2019-19 ash full-deck v2(withars)(12.5.19) …remaining up-to-date with advances in primary immune...

PARTICIPATING FACULTY

Satish Shanbhag, MBBS, MPH, FACP (Chair)Associate Professor of Medicine and Oncology

Johns Hopkins School of MedicineBaltimore, Maryland

James B. Bussel, MDEmeritus Professor of Pediatrics

Medicine and Obstetrics and GynecologyWeill Cornell Medicine

New York, New York

FULL DISCLOSURE POLICY AFFECTING CME ACTIVITIES – As a provider approved by the Accreditation Council for Continuing Medical Education (ACCME), Johns Hopkins University School of Medicine Office of Continuing Medical Education (OCME) requiresattested and signed global disclosure of the existence of all financial interests or relationships with commercial interest from any individual in a position to control the content of a CME activity sponsored by OCME.

The following relationships have been reported for this activity:

James B. Bussel, MD, reports receiving a consulting fee for serving on an advisory board for Amgen, Inc., Novartis AG, and Rigel Pharmaceuticals, Inc.; receiving a consulting fee for serving on an advisory board and as a consultant for Momenta Pharmaceuticals, Inc., and UCB, Inc.; receiving honoraria from Novartis AG; and for serving on the Data Safety Monitoring Board for CSL Behring.

Satish Shanbhag, MBBS, MPH, FACP, reports performing contracted research as a co-principal investigator for DaiichiSankyo Company Ltd and receiving consulting fees from GlaxoSmithKline and Takeda Pharmaceutical Company Limited.

No one else in a position to control the content of this educational activity has disclosed a relevant financial interest or relationshipwith any commercial interest.

Note: Grants to investigators at the Johns Hopkins University are negotiated and administered by the institution whichreceives the grants, typically through the Office of Research Administration. Individual investigators who participate in thesponsored project(s) are not directly compensated by the sponsor, but may receive salary or other support from the institutionto support their effort on the project(s).

POLICY ON PRESENTER AND PROVIDER DISCLOSURE – It is the policy of the Johns Hopkins School ofMedicine that the presenter and provider globally disclose conflicts of interest. The Johns Hopkins School of MedicineOCME has established policies that will identify and resolve conflicts of interest prior to this educational activity.Detailed disclosure will be made prior to presentation of the education.

DISCLOSURES

Registration and Lunch

Conference Goals and PreassessmentSatish Shanbhag, MBBS, MPH, FACP

Advances in Thrombocytopenia Management DuringElective Procedures in Liver DiseaseSatish Shanbhag, MBBS, MPH, FACP

Anticipating Bleed Risk to Inform Treatment Decision-Making:Appropriately Utilizing Available Laboratory Measures

Satish Shanbhag, MBBS, MPH, FACP

Thrombopoietin Receptor Agonists:Mechanism of Action and Rationale for Use

James B. Bussel, MD

Presentations 1-3: ARS Assessment and DiscussionFaculty Panel

AGENDA

(Continued on next slide)

Remaining Up-to-Date with Advances in Primary ImmuneThrombocytopenia Management

James B. Bussel, MD

Considering the Future of Thrombopoietin Receptor AgonistsJames B. Bussel, MD

Presentations 4-5: ARS Assessment and DiscussionFaculty Panel

Applying TRAs To Practice: Clinical Pearls for the HematologistJames B. Bussel, MD

Final Remarks and PostassessmentSatish Shanbhag, MBBS, MPH, FACP

Question and Answer SessionFaculty Panel

AGENDA (Cont’d)

After attending this activity, the participant will demonstrate the ability to:

• DESCRIBE hemostatic pathological processes contributing to bleeding/thrombosis in liver disease and available laboratory measures to assesscoagulation.

• EVALUATE the role efficacy and safety of second-generation recently approvedTRAs in the management of thrombocytopenia in adults with chronic liver disease.

• IDENTIFY strengths of currently approved TRAs and develop strategies to select aTRA based on patient and procedural factors.

• ASSES the potential of TRAs in the management of chronic immunethrombocytopenia, chemotherapy-induced thrombocytopenia, and severe aplastic anemia.

The Johns Hopkins School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.

LEARNING OBJECTIVES

ACCREDITATION STATEMENT – The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians..

CREDIT DESIGNATION STATEMENT – The Johns Hopkins School of Medicine designates this live activity for a maximum of 2.0 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

ACCREDITATION & CREDIT DESIGNATION STATEMENTS

The Johns Hopkins School of Medicine would like to acknowledge an

educational grant from Dova Pharmaceuticals

which helped to make this activity possible.

EDUCATIONAL GRANT

Advances in Thrombocytopenia Management During Elective Procedures in Liver Disease



Overview: Advances in Thrombocytopenia Management During Elective Procedures

in Liver Disease

• Pathophysiology of thrombocytopenia in liver disease and impact on treatment strategies

• Recognizing the efficacy and limitations of standard treatment

• Evaluating the potential of novel thrombopoietin receptor agonists

Pathophysiology of Thrombocytopenia in Chronic Liver Disease

Mitchell et al. Hepat Med. 2016;8:39–50. For educational purposes only.DITP = drug-induced thrombocytopenia; HCV = hepatitis C virus; ITP = idiopathic thrombocytopenic purpura; TPO = thrombopoietin.

Pathophysiology of Thrombocytopenia in Chronic Liver Disease

• 70% of patients with cirrhosis are thrombocytopenic• Degree of thrombocytopenia directly correlates with the

severity of liver disease

Mitchell et al. Hepat Med. 2016;8:39–50.

Normal Thrombopoiesis

G-CSF = granulocyte-colony stimulating factor. Maan et al. Drugs. 2015;75:1981–1992. For educational purposes only.

Etiology of Thrombocytopenia

in Liver Disease

Mitchell et al. Hepat Med. 2016;8:39–50. For educational purposes only.

