The Role of Thrombopoietin in Immune Thrombocytopenia

Benign Hematology Update: ASH, ISTH, and the Literature 2013 Craig M Kessler, MD, MACP Professor of Medicine and Pathology Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC

Disclosures • Research- Amgen, Baxter, Bayer, Biogen, Eisai, Grifols, NovoNordisk, Octapharma

• Advisory Boards-Amgen, Baxter, Bayer, Biogen, Eisai, Grifols, NovoNordisk, Octapharma • Stock- Not applicable • Employment – Not applicable • Speakers’ Bureau – Not applicable

Topics • • • •

Autoimmune thrombocytopenia Target specific oral anticoagulation Duration of anticoagulation for VTE New developments in von Willebrand disease • Advances in the treatment of sickle cell anemia • Miscellaneous

Pathophysiology of Immune Thrombocytopenic Purpura • Phagocyte-mediated accelerated clearance of antiplatelet AB coated platelets in the RES • Dysregulated T-cell function • Direct cytotoxicity against megakaryocytes and

• •

platelets T-helper cell support for biosynthesis of Abs by Bcells Abnormal number and function of T-regs

• Suboptimal platelet production

What is the best approach to corticosteroids for de novo ITP? Abs 325: A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment of Naïve Patients With Idiopathic Thrombocytopenic Purpura Matsche J et al

Week 1: All pts received prednisone (1 mg/kg/d) followed by a 1:1 randomization between daily prednisone and pulsed dexamethasone Prednisone given at 1 mg/kg/d; after remission dose tapered 19 weeks to maintenance dose ≤ 25 mg/d at wk 13 and < 7.5 mg/d at wk 19 If no remission at 2 wks, prednisone increased to 2 mg/kg/d for another 2 weeks. If remission, tapered as above (≥ 50K platelets) Dexamethasone given q 3 wks for 6 courses (0.6 mg/kg day 1 to 4) Failure to achieve a remission: pts crossed over to the alternative treatment Prednisone: no remission after 4 wks at 1-2 mg/kg/d Dexamethasone: no remission after two cycles

Abs 325: A Randomized Trial Of Daily Prednisone Versus Pulsed Dexamethasone In Treatment of Naïve Patients With Idiopathic Thrombocytopenic Purpura Matsche J et al No statistically significant difference in time to remission (p=0.55) Remission duration significantly longer with dex vs prednisone (p=0.0139) Median tx duration = 85 d (range: 28 – 153) for pred; Median tx cycles 5 (range: 3 – 7) for dex Median cumulative cortisol equivalent dose = 15.780 mg for pred; and 34.560 mg for dex

Remission duration (platelets >50x109/l) in ITP pts receiving daily prednisone versus pulsed dexamethasone

No difference in Grade 3 or 4 bleeding events No difference in Grade 3 or 4 adverse events: 1 pt on pred (hypertension) and 2 pts on dex (hyperglycemia, hypokalemia).

Suppression of Megakaryocyte Maturation and Platelet Production by ITP Plasma % Control Megakaryocytes

100 75 50 25 0

ITP-1 ITP-2 ITP-3 ITP-4

ITP-5 ITP-6 ITP-7 ITP-8 ITP-9 ITP-10 ITP-11 ITP-12

Heterogeneous responses in vitro: Anti-platelet ABs affect megakaryocytes and circulating platelets McMillan R, et al. Blood. 2004;103:1364-1369.

How Does Rituximab Affect ITP Outcome? Abs 449: Rituximab As Second Line Treatment For Adult Immune Thrombocytopenia (ITP): A Multicentre, Randomized, Double Blind, Placebo-Controlled Study – The Ritp Study Ghanima W et al

• First randomized placebo-controlled, double blind study to assess both short and long-term efficacy and safety of RTX in steroid-unresponsive ITP • Pts randomized to 4 weekly infusions of 375mg/m2 RTX or placebo Steroids allowed throughout the study • Main inclusion criteria: 1- unsplenectomized with primary ITP; platelets 2 wks or relapse during steroid-tapering/discontinuation

Per Cent of Patients NOT Achieving Complete Response

Abs 449: Rituximab As Second Line TreatmentFor Adult Immune Thrombocytopenia (ITP): A Multicentre, Randomized, Double Blind, PlaceboControlled Study – The Ritp Study Ghanima W et al

• RTX did not reduce the rate of overall treatment failure • Lower rate of splenectomy in the RTX-arm • RTX induced significantly higher rate of CR at 24 wks

