Hemophagocytic Lymphohistiocytosis (HLH) is an aggressive and life threatening syndrome which results from excessive immune activation, that can rapidly deteriorate and lead to multiple organ failure and death.

1. Hemophagocytic Lymphohistiocytosis (HLH)
Bincy Thankachan, Pharm.D Candidate
Preceptor: Clement Chung Pharm.D, BCOP, BCPS
Lyndon B. Johnson General Hospital
June 28, 2016

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OBJECTIVES
 Present a HLH Patient Case
 Review the diagnostic criteria and the treatment
options for HLH
 Justify the pharmacy intervention on the
monitoring and management of HLH

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PATIENT CASE PRESENTATION
34 y/o AA male admitted to the ER on May 31,
2016
General admission status –
Awake/Alert/Oriented; but nonverbal, weak
in both lower extremities
Hyperthermia of 106F and undetectable BP,
after given 250 mL NS, 70/40.

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PATIENT CASE PRESENTATION
 v
145 107 30
80
3.3 25 1.8
Pertinent Labs
Hemoglobin 9.7
Platelets 48 (150-400)
ANC 10.19 (1.78-5.36)
Ferritin >40,000 (26-388)
Lactic Acid 9.7 (0.4-2)
LDH 2,725 (84-246)
Hgb:7.8 (14-18g/dL)
Hct: 25.4 (40-54%)
WBC: 18.4 (4.5-12)
PMH:
 HIV
 Disseminated Cryptococcal
meningitis
 Retropharyngeal abscess
 FH:
o None

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INTRODUCTION
What is HLH?
 Hemophagocytic Lymphohistiocytosis
(HLH) is an aggressive and life
threatening syndrome that results from
excessive immune activation of
lymphocytes and macrophages, resulting
in excessive, unregulated cytokine
production, so-called
“hypercytokinemia”, results in
multiorgan dysfunction that can rapidly
lead to death.

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ETIOLOGY

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CLINICAL FEATURES
 Fever (91%)
 Hepatomegaly (90%)
 Splenomegaly (84%)
 Neurologic abnormalities (47%)
 Seizures
 Ataxia
 Retinal hemorrhages
 Altered consciousness or coma
 Rash (43%)
 Lymphadenopathy (42%)

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Two Clinical Trials - International
Histiocytic Society
I. HLH Protocol -1994
II. HLH Protocol-2004

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CLINICAL TRIALS:
HLH Protocol 1994
The first prospective international treatment protocol
8 weeks induction therapy with corticosteroids & etoposide
From Week 9 on, cyclosporine added in select patients.
Dexamethasone : suppresses hypercytokinemia, penetrates the
blood brain barrier and also treats CNS disease (first line therapy)
Etoposide blocks cell division and proliferation
Intrathecal Methotrexate added for patients in whom CNS HLH did
not remit with two weeks of dexamethasone
Mortality reduced from 95 to 30-35 %
3 year survival: 55 %

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CLINICAL TRIALS:
HLH Protocol 2004
 New protocol: HLH-2004)
 Major modifications from HLH-94:
i. cyclosporine was moved to the beginning of induction
ii. Hydrocortisone added to intrathecal therapy.
 Cyclosporine inhibits T cell activation (through IL-2 inhibition)
 Final results of this trial are not available yet, so the risks and
benefits of adding cyclosporine remain unconfirmed.

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DIAGNOSTIC CRITERIA
According to the HLH-2004 protocol, The diagnosis of HLH
can be made if either I or II is met.
I. Molecular diagnosis:
HLH-associated gene mutation
(Eg: PRF1, UNC13D, STX11, STXBP2,
etc.…)
Documentation of homozygosity
II. Clinical and Laboratory Criteria

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DIAGNOSTIC CRITERIA
II. Clinical and Laboratory Criteria (Requires 5/8)
1. Fever ≥38.5°C
2. Splenomegaly
3. Cytopenia, with at least two of the following:
a. Hgb <9 g/dL (for infants <4 weeks, Hgb <10 g/dL);
b. Platelets <100,000/microL
c. Absolute neutrophil count <1000/microL
4. Hypertriglyceridemia
Fasting triglycerides >265 mg/dL AND/OR
Hyperfibrinogenemia (fibrinogen <150 mg/dL)
5. Hemophagocytosis in bone marrow, spleen, lymph node, or liver
6. Low or absent NK cell activity
7. Ferritin >500 ng/mL
8. Elevated soluble CD25 (soluble IL-2 receptor alpha) > 2400U/ mL

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TREATMENT GOALS
I. Suppress life-threatening inflammation by
destroying immune cells.
II. Identify and treat underlying triggers of HLH

