This document provides an overview of hemophagocytic lymphohistiocytosis (HLH). It begins by introducing HLH and describing its characteristics such as fever, hepatosplenomegaly, and cytopenias. It then discusses the classification of primary and secondary HLH, epidemiology, genetic causes, clinical features, diagnostic guidelines, treatment protocols, and long-term follow up recommendations. For the patient presented, the document recommends following the HLH-2004 treatment protocol initially and considering continuation therapy or stem cell transplant depending on the disease response and severity.

1. Presenters:
DR. RENESHA ISLAM
RESIDENT (PHASE-B)
PEDIATRIC HEMATOLOGY & ONCOLOGY DEPARTMENT
WELCOME TO SEMINAR

2. Quick peek
Clinical criteria: -Fever
-Hepatosplenomegaly
Laboratory: -Bicytopenia
-Increased Ferritin, TG
-Decreased Fibrinogen
-Decreased NK cell activity
History: Fever, Progressive pallor, Abdominal
Distension, previous H/O convulsion & blood
transfusion.
O/E: Moderately pale, Hepatosplenomegaly
Provisional Dx: ALL
D/D: AML, Chronic Malaria
Abdominal TB
Kala azar, Lymphoma
Dx:
Hemophagocytic
Lymphohistiocytosis

3. Hemophagocytic Lymphohistiocytosis
(Hemophagocytic Syndromes)
Topic of the day

4. Introduction
• Hemophagocytosis:
Phagocytosis of erythrocytes,
leukocytes, platelets & their
precursors in bone marrow & other
tissue by macrophages.

5. Hemophagocytic lymphohistiocytosis
• Hemophagocytic lymphohistiocytosis (HLH)
is a histiocytic disorder characterized by a
highly stimulated but ineffective, immune
response to antigens, which results in life
threatening cytokine storm & inflammatory
reaction.
• Uncommon.
• Aggressive.
• Life threatening.

6. Epidemiology
Young age

7. Epidemiology

8. Incidence in PHO, BSMMU

9. HLH patients of PHO
Amena
5years
Shahin
7years

10. Classification

11. Primary
Primary (Genetic)
• Familial
Known/Unknown gene defect
Such as-
-FHL1-5 -ITK
-GS2 -LYST
-CD27 -MAGT1
-XLP1 -XIAP
-HSP2
Inherited
 Chediak Higashi syndrome
 Griscelli syndrome
 X-linked lymphoproliferative
disease (XLP)
 Hermansky Pudlak syndrome
 Lysinuric protein intolerance

12. Secondary
• Infections (Infection associated hemophagocytic syndrome/IAHS)
• Malignancy (malignancy associated hemophagocytic syndrome/
MAHS)
• Rheumatologic disorders or immune system modifying treatments
• Immunosuppressive agents.

13. Comparison
Points Primary Secondary
Age of onset Usually <1 year Usually >1 year
Nature Extensive disease activity causes
irreversible organ damage
Less aggressive than
primary
Presentation No specific diagnostic feature Can be fall in diagnostic
criteria
Laboratory findings Similar Similar
Treatment Similar Similar

14. Familial or Primary HLH
• Younger age at presentation (<1 year).
• Incidence: 1.2/1,000,000 per year.
• Median survival <2 months, if untreated.
• Divided into-
-Mutation at FHL loci
-Immunodeficiency syndromes.

15. Mutation at FHL Loci
• Several HLH gene mutations map to
loci that code for elements of the
cytotoxic granule secretion & release
pathway.
• These are labeled as Familial
Hemophagocytic Lymphohistiocytosis
(FHL) loci.

16. Primary HLH
Gene Syndrome Inheritance Protein
PRF1 FHL2 AR Perforin
UNC13D FHL3 AR Munc13-4
STX11 FHL4 AR Syntaxin 11
STXBP2 FHL5 AR Munc18-2
RAB27A GS2 AR RAB27A
LYST CHS1 AR LYST
SH2D1A XLP1 XL SAP
XIAP XLP2 XL XIAP

17. Non familial HLH
Infection associated hemophagocytic syndrome/IAHS
• Similar to those in FHLH.
• Innumerable pathogens
are associated.

