Post ASH speaker abstracts 2018


Abstracts to support presentations from Tina Dutt

Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 Hercules Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura

Result Type: Paper
Number: LBA-1
Presenter: Marie Scully
Program: General Sessions
Session: Late-Breaking Abstracts Session

Marie Scully, MD1*, Spero R Cataland, MD2, Flora Peyvandi, MD, PhD3, Paul Coppo4*, Paul Knöbl, MD, PhD5*, Johanna A. Kremer Hovinga, MD6*, Ara Metjian, MD7, Javier de la Rubia, MD8*, Katerina Pavenski, MD9, Filip Callewaert, PhD10*, Debjit Biswas, PhD10*, Hilde De Winter, MD11* and Robert K. Zeldin, MD12*

1Department of Haematology, University College London Hospitals NHS Trust, London, United Kingdom
2Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
3Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico; University of Milan, Milano, Italy
4Department of Hematology, Saint-Antoine University Hospital, Paris, France
5Department of Medicine 1, Division of Hematology and Hemostasis, Vienna University Hospital, Vienna, Austria
6University Clinic of Hematology and Central Hematology Laboratory, Bern University Hospital, Inselspital, Bern, Switzerland
7Division of Hematology, Duke University School of Medicine, Durham, NC
8Hematology Department, Universidad Católica de Valencia Hospital Dr. Peset, Valencia, Spain

9Department of Laboratory Medicine and Pathobiology, St. Michael’s Hospital/Research Institute, Toronto, ON, Canada
10Clinical Development, Ablynx NV, Zwijnaarde, Belgium
11Clinical Development, Ablynx NV, Zwijnaarde, Oost-Vlaanderen, Belgium
12Chief Medical Officer, Ablynx NV, Zwijnaarde, Belgium


Introduction: Acquired or immune-mediated thrombotic thrombocytopenic purpura (aTTP) is a life-threatening thrombotic microangiopathy characterized by severe thrombocytopenia, microangiopathic hemolytic anemia, and organ ischemia. Inhibitory autoantibodies cause a severe deficiency of the von Willebrand factor (vWF) cleaving enzyme ADAMTS13, leading to intravascular vWF-platelet aggregation and microvascular thrombosis. The mainstays of treatment are plasma exchange (PE) and immunosuppression. Caplacizumab, a bivalent Nanobody, targets the A1 domain of vWF, inhibiting the interaction between ultra-large vWF and platelets.

Methods: Patients with an acute episode of aTTP who had received one PE treatment were randomized 1:1 to placebo or 10 mg caplacizumab, in addition to daily PE and corticosteroids. A single IV dose of study drug was given before the first on-study PE and a SC dose was given daily during the PE period and 30 days thereafter. If at the end of this period there was evidence of ongoing disease, such as suppressed ADAMTS13 activity, investigators were encouraged to extend the blinded treatment for a maximum of 4 weeks together with optimization of immunosuppression. All patients entered a 28-day treatment-free follow up period after the last dose of study drug (Figure 1). Primary endpoint was time to platelet count response, defined as platelet count ≥ 150×109/L with stop of daily PE within 5 days. There were 4 key secondary endpoints, hierarchically ranked. The 1st was a composite of aTTP-related death, aTTP recurrence, or major thromboembolic event during the study drug treatment period. A blinded, independent committee adjudicated aTTP-related deaths and major thromboembolic events. The 2nd looked at recurrences during the entire study period, including the follow up period. The 3d evaluated refractoriness to therapy, defined as absence of platelet count doubling after 4 days of treatment and LDH still above normal. The 4th was the time to normalization of 3 organ damage markers: LDH, cardiac troponin I and serum creatinine.

Results: 145 patients were randomized, 73 to placebo and 72 to caplacizumab. Demographics and baseline disease characteristics were balanced between groups, except for a higher proportion of initial episodes in the caplacizumab arm. Compared to patients treated with placebo, those on caplacizumab were >50% more likely to achieve a platelet response at any given time point (platelet count normalization rate 1.55, 95% CI 1.10 – 2.20, p <0.01). During the study drug treatment period, treatment with caplacizumab resulted in a 74% reduction in TTP-related death, recurrence of TTP, or a major thromboembolic event (p <0.0001, Table 1). During the overall study period, 28 patients in the placebo group experienced a recurrence versus 9 patients in the caplacizumab group, a 67% reduction (p <0.001, Table 2). In all 6 caplacizumab-treated patients with a relapse during the follow up period, ADAMTS13 activity was still <10% at stop of study drug, reflecting ongoing disease. No caplacizumab-treated patients were refractory to therapy, while 3 patients on placebo were (p =0.057). Treatment with caplacizumab was associated with a trend toward faster normalization of the 3 organ damage markers. Safety is summarized in Table 3. In the caplacizumab group, the most common study drug-related TEAEs were epistaxis, gingival bleeding, and bruising. During the study drug treatment period, 3 patients on placebo died. One death occurred during the follow up period in a caplacizumab-treated patient and was assessed by the investigator as not related to study drug.

