WHAT’S NEW IN ITP?

BUNDARIKA SUWANAWIBOON, MD.

DIVISION OF HEMATOLOGY

DEPARTMENT OF MEDICINE

FACULTY OF MEDICINE SIRIRAJ HOSPITAL

MAHIDOL UNIVERSITY

WHAT’S NEW IN ITP TREATMENT ?

Update on refractory ITP management

New Agent?No

New evidence?Yes

SECOND-LINE TREATMENT OF ADULT ITPTreatment Dose Time to initial

responseTime to peak

response• Rituximab 375 mg/m2/dose iv (4 weekly dose) 7-56 d 14-180 d

• Splenectomy 1-56 d 7-56 d

• Vincristine Up to 2 mg/dose iv (4-6 weekly doses) 7-14 d 7-42 d

• Vinblastine 0.1 mg/kg/dose iv (6 weekly doses) 7-14 d 7-42 d

• Danazol 400-800 mg po OD 14-90 d 28-180 d

• Azathioprine 2 mg/kg po OD 30-90 d 30-180 d

• Romiplostim 3-10 µg/kg weekly SC 5-14 d 14-60 d

• Eltrombopag 25-75 mg po OD 7-28 d 14-90 d

Rhodeghiero F et al. Blood.2009;113:2386-93, Provan D. Blood 2010;115:168-186

Thrombopoietin Receptor Agonists

Imbach P and Crowther M N Engl J Med. 2011;365:734-41

COMPARISON BETWEEN SPLENECTOMY, TPO-RA AND RITUXIMAB

Splenectomy Rituximab TPO-RAEfficacy High cure rate, Long-

term response 60%-70% at 5-10 y

Initial response 50%-60%, sustained response 20% at 3-5 y

Maintenance treatment response rate 60%-80%

Platelet count returns to baseline 2 wks after

d/c’d RxSafety Surgery related

morbidty, infectionInfusion-related side

effects, neutropenia, viral reactivation, serum

sickness

BM reticulin fibrosis, thrombosis, rebound

thrombocytopenia

Contraindication Unfit for surgery, Immunodeficiency,

secondary ITP

Active hepatitis B, allergy e.g. Serum sickness

Pregnancy, lactation

ASH 2011 recommendation

1B after failure of steroids

2C after failure of steroids 2C after failure of steroids

IS LONG-TERM ELTROMBOPAG USE SAFE AND EFFECTIVE?

Blood. 2013;121(3):537-545

Interim analysis of the ongoing open-label Eltrombopag eXTENded Dosing study Evaluate the safety and efficacy of eltrombopag in 299 pts treated up to 3 years Chronic ITP who completed a prior eltrombopag study (plt.< 30,000/µL and

insufficient response to ≥ 1 previous ITP treatment) Concomitant ITP treatment was allowed

EXTEND: STUDY DESIGN1. Eltrombopag initiated at 50 mg OD adjusted to keep plt. ≥ 50,000/µL

2. Reduce concomitant ITP medications, keep plt. ≥ 50,000/µL

3. Identify the minimal dose to maintain plt. ≥ 50,000/µL (25-75 mg OD or less frequently) ± minimal concomitant medication

4. Evaluate safety and efficacy of long-term dosing ± minimal concomitant medication

Blood. 2013;121(3):537-545

Study end points

■ Primary end points■ Safety and tolerability

parameters: AEs, lab test and ocular examination

■ Secondary end points■ Efficacy: proportion of pts

with plt ≥ 50,000/µL once, maximum duration of plt ≥ 50,000/µL, reduction in ITP medication, HRQoL, and WHO bleeding grades

Blood. 2013;121(3):537-545

Median platelets during EXTEND

Blood. 2013;121(3):537-545

Efficacy end points n = 299

Platelet count ≥ 50,000/µL at least once Splenectomized Nonsplenectomized Baseline plt. < 30,000/µL

