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JOURNAL PRESENTATION

Dr. Nasrin Akhter

Resident (Phase B)

Department of Haematology,

BSMMU

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Review article�� First Published: 13^TH February, 2020� on American Scociety of Haematology.�� Authors: Oriana Miltiadous, Ming Hou and James B.Bussel

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Introduction

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with thrombocytopenia resulting from increased platelet destruction and inhibition of platelet production.

It is the most common acquired thrombocytopenia after chemotherapy-induced thrombocytopenia.

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Introduction

Patients classiﬁed as refractory have a diagnosis that is not really ITP or have disease that is difﬁcult to manage.

ITP is a diagnosis of exclusion.

Response to treatment is the only afﬁrmative conﬁrmation of diagnosis.

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Introduction

However, refractory patients do not respond to front-line or other treatments; thus, no conﬁrmation of diagnosis exist.

The biology of refractory ITP is largely unexplored and includes oligoclonality, lymphocyte pumps, and other possibilities.

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OBJECTIVE

The second section describes

Combination treatment for refractory cases of ITP

The ﬁrst section carefully evaluates

The diagnostic considerations in patients with refractory ITP

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Refractory ITP

Deﬁning refractory as “no response to treatment” is subjective.

The deﬁnition of response as outlined by Rodeghiero et al, achieving a platelet count of 30000/µL and doubling baseline platelet counts.

Ideally the treatment would be repeated to enhance validity of the lack of response.

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Refractory ITP

Failure to respond to splenectomy is included in the deﬁnition of “refractory” according to Rodeghiero et al, although this is disputed in children.

Currently, there is increasing reluctance to undergo or recommend splenectomy among patients and physicians.

So that refractory needs to be deﬁned without reference to splenectomy.

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Refractory ITP

There the description of “refractory” reserved for the patients :

whose platelet counts do not respond to ≥2 treatments

there is no single medication to which they respond

their platelet counts are very low and accompanied by bleeding

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Diagnosis

At diagnosis, recommended laboratory testing is a complete blood cell count (CBC) with differential and review of the smear plus/minus immunoglobulin levels, as well as hepatitis C and HIV testing.

The general practice of performing only a limited number of tests creates a higher likelihood of an incorrect diagnosis.

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Common misdiagnosis are:

Secondary ITP

MDS

Inherited thrombocytopenia

Drug induced thrombocytopenia

BM failure syndrome with primarily thrombocytopenia

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	Primary ITP	SLE	Evans Syndrome	ALPS	CVID	CLL
Age at present	Any age, more common age>65years	Teenagers and older	Mostly adult	Any age	Young adult	>70 years
Incidence	1.6-3:100000	1-10:100000	1:80000	rare	1:25000	4.9:100000
Distinguishing feature	Isolated thrombocytopenia with petechiae /bruising	Multisystem involvement	Hemolysis , hepatosplenomegaly/lymphadenopathy	Splenomegaly/lymphadenopathy	10% ITP, 10% AIHA,5% Evans syndrome	Increased number of small mature lymphocytes
Diagnostic test	CBC, PBF, Low plt, normal or increased in size.	CBC: Low Hb,low plt ±low WBC			↓Ig G + ↓IgM/ IgA	Inc. lymphocyte, flow cytometry
	CBC, PBF, Low plt, normal or increased in size.	CRP,ESR, dsDNA, ANA	↓ANC;↑reticulocytes, ↑bilirubin; ↓haptoglobins Coombs+,↓IgG; BM :normal	Flowcytometry: CD4-,CD8- Tcells	↓Ig G + ↓IgM/ IgA	Inc. lymphocyte, flow cytometry
Molecular characteristics	Not identified	Not identified	Not identified	Defect in FAS gene	10% various genetic defect identified	Possible ch abnormality: 11q del , 13qdel
Clinical Approach	Standard first&2^nd line rx	Treat underlying disease	IVIG, Rituximab, sirolimlus , MMF	IvIG / steroids, MMF , Sirolimus, rituiximab	IVIG, Rituximab	Chemotherapy, Rituximab

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	HIV	Hepatitis C	H. Pylori	Drug induced	Post vaccine	Other infections
Age at present	Any, common at 20-40y	30-49Y,rare in younger	Any, common at age >60y	Any	Children and young adult	Any
incidence	10:100000	1:100000	3-14:100	rare	rare	rare
Distinguishing feature	Flu like illness, lymphadenopathy, opportunistic infections; thrombocytopenia secondary to high viral load	Arthralgia , pruritus , multifactorial thrombocytopenia	Nausea, vomiting abdominal pain	History of new drug treatment, difficult to diagnose	H/O recent vaccination, most commonly ,<6weeks after and secondary to live vaccine	variable
Diagnostic tests	P24 by ELISA, HIV IgM/IgG, HIV DNA PCR		Urea breath test, fecal H.Pylori antigen	Stopping offending agent should increase plt withtin few days	none	PCR, serum antibodies
Molecualr characterstics	None	None	None	None		None
Clinical Approach	HAART, TPO-RA, anti - D	Anti viral	Eradicate H.pylori	Stop offending agent		Treat underlying cause