Conclusions: Results of the Phase 3 HERCULES study confirm that treatment with caplacizumab reduces the time to platelet count response, resulting in faster resolution of aTTP. Treatment with caplacizumab also resulted in a highly clinically meaningful reduction in aTTP-related death, recurrence of aTTP, or a major thromboembolic event during study drug treatment. The relapses after stop of study drug in patients with ADAMTS13 activity <10% suggest that treatment should be continued until complete resolution of the underlying disease. Caplacizumab has a favorable safety profile, with mucocutaneous bleeding the most frequently reported AE. Caplacizumab, through rapid blocking of vWF-mediated platelet aggregation, represents a novel treatment option for patients with aTTP. ( NCT02553317)

Characterizing the United Kingdom Congenital Thrombotic Thrombocytopenic Purpura Population

Result Type: Paper
Number: 3616
Presenter: Ferras Alwan
Program: Oral and Poster Abstracts
Session: 311. Disorders of Platelet Number or Function: Poster III

Ferras Alwan, MBBS1, Chiara Vendramin1*, Ri Liesner2*, Tina Dutt3*, Amanda Clark4*, Jayashree Motwani5*, Will Lester6*, Vickie McDonald7*, Rachel Rayment8*, Nichola Cooper, MA, MD, MRCP, FRCPath9, Richard Gooding10*, Hamish Lyall11*, Tina Biss, MD12*, Joost van Veen13*, Henry G Watson14*, John-Paul Westwood1*, Mari Thomas1,15*and Marie Scully, MD1,15*

1Department of Haematology, University College London Hospitals NHS Trust, London, United Kingdom
2Haemophilia Comprehensive Care Centre, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom
3Royal Liverpool University Hospital, Roald Dahl Haemostasis and Thrombosis Centre, Liverpool, United Kingdom
4Bristol Haematology Oncology Centre, Bristol, GBR
5Birmingham Children’s Hospital, Birmingham, United Kingdom
6Queen Elizabeth Hospital Birmingham, Edgbaston, United Kingdom
7Guys and St Thomas’ NHS Foundation Trust, London, United Kingdom
8Cardiff & Vale University Health Board, Cardiff, United Kingdom
9Imperial College London, Imperial NHS Trust, London, GBR
10Leicester Royal Infirmary, Leicester, United Kingdom
11Norfolk and Norwich University Hospital, Norwich, United Kingdom
12The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom
13Royal Hallamshire Hospital, Sheffield, United Kingdom
14Department of Haematology, Aberdeen Royal Infirmary, Abderdeen, United Kingdom
15University College London (UCL) Hospitals/UCL Biomedical Research Centre, National Institute for Health Research Cardiometabolic Programme, London, United Kingdom


Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare thrombomicroangiopathy in which there is an inherited deficiency of ADAMTS13. The prevalence of cTTP has been estimated at one per million per year and accounts for 5-10% of all TTP cases in international registries. Two main peaks of presentation are seen, in childhood and in pregnancy. The ADAMTS13 gene consists of 29 exons whilst the ADAMTS13 protein consists of 16 domains. Over 150 mutations spanning the entire length of ADAMTS13 have been discovered, but there is little evidence on their respective impact on the disease phenotype and evidence is lacking on the optimal management of patients.

Since January 2009, the United Kingdom TTP registry has been collecting information on all acute presentations of TTP across the country. Whilst patients were primarily taken from the registry, additional cases from before its formation were also identified from the major TTP treating centers in the UK. Using this combined cohort we undertook a review of all suspected cases of congenital TTP to evaluate the potential impact of the genotype on disease outcomes.

Method: Congenital TTP was considered in patients who presented with thrombocytopenia and microangiopathic hemolytic anemia with ADAMTS13 protease activity below 10IU/dL (NR: 60-146IU/dL) and no evidence of anti-ADAMTS13 IgG antibodies. Prior to Sanger sequencing, DNA was extracted from whole blood samples and the 29 ADAMTS13 exons amplified using a polymerase chain reaction method and custom oligonucleotide primers. NCBI NG_011934.2 was used as the reference sequence.

Results: 69 patients from across the United Kingdom were confirmed to have congenital TTP by genetic analysis. Of those diagnosed in childhood 68% were male whilst 93% diagnosed in adulthood were female. 36% of patients had symptom onset in the neonatal or childhood period and 41% first experienced symptoms in pregnancy. 32% had homozygous mutations, 43% were compound heterozygotes and the remaining patients had insertion or deletion mutations. The most common mutation seen was the exon 24 R1060W missense mutation (rs142572218).

Over two thirds of pre-spacer mutations were seen in patients who first presented with TTP symptoms in childhood. Those seen in adult presentations were all heterozygote mutations and in all but three cases, the accompanying mutation was the rs142572218 (R1060W) mutation presenting in pregnant women. 95% of patients with first presentation in adult life had a mutation in post spacer exons.