Coagulopathy of Liver Disease

• ESLD/CLD leads to decreased levels of most procoagulant factors except factor VIII and VWF leading to bleeding

• ESLD/CLD also leads to reduced anticoagulants such as antithrombin and protein C

• Levels of ADAMTS 13, a naturally occurring plasma metalloprotease that limits the functions of VWF on platelets, are reduced in patients with cirrhosis, which may help restore platelet function

• PT/PTT are not great predictors of bleeding (GI or procedural)

ESLD/CLD = end-stage liver disease/chronic liver disease; GI = gastrointestinal; PT = prothrombin time; PTT = partial thrmobplastin time; VWF = von Willebrand factor.

Procoagulant and Anticoagulant Balance

Tripodi et al. N Engl J Med. 2011;365:147-156. For educational purposes only.

Coagulopathy of Liver Disease

• Thrombin generation in vivo and in vitro is down-regulated by thrombomodulin, a transmembrane protein on vascular endothelial cells, which activates protein C. Plasma and PT reagents do not contain thrombomodulin

• PT/PTT do not truly represent the balance of coagulation in vivo. Relative deficiency of both coagulation-system drivers makes the balance fragile in patients with liver disease and may tip it toward hemorrhage or thrombosis, depending on the prevailing circumstantial risk factors

Tripodi et al. N Engl J Med. 2011;365:147-156. For educational purposes only.TAFI = thrombin activatable fibrinolysis inhibitor; t-PA = tissue plasminogen activator.

aPTT = activated partial thromboplastin time.Ahmad et al. Coagulopathy of liver disease. In: Gonzalez et al, eds. Trauma Induced Coagulopathy. Switzerland: Springer International Publishing; 2016:471-482. For educational purposes only.

Tx of Chronic Thrombocytopenia in Liver Disease

Therapy Pros Cons

Lap splenectomy

• Effective in low splenic volume (<400 mL)

• Very effective

• Up to 15% complication rate• Intraoperative and postoperative

bleeding• 20%–50% portal/splenic vein

thrombosisPartial splenic artery embolization

• Low morbidity over splenectomy • Splenic abscess, peritonitis, and portal vein thrombosis

RFA of spleen • Low complication, convenience• High response rates (>70%) sustained

• Newer technique with limited availability

Platelet transfusion

• Effective • Temporary and c/b lack of response after multiple treatments. Treatment risks

TPO mimetics • Highly effective, safe even in poor surgical candidates

• Portal vein thrombosis

RFA = radiofrequency ablation.

Potential Role for TPO Mimetics

• Recombinant human thrombopoietin (rhTPO) and pegylated human recombinant megakaryocyte growth and development factor (Peg-rHuMGDF) highly effective, but neutralizing autoantibodies formed, showing cross-reactivity with endogenous TPO

• In the early 2000s, thrombopoietic agents that did not have any homology to endogenous TPO were developed.

• c-MPL receptor agonists successfully enhance platelet production.

TPO Mimetics/TRAs Approved forElective Procedures in CLD

Therapy Dosing Procedure Occurrence

Avatrombopag1 Platelet Count (x109/L)

1x Daily Dose Duration

5–8 days after last dose

<40 60 mg (3 x 20 mg)

5 days

40 to <50 40 mg (2 x 20 mg) 5 days

Lusutrombopag2 No platelet threshold indication; platelet count <50 evaluated in trials

1 x Daily Dose Duration 2–8 days after last dose3 mg 7 days

1. Highlights of prescribing information Doptelet (avatrombopag). Revised 6/2019. Dova Pharmaceuticals; 2. Highlights of prescribing information Mulpleta (lusutrombopag). Revised 5/2019. Shinogi Inc.

TRA = thrombopoietin receptor agonist.

Avatrombopag in CLD Clinical Trial OverviewProportion of Patients Not Requiring a Platelet Transfusion or Any Rescue Procedure for Bleeding

Low Baseline Platelet Count Cohort (<40 x109/L)

ADAPT-1 ADAPT-2

Treatment (60 mg) Placebo Treatment (60 mg) Placebo

Responders (%) 66 23 69 35

P value ˂.0001 <.001

High Baseline Platelet Count Cohort (≥40 to <50 x109/L)

ADAPT-1 ADAPT-2

Treatment (40 mg) Placebo Treatment (40 mg) Placebo

Responders (%) 88 38 88 33

P value ˂.0001 ˂.001

Avatrombopag [package insert]. Durham, North Carolina: Dova Pharmaceuticals; 2019; Terrault N et al. Gastroenterology. 2018;155:705-718.

• Treatment protocol: 40 mg or 60 mg TDD, taken 1x daily with meal for 5 days; procedure scheduled 5-8 days after last dose (could be delayed if pre-procedural platelet counts were ≥200 × 109/L)

• Incidence of treatment-related AEs comparable between all groups• Most AEs mild-to-moderate; most common: abdominal pain, dyspepsia, nausea, pyrexia, dizziness, headache

AE = adverse event; TDD = total daily dose.

Lusutrombopag in CLD Clinical Trial OverviewTrial Outcomes

L-PLUS 1

Not requiring platelet transfusion prior to invasive procedure* Responder† during study

Treatment (%) Placebo (%) Treatment (%) Placebo (%)

78 13 76 6

P ˂.0001 P ˂.0001

L-PLUS 2

Not requiring platelet transfusion prior to invasive procedure* or rescue therapy for bleeding from randomization through 7 days after

invasive procedureResponder† during study

Treatment (%) Placebo (%) Treatment (%) Placebo (%)

65 29 65 13P ˂.0001 P ˂.0001

Lusutrombopag [package insert]. Florham Park, NJ: Shionogi Inc; 2019; Izumi N, et al. Hepatology. 2015;62:1397A–1398A, Peck-Radosavljevi M, et al. Hepatology. 2019;70:1336-1348.

