ohio state's ash review 2017 - benign hematology

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Ohio State 2016ASH Review: Benign Hematology

Spero R. Cataland, M.D.Professor of Clinical Internal MedicineDivision of HematologyOhio State University


SUSTAIN: A Multicenter, Randomized, Placebo-Controlled, Double-Blind, 12-Month Study to Assess Safety and Efficacy of SelG1 with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle Cell-Related Pain Crises

Kenneth I. Ataga, MD, Abdullah Kutlar, MD, Julie Kanter, MD, Darla Liles, MD, Rodolfo Cancado, M.D., Ph.D., João Friedrisch, MD, PhD, Troy H. Guthrie, MD, Jennifer Knight-Madden, MBBS, PhD, Ofelia A. Alvarez, MD, Victor R. Gordeuk, MD, Sandra Gualandro, MD, PhD,MarinaPereira Collela, MD, PhD, Wally R. Smith, MD, Scott A. Rollins, PhD, Jonathan W. Stocker, PhD and Russell P. Rother, PhD

Adhesive interactions involving SS RBCs. (A) Multiple interactions between SS RBCs and endothelial cells, extracellular matrix, and plasma proteins.

Marilyn J. Telen Blood 2016;127:810-819

©2016 by American Society of Hematology

Double-blind, placebo-controlled, multinational study 16 to 65 years of age Diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia or HbSβ+ thalassemia) 2 to 10 SCPC in the previous 12 months. Patients receiving HU or erythropoietin eligible

On therapy for at least 6 months and dose was stable for at least 3 months.

Patients were randomized to receive placebo, 2.5 mg/kg or 5.0 mg/kg SelG1 Initial dose, dose 14 days later, and then every 4 weeks through week 50

Primary Endpoint: Annual rate of SCPC in the 5.0 mg/kg SelG1 group vs. placebo

Secondary Endpoints: Days hospitalized, time to 1st and 2nd SCPC Number of uncomplicated SCPC

4

Study Design/Eligibility Criteria

Sustain Study Results

Ataga KI et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1611770

Kaplan–Meier Curve for the Median Times to the First Sickle Cell–Related Pain Crises


A Prospective, Randomized Study of Cyclosporine or Corticosteroids as an Adjunct to Plasma Exchange for the Treatment of Acquired TTP

Spero R. Cataland, Shangbin Yang, Camila Masias, Peter J. Kourlas, Michael McGookey, Lauren Jay, Haiwa Wu, Susan Geyer, James N. George, and Haifeng Wu*

*Deceased

Study based upon results of two single arm studies of cyclosporine (CSA) or prednisone (Pred) as adjuncts to plasma exchange therapy (PEX)1

Exacerbation rates in each study1 :− Pred/PEX 6/10 (60%)− CSA/PEX: 0/8 (0%)

Study objectives: Primary:

Exacerbation rate CSA/PEX v. Pred/PEX − Recurrent thrombocytopenia requiring PEX in <30 d. after the

last PEX procedure Secondary

Comparative effect on: − ADAMTS13 activity, inhibitor titer, and inhibitor concentration

7

Study Rationale and Objectives

1. Cataland et al. BJH October 2006. p.146-9.

8

Study Methods: Treatment Plan

EligibilityClinical diagnosis of Acquired TTP

-(MAH, Platelet <100K)

-Additional explanations excluded

-Serum Creatinine <2.5 mg/dl

Plasma Exchange(1.0 Plasma Volume)

Daily until Remission:− Normal platelet count

and LDH

Cyclosporine

2-3 mg/kg/day for 6 months

Prednisone

1 mg/kg/day for 1 month

(tapered over 4 weeks)

+

+

9

Clinical and ADAMTS13 Outcome Data

* One death in each arm of study** 2 patients refractory to prednisone crossed over to CSA arm

10

Results: Anti-ADAMTS13 IgG : First 30 Days and Beyond

0.0

10.0

20.0

30.0

40.0

50.0

60.0

Pre‐Treat week 1 week 2 week 3 week 4

Anti‐AD

AMTS13

IgG

(1.1‐11.8 U/m

l)

CSA

Prednisonep=0.339

p=0.342p=0.029

p=0.028 p=0.039

*Week 1 sample at least 5 days after last PEX procedure

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

1 2 3 4 5 6

Anti‐AD

AMTS13

IgG

(Normal 1.1‐11.8)

Months Since Remission

CSA

Prednisone

p=0.039

p=0.086

p=0.480 p=0.865 p=0.850 p=0.302

Study confirms the role of immune suppressive therapy with Pred as an adjunct to PEX

No significant difference in the exacerbation rates between the CSA/PEX and Pred/PEX treated patients

− Suggestion of lower exacerbation rate on Pred/PEX arm− Increases in ADAMTS13 activity and decline in anti-ADAMTS13 antibodies significantly

better with Prednisone v. CSA over the first 30 days

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Conclusions


Splenectomy or Rituximab in Steroid-Refractory Immune Thrombocytopenia (ITP): The Mayo Clinic Experience

William A. Hammond, MD, Elisa M. Rodriguez, Zhuo Li, M.S, Bhagirathbhai Dholaria, MBBS, Amanda Shreders, MD, Prakash Vishnu, MD and Candido E. Rivera, MD

Study Design

Retrospective cohort study of adults with ITP Treated at one of the Mayo Clinic sites (Arizona,

Florida, or Minnesota) between 1990 – 2015 Received second-line treatment with either rituximab

or splenectomy Primary end-points were freedom from relapse after

2nd and 3rd line treatment with rituxumab or splenectomy

Response = platelet count >30,000

Results

222 ITP patients: 191 primary and 31 secondary Splenectomy patients were younger at diagnosis (49

vs 60 years, P=0.003) and time of 2nd line treatment (51.5 vs 61 years, P=0.018)

Splenectomy patients: More likely to achieve CR (86.6% vs 44%, P<0.0001) Higher 5y freedom from relapse (53.57% v. 14.96%,

P<0.0001).

