Management of Primary Immune Thrombocytopenia (ITP) in Adult

MANAGEMENT OF PRIMARY IMMUNE THROMBOCYTOPENIA

(ITP) IN ADULT

SUMONPHAN PATTHANOTHAI, MD.

KHON KAEN HOSPITAL

OUTLINES • DEFINITION/CLASSIFICATION (IWG)

• PATHOPHYSIOLOGY

• DIAGNOSIS

• MANAGEMENT OF ADULTS WITH ITP

HARRINGTON’S CLASSIC EXPERIMENT

• IN CLASSIC 1951 STUDY, WJ HARRINGTON VOLUNTEERED TO INFUSE HIMSELF

WITH BLOOD FROM AN ITP PATIENT

• DR. HARRINGTON QUICKLY DEVELOPED SEVERE, BUT TRANSIENT

THROMBOCYTOPENIA

• HE LATER RECRUITED SEVERAL VOLUNTEERS TO UNDERGO THE SAME

EXPERIMENT

• CONFIRMED THAT THERE WAS A THROMBOCYTOPENIC FACTOR IN ITP

PLASMA

Harrington WJ, et al. J Lab Clin Med. 1951; 38:1-10.

https://onlinelibrary.wiley.com

DEFINITION OF IMMUNE THROMBOCYTOPENIA: ITP WORKING GROUP

• PRIMARY ITP

• ISOLATED THROMBOCYTOPENIA

• PLATELET COUNT <100,000/MICROLITRE

• ABSENCE OF CAUSES THAT MAY BE ASSOCIATED WITH

THROMBOCYTOPENIA

• DIAGNOSIS OF EXCLUSION

• NO CLINICAL OR LAB PARAMETERS ARE AVAILABLE TO ESTABLISH THIS

DIAGNOSIS WITH ACCURACY

• MAIN CLINICAL PROBLEM IS AN INCREASED RISK OF BLEEDING

• BEST DIAGNOSTIC PARAMETER IS RESPONSE TO THERAPY

• SECONDARY ITP

Rodeghiero F, et al. Blood 2009; 113:2386-2393.

DIFFERENTIAL DX. AND SECONDARY CAUSES OF ITP

• PSEUDOTHROMBOCYTOPENIA

• RENAL OR LIVER DISEASE

• MDS/ACUTE LEUKEMIA/APLASTIC ANEMIA

• GENETIC DISEASES; BERNARD-SOULIER SYNDROME, MYH9-RELATED

DISORDERS

• THROMBOTIC THROMBOCYTOPENIC PURPURA(TTP)

• HEPARIN-INDUCED THROMBOCYTOPENIA(HIT)

• DRUGS; QUININE, ABCIXIMAB,CARBAMAZEPINE, RIFAMPICIN, VANCOMYCIN

• LYMPHOPROLIFERATIVE DISORDER

• INFECTION; HIV, HBV, HCV, CMV, EBV, H.PYLORI

• AUTOIMMUNE DISEASE; SLE, RHEUMATOID ARTHRITIS, ANTIPHOSPHOLIPID

SYNDROME, EVANS SYNDROME

PSEUDOTHROMBOCYTOPENIA

http://www.journalagent.com

INTERNATIONAL WORKING GROUP(IWG) DEFINITION AND CLASSIFICATION

• NEWLY DIAGNOSED : DIAGNOSIS TO <3 MONTHS

• PERSISTENT : 3-12 MONTHS FROM DIAGNOSIS

• CHRONIC : > 12 MONTHS

Diagnosis

Newly diagnosis

3 months

Persistent

12 months

Chronic

Blood. 2009;113(11):2386-2393.

ITP MANIFESTATION

• ASYMPTOMATIC, MILD MUCOCUTANEOUS TO LIFE

THREATENING BLEEDING

• INCIDENCE: 2-4 CASES/100,000 PERSONS-YEARS

• 2 PEAKS: 20-30 YEARS OF AGE (F>M)

>60 YEARS OF AGE (F=M)

PRESENTING SYMPTOMS OF ADULTS ITP

Platelet count

(x109/L)

Hemorrhage, % Purpura, % Asymptomatic,

%

0-9 16 66 18

10-19 12 67 22

20-29 15 46 38

30-49 4 42 54

Overall

(N=245)

12 59 29

Neylon AJ, et al. Br J Haematol. 2003;122:966-974.