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	Primary ITP	WAS	XLT	BSS	TAR	Gray plt syn
Incidence	1-6.4:10000	1-4:1 million, male	1:10 million, male	<1:1 million	0.4: 100000	rare
Distinguishing features	Isolated thrombocytopenia with petechiae /bruising	Male with eczema, petechiae, and infection	Isolated severe thrombocytopenia, very small plt, milk allergy related GI bleeding	Very large plt, falsely decrease number, and epistaxis	Missing radii, other skeletal abnormalities, spontaneous improvement of counts within ﬁrst year of life	Variable thrombocytopenia, missing α granules, myeloﬁbrosis due to “leakage” of α granule contents into the marrow
Diagnostic tests	CBC, peripheral blood smear. ↓↓ plt: normal or increased in size.	Peripheral bloods mear: small plt. Decreased number/ function of T cells.↓ IgG, ↓IgM,↑IgE, ↑IgA	Peripheral blood smear: small plt;	Peripheral blood smear: gianplt. No platelet aggregation in response to ristocetin. Flow cytometry.	XR forearm Fetal US. If plt don’t normalize, they may deteriorate;	count, large-sized gray platelets.BM shows myeloﬁbrosis
Molecular characteristics	Not identified	mutations of WAS gene on X chromosome	Mutations of WAS gene on X chromosome	Mutation of GP1BAgene,	Mutations in RBM8Agene	EAL2or GFI1Bmuta
Clinical Approach	Standard first and 2^nd line rx	HSCT, Future: gene rx	TPO-RA, Splenectomy, HSCT, future: gene rx	Transfusions,desmopressin, anti fibrinolytic	Transfusion, antifibrinolytic	HSCT

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	Primary ITP	FA	CAMT	DC	SDS	MDS
Age at presentation	Any age, more common after age 65y	Young children(6-9y), but upto 40y	Type I: new born. TypeII:3-6y	Young children(<5y)and upto 40y of age	Infancy/early childhood and upto 30y of age	Most common in older adults
Incidence	1-6.4:10000	1:1million	rare	<1:1 million	rare	1-4:1million
Distinguishing features	Isolated thrombocytopenia with petechiae /bruising	isolated thrombocytopenia at any age; thumb/skeletal abnormalities	Isolated severe thrombocytopenia in neonate; often progresses to complete AA within several years; 1/3with skeletal abnormalities	BM evaluation. Telomere length. Genetic panel and WES	pancytopenia, BM, fecal studies ,elastase, trypsinogen, isoamylase; genetic panel and WES	BM evaluation. Cytogenetics: 5qdel, 7del, trisomy8; genetic panel and WES
Diagnostic tests	CBC, periphera l blood smear. ↓↓ plt: normal or increased in size.	BM evaluation ,DEB, MMC. Genetic panel and WES	BM evaluation : reduced/ absent megakaryocytes; genetic panel and WES	BM evaluation. Telomere length. Genetic panel and WES	Exocrine pancreas dysfunction	BM evaluation. Cytogenetics:5qdel, 7del,trisomy8;genetic panel and WES
Molecular characterstics	Not identified	Mutation in FANCA, FANCC ,FANG genes	Mutation inc-Mplgen	11genemutation	Mutation s in BDS gene	Monosomy7,trisomy8or 21
Clinical Approach	Standard first and 2^nd line rx	Transfusions, androgens, HSCT,TPO-RA,G-CSF	Transfusions, HSCT	Transfusions,androgens, HSCT,TPO-RA,G-C	Supportive. HSCT. Plt transfusion	Chemotherapy.HSCT. TPO-RA (controversial

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PRIMARY

ITP ~50%

Drug Induced ~5%

Figure: Incidence of primary ITP vs others diagnoses defined as having “refractory ITP”

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Diagnostic tests	Possible diagnosis to be identiﬁed
CBC with differential	Leukemia, Evans syndrome
Reticulocytes	FA, DC, SDS, MDS
Smear review	WAS, XLT, BSS, X-linked gray plt syndrome, gray plt syndrome, MYH9RD
Immunoglobulins (IgM, IgG, IgA)	CVID, WAS
Liver Function Test	Hepatitis C
H pylori stool antigen/urea breath test	Infectious-associated thrombocytopenia
Flow cytometry for lymphocyte subsets	ALPS, WAS, CLL, HIV
ESR, CRP	SLE, other inﬂammatory causes
ANA, dsDNA	SLE, other inﬂammatory causes
Bone marrow aspirate/biopsy/cytogenetics	MDS, FA, CAMT, DC, SDS, CLL
Genetic testing: whole-genome sequencing vs speciﬁc panel	WAS, XLT, BSS, X-linked gray plt syndrome
Telomere length	DC
Stool elastase, trypsinogen	SDS
Plt aggregation	BSS, vWF type IIb, plt-type vWD
vWD panel	vWF type IIb, plt-type vWD

