This document summarizes recent developments in the treatment of immune thrombocytopenia (ITP). It discusses new evidence on treatments for refractory ITP including rituximab, thrombopoietin receptor agonists (TPO-RAs), and long-term use of eltrombopag. A randomized controlled trial found that rituximab did not significantly reduce long-term treatment failure compared to placebo in previously steroid-treated ITP patients. Long-term use of eltrombopag for up to 3 years was found to be generally safe and effective at maintaining platelet counts. The document concludes that large, randomized studies are still needed to better understand new ITP treatment options and balancing risks versus benefits requires consideration

1. WHAT’S NEW IN ITP?
BUNDARIKA SUWANAWIBOON, MD.
DIVISION OF HEMATOLOGY
DEPARTMENT OF MEDICINE
FACULTY OF MEDICINE SIRIRAJ HOSPITAL
MAHIDOL UNIVERSITY

2. WHAT’S NEW IN ITP TREATMENT ?
 Update on refractory ITP
management
 New Agent?
 No
 New evidence?
 Yes

3. SECOND-LINE TREATMENT OF ADULT ITP
Treatment Dose Time to initial
response
Time 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

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

5. COMPARISON BETWEEN SPLENECTOMY,
TPO-RA AND RITUXIMAB
Splenectomy Rituximab TPO-RA
Efficacy 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 Rx
Safety Surgery related
morbidty, infection
Infusion-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

6. IS LONG-TERM ELTROMBOPAG USE SAFE
AND EFFECTIVE?

7. 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

8. EXTEND: STUDY DESIGN
1. 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

9. 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

10. 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

11. Incidence (%) Remarks
 Thromboembolic
events
5 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
HBLAs
HBLA resolved despite continued Rx
or after interruption of Rx
 Cataracts 5
 Headache 10 All grade 1 or 2
EXTEND: ADVERSE EVENTS

12. 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

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

14.  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

15. STUDY DESIGN
1:1 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

16. 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

17. Rituximab
(n=55)
Placebo
(n=54)
p value
 Treatment failure
Splenectomy
32 (58%)
8 (15%)
37 (68%)
14 (26%)
0.65
0.12
 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)
0.15
0.01
0.01
 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)
0.12
0.19
0.19
 Bleeding 21 (38%) 27 (50%) 0.08
 Infection 22 (40%) 13 (24%) 0.09
RESULTS (2)
Lancet 2015;385:1653-1661

18. Time to treatment failure within 78 weeks
Lancet 2015;385:1653-1661

19. 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

20. 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

21. THANK YOU FOR YOUR ATTENTION

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Group 1 Group 2
Class 1 82 95
Class 2 76 88
Class 3 84 90

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