Immune thrombocytopenia

Figures & data

Box 1. Diagnosis of ITP in children and adults. Adapted from Provan et al. 2019 [23]

Basic evaluation	Assays of Potential Value	Tests of unproven/uncertain benefit
Patient history	Direct platelet glycoprotein-specific antibodies	Thrombopoietin (TPO)
Family history	Antiphospholipid antibodies^c	Reticulated platelets/immature platelet fraction
Physical examination	Antithyroid antibodies and thyroid function	Bleeding time
Complete blood count	Pregnancy test^d	Serum complement
Reticulocyte count	Antinuclear antibodies
Peripheral blood film	Viral polymerase chain reaction (PCR) for Epstein-Barr virus (EBV), parvovirus and cytomegalovirus (CMV)
Quantitative immunoglobulins^a	Bone marrow biopsy^e
Blood group (Rhesus)	Direct antiglobulin test
Human immunodeficiency virus (HIV)^b	Helicobacter pylori^b
Hepatitis C virus (HCV)^b
Hepatitis B virus (HBV)

^aConsidered in children with ITP and recommended in children with persistent or chronic ITP for reassessment evaluation. ^b In the appropriate geographical setting. ^c Including anticardiolipin and lupus anticoagulant. ^d In women of childbearing potential. ^e In selected patients, including patients who have other abnormalities identified on their blood smear, such as white cell dysplasia or anemia that cannot be explained by bleeding or iron deficiency

Box 2. Outline of 2019 ICR guidelines for ITP in pregnancy, emergency treatment, and patients failing multiple therapies [23]

ITP in pregnancy	Emergency treatment	Patients failing multiple therapies
Initial treatment is with oral corticosteroids or IVIg	Combination of initial treatments including IV corticosteroids & IVIg (usually), where there is an urgent need to increase platelet count; platelet transfusions	Accessory splenectomy
IV anti-D in Rh(D)-positive non-splenectomized women can be well tolerated and effective, but potentially can cause maternal or fetal hemolysis	TPO-RAs should be considered in a patient receiving corticosteroids with life-threatening bleeding and absence of a significant response to IVIg and platelet transfusion	Alemtuzumab
Combination therapy (prednisone + IVIg and/or IV anti-D) can be effective in patients’ refractory to single agents alone		Combination of initial and subsequent therapies
Rituximab can be considered for very severe cases, but potential complications are perinatal and neonatal immunosuppression and subsequent infection		Combination chemotherapy
TPO-RAs and recombinant human TPO (only available in China) may be considered in late pregnancy when other treatments have failed, but limited data available.		Enrollment in a clinical trial
		HSCT
		Splenectomy (if not already performed) with pre-splenectomy predictive tests
		Supportive care

HSCT, human stem cell transplant; IVIg, intravenous immunoglobulin; TPO, thrombopoietin; TPO-RA, thrombopoietin receptor agonist

Figure 1. Overview of therapies for the treatment of adult ITP. Reproduced from [23] with permission from Elsevier

Figure 2. 2019 ASH guidelines: treatment algorithm for selecting second-line therapy in adults with ITP [25]

Figure 3. Proposed mechanism of action of fostamatinib in ITP [From 68, with permission from Future Medicine]

FcγR, IgG receptor; PLT, platelet; Syk, spleen tyrosine kinase

Table 1. Comparison of 2019 International Consensus Report (ICR) and American Society of Hematology (ASH) guidelines for ITP: main similarities and differences

	International Consensus Report (ICR) 2019 guidelines [23]	American Society of Hematology (ASH) 2019 guidelines [25]
Diagnosis	Little change	Little change
Corticosteroids	Limit corticosteroid exposure	Limit corticosteroid exposure; dexamethasone or prednisone
Subsequent treatment	Robust evidence for TPO-RAs, rituximab and fostamatinib as viable options	Second-line TPO-RAs
	Earlier use of TPO-RAs	Earlier use of TPO-RAs
Splenectomy	Consider only after failure of medical (pharmacological) therapies	Patient preference
Pediatrics	More aggressive treatment
Patient-specific	QoL plays a role in decision-making

Table 2. New agents for immune thrombocytopenia (ITP)

	Mode of action	Study	Main efficacy outcome	Reference
Rilzabrutinib	Bruton Tyrosine Kinase (BTK) inhibition	Open-label Phase 1/2 (n = 47)	43% of patients achieved primary endpoint (≥ 2 consecutive platelet counts ≥ 50 x 10^9/L)	[88]
		Placebo-controlled Phase 3	Ongoing	[NCT04562766]
Rozanolixizumab	Neonatal Fc receptor (FcRn) inhibition	Open-label Phase 2 (n = 66)	66.7% and 54.5% patients treated with single-dose 15 and 20 mg/kg rozanolixizumab, respectively achieved Day 8 platelet count ≥ 50 x 10^9/L	[89]
		Placebo-controlled Phase 3	Ongoing	[NCT04200456]
Efgartigimod	Neonatal FcRn inhibition	Placebo-controlled Phase 2 (n = 38)	Efgartigimod vs. placebo: 46% vs. 25% achieved platelet count ≥50 × 10^9/L on ≥2 occasions; 38% vs. 0% achieved ≥50 × 10^9/L for ≥10 cumulative days	[90]
		Open-label Phase 3	Planned	[NCT04812925]
Oseltamivir	Reduction of platelet glycoprotein desialylation [91]	Randomized, Phase 2: oseltamivir + DXM vs. DXM (n = 90)	Oseltamivir + DXM vs. DXM: day-14 initial response (platelet count ≥30 x10^9/L, ≥2-fold increase from baseline, no bleeding), 86% vs. 66% (p = 0.030), 6-month sustained response, 53% vs. 30% (p = 0 · 032)	[92]
		Placebo-controlled Phase 3	Ongoing	[NCT03520049]
Sutimlimab (BIVV009)	Complement subcomponent C1 (C1s) inhibition [93]	Phase 1 (n = 12)	42% achieved a durable response (platelet counts ≥50 x 10^9/L & >2-fold increase from baseline on 2 consecutive occasions) at 21 weeks	[94]
Bortezomib	Proteosome inhibition	Case report	Bortezomib increased platelet counts resulting in hospital discharge	[95]
Daratumumab	Anti-CD38	Case report	Sustained complete remission in refractory ITP	[96]
Belimumab	B-cell activating factor (BAFF) inhibition	Open label Phase 2 (n = 15)	Combination belimumab + rituximab: 80% overall response rate (platelet count >30 x10^9/L & ≥2-fold increase from baseline) & 67% complete response (platelet count >100x10^9/L) at 1 year	[97]
All-Trans Retinoid Acid (ATRA)	Regulation of complement-IL-1β loop & TNFAIP3/NF-κB/SMAD7 signaling pathway [99,100]	Open-label, randomized, Phase 2: ATRA + danazol vs. danazol (n = 93)	ATRA + danazol vs. danazol: 1-year sustained response (platelet count ≥30 x10^9/L & ≥2-fold increase from baseline) 62% vs. 25% (p = 0 · 00037)	[98]
		Open-label, randomized, Phase 2: ATRA + HD-DXM vs. HD-DXM (n = 300)	ATRA + HD-DXM vs. HD-DXM: 6-month sustained response (platelet count > 50 × 10^9/L) 61% vs. 37% (p = 0.009)	[101]

DXM, dexamethasone; HD-DXM, high-dose dexamethasone

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