Time to Complete Response (days) ▬ Placebo ▬ Rituximab

Do TPO-RAs Enhance Rituximab Effectiveness? Abs 329: Recombinant Human TPO and Rituximab vs Rituximab Monotherapy in Corticosteroid-Resistant Primary ITP: a Multicenter Randomized Controlled Study Xiu M et al parameter Age, median (range)

RTX (n = 35)

P value rhTPO + RTX between (n = 79) groups

46 (14-68)

42 (13-82)

.664

Female / Male (n)

23/12

51/28

.905

Baseline platelet count, median(range)

13 (3-36)

8 (0-32)

.221

OR, %

71.4% (25/35) 78.5%( 62/79) .414

CR, % NR, %

0.286 28.6%

0.43 21.5%

.143 .414

Time to Response, day(s)

28(4-90)

7(4-28)

.002*

Kaplan-Meier plot of time to relapse in patients achieving response or complete response

• •

RTX + rhTPO yields shorter time to response vs RTX only Combination extended time to relapse

Thrombopoietin (TPO): Properties and Pertinent Facts • TPO = c-mpl ligand; c-mpl = TPO receptor – c-mpl is the murine retroviral oncogene causing a “myeloproliferative leukemia (mpl)” in mice – c-mpl found in platelets and megakaryocytes – TPO gene on human chromosome 3

• TPO is synthesized predominantly by hepatocytes

– TPO mRNA also found in kidney, marrow, and brain-? Hematopoietic importance

TPO affects viability of early progenitors of all lineages but affects the late maturation only of megas: TPO only stimulates production of platelets but not RBCs or WBCs Increasing ploidy

The Oncologist January 1, 2009 vol. 14 no. 1 12-21

Normal Levels

Increased Levels

The Physiological regulation of TPO levels Kuter DJ. The Oncologist 1996, 1:98-106.

Endogenous TPO Concentrations Are Minimally Elevated in ITP Patients

Nichol J. In: Kuter DJ et al, eds. Thrombopoiesis and Thrombopoietins: Molecular, Cellular,

AA, aplastic anemia

Can Serum TPO Levels Predict Response to TPO mimetics?

21 patients with ITP (ELISA, R&D Systems, Minn, MN).

Serum TPO levels >95 pg/mL predicts for reduced and less durable responses to TPO receptor agonists in ITP patients = inadequate megakaryopoiesis as basic pathology Makar, R. S., et al. Am. J. Hematol.. doi: 10.1002/ajh.23562

AMG 531: Mechanism of Action AMG 531

Thrombopoietin Receptor

Active Receptor

Inactive Receptor Cell Membrane

SHC GRB2

RAS/RAF

SOS

P

P

P

Cytoplasm

STAT

P

JAK MAPK

Promotion of cell growth

p42/44

Potentiate maturation

Signal Transduction

Increased Platelet Production Kuter DJ. Int J Hematol (2013) 98:10–23

Anti-apoptosis

Practical Considerations for Romiplostim • T1/2 = 120 – 140 hours whether IV or SQ – Not formulated for IV use

• T1/2 not affected by renal or hepatic function • Not recommended during pregnancy since can cross placental barrier via FcRn receptor • Pregnancy registry- ? Safety with breastfeeding • Start at 1 µg/Kg/wk; titrate up to 10 µg/Kg/wk – Effective mean dose in most studies = 4-5 µg/Kg

• Do not withhold dose → precipitous nadirs • Dose reduce 25-50% for >400K platelets

Eltrombopag (SB497115): Mechanism of Action Thrombopoietin Receptor

Eltrombopag

Active Receptor

Inactive Receptor Cell Membrane

SHC GRB2

SOS

P

P

RAS/RAF

P

Cytoplasm

STAT Promotion of cell growth

P

JAK MAPK

p42/44

Potentiate maturation

Signal Transduction Increased Platelet Production Kuter DJ. Int J Hematol (2013) 98:10–23

Antiapoptosis

Pharmacologic Considerations for Eltrombopag • Activates signal transduction pathways differently than TPO or romiplostim • Weaker stimulator of JAK and STAT phosphorylation • Does not activate AKT pathway at all, unlike TPO or romiplostim • Eltrombopag effect is additive to TPO in vitro. ? In vivo significance Growth of TPO-dependent cell line Kuter DJ. Internat J Hematology. 2013;98(1):10-23

Long-term safety and tolerability of romiplostim in ITP: Pooled analysis of 13 clinical trials (653 patients)

All received ≥ 26 wks tx; all 8- 18 µg/kg/wk; 5/13 > 10µg/kg/wk (Baseline cytogenetics consistent with MDS)

(PMF) HM=hematological malignancies: • Rom-CLL, AML, lymphoma (2), MPN • SOC/placebo: lymphoma, MDS HM = Hematologic malignancies Rodeghiero F et al. Eur J Haematol 2013;91(5) doi:10.1111/ejh.12181

Can Patients Eventually Discontinue TPO Agonists? Abs 327: Prolonged Remission After TPO-Receptor Agonist Discontinuation In Adults With Chronic ITP. Results Of a French Observational Study Mahévas M et al.