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TREATMENT PLAN

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HLH 1994 Protocol – Treatment Regimen
Two phases; Initial phase (8 weeks); continuation
phase (9-24 weeks)
 Dexamethasone
 10 mg/m2
per day for the first 2 weeks (Week 1-2)
 5 mg/m2
per day for Week 3 and 4
 2.5 mg/m2
per day for Week 5 and 6
 1.25 mg/m2
per day for Week 7
 Taper down to zero during the 8th
Week.
 Etoposide
 150 mg/m2 for adults, and 5mg/kg for children weighing <10 kg,
 Twice weekly for the first 2 weeks (Week 1-2)
 Then Once weekly for the next 6 weeks (weeks 3-8)
 IT Methotrexate + Hydrocortisone is recommended for patients with
signs of persistent active CNS (leptomeningeal) disease.
 12 mg once weekly for patient >3 year old for 4 weeks (Week 3-6)
 Max 4 doses

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HLH TREATMENT:
Long Term Cure
Allogenic Hematopoietic Cell Transplantation (HSCT)
Replace the defective immune system
Best overall cure rate in HLH
For patients with genetic mutations or family history
Lack of response to initial HLH therapy
CNS involvement
Hematologic malignancy

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SUPPORTIVE TREATMENT
 Prophylactic Trimethoprim/Sulfamethoxazole
(TMP/SMX), 2-3 times weekly, from Week 1-9
 Antiviral therapy
 IVIG (0.5g/kg IV) once every 4 weeks
 Ranitidine/ any other gastro protective agent

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PATIENT CASE FOLLOW UP
 Fever
 Cytopenia
 Hypertriglyceridemia
 Hyperferritinemia
¾ Clinical Criteria
¼ Immune Markers
Pertinent
Labs
Hemoglobin 9.7
Platelets 48 (150-400)
ANC 10.19 (1.78-5.36)
Ferritin >40,000 (26-388)
Lactic Acid 9.7 (0.4-2)
LDH 2,725 (84-246)

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Dexamethasone Administration
(6/1-15): 20mg (6/15-29):10mg (6/29-7/13): 5mg (7/13-27):2.5 mg
6/1/2016 1419 6/15/2016 0819
6/11/2016 0853 6/16/2016 0939
6/12/2016 0829 6/17/2016 1001
6/13/2016 0932 6/18/2016 0930
6/14/2016 0902 6/19/2016 0951
6/20/2016 0822
6/21/2016 0836
6/22/2016 0859
6/23/2016 0834
6/24/2016 0838
6/25/2016 0900
6/26/2016 0841
6/27/2016 0925
Received 12 doses total

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PATIENT CASE FOLLOW UP
Platelet Count (Ref : 150-400 K/uL)
** Thrombocytopenia had initially improved with dex, but worsening with taper.**

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PATIENT CASE FOLLOW UP
Ferritin (Ref : 26-388 ng/mL)
Date Ferritin level
5/31/2016 >40000.00
6/7/2016 2287.00
6/10/2016 2479.30
6/13/2016 3285.70
6/16/2016 3297.00
6/19/2016 3433.00
6/21/2016 3812.00

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PATIENT CASE FOLLOW UP - TREATMENT
TMP/SMX for PJP ppx
PPI (Omeprazole/Esomeprazole) for GI ppx
Fluconazole 400 mg daily for disseminated
Cryptococcal infection
Azithromycin 1200 mg weekly for MAC prophylaxis
Ertapenam 1g IV Q24h for ESBL coverage
Ferritin still trending up at time of writing, overall
clinical status: stable
To be followed up outpatient by Hematology team

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ROUTINE FOLLOW UP LABS
Complete blood count (CBC)with differential daily
Comprehensive metabolic panel (CMP) daily
Coagulation studies including Fibrinogen, Ferritin, PT,
PTT daily
D-dimer, LDH, uric acid every other day
Soluble CD25 (IL-2 α receptor) weekly

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CONCLUSION
HLH is an aggressive and life-threatening syndrome,
which is very rare and likely under diagnosed.
Most patients are acutely ill with multi-organ
involvement.
The response to initial therapy is the major factor to
predict the response
For patients with gene mutations, refractory diseases,
CNS involvement, hematologic malignancies,
hematopoietic stem cell transplant is recommended
following initial therapy (if patients respond).

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REFERENCES
1. Hemophagocytic Syndromes. Histiocytosis Association.
“http://www.histio.org/hemophagocyticsyndromes. Accessed June 16, 2016.
2. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis .
“upToDate.com”. Updated: Jun 10, 2016 ; Accessed June 14, 2016.
3. Treatment and prognosis of hemophagocytic lymphohistiocytosis .
“upToDate.com”. Updated: Oct 15, 2015; Accessed June 14, 2016
4. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic
lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow
transplantation. Blood. 2002;100:2367-237
5. Henter JI, Horne AC, Arico M, et al. HLH-2004: diagnostic and therapeutic
guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood
Cancer.2007;48:124-131
6. Fujiwara F, Hibi S, Imashuku S. Hypercytokinemia in hemophagocytic syndrome. Am
J Pediatr Hematol Oncol. 1993;15:92-98.
7. Henter JI, Incidence in Sweden and clinical features of familial hemophagocytic
lymphohistiocytosis. Acta pædiatrica Scandinavica. 1991; 428-435
8. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21:245-253.

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