Hemophagocytic Lymphohistiocytosis (HLH)

Bincy Thankachan, Pharm.D CandidatePreceptor: Clement Chung Pharm.D, BCOP, BCPS

Lyndon B. Johnson General HospitalJune 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

v145 107 30

803.3 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 -1994II. 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 dexamethasoneMortality 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 CRITERIAII. Clinical and Laboratory Criteria (Requires 5/8)

1. Fever ≥38.5°C2. Splenomegaly3. 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/microLc. 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 liver6. Low or absent NK cell activity7. Ferritin >500 ng/mL 8. Elevated soluble CD25 (soluble IL-2 receptor alpha) > 2400U/ mL

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TREATMENT GOALSI. 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 RegimenTwo 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 systemBest overall cure rate in HLHFor patients with genetic mutations or family historyLack of response to initial HLH therapyCNS involvementHematologic 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 LabsHemoglobin 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 mg6/1/2016 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 UPPlatelet Count (Ref : 150-400 K/uL)

** Thrombocytopenia had initially improved with dex, but worsening with taper.**

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PATIENT CASE FOLLOW UPFerritin (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 ppxFluconazole 400 mg daily for disseminated

Cryptococcal infectionAzithromycin 1200 mg weekly for MAC prophylaxisErtapenam 1g IV Q24h for ESBL coverageFerritin still trending up at time of writing, overall

clinical status: stableTo be followed up outpatient by Hematology team

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ROUTINE FOLLOW UP LABSComplete blood count (CBC)with differential dailyComprehensive metabolic panel (CMP) dailyCoagulation studies including Fibrinogen, Ferritin, PT,

PTT dailyD-dimer, LDH, uric acid every other daySoluble CD25 (IL-2 α receptor) weekly

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CONCLUSIONHLH 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, 20164. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100:2367-2375. Henter JI, Horne AC, Arico M, et al. HLH-2004: diagnostic and therapeuticguidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer.2007;48:124-1316. 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; 428-4358. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21:245-253.

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