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Role of combination treatment to manage refractory patients with ITP

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Combination therapies for refractory ITP – Pre TPO era

References	Arms	Medication	Dosing	Cycles	Patients	Reported response
Figueroa et al	1	Cyclophosphamide Prednisolone Vincristine Procarbazine or Etoposide	400-650 mg/m2 IV, days 1 and 8 40 mg/m2 PO, days 1 and 14 2 mg IV, days 1 and 8 100 mg/m2 PO, Day 1 and 14 or 100mg/m2 IV, Day 14-16	3-8	10	CR 60% PR 20%
McMillan	1	Cyclophosphamide Prednisolone Vincristine Procarbazine or Etoposide	400-650 mg/m2 IV, days 1 and 8 40 mg/m2 PO, days 1 and 14 2 mg IV, days 1 and 8 100 mg/m2 PO, Day 1 and 14 or 100mg/m2 IV, Day 14-16	3-8	12	CR 42% PR 8%
Arnold et al	1	Azathioprine CSA MMF	2 mg/kg/d 2 mg/kg/d 1-2 g/d		19	CR 11%, PR 63% 57% relapsed
Boruchov et al	Acute Maintenance	IVIG Anti-D Vincristine Vinblastine Danazole Azathioprine	1 g/kg IV		17 18	66% responded to acute IV therapy Response, 65% at 2 mo and 71% at 4 mo
Hasan et al	1 2 3	2^nd dose Rituximab Rituximab Cyclophosphamide Vincristine Prednisolone DDR	375 mg/m2 IV, weekly x4 week 375 mg/m2 IV, weeks 1,2,5 and 8 750 mg/m2 IV, every 4 week 1.4mg/m2 IV,every4wk 100mg po,day 1-5,every 4 wk 750 mg/m2 IV, weekly	4 wk 4 infusion 3 3 3 4 wk	20 8 8	None with benefit over standard dose Rituximab

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Combination therapies for refractory ITP – Post TPO era

References	Arms	Medication	Dosing	Cycles	Patients	Reported response
Wang et al	1 2	rh TPO Danazol Danazol	1µg/kg S/C ,daily for 15d 200mg PO, TID 200mg PO TID		73 19	TRR 60% TRR 45%
Li et al	1 2	CSA Prednisone Rapamycin Prednisone	3mg/kg PO,BID 10-20mg PO daily 6 mg PO, then 2 mg PO, daily 10-20mg PO daily	3-6 mo 3-6 mo	45 43	SR 37% SR 68%
Zhou et al	1 2	Rituximab rhTPO Rituximab	100mg I.V weekly 400 U/kg s/c 100 mg I.V. weekly	4week 4week	77 38	CR 45%, SR 44% CR 23%, SR 30%
Li et al	1	Rituximab rhTPO	100mg IV weekly 300µg/kg/d	4week 14day	14	CR 50%
Gudbrandsdottir et al	1	CSA/MMF, TPO and IVIG			18	CR 72%
Feng et al	1 2	DANAZOL ATRA DANAZOL	200mg PO, BID 10mg PO, BID 200mg PO, BID	16wk	45 48	OR 82% OR 44%

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Figure : Illustration of the different mechanisms of action of ITP medications

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Biology of refractoriness

Patients with very difﬁcult cases of chronic ITP may lose responsiveness to treatment over time.
Possible mechanisms are:

Evolution to MDS

Antigen/epitope spread

Upregulation of “pumps” that expel treatment molecules from inside cells

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Rituximab Refractoriness

Possible mechanisms accounting for rituximab resistance in ITP include expansion of long-lived plasma cells in spleen.

Associated with oligo/monoclonal expansion of Vb T-cell receptor (VBTCR).

Clonal expansions have been reported in other small series of patients with ITP who are unresponsive to different treatments.

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CONCLUSION

First, refractory ITP is even harder to treat in patients unresponsive to TPO agents and rituximab than it was before the advent of these treatments.

Second, when choosing agents to combine, select agents with different mechanisms of effect and different primary toxicities.

Third, if a treatment is not effective, instead of stopping it and starting another treatment, it may be better to add the new treatment to the one already being given.

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CONCLUSION

Fourth, oligoclonal/ monoclonal T-cell populations may be important biomarkers, indicating a higher likelihood of refractory disease.

Finally, patients with the most difﬁcult to treat disease are reasonably likely not to have ITP. MDS and inherited thrombocytopenias would be the most likely “misdiagnose”.

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