BLEEDING MANIFESTATION

The Open Dentistry Journal. 2020;14: 1874-2106.

https://bloodspecialistclinic.com

Petechiae

MUCOCUTANEOUS BLEEDING

ecchymosis

PATHOPHYSIOLOGY

NEJM. 2019; 381:945-955.

THROMBOPOIETIN LEVELS IN ITP

• HEALTHY VOLUNTEERS

• PLATELET COUNT: 200,000 CELLS/L

• SERUM TPO: < 1 FMOLES/ML

• AMEGAKARYOCYTIC THROMBOCYTOPENIA PATIENTS


• SERUM TPO: 13.7 FMOLES/ML

• ITP PATIENTS


• SERUM TPO: 1.25 FMOLES/ML

Mukai HY. et al. Thromb Haematol. 1996;76:675-678.

DIAGNOSIS APPROACH

• ITP: PATIENTS WITH PLATELET COUNT < 100,00/L

• EXCLUSION OF OTHER CAUSES OF ISOLATED THROMBOCYTOPENIA

• COMPLETE HX. AND PE, FULL BLOOD COUNT

• BONE MARROW EXAMINATION IS NOT REQUIRED IN THE INITIAL

DIAGNOSIS, BUT SHOULD BE DONE IN:

• RELAPSING AFTER REMISSION

• NOT RESPONDING TO INITIAL TREATMENT

• PLAN TO SPLENECTOMY

• OTHER ABNORMALITIES ARE DETECTED IN BLOOD COUNT

https://www.chop.edu/news/itp-update-immune-thrombocytopenia-not-

idiopathic-and-not-purpuric

Giant platelet

BONE MARROW ASPIRATION

https://imagebank.hematology.org

MANAGEMENT OF ADULTS WITH ITP

RECOMMENDATIONS FOR TREATMENT GOALS

1. INDIVIDUALIZED TO THE PATIENT AND PHASE OF THE DISEASE

2. PREVENT SEVERE BLEEDING EPISODES

3. MAINTAIN A TARGET PLATELET LEVEL > 20-30 X109/L AT LEAST FOR

SYMPTOMATIC PATIENTS

4. MINIMAL TOXICITY

5. OPTIMIZED HEALTH-RELATED QUALITY OF LIFE (HRQOL)

TREATMENT OF ITP

• INHIBIT RETICULOENDOTHELIAL CLEARANCE OF ANTIBODY-COATED

PLATELETS

• INHIBIT AUTOANTIBODY PRODUCTION

• BLOCK T- AND B-CELL INTERACTIONS

• ENHANCE PLATELET PRODUCTION

• OTHERS

• RESPONSE

• PLATELET COUNT ≥ 30 X 109/L AND AT LEAST A DOUBLING OF BASELINE

• TERMINOLOGY FOR THE TIMING OF RESPONSE

• EARLY RESPONSE: 1 WEEK

• INITIAL RESPONSE: 1 MONTH

• DURABLE RESPONSE: 6 MONTHS

• REMISSION

• PLATELET COUNT > 100 X 109/L AND AT 12 MONTHS

• STEROID DEPENDENT

• AN ONGOING NEED FOR CONTINUOUS PREDNISOLONE > 5 MG/DAY OR FREQUENT

COURSES OF CORTICOSTEROIDS TO MAINTAIN PLATELET COUNT ≥ 30 X 109/L AND/OR

TO AVOID BLEEDING

DEFINITION OF TERMS IN 2019 ASH GUIDELINES

Neunert C, et al. Blood Advances. 2019;3:3829-66.

NEUNERT C, ET AL. BLOOD ADVANCES. 2019;3:3829-66.

OUTPATIENT VS INPATIENT MANAGEMENT

Criterion Management

Newly diagnosed patient with platelet count < 20 x 109/L

and asymptomatic or minor mucocutaneous bleeding Hospital admission

Established ITP diagnosis and platelet count < 20 x 109/L

and asymptomatic or minor mucocutaneous bleeding Outpatient managementa

Patient with platelet count ≥ 20 x 109/L

and asymptomatic or minor mucocutaneous bleeding Outpatient managementa

a Patients who are refractory to treatment, with social concerns, uncertainty about the diagnosis, significant comorbidities, risks of bleeding, or more significant

mucosal bleeding may benefit from hospital admission. Patients not admitted to the hospital should receive education and an expedited follow-up with a

hematologist. The need for hospital admission varies across the range of platelet counts represented here.