62% of all patients received regular prophylactic therapy with the intermediate purity Factor VIII concentrate, BPL 8Y, the most common choice for children and solvent/detergent fresh frozen plasma (SD-FFP) for adults. 72% of patients had treatment during their pregnancy with 41% continuing with regular prophylactic SD-FFP treatment postpartum. Half of these patients needed treatment for persistent thrombocytopenia whilst the other half were symptomatic patients with normal platelet counts. The most common symptoms were persistent headaches and lethargy with considerable symptom improvement seen in all patients. Additionally, five patients were not diagnosed with cTTP until presenting with strokes; one aged 26, 2 in the 5th decade and 2 in the 6th decade who had both also had prior strokes when younger. All six gave clear histories of pregnancy loss with thrombocytopenia that were not linked to a cTTP diagnosis at the time. One patient died and the remaining four receive regular prophylactic therapy.

Conclusion: Pre-spacer mutations are more common in childhood presentations of congenital TTP and post-spacer mutations more common in adult presentations. Prophylactic treatment should be considered for symptomatic patients despite a normal platelet count. The cohort of cases presenting later in life with cerebrovascular events suggests prophylaxis in cases presenting in adulthood should be considered to prevent early morbidity. The data also suggests that routine laboratory parameters, including platelet count are not sensitive in identifying symptoms related to cTTP.

Relationship between Hospital Volume and Inpatient Mortality Among Patients Diagnosed with Thrombotic Thrombocytopenic Purpura (TTP) in the United States

Result Type: Paper
Number: 675
Presenter: Smith Giri
Program: Oral and Poster Abstracts
Session: 901. Health Services Research—Non-Malignant Conditions: Consultative Hematology

Smith Giri, MBBS1, Ranjan Pathak, MD2, Robert Franklin, MD3*, Nikolai A. Podoltsev, MD, PhD4, Scott Huntington, MD, MPH5, Kathan Dilipbhai Mehta, MBBS, MPH6 and Amer M. Zeidan, MD7

1Yale University School of Medicine, New Haven, CT
2Department of Hematology/Oncology, Yale School of Medicine, New Haven, CT
3University of Cincinnati, Cincinnati, OH
4Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT
5Department of Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT
6University of Pittsburgh Medical Center, Pittsburgh, PA
7Section of Hematology, Department of Internal Medicine, Yale Cancer Center, East Haven, CT


Introduction: Thrombotic Thrombocytopenic Purpura (TTP) is a hematological emergency with high inpatient mortality that requires prompt diagnosis and treatment. Studies outside the setting of hematologic emergencies have established hospital volume as a factor associated with clinical outcomes. We tested whether hospital volume was associated with important inpatient outcomes among patients with TTP

Methods: We utilized the Nationwide Inpatient Sample (NIS) to identify adult patients ≥18 years, diagnosed with TTP using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 446.6 from the years of 2010 to 2013. We only included patients who received therapeutic plasmapheresis (ICD-9-CM procedure code 99.71) during hospitalization to capture active cases of TTP and improve coding accuracy. Using unique hospital identifier, hospital volume was computed and defined as total hospitalizations for TTP per year. Hospital volume was then divided into four quartiles. The primary outcome of interest was inpatient mortality rate, with time to initiation of plasmapheresis as our secondary outcome. Baseline age, gender, race, demographics, insurance payer, hospital region, hospital type (rural versus urban, teaching versus non-teaching), and bed sizewere collected. All analyses were survey adjusted to account for the complex sampling nature of the database. Appropriate bivariate methods included ANOVA and tests of trend (nptrend). Mixed effects hierarchical logistic regression analysis was used to calculate adjusted odds ratio of in-hospital mortality adjusting for potential confounders at the patient level (age, race, comorbidity, gender, insurance status) and at the hospital level (hospital location, bedsize and teaching status). All p values were two sided and the level of significance was chose was 0.05.

Results: A total of 1128 unique hospitalizations for TTP were identified during the study period. The mean age was 46.3 ± 16.6 years, out of which 66% were females (n=754) and 44% were whites (n=458). The overall inpatient mortality rate was 10.9%. The distribution of hospital volume by quartiles was as follows; 1st quartile, Q1 (2 or less hospitalizations of TTP per year), 2nd quartile, Q2 (3-5/year), 3rd quartile, Q3, (6-11/year), 4th quartile, Q4 (12 and above). The mean length of stay was 14.4 ± 11.5 days and the mean cost of hospitalization was $ 177546 ± 7736.

Overall there was decreasing trend in inpatient mortality with increasing hospital volumes (14.4% vs 12.8% vs 9.8% vs 6.5% from Q1-Q4 respectively; p trend 0.002). This effect was also retained in multivariate analysis adjusting for potential confounders (aOR 0.50; 95% CI 0.26-0.98; p 0.04) (Table 1). Also there was a decreasing trend in the time to plasmapheresis with increasing hospital volume (3.02 vs 2.48 vs 2.27 vs 2.09 from Q1-Q4 respectively, ANOVA p value 0.04) with post hoc analysis significant difference between 4th versus 1st quartile (Tukey p value 0.04).

