inhibitor-naive patients with PNH regardless of transfusion history, baseline hemolysis level, sex, age, race, or geographic region. Figure. Figure. Disclosures Weitz: Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Kulagin:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Nakao:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria. Szer:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support , Research Funding. Rottinghaus:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Volles:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Damokosh:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Aguzzi:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Larratt:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding. Risitano:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ra Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amyndas Pharmaceuticals: Consultancy.

Description: Abstract 1104 Background: Venous thromboembolism (VTE) is a major complication in cancer patients. The traditional treatment algorithm for VTE of UF or LMW heparin followed warfarin is associated with a higher risk of recurrent VTE and bleeding in cancer patients. A recent randomized trial has demonstrated that initial treatment and secondary prophylaxis with LMWH is associated with a lower VTE recurrence when compared to secondary prophylaxis with warfarin. We initiated a single arm Phase 2 IRB approved study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis (6 months) of VTE in cancer patients. Included in this study was a prospective analysis of plasma biomarkers to assess whether any biomarkers could predict treatment failure or be predictive of patient survival. Methods: Patients (pts)with objectively confirmed symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) or unexpected PE detected on staging CT scans by the criteria of OConnell et al. (JCO 24:4928, 2006) were eligible for this study, if they had an ECOG score

Description: Abstract 4644 Background: Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and renal failure in the absence of Shiga toxin exposure. Dysregulation of the alternative pathway by mutations in complement regulatory proteins or antibodies to these proteins have been implicated in the pathogenesis of the disorder. Aims: We report the late onset of aHUS in association with heterozygous deletion of two genes, CFHR1 and CFHR3, and a mutation in CFH, c.497G〉T, p.Arg166Leu. The latter mutation has not previously been reported with aHUS. Methods: A 20-year-old female whose past history was unremarkable with the exception of a spontaneous abortion 3 months earlier, presented to an emergency room with abdominal pain and bloody diarrhea three days after eating raw fish. Within 4 days of hospitalization she developed MAHA, thrombocytopenia and renal failure. Studies were negative for Shiga toxin and showed an ADAMTS13 level of 40%. A diagnosis of aHUS was made. Treatment was initiated with daily plasma exchange (PE) which was increased to twice daily for 6 weeks. Response was poor. After discontinuing PE, the patient was treated on an IRB-approved compassionate-use protocol with eculizumab 900 mg weekly for four weeks followed by 1200 mg every two weeks. Results: The patient responded slowly to eculizumab. PK values of eculizumab were sub-therapeutic at week 4. On week 5, she was switched to the maintenance dose of 1200 mg every two weeks, which resulted in a rapid normalization of her platelet count and LDH, with further improvement of her renal function and normalization of her mental status. The patient is doing well on continued eculizumab treatment. Genetic testing revealed a known copy-number variation (CNV), hemizygosity for CFHR1 and CFHR3, and a mutation in short consensus repeat (SCR) 3 of CFH, p.Arg166Leu. Summary/Conclusions: This patient presented with aHUS unresponsive to PE, but responsive to eculizumab treatment. Genetic testing of complement regulatory genes identified a known CNV and a mutation in CFH, p.Arg166Leu. This mutation lies in SCR3 of CFH, a region of the protein important for fluid-phase regulation of the C3 convertase. Although it has been seen in a rare case of dense deposit disease, it has not has not been reported with aHUS. This patient's poor response to PE suggests that additional genetic factors may be present in this patient that affected the course of disorder. Her slow response to eculizumab may have been due to third spacing of the drug secondary to hypoalbuminemia with anasarca as documented sub-therapeutic levels were present on week 4. When the dose was increased to 1200 mg every two weeks, the patient rapidly improved with resolution of the aHUS. Disclosures: No relevant conflicts of interest to declare.