*A platelet transfusion was required if the platelet count was <50 x 109/L; †Platelet count reached at least 50 x 109/L and increased at least 20 x 109/L from baseline.

L-PLUS 2 = Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients wth Chronic Liver Disease Undergoing Elective Invasive Procedures.

• Treatment protocol: 3 mg once daily up to 7 days; procedure scheduled 2 to 8 days after last dose• Similar safety profile to placebo; headache most common AE vs placebo

Anticipating Bleed Risk to Inform Treatment Decision-Making:

Appropriately Utilizing Available Laboratory Measures



Overview: Anticipating Bleed Risk to Inform Treatment Decision-Making

• Assessing bleed versus thrombotic risk• Standard coagulation tests – PT/INR, aPTT• Platelet count• Viscoelastic tests – thromboelastography (TEG),

ROTEM

INR = international normalized ratio; ROTEM = rotational thromboelastometry.

Thrombosis in Liver Disease

• Portal vein thrombosis in 8%-25% of liver transplant candidates

• Reduced flow velocity + procoagulant imbalance + vessel-wall abnormalities (Virchow’s triad)

• Anticoagulation can be attempted when variceal bleeding is controlled and thrombocytopenia not severe – warfarin or heparin-based drugs.

• DOACs are liver metabolized – not advised in patients with Child-Pugh score worse than A.

DOAC = direct oral anticoagulants.

Tapper et al. J Hepatol. 2013;59:889-890. For educational purposes only.

Coagulopathy in Cirrhosis

Standard Coagulation Tests (PT, aPTT)

• The prothrombin time (PT) measures vitamin K–dependent factors (factors II, VII, IX, and X) and is an accurate predictor of liver damage and likelihood of progression to end-stage liver failure

• PT is incorporated into commonly used prognostic indices of CLD such as the Child–Pugh or Mayo End-Stage Liver Disease (MELD) scores

Standard Coagulation Tests• PT, aPTT were developed to investigate coagulation factor

deficiencies in patients with a bleeding history by providing an end-assessment of thrombin generation by fibrin formation.

• PT and aPTT do not assess the effect of fibrinolytic factors. So PT, aPTT do not mimic the process of clot formation in vivo, especially in cirrhotic patients and correlate poorly with procedure-related bleeding.

• Mild-to-moderate prolongation of PT/aPTT is not associated with prolonged bleeding following liver biopsy, but normal PT/aPTT does not indicate an absence of risk for post liver biopsy bleeding!

Dillon et al. J Gastroenterol Hepatol. 1994;9:269-271.

Whole blood clotting assays (TEG, ROTEM) assess overall

hemostasis including primary

hemostasis, coagulation, and

fibrinolysis

Northup et al. Clin Gastroenterol Hepatol. 2013;11:1064 –1074.

Fibrinolysis in Liver Disease – A

Complicated Story

• Fibrinogen is normal or increased in most patients with stable disease, but hypofibrinogenemia is seen with advanced cirrhosis (impaired synthesis, loss into ascites, and increased catabolism).

• Dysfibrinogenemia due to abnormal post-translational modification or excessive sialic acid content

• Hyperfibrinolysis is frequently seen in cirrhosis (decreased clearance of t-PA and reduced synthesis of a-2 antiplasmin and TAFI) and contributes to the increased bleeding.

• In balance, concentrations of plasminogen are reduced and PAI-1 are high in liver disease.

Thachil. Postgrad Med J. 2008;84:177–181. For educational purposes only.AP = antiplasmin; PAI-1 = plasminogen activator inhibitor-1; TAFI = Thrombin-Activatable Fibrinolysis Inhibitor.

Tests for Global Hemostasis (VHAs – TEG or ROTEM)

• Thromboelastograms analyze whole blood coagulation by including the effects of red blood cells and platelets along with the clotting factors, and could be a better measure than PT/aPTT

Olson JC. Clin Liver Dis. 2019;13:102-105. For educational purposes only.VHA = viscoelastic hemostatic assay.

Typical ROTEM Versus TEG Tracings

Anderson et al. J Cardiothorac Vasc Anesth. 2014;28:1550–1557. For educational purposes only.

Normal TEG from a patient with well-compensated (Child-Pugh class A)

alcoholic cirrhosis.

Abnormal TEG with low MA due to thrombocytopenia in a patient with mildly

decompensated (Child-Pugh class B) cirrhosis due to HCV.

Stravitz RT. Gastroenterol Hepatol. 2012;8(8 ):513-520. For educational purposes only.MA = maximum amplitude.

Abnormal TEG with high kinetic time, low α-angle, and low MA due to

thrombocytopenia and hypofibrinogenemia in a patient with severely decompensated (Child-Pugh

class C) alcoholic cirrhosis.

Stravitz RT. Gastroenterol Hepatol. 2012;8:513-520. For educational purposes only.

TEG in Cirrhosis

• Multiple small RCTs showing reduced blood factor replacement with using TEG-directed thresholds versus standard coagulation parameters (Wang 2010, Kumar 2014, Rout 2019, De Pietri 2016)

• TEG-based transfusion strategy can be safe and potentially beneficial in cirrhotic patients undergoing major hemostatic challenge (eg, liver transplant)

RCT = randomized controlled trial.

Discussion Section 1



Which treatment option are you MOST LIKELY to utilize to treat thrombocytopenia in your patients with chronic liver disease who are going for an elective surgical procedure?

1. Laparoscopic splenectomy2. Partial splenic embolization3. Platelet transfusion4. RFA of spleen5. Thrombopoietin receptor agonist

Which coagulation test(s) are you MOST LIKELY to use to inform the need for thrombocytopenia treatment in patients with chronic liver disease who will undergone elective surgery?

1. Prothrombin time (PT) aka International Normalized Ratio (INR) aka PT/INR

2. Prothrombin time (PT) or activated thromboplastin time (aPTT)

3. Whole blood clotting assay – ROTEM or TEG4. Another coagulation test not listed5. I would consult a colleague to determine which test

would be most appropriate

Which of the following statements is true about therapies approved for the treatment of thrombocytopenia in adults with chronic liver disease who need to undergo a procedure?