Conclusion: In this retrospective cohort study using a large US inpatient database, we identified a significant association between hospital volume and inpatient mortality. Furthermore, plasmapheresis was initiated earlier in the hospital course at higher volume hospitals and provides a potential mechanism for the survival improvement.

Factors Associated with Mortality in Immune-Mediated Thrombotic Thrombocytopenic Purpura:  Results from the United States Thrombotic Microangiopathy TTP Registry

Result Type: Paper
Number: 3624
Presenter: Todd Clover
Program: Oral and Poster Abstracts
Session: 311. Disorders of Platelet Number or Function: Poster III

Todd Clover, MD, MS1,2, Ronald S. Go, MD3, Ana G. Antun, MD4, Spero R Cataland, MD5, Shruti Chaturvedi, MBBS, MS6, Elizabeth Davis, BA7*, Andrew Johnson, MD8*, Ming Yeong Lim, MBBChir9, Meera Sridharan, MD10, Keith McCrae, MD11, J. Evan Sadler, MD, PhD12, Marshall A. Mazepa, MD13 and Lisa Baumann-Kreuziger, MS MD14*

1Blood Center of Wisconsin, Medical College of Wisconsin, Milwaukee, WI
2Medical College of Wisconsin, Milwaukee, WI
3Division of Hematology, Mayo Clinic, Rochester, MN
4Emory University, Atlanta, GA
5Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
6Vanderbilt University, Nashville, TN
7University of Minnesota, Minneapolis, MN
8University of Minnesota, MInneapolis, MN
9Department of Medicine, Division of Hematology/Oncology, Medical University of South Carolina, Mount Pleasant, SC
10Mayo Clinic, Rochester, MN
11Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
12Washington University in St. Louis, St. Louis, MO
13University of Minnesota, Minneaplis, MN
14Blood Center of Wisconsin, Milwaukee, WI


Background: Thrombotic Thrombocytopenic Purpura (TTP) is a life threatening microangiopathy used by a deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). ADAMTS13 cleaves von Willebrand factor, and ADAMTS13 deficiency leads to an excess of high molecular weight multimers of von Willebrand factor which, in turn, causes platelet aggregation and congestion in small arteries and organ damage. TTP occurs in two forms: inherited due to a congenital defect in either production or function of the protein, and immune-mediated due to autoantibody formation either leading to immune clearance or inhibition of the function of the enzyme. TTP is a medical emergency and if untreated carries a mortality rate of approximately 90 percent. Current therapies (plasma exchange, immunomodulatory agents) have improved outcome in this disease, but mortality remains unacceptably high at approximately 10 percent. Attempts have been made to identify factors placing patients at higher risk for adverse outcomes, perhaps signaling the need for more aggressive treatment in these patients.

Design and Methods: We queried the United States Thrombotic Microangiopathy (USTMA) immune-mediated TTP registry which currently contains data from 181 patients with 316 distinct episodes of TTP in order to evaluate the French TMA consortium predictive model and identify additional factors associated with mortality.(Benhamou, 2012) There were 269 TTP episodes in 149 patients with sufficient data available to calculate the prognostic scoring system under review. Clinical and demographic variables from episodes resulting in death less than thirty days from diagnosis were compared with those in which patients survived. In the group of patients succumbing to the disease (n=13), 3 had multiple episodes of TTP captured in the registry. For two patients, episodes of TTP were separated by greater than 12 months. For a third patient, the initial episode of TTP was followed by an early relapse resulting in death 29 days after the first day of the first event. This death was counted once and attributed to the second episode.

Results: There were thirteen deaths in the cohort, yielding a mortality of 4.8%. Demographic factors associated with mortality were increasing age (mean age 55 vs. 44, p=0.01), and male gender (46% vs. 25%, p=0.30). Precipitating factors (surgery, infection, new medication) were more often present in those succumbing to the disease than those surviving (46% vs. 27%, p=0.20). Presenting symptoms seen more frequently in the mortality group were fever (38% vs. 13%, p=0.02) and neurologic symptoms (77% vs. 47%, p=0.02). Patients in the mortality cohort were more likely to have abnormal renal function with a higher mean creatinine (1.91 vs. 1.23, p=0.0004) and a higher proportion of patients with a creatinine over 1.3 (61% vs. 32%, p=0.04). Elevated troponin was also more common in the mortality group (39% vs. 16%, p=0.05). A mortality risk score using LDH 10 times normal, CNS involvement and age was calculated for each patient. When applied to our patient population, we found this score to have a sensitivity (% non-survivors with score ≥ 3) of 23% compared to 52% previously reported. We calculate a specificity (% of survivors scoring < 3) of 87% which is similar to previous reports of 90%. The positive predictive value for mortality with a score greater than or equal to 3 was 8%, and the negative predictive value of a score less than 3 was found to be 96% in the USTMA registry, compared to 41% and 93% reported by the French TMA consortium.