85%80%88%80%

Median no. of cumulative wk with plt. ≥ 50,000/µL 44

Incidence (%) Remarks Thromboembolic

events5 VTE n = 12, ATE n = 9

Platelet prior to TEE 14,000-482,000/µL

Reoccurrence of thrombocytopenia

8

Bone marrow fibrosis

12 MF grade 0 n = 88, grade 1 n = 48, grade 2 n = 11

Hyperbilirubinemia

ALT increases

6

2

No pattern in the time to onset of HBLAsHBLA resolved despite continued Rx or after interruption of Rx

Cataracts 5 Headache 10 All grade 1 or 2

EXTEND: ADVERSE EVENTS

EXTEND STUDY: SUMMARY Long-term treatment with eltrombopag was generally safe.

No new or increased incidence of safety issues was identified

Treatment with eltrombopag for up to 3 years was effective in increasing and maintaining platelet counts

Blood. 2013;121(3):537-545

WHAT IS THE EFFICACY OF RITUXIMAB AS A SPLENECTOMY-SPARING OPTION IN PATIENTS PREVIOUSLY TREATED WITH STEROIDS ?

Multicenter, randomized, double-blinded, placebo-controlled trial Inclusion criteria: corticosteroid unresponsive primary ITP pts with

plt < 30,000/µL Primary outcome: rate of treatment failure within 78 weeks

Splenectomy or meeting criteria for splenectomy after week 12 Secondary outcome: response rate, relapse rate and duration of response

Lancet 2015;385:1653-1661

STUDY DESIGN1:1 randomization to receive rituximab or placebo in a double-blinded fashion

Treatment: 4 weekly infusion of rituximab 375 mg/m2 or placebo

Corticosteroid use with dose tapering to keep plt count >20,000/µL was allowed

Follow up visit q 6 wks during the study for 78 wks or for 12 wks after splenectomy

Lancet 2015;385:1653-1661

Rituximab (n=55)

Placebo (n=54)

Median age, yr 46 (27-61) 46 (28-60)

Female 40 (73%) 39 (72%)

Median plt, /x 109 cells/L 16 (6-27) 21 (9-29)

Median bleeding score 2 4

Treatment with corticosteroids 32 (58%) 24 (44%)

Median duration of ITP, weeks Newly diagnosed (0-3 mo) Persistent (3-12 mo) Chronic (>12 mo)

37 (8-288)18 (33%)13 (24%)24 (44%)

50 (14-211)12 (22%)16 (30%)26 (48%)

RESULTS (1)

Lancet 2015;385:1653-1661

Rituximab (n=55)

Placebo (n=54)

p value

Treatment failure Splenectomy

32 (58%)8 (15%)

37 (68%)14 (26%)

0.650.12

Overall response Loss of overall response Median duration of OR, wk

40 (73%)27 (68%)

36 (13-not reached)

36 (67%)28 (78%)7 (5-69)

0.150.010.01

Complete response Loss of complete response Median duration of CR,wk

28 (51%)14 (50%)

76 (32-not reached)

21 (39%)13 (62%)

49 (20-95)

0.120.190.19

Bleeding 21 (38%) 27 (50%) 0.08

Infection 22 (40%) 13 (24%) 0.09

RESULTS (2)

Lancet 2015;385:1653-1661

Time to treatment failure within 78 weeks

Lancet 2015;385:1653-1661

RITP STUDY: SUMMARY First double-blinded, placebo-controlled study to assess the long-term efficacy (78

weeks) of rituximab as second-line treatment in ITP

Rituximab does not significantly reduce the rate of long-term treatment failure compare with placebo

A small benefit of rituximab cannot be ruled out A longer duration of response and higher response rate was observed in the rituximab

group

TAKE HOME MESSAGE

Long-term data and results from large scale, randomized controlled studies of new agents/combination treatment is in needed in ITP

Balancing the risks and benefits of treatment on a case by case basis is necessary until more evidence is available

THANK YOU FOR YOUR ATTENTION

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