•

Romiplostim & eltrombopag: 70-80% lasting response-rate in long-term studies

•

Platelets ↓ to baseline or lower within 10 d post TPO-RA withdrawal in majority of cases

•

54 pts (35 females) studied: 46 (85%) with chronic; 8 (15%) with newly-diagnosed ITP Median of 4 treatment-lines (rituximab in 59%; splenectomy in 33%) 18 received eltrombopag; 22 romiplostim; 14 received both TPO-RAs sequentially

•

Overall response rate on TPO-RA: 81.5%; CR (51.8%); PR (29.6%)

•

In 20 out of 28 pts achieving a CR, TPO-RA was discontinued after median 10 mos (1-70) Among the 14 evaluable pts: 6 (30%) relapsed within 10 d, requiring rescue therapy

8 pts (70%) with CR over median follow-up of 13.5 mos (range: 5-27) •

No predictors of sustained response (age, gender, duration of ITP, previous types/number of therapies before TPO-RA)

• Summary: 15 % pts treated with TPO-RA achieve a durable response after treatment discontinuation. A prospective trial is needed

Thrombotic Events in Adult ITP: Metaanalysis • Estimated frequency of thromboembolism: – 3.1% (95% CI, 1.8-4.4%) for TPOr agonists – 1.7% (95% CI, 0.3-3.1%) for controls

• TPOr agonists show a numerically but nonstatistically significant trend to increase the occurrence of thromboembolic events • Underpowered • Use of IVIg, ASA, splenectomy not accounted for Catala-Lopez F et al. Med Clin (Barc). 2012 Oct 20;139(10):421-9. doi: 10.1016/j.medcli.2011.11.023. Epub 2012 Jan 23

Novel Approaches to the Treatment of ITP • Oral Syk inhibitor R788 – Syk is downstream signal transduction regulator of monocyte and macrophage phagocytosis – Blockage of Syk pathway hypothetically should inhibit platelet destruction – Pilot study (N=16), 50% ITP pats demonstrated sustained platelet counts >50K 1 • Anti-CD40 ligand – CD40L is critical for T-cell-dependent B-cell expansion; autoreactive CD4+ T-cells increased in ITP – IDEC-131 and hu5c8 (anti-CD40L monoclonal AB) had overall response rate of 13-16% 2 1. Podolanczuk A et al. Blood.2009;113:3154; 2. Patel VL et al. Br J Haematol.2008;141:545

Clinical Comparisons of the Novel Oral Anti-Xa Anticoagulants Dabigatran Rivaroxaban

Apixaban

Edoxaban

tmax

1.5 - 3 hrs

2 - 4 hrs

1 - 3 hrs

1-2 hrs

Half life

12 - 14hrs

9 - 13 hrs

8 - 15hrs

9-11 hrs

Renal excretion

80%

66 %

ca. 25 %

35%

FDA approval

• A. fib

• A. fib • VTE prevention • VTE treatment

• A. fib

• N/A

In clinical development: Betrixaban (not FDA approved)

Edoxaban • Oral direct factor Xa inhibitor with a rapid onset of action

and half-life of 10–14 hours • 60 mg once daily dose was selected based on phase II

data • Dose of 30 mg in case of • moderate renal impairment (CrCl 30 - 50mL/min) • low body weight, i.e., ≤ 60 Kg • concomitant use of P-gp inhibitors

Aim: To evaluate whether initial (LMW)heparin followed by edoxaban only is non-inferior to initial (LMW)heparin overlapping with warfarin, followed by warfarin only in the treatment of subjects with acute symptomatic venous thromboembolism for the prevention of symptomatic recurrent venous thromboembolism during a 12-month study period edoxaban

Sham INR

Symptomatic confirmed VTE event

R INR

warfarin

Day 1- 5

Day 6- 12

initial (LMW)Heparin placebo warfarin placebo edoxaban

3M

6M

12 M

Efficacy outcomes Edoxaban (N=4118)

Warfarin (N=4122)

Hazard ratio (95% CI)

P Value

130 (3.2)

146 (3.5)

0.89 (0.70-1.13)