1. Romiplostim is dose titrated to response up to a platelet count of 200k / cu mm

2. Avatrombopag dosing is dependent on the platelet count prior to initiation of the drug

3. Eltrombopag is the only oral agent approved by the FDA for treatment of thrombocytopenia in chronic Liver disease patients requiring procedures

4. Both lusutrombopag and avatrombopag are associated with severe adverse events requiring inpatient monitoring

Update on Thrombocytopenia: Immune Thrombocytopenia (ITP),

Severe Aplastic Anemia (SAA), and Chemotherapy-induced Thrombocytopenia (CIT)

James B. Bussel, MDEmeritus Professor of Pediatrics,

Medicine, and Obstetrics and GynecologyWeill Cornell MedicineNew York, New York

Thrombopoietin Receptor Agonists: Mechanism of Action and Rationale for Use

Platelet count after infusion with patient plasma

Antiplatelet Antibodies: 19511 Inhibition of MKs byPlasma from ITP Patients: 20042

Evidence That ITP Is A B-Cell Disease

1. Harrington WJ et al. J Lab Clin Med. 1951;38:1–10; 2. McMillan R et al. Blood. 2004;103:1364–1369.

Time

Pla

tele

ts (x

109 /L

)

0

400

600

800

1000

200

1 2 3 1 2 3 4 5 6 7 8 9Hours Days

Con

trol m

egak

aryo

cyte

s(%

)

100

75

50

25

0

MK = megakaryocyte.

MK Development:GATA1, RUNX1, FLI1,

ANKRD26, NBEAL2, GFI1N

TPO

Stem cell nicheStem cell niche Vascular nicheVascular nicheMigration: SD1a

Proplatelet Development: Cytoskeleton: Rock, myosin

(inhibition Inc)

Collagen, VWF, fibrinogen (GpIb-IX-V, aIIbB3)

Sheerstress

Blood vesselBlood vessel

Bon

e

Adapted from Pecci A & Balduini CL. Br J Haematol 2014;165:179–192. For educational purposes only.

TPO = thrombopoietin

TPO Makes Megakaryocytes but not Platelets

TRAs for ThrombocytopeniaTherapy Structure/TPO-R Binding

SiteApproved Indications for Thrombocytopenia

Select Investigational Indications

Romiplostim(Nplate)1

Peptide/extracellular domain“peptibody”

• Second-line chronic ITP in children and adults ---- also newly diagnosed and persistent ITP in adults

• CIT, MDS,

Avatrombopag(Doptelet)1

Small molecule/transmembrane domain

• Second-line chronic ITP – adults with• CLD undergoing elective surgery or

needing a procedure

• CIT

Eltrombopag(Promacta, Revolade)1

Small molecule/transmembrane domain; chelator

• Second-line chronic ITP – children and adults

• Chronic HCV to allow initiation and maintenance of IFN-based therapy

• First-line SAA– pediatric (ages 2+) and adults in combination with standard immunosuppressive therapy

• Second-line SAA

• Newly diagnosed and persistent ITP in adults

• Inherited thrombocytopenias• CIT

Lusutrombopag(Mulpleta)2

Small molecule/transmembrane domain

• CLD undergoing elective surgery • Chronic ITP studies terminated (NCT01054443) or have no published results (NCT01129024)

Abbreviations: CIT – chemotherapy-induced thrombocytopenia; CLD – chronic liver disease; HCV – hepatitis C virus; ITP – immune thrombocytopenia; IFN – interferon; MDS – myelodysplastic syndromes; SAA – severe anaplastic anemia; TPO-R – thrombopoietin receptor1. Al-Samkari H et al. Ther Adv Hematol. 2019;10:2040620719841735; 2. Lusutrombopag [package insert]. Florham Park, NJ: Shionogi Inc; 2019.

Cytoplasm of Megakaryocyte

STAT PP

RAS/RAF

MAPKK

p42/44

SOSSOS

GRB2

P P

JAK

SHC

Cell membrane

TPOreceptor

Inactive receptor Active receptor

Therapy

Signal Transduction

Increased platelet production

Romiplostim, 3S BIO Therapy+: Mechanism of Action

AKT

+Licensed in China but not in the US,

Cytoplasm of Megakaryocyte

STAT PP

RAS/RAF

MAPKK

p42/44

SOSSOS

GRB2

P P

JAK

SHC

Cell membrane

Avatrombopag, Eltrombopag, Lusutrombopag:Mechanism of Action

TPOReceptor

Inactive receptor Active receptor

Signal Transduction

Increased platelet production

Therapy

AKT

Remaining Up-To-Date with Advances in Primary Immune

Thrombocytopenia Management


Medicine and Obstetrics and GynecologyWeill Cornell MedicineNew York, New York

ITP: Special Considerations

• In patients with ITP who have very low platelet counts, some will bleed, but most will not. Patients older than 60 years of age, those with a history of or ongoing bleeding, and those on anticoagulant or antiplatelet agents are the most likely patients to develop major bleeding. Head trauma and hematuria have been linked to intracranial hemorrhage.

• ITP is also a mildly prothrombotic disorder; the tendency to thrombosis can be aggravated by several treatments (eg, TPO-RA) and is both arterial and venous.

• ITP patients often have impaired quality of life. This is relatively common and can arise from multiple etiologies. Reduced HRQoL and fatigue may often be improved by increasing the platelet count with treatment.

ITP Treatment: First-Line Steroids• The ongoing IVIG shortage reinforces first line use of

steroids, dexamethasone or prednisone, as initial treatment of ITP

• Dexamethasone compared to prednisone1 (metanalysis):• Dexamethasone is 40 mg/day for 4 days in 1 to 3 cycles at

2- to 4-week intervals; prednisone is usually dosed at 1mg/kg/day for 2 to 4 weeks followed by variable tapering

• At these doses, dexamethasone increases the platelet count faster than prednisone.