Criterion Management

Platelet count ≥ 30 x 109/L

and asymptomatic or minor mucocutaneous bleeding Management with observationa

Platelet count < 30 x 109/L

and asymptomatic or minor mucocutaneous bleeding Treatment with corticosteroidsb


OBSERVATION VS TREATMENT

a Corticosteroids may be considered for patients with a platelet count of approximately 30 x 109/L, comorbidities, anticoagulant/antiplatelet medications,

upcoming procedures, or age > 60 years.

b Consider the severity of thrombocytopenia, comorbidities, anticoagulant/antiplatelet medications, upcoming procedures, and age of the patient.

MANAGEMENT OF ADULTS WITH NEWLY DIAGNOSED ITP

CORTICOSTEROIDS

• PREDNISOLONE

• A SHORT COURSE OF < 6 WEEKS(INCLUDING TAPERING)

• 0.5-2.0 MKD THEN TAPER

• RESPONSES IN 7-10 DAYS, PEAK IN 2-4 WKS

• ONLY 5-30% SUSTAIN RESPONSE AFTER DISCONTINUATION

• TOXICITY: GLUCOSE INTOLERANCE, PSYCHOSIS, OSTEOPOROSIS,

CUSHINGOID HABITUS, WEIGHT GAIN, INFECTIONS

• DEXAMETHASONE

• BETTER RESPONSE AT 7 DAYS AFTER TREATMENT INITIATION

• 40 MKD FOR 4 DAYS

IVIG • DOSE

• 0.4-1.0 G/KG FOR 2-5 DAYS

• EFFICACY

• 65% ACHIEVE PLATELET COUNT >100,00/ L ; 85% > 50,000/L

• TRANSIENT RESPONSES

• 30% REFRACTORY

• TOXICITY

• HEADACHE

• POSITIVE DAT

• ANAPHYLAXIS IN IGA DEFICIENCY PATIENTS

• THROMBOSIS

INTRAVENOUS ANTI-RH(D) THERAPY

• RBC HEMOLYSIS AND FC RECEPTOR BLOCKADE

• DOSE: 50 MICROGRAM/KG IV OVER 2-5 MINS, REDUCE IF HB < 10 G/DL

• >70% RESPONDERS, DURATION > 21 DAYS IN 50%

• ALL PATIENTS DROP HB(0.8 G/DL)

• NOT EFFECTIVE IN RH- OR SPLENECTOMIZED PATIENTS

• RARE BUT SEVERE AE: INTRAVASCULAR HEMOLYSIS AND DIC

RECOMMENDATIONS FOR MANAGEMENT OF ITP IN ADULTS

PROVAN D, ET AL. BLOOD ADV. 2019 NOV 26;3(22):3780-3817.

Initial therapies for newly diagnosed ITP in adults

High risk for bleeding, who require a surgical procedure, or who are unresponsive to prednisolone or with contraindications to high-

dose corticosteroid therapy**

IVIg (1 gm/kg on 1-2 days) or 0.4 g/kg per day for 5 days

IV anti-D (50-75 µg/kg once)

Standard I line*: Prednisolone 1 mg/kg/day (max: 80 mg) for 2-3 weeks

No difference in PLTs but faster response with Dexamethasone

Response achieved (platelet >50 x 109/L): Taper and stop by 6

weeks (maximum 8 weeks) irrespective of platelet count

No response within 2 weeks: tapered rapidly over 1 week

and stopped

*Longer courses of steroids should be avoided, despite benefit form continuous low-dose steroids (≤2.5-5 mg prednisone) without incurring major side effects in occasional patients. Probably the most consistent and prevalent error in ITP management is over usage and reliance on steroids

**Patients with relevant contraindications to high-dose corticosteroid therapy: insulin-dependent diabetes, uncontrolled diabetes, psychiatric disorders, active infection may be managed with only IVIg or IV anti-D as initial therapy

TREATMENT GOALS: AVOID TREATMENT-RELATED TOXICITY, OPTIMIZE HRQOL AND INDIVIDUALIZE

TREATMENT DECISIONS


PROVAN D, ET AL. BLOOD ADVANCES. 2019;3:3780-3817.