18. Non familial HLH
Malignancy associated hemophagocytic syndrome/ MAHS
1. Development of a hemophagocytic
syndrome before &/during the treatment of
malignancy
Acute lymphoblastic leukemia
Acute myeloid leukemia
Multiple myeloma
Germ cell tumor
Thymoma
Carcinoma
2. Development of a hemophagocytic
syndrome with a masked
hematolymphoid malignancy in the
background
T/NK cell leukemia
Lymphoma
Large cell anaplastic lymphoma
Adult B cell lymphoma
Hematology oncology journal Janka etal 1998

19. Non familial HLH
Reactive HLH (Macrophage Activation Syndrome in
SLE/JRA/Other chronic conditions)
• Cause: Excessive activation & proliferation of mature
macrophages by triggering agent.
• Observed in:
-Rheumatological diseases
-Infection
-Neoplasm

20. Pathophysiology

21. Clinical features
Most common early findings Less common
Fever (91%) Lymphadenopathy (17%)
Splenomegaly (98%) Skin rash (7%)
Hepatomegaly (94%) Neurological abnormalities
(Irritability, Convulsion, neck
stiffness, hypotonia, hypertonia,
cranial nerve palsies)
Clinical features are similar regardless of whether an underlying
genetic defect has been identified

22. Clinical features
Multisystem involvement
Most common Less common
Lungs Ocular
Bone marrow Heart
Leptomeninges Skeletal muscle
Kidney

23. Diagnostic guidelines of HLH
The diagnosis HLH can be established if 1 of either 1 or 2
below is fulfilled:
Hemophagocytic lymphohistiocytosis study group 2004

24. 1. Molecular diagnosis of HLH
Pathologic mutations of –
PRF1
UNC13D
MUNC18-2
Rab27a
STX11
SH2D1A
BIRC4

25. 2. Diagnostic criteria for HLH fulfilled
(5/8 criteria)
a. Initial diagnostic criteria
i. Fever
ii. Splenomegaly
iii. Cytopenias (affecting ≥2 of 3 lineages in PBF):
• Hb: <9g/dl
• Platelets <1,00,000/mm3
• Neutrophils <1000/mm3
iv. Hypertriglyceridemia and/or hypofibrinogenemia:
• Fasting TG >3.0 mmol/l (i.e. >265 mg/dl)
• Fibrinogen <1.5 g/l
v. Bone marrow/spleen/lymph nodes: Hemophagocytosis
vi. No evidence of malignancy
b. New diagnostic criteria
i. Low or absent NK-cell
activity (according to local
laboratory reference)
ii. Ferritin >500 μg/l
iii. Soluble CD25 (i.e., soluble
IL-2 receptor) >2400 U/ml

26. Hemophagocytic lymphohistiocytosis study group 2004

27. Diagnostic approach
• Clinical
Complete history:
Family history (consanguinity, previous
childhood deaths in this family/relatives, late
miscarriages of mother), recent infections &
vaccinations, previous bouts with similar
symptoms, fever (duration and level),
neurological symptoms (including irritability,
ataxia, convulsions), edema, jaundice, skin rash.

28. • Complete physical examination:
Temperature, height, weight, skin rashes,
jaundice, purpura, bleeding, edema,
tonsillitis, lymphadenopathies, dyspnea,
tachypnea, liver size, spleen size, ascites,
blood pressure, neurological examination
and cerebellar dysfunction.

29. Investigation
Baseline evaluations for all patients:
• CBC with PBF, reticulocytes, S. ferritin
• Liver function test
• Coagulation profile
• Lipid Profile
• Renal function test and serum electrolytes
• Soluble IL-2 receptor (sCD25) (suggested if available).

