Hemophagocytic lymphohistiocytosis HLH

1
Hemophagocytic lymphohistiocytosis (HLH)

• Janakiraman Subramanian MD

2
Case Presentation

• 38 yo caucasian male presenting with 1 week
  history of
• Mental status changes
• Fever
• Fatigue and lethargy
• Pancytopenia

3

• Past History
• Hepatitis C diagnosed 1 year ago. Receiving
  ribavirin and peg interferon. Last treatment two
  weeks ago. Most recent viral loads undetectable
• Leucopenia due to Hep C treatment
• GERD
• Chronic diarrhea

4

• Allergies
• NKDA
• Family history
• Non contributory
• Social history
• 20 pack year smoker
• EtOH abuse in the past
• No drug abuse

5

• On exam
• HEENT PERRLA, EOMI, no pallor or icterus
• Neck Supple, no lymphadenopathy.
• Chest S1 and S2 , RRR,
• Lungs Coarse bilaterally.
• Abdomen Soft, NT, splenomegaly (). Bowel sounds
  
• Extremities No pitting pedal edema or tenderness
  or cyanosis.
• Neurologic Alert, awake, and oriented x2.
  Appears to be drowsy. Otherwise non-focal,

6
Initial Labaratory Values

• WBC 2.6
• Hgb 8.2
• Plts 78
• Retic count 2.4
• Creatinine 0.7
• T. bilirubin 0.5
• AST 377
• ALT 110
• LDH 12015

• Ferritin 12,534
• Fibrinogen 412
• Hep C antibody ()
• Hep C RNA (-)

7
Bone Marrow Biopsy

• Normocellular marrow with enhanced
  hemophagocytosis
• Multilineage dyspoiesis

8
Clinical course

• Started on broad spectrum antibiotics
• Infectious workup negative
• Worsening MS changes
• Started treatment with corticosteroids
• Subsequently cyclosporin added
• Patients leucopenia and thrombocytopenia
  improved (WBC 9 and plts 349)
• Discharged home

9
Differential diagnosis

• Sepsis
• Macrophage activation syndrome
• Malignancy
• Acute leukemias
• Langerhans cell histiocytosis
• Large cell anaplastic lymphoma (malignant
  histiocytosis)

10
Background

• Rare
• Potentially fatal
• All age groups
• Predominantly in children but adults are also
  affected

Henter, Acta Paediatr Scand 1991
Apr80(4)428-35 Janka, Br J Haematol 2004
Jan124(1)4-14
11
Janka, Eur J Pediatr (2007) 166 95-109
12
Classification

• Genetic (Primary)
• Autosomal recessive or X linked
• 1 in 50,000 births
• Predominantly in children of age lt 1year
• 1.2 cases per million persons per year
• Male-to-female ratio close to 11

13
Classification

• Acquired (secondary)
• Occurs in all age groups
• Usually triggered by an infection viral and non
  viral
• Other associations malignancies and auto immune
  disorders

Risdall, Cancer 44 (1979), pp. 9931002 Janka,
Hematol Oncol Clin North Am 12 (1998), pp. 435444
14

• Elevated levels of pro-inflammatory cytokines
• Due to activation of antigen presenting cells and
  lymphocytes
• Both inherited and acquired HLH are associated
  with abnormal NK cell activity

Egeler, Am J Ped Hem Onc 1996 18340345
15

• Clinical studies have reported abnormal cell
  mediated immnuity
• In one study of 13 consecutive patients
• Decreased NK cytotoxic function (13/13)
• Severely decreased to absent T cell cytotoxicity
  (11/12)

Egeler, J Pediatr Hematol Oncol 1996
Nov18(4)340-5
16

• Genome wide genetic linkage analysis studies in
  familial HLH
• 10q21-22 was identified as a locus for familial
  HLH in 10 out of 17 FHL families in Europe and
  Australia
• 9q21.3-22 was identified by homozygosity mapping
  in four inbred FHL families of Pakistani descent

Ohadi, Am J Hum Genet. 1999 Jan64(1)165-71 Dufou
rcq-Lagelouse, Am J Hum Genet. 1999
Jan64(1)172-9.
17
Perforin

• Perforin is an important mediator of lymphocyte
  cytotoxicity
• Gene encoding for perforin is located at 10q21-22
  