• Dexamethasone seems to have less side effects than prednisone probably because of its shorter period of use.

• However, surprisingly, dexamethasone does not have a higher cure rate than prednisone.

1. Mithoowani S, et al. Lancet Haematol. 2016; http://dx.doi.org/10.1016/S2352-3026(16)30109-0.

ITP Treatment: First- to Second-LineThe ongoing international IVIG shortage reinforces use of steroids, especially dexamethasone, as initial treatmentBoth ASH Guidelines and International Consensus recommendations (both to appear in Blood Advances):

• Do not use steroids past 6 to 12 weeks• Do not resort to splenectomy before 1 year from Dx • These recommendations leave TPO-RA and anti-CD20

(off label) as the primary second-line treatments in patients with newly diagnosed and persistent ITP (ieafter first line steroid failure*)----limited data in this setting in other “second line” agents

* Only romiplostim is licensed for adults with ND and persistent ITP

ITP Treatment: Second-Line

• Immunosuppressives: The least exciting kid on the block since they are the least effective

• Rituximab with dexamethasone: The most polarizing kid on the block – love it or hate it

• Splenectomy: The oldest kid on the block• TPO-RA: The biggest kid on the block• Fostamatinib: The new kid on the block• FcRn and Btk inhibitors: The kids who will be moving in

next door.

Overall Comparisons

Chi-Square df Sig.

Log Rank (Mantel-Cox) 13.388 3 .004

Breslow (Generalized

Wilcoxon)13.821 3 .003

Tarone-Ware 14.247 3 .003

Test of equality of survival distributions for the different levels of

Dur_ITP_12.

Response to Rituximab-Dexamethasone Therapy

Chapin J et al. Am J Hematol. 2016;91:907-911. For educational purposes only.

Side Effects of SplenectomyApproaches to Minimization of Side Effects

1. Complications of surgery itself even laparoscopic:• Infection, poor wound healing, bleeding, thrombosis especially of the portal

vein Perioperative anticoagulant prophylaxis

2. OPSS: Overwhelming PostSplenectomy Sepsis• Plus malaria, babesia, dengue (eg, intracellular parasites)

Better vaccination; avoid endemic areas for the latter, job choice3. Thrombosis/stroke: Steady increased lifetime rate

Consider baby aspirin 4. No pulmonary hypertension, confirmed findings of myocardial infarction, increased infections (eg pneumonia), or dementia

• l

TPO-R Agonists Approved for ITP in the US Have Multiple Names

• Romiplostim (Nplate, AMG531)• Weekly subcutaneous therapy administered by HCP at an initial

once weekly dose of SQ 1 to 3 mcg/kg (package insert says 1 mcg/kg, but this is slow) up to a maximum of 10 mcg/kg/dose

• Approved for pediatric (1 year or older) and adult patients• Approved for newly diagnosed and persistent adult ITP patients who

have failed at least 1 treatment (eg, steroids)• Activates TPO receptor by binding at the TPO binding site

50


• Eltrombopag (Promacta, Revolade)• Orally available once daily – must be taken on an empty stomach, 1

hour before or 2 hours after a meal and at least 2 hours before or 4 hours after consuming more than 50 mg of calcium (eg dairy, broccoli, medications, calcium-containing supplements)

• Approved for pediatric (1 year or older) and adult patients• Patients 6 years of age and older start at 50 mg/daily and can be

increased to 75 mg or reduced to 25 mg as needed• Liver tests required at regular intervals; predisposition to cataracts

remains unknown 51


• Avatrombopag (Doptelet)• Orally available once daily ideally taken with food so absorption is

consistent; no dietary restrictions • No obvious drug specific toxicity but has class toxicities (eg,

thrombosis)• Approved for adults but currently very limited data on long-term use

• Both EPAG and AVA (and Lusu) activate TPO receptor by binding at the transmembrane domain

52

Adverse Consequences of Thrombopoietic Growth Factors

• Thrombocytosis• Thrombosis* R=E • Stimulation of tumor • Stimulation of leukemia cell

growth (MDS/AML) R>E• Cataracts-? E• Abnormal LFTs-E• Platelet count oscillation R>E

• Alloantibody formation-R• Stem cell depletion• Reduction in threshold for

platelet activation• Rebound worsening of

thrombocytopenia• Increased marrow reticulin R = E• Headaches, muscle aches R> E

*most important toxicity appears to be thrombosisE = eltrombopag; R = romiplostim; Limited evidence for avatrombopag.

Treg Activity Normalized in Responding Patients on TPO Agents

Treg: Teffector 1:1 ratioOn treatment >3 months

Bao W et al. Blood. 2010;116:4639-4645.

Cheng et al. Lancet. 2011;377:393-402; Erratum: Lancet. 2011;377:382 Cheng et al Amer J Hem 2018. For educational purposes only.

RAISE: Eltrombopag Led to a Significant Improvement in Several QoL scores

• Eltrombopag led to significantly greater improvements from baseline in many of the recorded quality of life scores (mean changes in SF-36v2 and FACT-Th6 scores) vs placebo