Description: Background Infection with Helicobacter pylori has been implicated as an etiologic agent for the development of immune thrombocytopenia (ITP). In a systematic review of the medical literature Stasi and colleagues reported wide regional variation in the prevalence of H. pylori infection in ITP patients with significant differences in improvement in platelet count with infection eradication. The largest report on H.pylori infection in ITP patients diagnosed in the United States found a lower prevalence of infection (21.6%) than the reported seroprevalence (32.5%) for the general United States population.1 Only 1 of 15 treated patients responded eradication of their infection.1 Based upon this report the American Society of Hematology ITP guidelines do not recommend routine H. pylori testing during the evaluation of newly diagnosed patients. Los Angeles County-University of Southern California Medical Center is the largest healthcare provider in the metropolitan Los Angeles region. It services a large and ethically diverse patient population. Screening for H.pylori infection in newly diagnosed and previously diagnosed ITP patients was begun as a routine part of the diagnostic algorithm in 2008. We initiated a retrospective review of H.pylori infection in patients screened during this period. Results At the time of this report the medical records of 80 ITP patients (M/F: 22/58) have been reviewed. 68 (F/M: 52/16) patients, 51 with 1o ITP and 17 with 2ry ITP, were screened for H.pylori. The median age of the screened patients was 50 yrs (23 to 85 yrs). Patients were screened with either the H. pylori stool antigen (46 pts; 65%) or H. pylori Breath test (10 pts; 16%). 12 patients (19%) were only screened for H.pylori antibodies. Of the screened patients, 29/68 (42.6%) tested positive for H. pylori. However, there were significant ethnic and racial differences in the prevalence of infection (Table ). 27 of the 29 positive patients were treated for their infection. H. Pylori eradication was documented in 20 of 22 (91%). An additional patient was successfully treated with a second course of antibiotics. Response to therapy could not be assessed in 14 of the 27 treated patients due to treatment with concomitant ITP medications. Of the 13 patients who could be evaluated for response using IWG criteria, there were 4 (30.8%) complete responses, 1 (7.7%) partial response and no response in 8 (61.5%). All complete responders were treated within 2 months of initial presentation. At the time of this report only 3 of the 29 patients remain on ITP treatment. Conclusion There are significant ethnic and racial differences in the prevalence of H. pylori infection in ITP patients diagnosed in the greater Los Angeles metropolitan region. Despite earlier reports from New York and Miami, early identification and treatment of H. pylori infected may result in remissions up to a third of patients. 1. Michel M et al. Blood 2004; 103: 890-896. Disclosures: No relevant conflicts of interest to declare.

Description: Background Thrombocytopenia (Tp) is frequently observed in individuals with advanced cirrhotic liver disease. Patients with HCV may develop Tp even in the absence of significant liver disease. Decreased thrombopoietin production may also contribute to the Tp. The current management of HCV infection includes the use of the Peg-interferon α (IFN) and ribavirin (RIB), which can induce a sustained viral remission in 40 to 50% of treated patients. However, Peg-INF is a known inhibitor of megakaryocyte growth and maturation and can result in treatment related Tp. Therefore, patients presenting with platelet counts 100,000/mcl to allow for HCV treatment with Peg-INF/RIB. Methods This is a two phase clinical trial of HCV infected patients with Child-Pugh class A liver disease. All patients were required to have platelet counts 100,000/mcl before initiating Peg-INF treatment. There are separate 1 to 1 randomizations for patients with platelets 70 to 50,000/µl and patients with platelets100,000/µl by week 8, blind is terminated and placebo patients can enter the romiplostim arm. Phase II is a dose escalation study of romiplostim during Peg-INF/Rib treatment up to week 24 of HCV treatment. If patients are viral load negative by week 24, romiplostim treatment is held to see if the patients can sustain a safe platelet count with continued HCV therapy. If not, romiplostim is continued until completion of HCV treatment. A protocol amendment allowed the addition of HCV protease inhibitors for genotype 1a patients. Results At the time of this report 21 patients (7F/14M; mean age 54.9 yrs, range 28-72yrs) have been enrolled in this trial; 13 with platelets 70 to 50,000/µl (Mean 62,000/µl; range 55 to 70,000µl) and 8 with platelet counts100,000/ul by wk 8; all on placebo and were rolled over to romiplostim. The mean romiplostim dose for patients completing Phase I with platelets 70 to 50,000/µl was 2.2 mcg/kg and 3.1 mcg/kg for patients with platelets of