Hemophagocytic Lymphohistiocytosis - HLH epidemiology, clinical presentation, treatments and outcomes.

1. April 28th 2017

2.  60 year old female with history of COPD, Hep C s/p harvoni treatment with clearance,
and SLE not on medication who in her relative normal state of health until about 4
weeks ago
 Developed weakness, nausea and SOB
 Went to hospital in Mississippi, diagnosed with bacterial pneumonia
 Completed antibiotics
 However over the last 3 weeks she again began feeling weak and now developed
yellowing of her skin along with confusion

3.  12/19/2016: re-admitted to an Outside Hospital, found to have an elevated lactate,
bilirubin and confusion
 Given Vancomycin, Merrem + IV fluids
 Transfused with platelets and given steroids.
 Underwent bone marrow biopsy
 12/27/2016: discharged to LTAC for rehab
 1/3/2017: she again was becoming confused and jaundiced
 1/4/2017: presented to Clements ED for evaluation

4. PAST MEDICAL HISTORY
 COPD – GOLD stage II
 SLE – dx 10 years ago, never on medications
 Hepatitis C - s/p Harvoni therapy - per family
completed all 12 weeks about 1 month ago
 Hypertension
ALLERGIES
 No known allergies
Social History
 ½ pack cigarettes x 15 years
 No ETOH
 No drugs
PAST SURGICAL HISTORY
 None
Family History
 DMII and CAD in aunt and uncle

5. OUTPATIENT Medications
 Amlodipine 5mg daily
 Cetirizine 5mg PRN

6.  Confused
 AAOx1

7. BP 125/67 mmHg | Pulse 97 | Temp(Src) 37.2 °C (98.9 °F) (Oral) | Resp 22 | BMI 31 kg/m2 | SpO2 100%
 Constitutional: Sleepy yet arousable to voice, but does not keep eyes opened or respond to questions. Jaundiced
throughout
 EYES: PERRL, EOMI, Scleral icterus
 ENT: No sinus tenderness. MMM. Unable to inspect OP clearly as patient requiring BiPAP
 NECK: No cervical LAD
 RESPIRATORY: Lungs CTAB w/o wheezes, rales, or rhonchi.
 CARDIOVASCULAR: Normal rate, regular rhythm w/o M/R/G.
 GASTROINTESTINAL: Abdomen soft, NT, ND w/ NABS. No HSM noted, no appreciable fluid wave
 MUSCULOSKELETAL: No joint swelling or tenderness.
 EXTREMITIES: 3+ bilateral LE swelling, warm to touch, pulses present
 SKIN: No rashes or other skin lesions.
 NEUROLOGIC: CN II through XII grossly intact. Moving all extremities. Normal sensation, no focal deficits

8. 12.0
37.7
3.23 236
LABORATORY WORK-UP
WBC 4.66
Hg 8.7
HCT 18.7
Platelets 8
MCV 87
RDW 15.9

9. 12.0
37.7
3.23 236
LABORATORY WORK-UP
Na 143
K 4.8
CL 102
CO2 74
Cr 0.94
Anion Gap 29
Mg 1.9
Ph 5.1

10. 12.0
37.7
3.23 236
LABORATORY WORK-UP
Alb 1.8
ALT 248
AST 444
Total Bilirubin 23
Direct Bilirubin >20

12. 60y F with history of SLE and HCV s/p recent completion of Harvoni.
Progressive illness over past several weeks after hospitalization for PNA, involving spiking fevers,
weakness, altered mental status and jaundice.
Clearly had some hematologic derangements as well, required platelet transfusions and even bone marrow
biopsy at an outside institution.
Exam is non-specific (altered but non-focal neuro exam, icteric, no abdominal findings, 3+ edema).
Labs:
• Severe acute liver injury/failure
• Bi-cytopenias (Hgb 8.7; platelets 8)
• hypoalbuminemia
Salient Features

13. Very broad differential diagnosis. A few pertinent ones….
Infection: A thorough workup for infection was done. Negative for:
- HCV PCR (negative), HBV PCR negative, HAV serologies negative
- EBV PCR negative
- CMV PCR negative
- HIV negative
- Endemic fungi negative, galactomannan negative, cryptococcal ag negative
- Quantiferon Gold negative
- Blood and urine cultures negative
SLE flare/autoimmune hepatitis: ANA negative, AIH antibodies negative
Drug hypersensitivity/toxicity: No eosinophilia present. On minimal meds. Harvoni…? No precedent for a
toxic reaction to Harvoni presenting like this, and no eos to suggest a DRESS-like reaction. HBV was
negative.
TTP: (platelets initially held)…no schistocytes
Malignancy: Outside bone marrow did not show leukemia.
Fevers, liver failure and cytopenias

14. A few additional items of note….
EXAM: my exam for adenopathy differed….she had palpable cervical,
supraclavicular and axillary adenopathy
Coags: Fibrinogen <70
Inflammatory markers: Ferritin >100,000