SF-36v2

p <.001

6.2

1.0

p <.001

8.7

3.2

0.7

-3.3

0.8

-0.8

p = .0074.2

-0.5-0.1

p = .018

4.7

p = .003

6.5

1.5

-1.4

1.8p = .045

1.7

-0.6

p <.001

2.1

0.7

p = .001

Mea

n ch

ange

from

bas

elin

e

Emotionalrole

Physicalfunction

Physicalrole

Bodilypain

Generalhealth

Vitality Socialfunction

Mentalhealth

Physicalcomponentsummary

Mentalcomponentsummary

FACT-Th6

Placebo

Eltrombopag

10

1.10.3

p Values for Difference in Score From Baseline to Week 26

8

6

4

2

0

-2

-4

Robust Series of Published Studies in Adults with ITP

Romiplostim• Short-term study• 6-month randomized

placebo controlled pivotal• Study of avoidance of

splenectomy• Long-term extension

studies• Blood; 2009• BJH; 2013

Pediatric StudiesMany others

Eltrombopag• Short-term 6-week study• Confirmatory 6-week

study• Six-month randomized

placebo-controlled• Repeat dosing study• Long-term extension

studies• Blood; 2012• Blood; 2017

Pediatric StudiesMany others

Avatrombopag• Short-term study

• 6-month randomized placebo-controlled phase II study 64 patients---Blood; 2014

• 12-month phase III 49 patients; 2018 BJH

• Overall: Avatrombopag is a highly effective TPO-RA with class action effects but no specific toxicity (eg, thrombosis)

• 20 mg pill once daily without dietary restrictions which can decrease in frequency or double to 40 mg (2 pills) in ITP patients

Ghanima W et al. Haematologica. 2019;104.

Maintenance TPO-RA: Mean Platelet Count and Romiplostim Dose Over 204 Weeks

0

50

100

150

200

250

300

4

n = 212 183 160 146 136 123 118 112 108 103 99 96 86 70 62 58 48 34 26 21 22 21 17 14 6

Mean Dose

0

2

4

6

8

10

1 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160 168 176 184 192 200Study Week

Mea

n (S

E) P

late

let

Cou

nt x

109 /L

Mea

n (S

D) D

ose

(µg/

kg)

Kuter DJ. et al Br J Haematol. 2013;161:411-423.

Remission with Romiplostim in Newly-Diagnosed and Persistent Primary ITP

75 70 64 62 55 52 45n

0Time to remission (weeks)

Pro

babi

lity

of a

chie

ving

ITP

rem

issi

on

10 20 30 40 50 600

0.2

0.4

0.6

0.8

1.0

Taper was to begin at 52 weeks; many patients entered remission

earlier per dosing rules

Patients with Primary ITP for ≤6 Months Who Were Treated with Romiplostim for ≤12 Months*

No predictive factors of sustained response were identified in this study.

Newland A et al. Br J Haematol 2016;172:262–273. For educational purposes only.

Eltrombopag Pilot Study in ITP: Study Design

• Single-arm, open-label, multicenter pilot studyPatients with newly diagnosed ITP,* platelet counts <30 or <50 x 109/L,significant bleeding (WHO bleeding scale ≥2), and no prior ITP therapyexcept transfusions(N = 45; planned N = 60)

Eltrombopag25 mg to 75 mg/day for 12 weeks +Pulsed Dexamethasone40 mg/day for 4 consecutive days Q4W x 1 to 3 courses

Cheng et al. Presented at ASH 2018. Abstract 733.

Successful Discontinuation of Eltrombopag

Thro

mbo

cyto

peni

a Fr

ee-S

urvi

val

Weeks

0

0.2

0.4

0.6

0.8

1.0

0 10 20 30 40 50 12011010090807060

González-López TJ et al. Am J Hematol. 2015;90:E40-E433. For educational purposes only.

Avatrombopag in ITP: Phase III Study Design

AVA = avatrombopag; CONMED = concomitant medication; E = extension; EOT = end‐of‐treatment; ITP = immune thrombocytopenia; PBO = placebo; qd = once‐daily; R = randomized.Jurczak W et al. Br J Haematol. 2018;183:479–490. For educational purposes only.

Avatrombopag in ITP

Jurczak W et al. Br J Haematol. 2018;183:479–490. For educational purposes only.

Use of TPO-R Agents in ITP: Questions

• How fast can the count increase? 5 to 7 days• What is the rate of response: 40% to 80% • Do romiplostim, eltrombopag, and avatrombopag work equally in all patients?

Can switch TPO-RA and observe efficacy.• Can you taper the TPO-RA and discontinue them? YES! 20% to 40% “Cure” at 6

to 24 months----beyond that, who knows ???????• Do TPO-R agonists work well with other treatments of ITP? Often brilliantly!• Biggest mistakes:

• Changing doses too frequently (eg, stopping when platelet levels are higher than 400,000/uL)

• Not adhering to eltrombopag diet restrictions: empty stomach and no cations

ITP Treatment: Second-Line

• Immunosuppressives: The least exciting kid on the block since they are the least effective

• Rituximab with dexamethasone: The most polarizing kid on the block – love it or hate it

• Splenectomy: The oldest kid on the block• TPO-RA: The biggest kid on the block• Fostamatinib: The new kid on the block• FcRn and Btk inhibitors: The kids who will be moving in

next door.

Challenges in Diagnosis:First- and Second-Line Treatment of ITP

• Review of diagnosis and first-line treatment• Second-line treatment• Experimental treatments and those with novel

mechanisms of action

SYK Inhibition with Fostamatinib in ITP:

Abrogation of Autoantibody-Coated Platelet Destruction as

Proposed Mechanism-of-

ActionPodolanczuk A, et al. Blood. 2009;113:3154-3160. For educational purposes only.

FOSTAMATINIB

X

X

Placebo Fostamatinib

Stable response

2% 18%

Overallresponse

14% 43%

Patients with Chronic ITP (Median Duration > 8 Years) and Refractory to Several Second Line-Treatments (Splenectomy 50%, Rituximab 40%,

Immunosuppressives 40%, TPO 47%)

Bussel J, et al. Am J Hematol. 2018; 93: 921-930 For educational purposes only.

