Acquired Hemophagocytic - PowerPoint Presentation

Slide1

Acquired Hemophagocytic Syndromes

Samin

Alavi

Pediatric hematologist oncologist

PCHD-RC,

Shahid

Beheshti

University of Medical Sciences

Tehran/Iran

Kish- Nov 2018

Slide2

Diagnosis of HLHDiagnostic criteria for HLH were proposed by the Histiocyte Society in 1991

Five of the eight following criteria must be present to make the diagnosis:

Alternatively, identification of one of the known genetic defects associated with the disease

Ferritin is the most sensitive at discerning HLH from other disordersFerritin >10,000 ng/ml is >90% specific for HLH in childrenFerritin >50,000 ng/ml is less specific in adults, but still very sensitive

Fever

Cytopenias

in 2 of 3 lineages

Splenomegaly

Hypertriglyceridemia and/or

hypofibrinogenemia

Hemophagocytosis

Low or absent NK cell activity

Hyperferritinemia

Elevated plasma levels of soluble CD25

Slide3

Cytokine Storm

Spectrum of Cytokine-Induced Disease

Normal response to infection

SIRS

Severe sepsis

Macrophage activation syndrome

Acquired HLH

Genetic HLH

Slide4

Causes of HLHHLH

Perforin deficiency

Munc 13-4 deficiency

Syntaxin 11 deficiency

Munc 18-2 deficiency

Unknown gene mutations

Immune deficiencies

Malignancy

Autoimmune diseases

Viral infections

Bacterial infections

Fungal infections

Helminthic

infections

Medications

Slide5

Subtypes of HLHGenetic HLH

D

isorders characterized by elevated risk for HLH

Includes Familial Hemophagocytic Lymphohistiocytosis (FHL) as well as certain immunodeficienciesCaused by defects in the cell-mediated cytotoxicity pathwaysAcquired HLH

Reactive Hemophagocytic

Lymphohistiocytosis

(RHL)

Varied group of disorders that result in hemophagocytic symptoms

Caused by dysregulated immune responses leading to lymphocyte and macrophage activation

Slide6

Primary HLHFHL can be divided into 5 subtypes:

FHL1 – caused by unknown defect on chromosome 9

FHL2 – caused by deficiency of Perforin

FHL3 – caused by deficiency of Munc 13-4FHL4 – caused by deficiency of Syntaxin 11FHL5 – caused by deficiency of

Munc

18-2

Chediak

-Higashi &

Griscelli

II syndromes

are characterized by partial albinism and immune deficiency

XLP is characterized by massive

lymphoproliferation and immune deficiency (type 1 and 2)

Slide7

Secondary HLH, currently more common than primary forms, affects older children or adults without known genetic cause. Infections may also represent the stimulus responsible for an acute exacerbation of primary forms of HLH or itself contributes to development of secondary HLH ‘

infection associated

hemophagocytic

syndrome’ (IAHS)Infections, mainly viral (EBV) , but also bacteria, fungi, and parasitic organisms, play a crucial role. ‘Virus associated

hemophagocytic

syndrome

’

Future Sci. OA

(2015) 1(4), FSO31

Secondary HLH

Slide8

Infections promote HLH in the context of compromised immune system due to cytokines produced by the infected T lymphocytesHLH could also develop in patients with malignancies, mainly lymphoproliferative disorders

due to the interaction between

tumor cells and immune system or due to chemotherapy and release of cytokines from tumoral

cells.

Among hematological malignancies,

lymphomas or

leukemias

of T or NK cell lines

, which are frequently related to EBV infection, are most frequently associated with HLH.

Future

Sci. OA

(2015) 1(4), FSO31

Secondary HLH/RLH

Slide9

Infection and HLH

Epstein-Barr virus

Escherichia coli

CMVSalmonella sp.

Varicella virus

Enterococcus

sp.

HHV6

Mycoplasma

sp.

Parvovirus B19

Tick-born bacteria

Hepatitis A

TuberculosisHIV

Visceral leishmaniasis

AdenovirusPlasmodium

sp.InfluenzaToxoplasma

sp.

Coxsackievirus

Pneumocystis jiroveci

Torovirus

Candida

sp.

Slide10

HLH is associated with several disorders of the immune system, including autoimmune disorders, SLE , acquired immune deficiencies (such as AIDS) or immune disorders even after HSCT.HLH develope in context of

autoinflammatory

diseases, principally in

systemic JIA, as a complication.various metabolic disorders, including lysinuric protein intolerance, multiple

sulphatase

deficiency and alterations of propionate metabolism

are known to be potential triggers for HLH.