30. Investigations
• Immunoglobulin levels
• Spinal tap
– cell and protein content
– morphological & immunological
analyses (if cells in CSF)
• Infection screening
• Bone marrow aspiration (hemophagocytosis)
• Fine needle aspiration biopsy of an enlarged lymph
node/liver.

31. Investigation
• NK-cell activity
• Molecular diagnosis (perforin, hMunc 13-4 and relevant other
genes).
Others:
• GFR
• HLA-typing of the patient and the family
• Imaging - Abdominal ultrasound (or CT)
– Chest X-ray (or CT of the chest)
– MRI of brain.

32. Treatment
• Counseling
• Supportive therapy:
-Prophylactic Cotrimoxazole: 5mg/kg (2-3times/wk)
-Oral antimycotic
-Antiviral therapy (ongoing viral infection)
- IVIG.
Hemophagocytic lymphohistiocytosis study group 2004

33. Treatment protocol for Hemophagocytic
Lymphohistiocytosis (HLH-2004)

34. Additional treatment in Secondary HLH
• Infection associated HLH:
Find out the causative agent & treat accordingly.
-Bacterial: Appropriate broad spectrum antibiotic.
-Viral:
Antiviral drug
EBV: Rituximab.

35. Additional treatment in Secondary HLH
• Malignancy associated HLH:
-Before treatment:
Therapy of malignancy &/ infection.
Early addition of dexamethasone.
-In association with infection during chemotherapy:
Cessation of chemo (if disease under control)
Treatment of infection.

36. Additional treatment in Secondary HLH
• Macrophage activation syndrome (Reactive HLH):
-Prompt treatment of the underlying disorder
-Corticosteroid
-IVIG
Anakinra & other cytokine directed therapy.
-If still no improvement: HLH regimen

37. Curative therapy
Allogeneic stem cell transplant
Indication:
• Familial HLH
• Non familial HLH: Poor responder
Reactivation of disease.
Timing: When the disease is non-active (cont. therapy).

38. Outcome after SCT in HLH-2004
Hemophagocytic lymphohistiocytosis study group 2004

39. Newer approach
Ongoing trial
Hemophagocytic lymphohistiocytosis study group 2004

40. Follow up of HLH
during therapy (HLH-2004)

41. • After 2 month of completion of therapy
• 6 months
• 12 months and
• later on once yearly.
Follow up of HLH
after therapy (HLH-2004)

42. Appropriate measure in our patient

43. Appropriate measures
If it is unknown (primary/2ndary) & thorough investigation
revealed no underlying malignancy/bacterial/parasitic infection &
no other cause of the immune-activation:
• Initial therapy (whether a viral infection is associated or not).
• Treatment is stopped after 8 weeks, if the disease has had a
complete resolution. If active disease, then continuation
therapy.
• If the disease is severe and persistent, or reactivating,
continuation therapy and SCT is suggested.
Hemophagocytic lymphohistiocytosis study group 2004

44. Subsequent therapy (non-SCT pt)
• Continuation therapy (week 9-40).
• Prolong the intervals between each etoposide &
dexamethasone pulse from 2-4 wks, & continue CSA as
previously. Thus, the patient will receive alternating
treatment every 2nd week (instead of weekly) with VP-16 or
dexamethasone pulse.
• Continue CSA and dexa only, in doses & interval as wk 9-40.
• Continue with CSA or dexa only.
Hemophagocytic lymphohistiocytosis study group 2004

45. Reactivation therapy
• Intensify therapy (restart from wk 2, but the initial
therapy may be less than 8 wks & then continue with
modified continuation therapy.
• Intrathecal therapy (in CNS-reactivation).
• Dexamethasone daily, also between the dexa-pulses,
in continuation therapy.
• Early SCT is then suggested.
Hemophagocytic lymphohistiocytosis study group 2004

46. Take home messages

47. Take home messages

48. THANK YOU ALL