NEWLY DIAGNOSED ADULT PATIENTS, ITP < 3 MONTHS

INTERNATIONAL

CONSENSUS REPORT

Prednisone

0.5–2.0 mg/kg/day for < 6

weeks including tapering

Dexamethasone

40 mg/kg/day for 4

days

1 cycle

Prednisone

1 mg/kg/day for 2 weeks

(maximum 3 weeks)

Dexamethasone

40 mg/kg/day for 4 days

Maximum 3 cycles

Taper over one week Taper and stop at 6 weeks

(maximum 8 weeks), even

if platelet counts drop

IVIg/IV anti-D

In case of bleeding, high

risk of bleeding,

corticosteroids

contraindication or

surgery

No response Platelets > 50 × 109/L

ASH GUIDELINE

MANAGEMENT OF ADULTS WITH ITP

PATIENTS WHO ARE REFRACTORY TO OR DEPENDENT ON

CORTICOSTEROIDS

A PATIENTS SHOULD HAVE APPROPRIATE IMMUNIZATIONS PRIOR TO SPLENECTOMY, AND

SHOULD RECEIVE COUNSELING ON ANTIBIOTIC PROPHYLAXIS AND ON THE PROMPT

RECOGNITION AND MANAGEMENT OF FEVER.


PATIENTS WITH ITP DURATION ≥ 3 MONTHS WHO ARE

STEROID-DEPENDENT OR NO RESPONSE TO STEROID

TPO-RAs Splenectomya

TPO-RAs

Rituximab

Rituximab

Splenectomya

Splenectomy should be delayed by at least 1 year after diagnosis because of the potential for spontaneous remission

Patient education and shared decision-making are encouraged

Treatment choice should be individualized based on comorbidities, age, ITP duration, rescue medication, hospitalization, frequency of bleeding episodes,

availability, cost, patient values and preferences, medical and social support networks, and medication adherence

TPO-RAs or splenectomy

are suggested

TPO-RAs rather than rituximab

are suggested

Rituximab rather than splenectomy

is suggested


TPO-RAS

PATIENTS WITH ITP DURATION ≥ 3 MONTHS

A DAILY ORAL MEDICATION: ELTROMBOPAG

A WEEKLY SUBCUTANEOUS INJECTION: ROMIPLOSTIM

INDIVIDUALIZED SELECTION OF SECOND-LINE THERAPY IN ADULTS BASED ON SHARED DECISION-MAKING

A OTHER FACTORS THAT MIGHT INFLUENCE TREATMENT DECISIONS INCLUDE FREQUENCY OF

BLEEDING SUFFICIENT TO REQUIRE HOSPITALIZATION OR RESCUE MEDICATION,

COMORBIDITIES, COMPLIANCE, MEDICAL AND SOCIAL SUPPORT NETWORKS, COST, AND

AVAILABILITY OF TREATMENTS.

ADAPTED FROM MANAGEMENT OF IMMUNE THROMBOCYTOPENIA. A POCKET GUIDE FOR THE CLINICIAN. AVAILABLE

FROM: WWW.HEMATOLOGY.ORG/CLINICIANS/GUIDELINES-QUALITY/DOCUMENTS/10115.ASPX. ACCESSED 9 JANUARY

2020.

Adult with ITP > 3 months

3–12 months > 12 months Assess duration of ITP

Assess patient values and

preferences Assess patient values

Patient wishes to avoid long-

term medication

Patient wishes to achieve a

durable response Patient wishes to achieve a

durable response

Patient wishes to avoid

long-term medication

Patient wishes to avoid surgery

TPO-RAs Rituximab TPO-RAs

Splenectomy

Rituximab

Splenectomy

TPO-RAs

Rituximab

TPO-RAs

Rituximab

TPO-RAs

Rituximab

Splenectomy

Patient

wishes to

avoid

surgery

Patient

wishes to

avoid

long-term

medication

TPO-RAs Splenectomy

Patient

wishes to

achieve a

durable

response

Patient

wishes to

avoid

surgery

Patient

wishes to

achieve a

durable

response

Patient

wishes to

avoid

long-term

medication

Splenectomy TPO-RAs Rituximab Rituximab

Patient characteristicsa

Actions

Treatment options

RECOMMENDATIONS FOR MANAGEMENT OF ADULTS ITP

PROVAN D, ET AL. BLOOD ADV. 2019 NOV 26;3(22):3780-3817.