Acquired/RHL

Future

Sci. OA

(2015) 1(4), FSO31

Slide11

Macrophage Activation Syndrome

Characteristic clinical features of MAS are high,

nonremitting

fever, hepatosplenomegaly, generalized lymphadenopathy, central nervous system dysfunction, and hemorrhagic manifestations. Typical laboratory abnormalities include

pancytopenia

,

hyperferritinemia

, increased liver

enzymesn

and LDH and TG,

D-dimers, and soluble IL-2 receptor [sCD25]), and

hypofibrinogenemia.A

typical histopathologic feature of MAS is hemophagocytic activity in bone marrow biopsy specimens or aspirates

Slide12

In most cases, there is not an inherent impairment of lymphocyte cytotoxic activity, Although some heterozygous mutations in genes that regulate the innate immune response and the NK function have been correlated with secondary types of HLH.

Hazen

MM, Woodward AL, Hofmann I

et al. Mutations of the hemophagocytic lymphohistiocytosis

-associated

gene

UNC13D

in a patient with systemic juvenile

idiopathic arthritis

.

Arthritis Rheum. 58(2), 567–570 (2008

Slide13

FHL/RHL OverlapAdult-onset HLH has been associated with homozygous and heterzygous mutations in multiple FHL genes

Striking number variants of FHL-associated genes have been identified in MAS patients

Current recommendation is to perform genetic analyses on

ALL patients suspected or confirmed to have HLH

Kaufman, et al.

Arthritis

Rheumatol

. 2014 Dec;66(12):3486-95.

Slide14

MAS and AutoimmunityMAS can be associated with a wide variety of autoimmune diseases

The Strongest associations is with

sJIA

, clinically apparent MAS is reported in 7-13% of JIA Subclinical bone marrow evidence of MAS in >50% of sJIA patientsHowever, MAS also occurs with SLE and adult-onset Still’s disease, along with multiple other diseases

Slide15

The 2004 diagnostic guidelines for HLH proposed by the Histiocyte Society are still the most widely used criteria to define and diagnose HLH in clinical

practice

.

Recently, alternative parameters have been evaluated to define a new diagnostic score: the H-score.

However, they have

only been validated

for the

diagnosis of reactive forms of HLH in an adult cohort

Slide16

H Score for Diagnosing RHL

Included Parameters

Known underlying immunosuppressionTemperatureOrganomegaly

No.

of

cytopenias

Ferritin

Triglycerides

Fibrinogen

AST

Hemophagocytosis

on BM biopsy

Fardet

, et al.

Arthritis

Rheumatol. 2014 Sep;66(9):2613-20

Slide17

Performances of the H-Score for Diagnosis of Hemophagocytic

Lymphohistiocytosis

in Adult

and Pediatric Patients, Am J Clin Pathol June 2016;145:862-870

Slide18

HLH 2004 guideline vs H-score

At diagnostic

confirmation, 88

% of children and 90% of adults with HLH met at least four of the six diagnostic criteria of the HLH-2004

guidelines.

The

median (IQR) H-score was

205 (174-268

) for

children

with HLH and 270 (193-300) fo adults

with HLH.

Slide19

MAS and Autoimmunity

Adult-onset

Still’s disease

Ankylosing spondylitisDermatomyositis

Inflammatory bowel disease

Kawasaki disease

Polyarticular

JIA , Systemic JIA

Sarcoidosis

Systemic lupus

erythematosus

Slide20

Medication-Induced HLH

Aspirin

Morniflumate

NSAIDsMethotrexate

Sulfasalazine

Infliximab

Etanercept

Penicillamine

Anakinra

Vancomycin

Gold salts

Parenteral lipids

Autologous stem cell transplantation

Slide21

Mediastinal germ cell tumorsPediatric neuroblastoma Rhabdomyosarcoma

Hepatocellular

carcinoma

Metastatic melanomaSCC of the neckLung cancerRenal cell carcinomaprostate cancer and colon cancer

Hemophagocytosis

and solid tumors

Future Sci. OA

(2015) 1(4), FSO31

Slide22

Early-onset hemophagocytic lymphohistiocytosis after start of chemotherapy for advanced neuroblastoma.

A

3-year-old boy with stage 4 neuroblastoma complicated by HLH immediately after the start of chemotherapy. The patient developed high fever on the 2nd

day of chemo,

and was diagnosed as having HLH of the 7th day of

chemotherapy.

Massive

tumor cell destruction resulting from

chemotherapy

was thought to be a cause of systemic cytokine response and HLH.

Methylprednisolone

pulse therapy was effective for the HLH, which did not recur thereafter.

* Pediatr Hematol

Oncol 2012 Feb;29(1):99-103.