Data remained similar when primary ITP and secondary ITP were considered seperately

Splenectomy v. Rituximab: Long-Term Outcomes


Rivaroxaban versus Fondaparinux in the Treatment of Superficial Vein Thrombosis – the Surprise Trial

Jan Beyer-Westendorf, MD, Sebastian Schellong, MD, Horst Gerlach, MD, KatjaJersemann, Eberhard Rabe, MD, Kurtulus Sahin and Rupert Bauersachs, MD, PhD

Study design

Randomized, open-label blinded evaluation, non-inferior comparison

Inclusion: Patients with SVT at high risk of VTE complications Supragenual SVT + Age > 65, male, h/o VTE, cancer,

autoimmune, non varicose veins Rivaroxaban 10 mg qd vs fondaparinux 2.5 mg qd for 45 d. Observed until 90 days

Primary efficacy outcome: Composite endpoint of DVT, PE, SVT progression and

recurrence, all cause mortality at day 45 Primary safety outcome: Major bleeding during treatment by ISTH criteria

Results

N=472 Rivaroxaban (n=211), Fondaparinux (n=224)

Mean age 60.3 years; 60.4% female, Mean treatment duration was 44 days

Day 45 primary efficacy outcome: 3.3% (95%-CI 0.90; 5.73) on rivaroxaban 1.8% (95%-CI 0.05; 3.52) on fondaparinux

p-value for non-inferiority 0.025

No major bleeding occurred Non-major, clinically relevant bleeding were 2.5% (R) vs. 0.4% (F) at d 45.

Results


Reversal of Betrixaban-Induced Anticoagulation in Healthy Volunteers By Andexanet Alfa

Mark Crowther, MD, Genmin Lu, PhD, Janet M. Leeds, PhD, Joyce Lin, BS, Pamela B. Conley, PhD, Alexander Gold, MD, Stuart J. Connolly, MD and John T. Curnutte, MD, PhD

Connolly SJ et al. NEJM 2016;375:1131-1141.

Andexanet alfa

• The ANNEXA-4 study (The Ability of Andexanet Alfa to Reverse the Anticoagulant Activity-4) study is to evaluate the efficacy and safety of andexanet for serious bleeding in patients on rivaroxban, apixaban, edoxaban, or enoxaparin

• Dose: a bolus followed by 2 hr infusion• Anti-Xa activity decreased by ~90% after infusion, with 79 achieving

effective hemostasis.

Anti–Factor Xa Activity and Percent Change from Baseline in Patients Receiving Rivaroxaban and Apixaban (Efficacy Population).

Connolly SJ et al. N Engl J Med 2016;375:1131-1141

• ANNEX-4 study, Multicenter, open label, ongoing study

• N = 67 with major bleeding who were on rivaroxaban, apixaban, edoxaban, or enoxaparin within the past 18 hr

• Effective hemostasis in 79%

Reversal of Betrixaban-Induced Anticoagulation

Betrixaban, a direct FXa inhibitor, recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX)

This is a study to test the reversal effects of andexanet again the new DOAC betrixaban in healthy volunteers Andexanet (n=13) v. placebo (n=6) Followed day 7 of betrixaban to steady state (80 mg/d)

Cohort 1: Andexanet 800 mg bolus 3 hours after last dose of betrixaban v. placebo Cohort 2: Andexanet 800 mg bolus 4 hours after last dose + 2 hr infusion (8mg/min) v. placebo

As prior studies on other anti-Xa inhibitors andexanet significantly and rapidly: Reduced the anti-Xa level, drug (betrixaban) concentrations, restored thrombin generation Could be a universal antidote for all four direct FXa inhibitors

apixaban, rivaroxaban, edoxaban, and betrixaban as well as indirect FXa inhibitors


Association of BW with Thromboembolic and Bleeding Outcomes in Phase III Randomized Controlled Trials of Direct Oral Anticoagulants: Systematic Review and Meta-Analysis

Kochawan Boonyawat, MD, Francois Caron, MD, Ang Li, MD, Chatree Chai-Adisaksopha, MD, Wendy Lim, MD, Iorio Alfonso, MD, PhD, Renato Delascio Lopes, MD, PhD, David A Garcia, MD and Mark Crowther, MD

Thrombotic outcomes – High body weight

• Meta Analysis of phase III RCT using DOACs for the prevention of stroke in AF and acute VTE

• Data on thromboembolic complications including stroke and VTE, and bleeding complications and comparator arm abstracted

• 9 Phase III RCT included:

Summary and Limitations

The “Obesity paradox” Patients with low body weight had an increased risk of

VTE The subgroup of AF patients with high body weight with

decreased risk of VTE There was no significant difference in the bleeding risk

in both low and high weight groups There was no interaction between types of

anticoagulation and thromboembolic outcomes This study supports fixed dose effects of DOACs Limitations: study level meta-analysis of subgroups Few extremely high weight patients

ohio state's ash review 2017 - benign hematology

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