Conclusion: We find lower rates of mortality in our patient population as compared to previously reported series. Increasing age, neurologic involvement, renal dysfunction, and cardiac involvement seem to herald increase risk of early mortality. Sensitive tools to identify those at highest risk remain elusive.

External Validation of the Plasmic Score: A Clinical Prediction Tool for Thrombotic Thrombocytopenic Purpura (TTP) Diagnosis and Treatment

Result Type: Paper
Number: 3646
Presenter: Ang Li
Program: Oral and Poster Abstracts
Session: 311. Disorders of Platelet Number or Function: Poster III

Parisa R Khalighi, BS1, Qian Wu, PhD2*, David A. Garcia, MD3 and Ang Li, MD3

1Case Western Reserve University School of Medicine, Cleveland, OH
2Fred Hutchinson Cancer Research Center, Seattle, WA
3University of Washington School of Medicine, Seattle, WA


Introduction: Acquired thrombotic thrombocytopenic purpura (TTP) is a rare hematologic disorder whose hallmark is severe ADAMTS13 protease deficiency. Bendapudi et al. recently published a validated clinical algorithm known as the PLASMIC score which was shown to be an excellent tool to distinguish patients with severe ADAMTS13 deficiency from those without (Lancet Haematol 2017;4:e157). While the score is prognostic for survival, it remains unclear if it can also serve as a marker predictive for response to plasma exchange (PEX) such that it may be safe to withhold treatment in the lower-risk group. In this independent external validation of the PLASMIC score, we aim to reproduce its prognostic value for TTP diagnosis and examine for the first-time its predictive value for response to PEX.

Methods: We performed a retrospective study of all consecutive patients with at least 1 ADAMTS13 activity testing from 2007 to 2016 from the University of Washington Medical Center. We excluded patients who did not meet laboratory criteria of microangiopathic hemolytic anemia (MAHA) or had inappropriate assay testing (Figure 1) but included patients who received prior fresh frozen plasma (FFP). Severe deficiency was defined as an ADAMTS13 activity level <15% in this study given possible interference from FFP. We collected clinical and diagnostic information similar to the original PLASMIC score manuscript. We tested the PLASMIC score model for discrimination with c statistic (bias-corrected 95% confidence interval) and goodness-of-fit validity with calibration curve and Hosmer-Lemeshow (HL) test. Kaplan Meier estimator was used for survival analysis.

Results: We identified 112 patients who met the appropriate MAHA criteria out of 239 consecutive patients (Figure 1). Among them, 108 (96%) had complete data for all 7 components of the PLASMIC score assessment. Twenty-seven patients received FFP prior to ADAMTS13 testing. Twenty patients had severe ADAMTS13 deficiency (including 2 patients with activities >10% at 11% and 12%). The percentage of patients receiving PEX treatment and the distribution of clinical diagnoses in each group were summarized in Table 1.

The PLASMIC score stratified 108 patients into 3 risk categories (Table 1). When dichotomized at high (score 6-7) versus low-intermediate risk (score 0-5), the model predicted severe ADAMTS13 deficiency with positive predictive value of 72%, negative predictive value of 98%, sensitivity of 90%, and specificity of 92%. The 7-point PLASMIC score model had excellent discrimination with a c statistic of 0.94 (0.88-0.98). Furthermore, the 3-category risk stratification had a near-perfect moderate calibration curve (HL test P of 0.79).

We then examined the treatment effect of PEX on survival probability separately in the high-risk (6-7) and low-intermediate risk (0-5) groups (Figure 2). In the high-risk group, despite the limited numbers, treatment with PEX versus not led to significantly improved survival (log-rank P of <0.01). In contrast, in the low-intermediate risk group where patients were predicted to not have severe ADAMTS13 deficiency, treatment with PEX versus not did not have a significant impact on the survival (log-rank P of 0.50).

Conclusion: In our independent external validation study of the PLASMIC score extended to include patients with prior FFP, the high-risk group (6-7) correlated well with severe ADAMTS13 deficiency and showed the expected response to PEX. In contrast, the low-intermediate risk group (0-5) had high negative predictive value for ADAMTS13 deficiency and showed a lack of response to PEX. Given these observations, the current PLASMIC score risk categories appear to be diagnostic for TTP with severe ADAMTS13 deficiency and potentially predictive for PEX treatment response. The ease of calculating the score makes this a valuable clinical tool when ADAMTS13 testing is not available and urgent therapy is needed.