Slide23

HLH secondary to or mimickinginborn errors of metabolism

Wolman disease

Biotinidase

deficiency Organic

acidemia

Gaucher

disease

Lysosomal

acid lipase deficiency

Galactosemia

Multiple

dulfatase

deficiency

Lysinuric

protein intolerance

These cases suggest that a careful metabolic workup should be performed, when facing to a pediatric patient with HLH especially if clinical features of the patient suggested a metabolic disorder including hypotonia

, irritability, or mild developmental delay.

Mediterr

J Hematol Infect Dis. 2017; 9; e2017057.

Mediterr

J

Hematol

Infect Dis. 2017; 9; e2017057.

Slide24

FHLH and lysinuric protein intolerance-related HLH

A

nine-month-old-boy with

Atypical Hemophagocytic Lymphohistiocytosis

Mediterr

J

Hematol

Infect

Dis. 2017

; 9; e2017057.

Slide25

As a severe condition, there should be no delay in starting therapy even in the setting of secondary cases

since we can not discriminate primary from secondary based on initial clinical and laboratory manifestations.

The

goal of treatment is to regulate the immune system dysfunction, suppressing the hyperinflammatory state.

It

is also important to treat the cause responsible for acquired

HLH.

*Jordan

MB, Allen CE, Weitzman S,

Filipovich

AH, McClain KL. How I treat

hemophagocyticlymphohistiocytosis. Blood 118(15), 4041–452 (2011).

Treatment of secondary/Acquired HLH

Slide26

Corticosteroids alone, or in association with IVIG,

represent

the main therapy in patients with rheumatology-associated HLH

(MAS), but may be also active for others secondary forms of HLH.

*Jordan

MB, Allen CE, Weitzman S,

Filipovich

AH, McClain KL. How I treat

hemophagocytic

lymphohistiocytosis

. Blood 118(15), 4041–452 (2011).

Treatment of secondary/Acquired HLH

Slide27

RHL/MAS TreatmentMutliple groups support

a graded-approach

, with corticosteroids alone as initial treatment

Initial

Therapy

High-dose corticosteroids (

prednisolon

e

30 mg/kg x3 days)

Elimination of suspected

triggers, infection control

Aggressive

supportive measures

Secondary Therapy

Intravenous immunoglobulin (1-3 g/kg)

Cyclosporine A, etoposide

Slide28

Patients who can be weaned off dexamethasone and etoposide without recurrence and have no identified HLH-associated gene defects may stop therapy after 8-week

induction.

HCT

is generally recommended in patients with CNS involvement, recurrent/refractory disease or

proven

familial/genetic disease

Slide29

Treatment of secondary/Acquired HLHUnfortunately, about 25% of patients fail to achieve complete remission with standard therapy.

At the moment, there are no standard salvage therapies.

No conclusive results are reported with the use of

infliximab, daclizumab, alemtuzumab, anakinra and other agents

* Jordan

MB, Allen CE, Weitzman S,

Filipovich

AH, McClain KL. How I treat

hemophagocytic

lymphohistiocytosis. Blood 118(15), 4041–452 (2011).

Slide30

Treatment NotesRHL triggered by leishmaniasis may be treated solely with amphotericin.

Etoposide is crucial for EBV-associated RHL , inhibits activated T cells, plus EBV NA in infected cells

Multiple groups agree that

HLH 2004 should be initiated for relapses of RHL, despite etiologyHSCT has best overall outcome among all single treatment modalities across all patient populations

Slide31

A 4-month-old girl infant was admitted to hematology deprtment due to pancytopenia and generalized maculopapular

rash whole over the body.

She was

febrile, generalized skin rash and splenomegaly.

Laboratory

tests showed

pancytopenia

and

serum

ferritin

of 1500 ng

/ml.A presumptive diagnosis of HLH was suggested for the patient.

Due to the presence of skin rashes, a specific array of tests including Ro/SSA and La/SSB antibodies

was performed which were positive with very high titers in two occasions. Mother serum was also highly positive for the anti-nuclear antibodies

.A course of corticosteroid was started for the baby, Skin lesions went away and she was discharged in good general condition. The mother was referred to rheumatology clinic for further follow-up.

 

Slide32

Hemophagocytic lymphohistiocytosis complicating erythroleukemia

in a child with

monosomy 7The first

case of childhood

hemophagocytosis

following chemotherapy for AML-M6

in a child with

monosomy

7

is reported.

Prolonged pancytopenia

accompanied by persistent fever and huge hepatosplenomegaly

became evident after 2 courses of chemotherapy.On bone marrow aspiration, macrophages phagocytosing

erythroid

precursors were observed and diagnosis of HLH was established.

Case

Rep

Hematol

.

 2013;2013:581073.

,

A

lavi

S

1

, 

Ebadi

M

2

, 

Jenabzadeh

A

1

, 

Arzanian

MT

1

, 

Shamsian