Subsequent therapies for adult patients with persistent and chronic ITP

Fostamatinib:

Response rate: 43%

Stable response: 18%

Rituximab:

Response rate: 60% of patients

Durable response: 20% to 25% of adult patients

TPO-RAs (eltrombopag, avatrombopag, romiplostim):

Response rate: >60% (irrespective of splenectomy)

Persistent response: for 6-8 years

Sustained response after taper or withdrawal: 10-30% of patients

Successful treatment discontinuation: 1/3rd of newly diagnosed ITP and 15%-30% of chronic ITP patients

Reversible fibrosis: romiplostim: 6.9%, eltrombopag, 3.8%

Treatment of patients failing multiple therapies: MMF, fostamatinib, rituximab, azathioprine, dapsone, danazol, switch TPO-RA, and combination chemotherapy, alemtuzumab and HSCT as a last resort

Response rate: ≤90% (no formal response, 19%) Response maintained for 10 years in 78% 20-year relapse-free survival: 67%

Postsplenectomy: higher risk for infections (eg, pneumonia, meningitis, and septicemia) and thromboembolism esp. in patients aged ≥60 years

Recommended to wait 12 to 24

months from diagnosis before

performing splenectomy because of

the chance of remission or

stabilization

Splenectomy was previously

considered a second-line surgical

therapy and is associated with long-

term treatment-free remissions

Subsequent therapy: surgical


PROVAN D, ET AL. BLOOD ADVANCES. 2019;3:3780-3817.

ADULT PATIENTS WITH ITP ≥ 3 MONTHS WHO ARE DEPENDENT ON

OR UNRESPONSIVE TO STEROID

ASH GUIDELINE INTERNATIONAL

CONSENSUS REPORT

• TPO-RAs over rituximab recommended

• Rituximab over splenectomy recommended

• Delay splenectomy by > 12 months due to

potential remission occurring during this period.

For patients with ITP ˃ 12 months, either TPO-

RAs or splenectomy is recommended

TPO-RAs (eltrombopag, avatrombopag, romiplostim)

• Response rate > 60% (irrespective of splenectomy)

• Persistent response for up to 6-8 years

• Sustained response off treatment in 30% of newly

diagnosed, and 10–30% of chronic, patients

• Reversible fibrosis: romiplostim: 6.9%, eltrombopag, 3.8%

Rituximab

• Response rate of 60%

• Sustained response in 20–

25% of adult patients

Fostamatinib

• Response rate of 43%

• Sustained response in up to

18% of patients

ASH guidelines provide a comparison of second-

line therapies one against the other whereas the

international consensus report states the response

rates, specificities and potential side effects of

each option.

The ASH guidelines do not mention avatrombopag

or fostamatinib, unlike the international consensus

report

Splenectomy

• Delay by > 12 months due to potential remission occurring during this period and concerns

about long-term side effects

• ≤ 90% initial response rate, maintained for 10 years in 78% of the patients

• 20-year relapse-free survival of 67%

ELTROMBOPAG IN ITP

DOSING OF ELTROMBOPAG

If no response

after 4 weeks at

maximum dose:

discontinue

eltrombopag

treatment

Age: ≥6 years, 50

mg/d; 1-5 years, 25

mg/d

Asian ancestry:

reduced dose of 25

mg/d

Hepatic impairment:

reduced dose of 25

mg/d

Standard dose adjustment:

Decrease or increase by 25

mg/d

On 25 mg every other day

dose: Increase to 25 mg/d

On 25 mg/d dose: Decrease

to 12.5 mg OD or 25 mg

dose once every other day

Wait ≥2 weeks prior to

another dose adjustment

Initial dose: 25 or 50 mg/d

Dose adjusted to achieve and

maintain a platelet count ≥50 x 109/L

Maximum dose: 75 mg/d

ELTROMBOPAG IN ADULT ITP

GONZA´ LEZ-LO´PEZ TJ, ET AL. INT J HEMATOL. 2017;106(4):508-516.