Atypical Hemolytic Uremic Syndrome-Clinical Presentation, Treatment, and Short Term Outcomes: The Mayo Clinic Experience

Result Type: Paper
Number: 2317
Presenter: Meera Sridharan
Program: Oral and Poster Abstracts
Session: 311. Disorders of Platelet Number or Function: Poster II

Meera Sridharan, MD1, Roshini Abraham, PhD1, Hatem Amer, MD1*, Fernando Fervenza, MD1*, C. Christopher Hook, MD2, Nelson Leung, MD3, Ariela L. Marshall, MD3, David L. Murray, MD, PhD4*, Rajiv K. Pruthi, MBBS3, Sanjeev Sethi, MD PhD5*, Maria Alice V. Willrich, Ph.D.1*, Jeffrey L. Winters, MD6 and Ronald S. Go, MD1

1Mayo Clinic, Rochester, MN
2Division of Hematopathology, Special Coagulation Laboratory, Mayo Clinic, Rochester, MN
3Division of Hematology, Mayo Clinic, Rochester, MN
4Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
5Mayo Clinic, Rochester
6Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN


Background: Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA) with an incidence of 1-2 cases per million. It is characterized by dysregulation of the alternative pathway of complement. Here we describe the clinical presentation and management of 25 patients with a diagnosis of aHUS including symptom presentation, complement serologic and genetic testing, and treatment (tx) approaches with total plasma exchange (TPE) and eculiuzmab (E).

Methods: In this retrospective study, after IRB approval, the electronic medical record was searched from 2011-2016 for patients with a clinical dx of aHUS. Inclusion criteria included: 1) presence of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia and/or pathologic evidence of TMA 2) ADAMTS13≥10%. Exclusions included 1) TMA secondary to other causes (hemolytic uremic syndrome, hypertension, scleroderma, bone marrow transplant, and medications). 2) Status post renal transplant or initial presentation to our institution for renal transplant.

Results: 25 aHUS patients (17 female) met our criteria. Of these, 16, median 40.5 (0-66) years old received initial diagnosis and management of aHUS while hospitalized (group 1) and 9 patients, median [42 (16-70)] years, were seen in the clinic after having been previously diagnosis with TMA elsewhere (group 2). Three had surgery 6-29 days prior to clinical presentation. Procedures included total knee arthroplasty, hysterectomy, and appendectomy. Ten patients had infections (7-80) days prior to presentation. Presenting symptoms in group 1 included fever (n=2), confusion (1), seizure (1), intractable headache (3), chest pain (2), abdominal pain (6), fatigue (3), and shortness of breath (2). Laboratory evaluation is presented in Table 1 and 2. Median ADAMTS13 at presentation in group 1 was 57 (22-91)%. Complement genetic testing was completed on 88% of patients. Pathogenic complement mutations (PCM) and variants of unknown significance (VUS) were each identified in 10 patients and two had no relevant complement genetic variants identified (Table 3). Four variants in CFH, classified as VUS, were novel variants but predicted to be pathogenic by in silico analysis. Renal biopsy was available on 18 patients, all with pathologic evidence of TMA.

11 patients received TPE and 10 had platelet (plt) recovery 9(1-16) days after initiation of TPE. Duration of daily TPE was 8 (1-10) days. 7 received prednisone (1mg/kg) for a total duration of 10 (1-27) days. In group 1, E was initiated in 10 patients 14(3-67 days after presentation). 5 started E despite plt recovery given worsening renal function and laboratory evidence of MAHA. In group 2, 8 were treated with E. 5 were started on E 43-187 days prior to initial visit while 3 were started on E at the visit because of worsening renal function. 77.8% of patients started on E had a PCM or VUS.

6 patients in groups 1 and 2 had neurological symptoms including vision changes (1), seizure (3), stroke (2), and posterior reversible encephalopathy syndrome (3). 15 required hemodialysis (HD). At last follow up (fu), 10/18 patients remained on E and 5 of these had fu 4 (1.63-55.8) months after initial presentation. Of those still on E, 5/ 9 remained on HD at last fu. Two underwent renal transplant (one had relapsed after stopping E and one in a patient whose renal function did not improve despite E). Of those alive, 7 discontinued E with total duration of tx ranging from < 1 month to 6 months (Figure 1). In those discontinuing E, 50% stopped HD with total HD duration of 3-31 days. There was one relapse in fu time. Of 25 patients, there were two deaths within acute tx of aHUS and two additional deaths during fu.

Conclusion: aHUS has a heterogeneous clinical presentation and response to tx. Complement serology in our study were variable, however complement serology was not always assessed prior to tx. PCM were present in 10 patients and 4 novel VUS in CFH were noted. Though TPE resulted in plt recovery in 91% of cases, it was not always sufficient for reversal of end organ damage. Addition of E led to renal recovery in 53% of those requiring HD.

