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.
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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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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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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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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
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
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lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow
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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.
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.