Fostamatinib: Key Clinical Considerations• Licensed in April 2018 in the US for ITP• Clinical studies:

• Phase I to II study; Blood. 2009• Licensing study; Amer J Hem. 2018 • Long-term extension study Amer J Hem. May 2018• Use >7 years in 2 patients in Brit J Haem 2019

• 43% overall response rate – 2/3 of responders maintained >1 to 3 years

• Antithrombotic with minimal effect to increase bleeding – Key niche• 34% response rate in TPO failures• Not always well tolerated: GI symptoms, high BP, and abnl LFTs

• l

Newland AC et al. Presented at 2019 ASH Annual Meeting. December 9, 2019; Orlando, Florida. Abstract 895. Available at: https://ash.confex.com/ash/2019/webprogram/Paper128022.html. For educational purposes only.

FcRn Inhibitors and BTK InhibitorsFcRn Inhibitors:1

• At least 4 companies have therapies in clinical trial; 2 are beginning phase III randomized clinical trials in ITP

• Blocking FcRn, lowers normal IgG and IgG autoantibody levels, but not IgA or IgM----it does not inhibit normal antibody production

• Are focused on autoantibody mediated diseases: ITP, Myasthenia Gravis, Pemphigus• Phase II preliminary results: >50% platelet response + IgG levels lowered from 1000 to 200

BTK Inhibitors:2

• Based on ibrutinib, which has been an excellent treatment for patients with CLL• Congenital absence of BTK: No B cells and no antibody (IgG-M-A) with platelets normal• Ibrutinib brings up platelets in CLL when low, but also rarely (1:100) causes bleeding• A newer agent, PRN1008 (and possibly acalabrutinib), may have similar effects on

increasing platelets but without the increase in bleeding• Encouraging Phase I/II results being presented at ASH 2019 meeting2

1 Robak T et al. Presented at 2019 ASH Annual Meeting. December 9, 2019; Orlando, Florida. Abstract 897. Available at: https://ash.confex.com/ash/2019/webprogram/Paper129839.html.2 Kuter DJ et al. Presented at 2019 ASH Annual Meeting. December 7, 2019; Orlando, Florida. Oral Presentation 87. Abstract available at: https://ash.confex.com/ash/2019/webprogram/Paper122336.html.

ITP: Conclusions

Complicated disease: still major issues to define and clarify1. Neither molecular markers nor other biomarkers exist to:

a. Confirm the diagnosis or b. Guide treatment

2. There are many studies of groups of patients but these studies do not transfer well to the care of individual patients: 70% versus 30% studies without ability to individualize the findings

3. Treatment decisions are hit or miss, trial and error 4. One of the best sources of information in a patient is

his/her response to specific treatment(s)

Considering the Future of Thrombopoietin Receptor Agonists: Severe Aplastic Anemia

(SAA) and Chemotherapy-induced Thrombocytopenia (CIT)



Olnes MJ et al. New Engl J Med. 2012;367:11-19. For educational purposes only.

SAA: Current Status of EPAG + IS1. Upfront eltrombopag started on day 1 with

immunosuppression (ATG 40x4 and cyclosporin) appears to result in 90+% responses in patients with idiopathic acquired SAA.

HOWEVER:1. At least 1/3 of responses are partial---not full remission

in HSCT patients the overall response rate may be similar but almost all responses are CRs

2. With the current regimen of stopping cyclosporin after 6 months, there is a relatively high relapse rate

3. Current studies are exploring longer slower taper of cyclosporin following the above 6 month regimen to see if relapses can be substantially reduced

4. Romiplostim report in recent Lancet Haem demonstrated similar efficacy in SAA with caveats

Townsley DM et al. New Engl J Med. 2017;376:1540-1550.

Considering the Future of Thrombopoietin Receptor Agonists: Severe Aplastic Anemia

(SAA) and Chemotherapy-induced Thrombocytopenia (CIT)



Fanucchi M et al. New Engl J Med. 1997;336:404-409.For educational purposes only.

Effect of PEG-MGDF During Induction Therapy of AML

Time

Plat

elet

Cou

nt

1204 4 4 4

820

1005 5 5 5

100

0

200

400

600

800

1000

TPO

Placebo

For educational purposes only.

Moskowitz CH et al. Ann Oncol. 2007;18:1842-1850.

Moskowitz CH et al. Ann Oncol. 2007;18:1842-1850. For educational purposes only.

Overall survival for all patients completing 3 cycles of ICE chemotherapy stratified by dose intensity maintained (ICE × 3 cycles administered ≤31 days) versus reduced dose intensity (ICE × 3 at >31 days). At 8.5 years median follow-up, KM estimates are 67% versus 22%, respectively (P = .06).

Patient #12: Enrolled 1/20/2015• 69-year-old man, metastatic colon cancer (liver and lungs)• FOLFOX: 11/4/2013 – 5/6/2014• FOLFIRI: 8/19/2014 –

Soff GA et al. J Clin Oncol. 2019;37:2891-2898.

Multiple dose delays and dose reductions

Randomized Study with 3 Regimens of High-Dose ARA-C in 55 Patients

1. Randomized giving 3S Bio TPO on day -4 and day -2 and daily for 9 days after chemotherapy versus giving 3S Bio TPO same dose daily SQ for 11 days after chemotherapy

2. Significantly better platelet recovery and avoidance of severe thrombocytopenia (both at levels <50k and <25k) with pre-chemo-therapy 3S Bio TPO

3. No evidence of stem cell exhaustion but no long-term data

4. No data on survival

Wang Z et al. Leuk Lymphoma. 2018;60:2821-2828.

Future Directions

• Randomized trials are exploring not only maintaining “full dose” “not delayed” chemotherapy with TPO-RA versus placebo but also:

• Is there a survival advantage with “full dose, on schedule” chemotherapy with TPO agent support, versus delayed, dose-reduced chemotherapy without TPO agent support?

• Is ongoing, long-term TPO agent administration safe with chemotherapy? Is stem cell exhaustion possible? Telomere length could be a surrogate marker in the future

• Is there an increased risk for thrombosis?