[VALUE]% [VALUE]% [VALUE]%

[VALUE]% [VALUE]%

[VALUE]%

Newly diagnosed ITP(n=30)

Persistent ITP(n=30)

Chronic ITP(n=160)

Response rates in ITP groups (N=220)

Response Complete response

Responses in persistent ITP and chronic ITP were similar

There was a trend toward better responses in newly diagnosed patients

PLATELET RESPONSE WITH ELTROMBOPAG IN ADULTS WITH CHRONIC ITP

1. PROVAN D, ET AL. BLOOD ADV. 2019 NOV 26;3(22):3780-3817; 2. YANG R, ET

AL. BR J HAEMATOL. 2017;176(1):101-110;

3. GONZA´ LEZ-LO´PEZ TJ, ET AL. EUR J HAEMATOL. 2016;97(3):297-302.

Response rates: 50% to 88.8%1

26-fold greater chance of achieving platelet counts ≥50 x 109/L (P<0.001) with eltrombopag over placebo2

Median platelet response rate, 75.2% over 15 months3

Splenectomy status, baseline platelet count, concomitant ITP treatments, and number of previous ITP treatments: no effect on response rates1

LONGER-TERM USE OF ELTROMBOPAG (EXTEND STUDY)

BRYNES RK, ET AL. AM J HEMATOL. 2015;90(7):598-601.

• 86% of patients achieved platelet counts ≥50×109/L at least once without rescue therapy

• 52% of patients achieved continuous platelet count ≥50×109/L or twice baseline for ≥25 weeks in absence of rescue therapy

0

50

100

150

200

250

BSL301

1 293

2 288

3 275

4 275

5 274

6 276

10 219

20 140

30 110

40 95

50 86

60 80

70 73

80 74

90 57

100 65

110 53

120 56

130 42

140 36

150 24

160 26

170 20

180 28

190 23

200 12

210 15

220 13

230 17

240 12

250 15

Media

n (

25%

, 75%

IQ

R)

Pla

tele

t C

ounts

(×

109/L

)

Weeks

Patients at

risk, n

Median platelets increased to >50x109/L by 2nd week, sustained throughout the median

treatment period of 2.37 years (range, 2 days to 8.76 years)

OVERVIEW OF THERAPIES FOR TREATMENT OF ADULT ITP

Initial treatment of newly diagnosed adult

Corticosteroids: Dexamethasone

Methylprednisolone

Prednisolone

IVIg Anti-D

Subsequent treatment MEDICAL

SURGICAL

Robust evidence:

Elthrombopag

Avatrombopag

Romiplostim

Fostamatinib

Rituximab

Less Robust evidence:

Azathioprine

Cyclosporin A

Cyclophosphamide

Danazol

MMF

Vinca alkaloids

Splenectomy

Blood. 2019;3(22):3785

SUMMARY OF RECOMMENDATIONS

ADULT WITH ITP < 3 MONTHS

First-line management strategy

If platelet count ≥ 30 x 109/L, observation is recommended

If platelet count < 30 x 109/L, steroids are suggested

Outpatient or inpatient management

If platelet count ≥ 20 x 109/L, outpatient management is suggested

If platelet count < 20 x 109/L, hospital admission is suggested

Duration of corticosteroids

Prednisone < 6 weeks is recommended (including tapering)

Type and dosage of corticosteroids

Prednisone (0.5–2.0 mg/kg/day) for < 6 weeks or dexamethasone

(40 mg/day) for 4 days is suggested

Role of rituximab in first-line

Corticosteroids > corticosteroids + rituximab

ADULT WITH ITP ≥ 3 MONTHS WHO

ARE DEPENDENT ON OR

UNRESPONSIVE TO STEROID

Patients for whom TPO-RAs are considered Eltrombopag or romiplostim is suggested

Second-line management strategy TPO-RAs > rituximab > splenectomy

Management of Primary Immune Thrombocytopenia (ITP) in Adult

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