• 8 unrelated 10q21-22-linked FHL patients were
  analyzed for perforin gene mutations
• Revealed homozygous nonsense mutations in 4
  patients missense mutations in the other 4
  patients

Stepp, Science 1999 32861957-9
18
Stepp, Science 1999 32861957-9
19

• 10 FHL patients who did not lack perforin the
  locus was mapped to 17q25
• Mutations involving hMunc13-4 family of genes
  were reported
• 6q24 was identified as a locus in Kurdish
  families with FHL
• Mutations of syntaxin 11 (STX 11) gene located on
  6q24 were also identifed in this population

Feldmann, Cell 2003 Nov 14115(4)461-73 zur
Stadt, Hum Mol Genet 2005 Mar 1514(6)827-34
20
Janka, Eur J Pediatr (2007) 166 95-109
21
Janka, Eur J Pediatr (2007) 166 95-109
22

• Mechanisms leading to impairment of NK cells and
  CTLs in acquired HLH are not well understood
• Possible role for viruses or high cytokine levels
  to inactivate these cells

23
Clinical features

• HLH is a hyperinflammatory condition
  characterized by
• Fever
• Cytopenias
• Hepatosplenomegaly
• Hemophagocytosis by activated, morphologically
  benign macrophages

24

• Others
• Lymphadenopathy
• Rash
• Icterus
• Seizures
• Cranial nerve palsies

25

• High levels
• Triglycerides
• Ferritin
• Transaminases
• Elevated bilirubin and LDH
• Low fibrinogen

Janka, Eur J Pediatr 140 (1983), pp.
221230. Arico, Arch Dis Child 63 (1988), pp.
292296
26
Janka, Eur J Pediatr 140 (1983), pp. 221230.
27

• The clinical presentation is due to
• Increased levels of inflammatory cytokines
• IL1 and IL6 ? fever
• TNF-a and IFN-? ? pancytopenia
• Organ infiltration by lymphocytes resulting in
  hepatosplenomegaly and neurologic symptoms
• Activated macrophages secrete ferritin and
  plasminogen activator

28
Pathologic findings

• Proliferation of normal histiocytes and
  T-lymphocytes
• Phagocytosis of RBC and WBC
• No atypia in the macrophages
• Organ infiltration by lymphocytes and histiocytes

29
(No Transcript)
30
(No Transcript)
31
Treatment

• Immunosuppression is the mainstay of treatment
• Corticosteroids
• Cyclosporine
• Etoposide

32

• Identify secondary causes and treat
• Infection
• Auto immune disorders
• malignancies
• In older patients with acquired HLH treatment
  with corticosteroids cyclosporin may be
  sufficient

33
HLH 94 protocol

• FHL mortality in 1980 was 90
• HLH 94, n 86
• 8 weeks of dexamethasone VP16 induction
• IT methotrexate in 11/24 patients with CNS
  disease
• Maintenance with cyclosporin and alternating
  weekly pulses of etoposide dexamethasone until
  SCT

Horne, Br J Haematol 2005 Jun129(5)622-30
34

• Pre transplant conditioning regimen at the
  discretion of the treating center
• Busulfan/Cytoxan/VP16 recommended conditioning
  regimen

35
Horne, Br J Haematol 2005 Jun129(5)622-30
36
Horne, Br J Haematol 2005 Jun129(5)622-30
37
Horne, Br J Haematol 2005 Jun129(5)622-30
38

• Retrospective review of 48 consecutive patients
  with FHL
• Overall survival - 58 with median f/u of 5.8
  years
• Non-myeloablative HCT was attempted in a series
  of 12 patients
• median f/u 30 months, 9/12 are alive in CR

Ouachee-Chardin M ,Pediatrics. 2006
Apr117(4)e743-50 Cooper, Blood. 2006 Feb
1107(3)1233-6
39
HLH 2004
Henter, Pediatr Blood Cancer. 2007
Feb48(2)124-31
40
HLH 2004
Henter, Pediatr Blood Cancer. 2007
Feb48(2)124-31
41
Conclusion

• HLH is a fatal disease if untreated
• Disease presentation is due to hyperinflammation
  due to inherited or acquired immune defects
• Allogenic SCT based on HLH 94 protocol results in
  cure rate of 50