Outcomes for Atypical Hemolytic Uremic Syndrome (aHUS) Treated with Eculizumab: A Single Center Analysis

Result Type: Paper
Number: 2331
Presenter: Julia Cunningham
Program: Oral and Poster Abstracts
Session: 311. Disorders of Platelet Number or Function: Poster II

Julia M Cunningham, MD1, Jaeil Ahn, PhD2* and Catherine Broome, MD3

1Georgetown University Hospital, Washington, DC
2Georgetown University, Washington
3Division of Hematology, Georgetown University, Washington, DC


Introduction: AHUS is a rare thrombotic microangiopathy (TMA), classically defined as microangiopathic hemolytic anemia, thrombocytopenia, and end-organ damage caused by alternative complement pathway abnormalities. Complement amplifying conditions (CACs) have been demonstrated to provoke or be associated with the emergence of aHUS manifestations, but their presence has also been associated with longer time to treatment initiation despite similar clinical presentation. (Cunningham et al. ASH 2016) Prior to effective therapy, more than half of patients progressed to death or end-stage renal disease within one year. (Noris et al. CJASN 2010) Eculizumab (ECU), a monoclonal C5 inhibitor, was approved for the treatment of aHUS in 2011. (Legendre et al. NEJM 2013) Here we report the results of the largest retrospective, single center series in the literature to date of 52 patients diagnosed with aHUS treated with ECU.

Methods: We performed a retrospective chart review of all patients diagnosed with aHUS who received at least one dose of ECU between December 2011 and February 2017 at MedStar Georgetown University Hospital.

Results: Fifty three patients received at least one dose of ECU for the treatment of aHUS between December 2011 and February 2017. One patient received a single dose of ECU, but was later found to have an ADAMTS13 level <5% and was removed from further analysis.

CACs were identified in 71% of the 52 patients and 29% had de novo aHUS. Ninety percent of patients received ≥1 month of ECU and 40% remain on chronic ECU therapy through 15 February 2017. Of the 21 patients on chronic therapy, 67% had CACs and 33% did not. Of the 31 patients not currently known to be on therapy, 81% discontinued therapy or died and the treatment status was unknown in 19%. Six patients (12%) are deceased.

Forty three patients were diagnosed while inpatients. Patients with CAC-associated aHUS had more pre-treatment days in the hospital than patients with de novo aHUS (35.73 and 12.92 days, respectively, p = 0.02). The lengths of hospital stays after ECU initiation were similar: 33.1 and 27.5 days, respectively. Presenting organ system involvement and laboratory data, including hemoglobin, platelet count and creatinine, were similar. (Table 1.) When adjusted for other variables, mean hemoglobin at presentation was lower in patients with CACs (p = 0.049). (Table 2.) After ECU initiation, similar trends in improvement of hemoglobin, platelet count, and creatinine were observed. (Figure 1)

Hemodialysis (HD) rates prior to ECU initiation were similar regardless of CAC status. (Table 1.) Thirty five percent were started on HD either prior to or on the day of ECU initiation. Seventeen patients remained on HD one month post ECU, 14 of whom received ≥1 month of ECU. Eleven patients remained on HD ≥ 3 months post ECU, 6 /11 received ≥ 3 months of ECU, 3/11 received ≤ 3 months of ECU, and 2/11 were lost to follow-up. Three patients were on HD ≥1 month but ≤ 3 months; 1 remained on ECU through the 3 month time-point and two discontinued ECU after 4 and 5 weeks of therapy. Three patients on HD at 1 month were subsequently lost to follow-up.

Six patient deaths (12%) were observed during the period of follow-up: 5 of 37 patients with CACs (14%) and 1 of 15 (6%) with de novo aHUS. CACs observed in the patients who died were non-renal solid organ transplant in 2 patients, renal transplant, rheumatoid arthritis, and ulcerative colitis. These patients had documented TMA involvement of between 2-5 organ systems. Survival after ECU initiation ranged from 2 to 24 weeks in the CAC associated group. The single patient death in the de novo aHUS group occurred at 20 weeks of follow-up. Four of the 6 patients remained on ECU through the date of death, including the single observed death in the de novoaHUS group, and 2 patients discontinued ECU after 4 and 9 weeks.

Conclusion: In a single center non clinical trial setting both CAC associated and de novo aHUS can be effectively treated with ECU. CAC status did not affect presentation characteristics. CAC status did not correlate with hematologic or creatinine response to ECU therapy. Our results suggest a higher rate of death among the CAC-associated aHUS patient population perhaps reflecting a longer time to diagnosis. Most patients remain on long-term therapy, regardless of CAC status at the time of diagnosis.