Diseases TPO-RA are Useful in

1. ITP: Children and Adults2. Hepatitis C (probably HIV)3. MDS: Myelodysplasia 4. Congenital Thrombocytopenia5. Platelet Donation6. Bone Marrow Aplasia7. Chemotherapy induced TP (CIT)8. Human Stem Cell Transplantation

(HSCT)

Discussion Section 2



If you start therapy in a treatment-naive patient with ITP, how long do you wait to change treatment if it is not working?

1. 2 weeks2. 4 weeks3. 8 weeks4. 12 weeks5. either 4 or 8 weeks depending on the treatment

If your patient has been diagnosed with ITP, responds to steroids, but relapses as the steroids are tapered, and is now 3 months into the ITP, what is your usual choice of second line treatment?1. TPO-RA2. Rituximab3. Splenectomy4. Fostamatinib5. Immunosuppressive medication6. Other

For which of the following TRAs is there long-term data available describing years of treatment in both adults and children?

1. romiplostim2. eltrombopag3. avatrombopag4. fostamatinib

If you started a second-line treatment for ITP and it is not working, how often do you add another treatment to the one that is not working, planning to continue the two treatments together (instead of discontinuing the one that is not working and trying the new treatment by itself not including any tapering)?

1. Never2. 10%3. 20%4. 33%5. 50% And Above

If you start an adult with persistent ITP and a platelet count of 15,000, but just skin bleeding, on romiplostim, what first dose do you give most commonly?

1. 3 mcg/kg2. 125 mcg vial3. a 250 mcg vial4. a 500 mcg vial5. other

Your patient takes eltrombopag, responds, and then loses their response. You review their oral intake and they are NOT inactivating the eltrombopag by the way they take it e.g. they are not taking it with milk or calcium-fortified orange juice. What is the chance that they would respond if you changed to romiplostim instead?

1. 5%2. 10%3. 20% 4. 50%5. 75%

Applying TRAs to Practice: Clinical Pearls for the Hematologist

James B. Bussel, MDEmeritus Professor of Pediatrics


Applying TRAs to Practice: Clinical Pearls for the Hematologist

• Indirect comparison of approved TRAs

• Selecting a TRA based on patient and procedural factors

• Dosing and administration considerations

• AE/tolerability and patient communication

Case Study A 78-year-old Caucasian female (weight 62 kg) with a history of mild ITP (untreated) is admitted to the neuro ICU with a subdural hemorrhage in the setting of severe thrombocytopenia. Despite a 5-day course of dexamethasone and IVIG, the platelet count does not budge, although there is no obvious expansion of the SDH. What recovery strategy would be best?1. Add eltrombopag 50 mg daily2. Start romiplostim at 1 mcg/kg SC weekly3. Rituximab 375 mg/m2 IV weekly4. Add mycophenolate

ICU = intensive care unit; IV = intravenous; IVIG = intravenous immunoglobulin; SC = subcutaneous; SDH = subdural hemorrhage.

So Many TRAs – Pick the Winner?!Romiplostim Eltrombopag Avatrombopag

Mode of administration SC Oral Oral

Initial US ITP approval 2008 2008 2019

Mechanism of action TPO peptide mimetic(“peptibody”)

TPO nonpeptide agonist small molecule; chelator

TPO nonpeptide agonist small molecule

Schedule Weekly Once daily Once daily

Interaction with food None Dairy products and broccoli may decrease the absorption of eltrombopag. Take on an empty stomach at least 1 hour before or 2 hours after a meal. Take eltrombopag at least 2 hours before and 4 hours after foods high in calcium and iron.

Administer with food to facilitate consistent absorption.

Drug interactions No known BCRP* inhibitor – avoid with alpelisib, cladribine, cyclosporine, deferiprone, pazopanib, rosuvastatin, topotecan, and talazoparib

Rifampin, enzalutamide, fluconazole, mifepristone

BCRP* = breast cancer resistance protein.

So Many TRAs – Pick the Winner?!Romiplostim Eltrombopag Avatrombopag

Cost (AWP 12/2019) USD

Per week125 mcg: $1115.15250 mcg: $2230.30500 mcg: $4460.59

Per day12.5 mg or 25 mg: $197.0650 mg: $356.6175 mg: $534.92

Per day20 mg: $356.40

Indication R/R cITP in adults and in pediatric patients ≥1 year of age

sAA, HCV-thrombocytopenia, R/R cITP in adults and in pediatric patients ≥1 year

R/R cITP in adults. CLD-associated thrombocytopenia in adults preprocedure

Dosing considerations

Wide window 1-10 mcg/kg. 125-, 250-, and 500-mcg vials

12.5 mg, 25 mg, 50 mg, 75 mg Dose level 6: 40 mg once dailyDose level 5: 40 mg 3 times per week and 20 mg on the other 4 daysDose level 4: 20 mg once daily (initial)Dose level 3: 20 mg 3 times per weekDose level 2: 20 mg twice per week or 40 mg once per weekDose level 1: 20 mg once weekly

Liver/Renal dosing

No adjustment needed Potential for hepatic decompensation. Black box warning

No adjustment needed

AWP = average wholesale price; cITP = chronic idiopathic thrombocytopenic purpura; USD = US dollars.

Individualizing TRA SelectionPatient Characteristics Optimal TRAUnreliable compliance with oral therapy RomiplostimITP with unrelated hepatic dysfunction Avatrombopag or RomiplostimDietary – drug compliance uncertain Avatrombopag or RomiplostimCLD-associated thrombocytopenia Avatrombopag or LusutrombopagChemotherapy-associated thrombocytopenia None licensed for this indication; studies in

progressUrgent inpatient therapy initiation Romiplostim may be more readily available in

hospitalNo Medicare-D (ie, no prescription benefit) RomiplostimConcern for possible underlying MDS Avoid romiplostimEveryone else Eltrombopag (largest market share)Health system cost-effectiveness (UK) Eltrombopag

2019-19 ash full-deck v2(withars)(12.5.19) …remaining up-to-date with advances in primary immune...

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