Response Rates, Non-Relapse Mortality, and Financial Implications of Transplant-Associated Thrombotic Microangiopathy Treated with Eculizumab

Result Type: Paper
Number: 1932
Presenter: Sumithira Vasu
Program: Oral and Poster Abstracts
Session: 721. Clinical Allogeneic Transplantation: Conditioning Regimens, Engraftment, and Acute Transplant Toxicities: Poster I

John L Vaughn, MD1, Qiuhong Zhao, MS2*, Parvathi Ranganathan, PhD3, Patrick Elder3*, Basem M. William, MRCP, MD4, Marcin Puto, PharmD3*, Julianna Roddy, PharmD3*, Rebecca Klisovic5*, William Blum, MD6, Don M Benson Jr., MD, PhD3, Samantha M. Jaglowski, MD, MPH3, Alice S. Mims, MD, MSCR7, Jonathan E. Brammer, MD8, Bhavana Bhatnagar, DO9, Yvonne A Efebera, MD3, Craig C Hofmeister, MD10, Leslie A Andritsos, MD1, Sam Penza, MD2, Alison R. Walker, MD11, Steven M. Devine, MD12, Spero R Cataland, MD2 and Sumithira Vasu, MD, MBBS2

1Division of Hematology, The Ohio State University, Columbus, OH
2Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
3The Ohio State University, Columbus, OH
4The James Cancer Center, Ohio State University, Columbus, OH
5Emory University, Atlanta, GA
6Emory University, Atlanta
7Division of Hematology, Department of Internal Medicine, The Ohio State University James Comprehensive Cancer Center, Columbus, OH
8Ohio State University, Columbus
9The Ohio State University, Belle Vernon, PA
10The Ohio State University, Atlanta, GA
11Division of Hematology, Department of Internal Medicine, The Ohio State Univ. Medical Ctr., Columbus, OH
12The Ohio State University Comprehensive Cancer Center, Columbus, OH


Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) shares common features with atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura. TA-TMA affects multiple organ systems resulting in multi-organ failure and non-relapse mortality (NRM). Recently, complement activation has been associated with TA-TMA leading to utilization of complement blockade in TMA. Eculizumab is a humanized monoclonal antibody that binds to C5 and prevents the formation of the membrane attack complex (C5b-9) or the terminal complement pathway. Eculizumab may be an effective treatment for pediatric TA-TMA patients; however, there are limited data regarding its use in adult TA-TMA patients. Furthermore, eculizumab is an expensive medication and there are no published data regarding the financial implications of TA-TMA treated with eculizumab. The purpose of this study was to examine the response rates, NRM, and financial implications of TA-TMA treated with eculizumab.

Methods: We performed a retrospective cohort study of patients with TA-TMA who received eculizumab at our institution between January 1, 2012, and April 9, 2017. TA-TMA was defined according to the BMT-CTN criteria with evidence of hemolysis, elevated LDH, renal dysfunction and negative Coombs’ test. Serum complement biomarkers (C5b-9) were used to support the diagnosis when platelet or red blood cell transfusion dependence occurred with organ dysfunction or tissue evidence of microangiopathy. Patients were vaccinated against Neisseria meningitides and received appropriate antibiotic prophylaxis. Eculizumab therapy was initiated at the Food and Drug Administration-approved dosing schedule for aHUS: 900 mg intravenously weekly for the first 4 weeks followed by 1200 mg intravenously every other week beginning on week 5 for a total of 8 weeks, with some patients requiring longer than an 8 week course. The primary outcome was complete response to eculizumab therapy and responders were defined by achievement of transfusion independence and improvement in creatinine. Secondary outcomes included non-relapse mortality (NRM), inpatient cost, number of comorbidities, number of infections, number of hospitalizations, and hospital length of stay (LOS). Comorbidities were defined as any documented medical problem other than the reason for transplant and TA-TMA.

Results: Twenty patients were included in the study (Table 1). The median (range) time from transplant to diagnosis of TA-TMA was 139 (14-388) days. The median (range) time from diagnosis of TA-TMA to first dose of eculizumab was 2 (0-272) days. The complete response rate was 55%. The median (range) number of doses of eculizumab was 6.5 (2-17) for responders compared to 3 (1-7) for non-responders including both inpatient and outpatient doses (p = 0.01). There were no significant differences between the number of hospitalizations for responders and non-responders. However, responders had shorter LOS and lower inpatient costs than non-responders. The median (range) LOS was 9 days (0-92) for responders compared to 61 days (26-94) for non-responders (p = 0.03). The median (range) total inpatient cost was $259,734 (0-1,670,070) for responders compared to $1,525,758 (385,092-1,948,190) for non-responders (p = 0.003). The itemized inpatient costs are shown in Figure 1. Patients who responded to eculizumab tended to be younger with less comorbidities. In fact, patients were 33% less likely to respond to eculizumab for every additional documented comorbidity at the time of TA-TMA diagnosis (HR=0.67 [95% CI 0.49-0.92]). The NRM was 1/11 (9%) for responders and 9/9 (100%) for non-responders (HR=0.07 [95% CI: 0.007-0.66]).

Conclusions: TA-TMA is an important complication of HCT that is associated with high NRM and financial toxicity. Our data suggests that patients who respond to eculizumab have lower NRM, LOS, and financial costs than non-responders. There was a statistically non-significant trend in incidence of steroid-refractory GVHD in the non-responder group; additionally non-responders received significantly fewer doses than responders, which may explain partly the lower response rates compared to the 80% response rates in aHUS. Patient age and the number of comorbidities at the time of diagnosis of TA-TMA may be important predictive factors for response to eculizumab.