16. Hyperactive, and dysregulated inflammatory responses
Systemic inflammation
Hypercytokinemia (“cytokine storm”)
Hyperactivation of tissue macrophages (histiocytes)
Multi-organ damage
Broadly divided into:
Primary/Familial HLH
Secondary/Acquired HLH
MAS - variant of HLH in setting of autoimmunity
Diagnostic considerations: HLH (Hemophagocytic
Lymphohistiocytosis) and MAS (Macrophage activation
syndrome)

17. Parvaneh N, et al 2013 British Journal of Hematology

18. • Proliferation
• Perforin/granzyme
• Cytokines (IFNg)
Cytotoxicity
Contraction
Infected cell
CTL
Macrophage
Inflammatory cytokines,
Engulf pathogens, dying cells

19. • Proliferation
• Cytokines (IFNg)
Cytotoxicity/Contraction
CTL
Infected cell
Macrophage
TNFa, IL-6, IL-1

20.  Fever: IL-1, IL-6 and TNFα
 Cytopenias: cytokines, hemophagocytosis
 Hyperferritinemia: cytokines increase expression; released from activated
macrophages and damaged tissue cells
 Hypofibrinogenemia: activated macrophages secrete plasminogen activator,
leading to hyperfibrinolysis
 Hypertriglyceridemia: TNFα and IFNγ inhibit lipoprotein lipase
 Elevation in Soluble IL2 receptor: shedding from increased number of activated
CTL/NK cells
 NK cell dysfunction: genetic defects and/or TNFa mediated inhibition
 Infiltrative disease/cytokine-mediated damage/multi-organ dysfunction:
 Liver
 CNS
 Lungs
 GI tract
 Skin

21.  Other predisposing mutations: SH2D1A, BIRC4, LYST, ITK, MagT1, Coronin 1a, STK4, PI3K
delta, CD27
Jordan MB 2011 Blood

22. HLH in adult patients…..usually SECONDARY
Usually a PREDISPOSING CONDITION is present:
• Malignancy (50% or greater)
• One study estimates 1-20% of patients with certain B and T cell lymphomas
• Autoimmune disease (10-15%)
• Immunodeficiency (primary or secondary) 40%
And there is a TRIGGERING EVENT:
• Infection most common
• Human herpesvirus (EBV, CMV, etc) 62%
• Drug hypersensitivity
• Surgery

23. Ramos-Casals M et al 2013 Lancet

24. HLH Epidemiology
Japanese population study: 1:800,000 (including pediatric and adult cases)
Pediatric literature: 1:3,000 inpatient admissions
Mayo Clinic study (ADULT-ONLY): 1:2,000 inpatient admissions (tertiary care
center)

25. HLH Mortality
Pediatric patients
• Left untreated 100% fatal
• Median OS 2 months
• Current treatment protocol:
5yr survival = 54%
Adult patients
• Overall survival 44% over 42 months f/u at Mayo
• Malignancy associated HLH worse prognosis

26. Treatment
Pediatric patients:
HLH94:
- Tapering doses of Dexamethasone
over 8 weeks
- Etoposide
- Intrathecal methotrexate if CNS dz
Allogeneic BMT if:
- Known familial or genetic disease
- Treatment failure or recurrence
Adult patients: Highly variable (ex. Mayo):
Tumor associated:
T cell lymphoma (19): 4 CHOP+ etoposide
12 CHOP without
DLBCL (6): 3 R-CHOP + etoposide
3 R-CHOP without
EBV-PTLD (3): Rituxan only
LHC (1): HLH94
Hemangioendothelioma (1): HLH94
Non-Tumor associated:
EBV (6): 4 HLH94
1 steroid only
1 died before tx
CMV (3): 1 HLH94+GCV
1 GCV only
1 no tx
Other viral (5) 5 Steroid-only
Fungal (5): 5 steroid + antifungal
Bacterial (2): 2 HLH94 + antimicrobial
1 antimicrobial alone
SLE/autoimmune dz (5): 3 HLH 94
2 CSA + steroid
Idiopathic (4): 4 HLH94
1 IVIG + steroid
*Steroid and Anakinra for
MAS
Transplant outcomes
>15 yrs old vs <15yo
57% vs 75% overall
survival

27.  Older age (56 vs 47)
 Lymphoma (T cell worse than B cell)
 Lower platelets (40 vs 75)
 Higher AST (529 vs 159)
 Higher LDH (2550 vs 1607)
 No etoposide given*
 Etoposide given at > 4 weeks
 Shock at ICU admission
 Hypoalbuminemia

28.  Older age (56 vs 47)
 Lymphoma (T cell worse than B cell)
 Lower platelets (40 vs 75)
 Higher AST (529 vs 159)
 Higher LDH (2550 vs 1607)
 No etoposide given*
 Etoposide given at > 4 weeks
 Shock at ICU admission
 Hypoalbuminemia

29. Henter JI 2007 Pediatr Blood CA
Decreased
41,900 (ref <1033)

31. VH, 92578280
• BM (outside, 1/4/2017)
• Left axillary lymph node, SU17-731,
1/13/2017

32. WBC 1.3 x10^3/µL
Hgb 6.8 g/dL
Hct 20.7%
MCV 84.5 fl
RDW 15.3%
Plt 7 x10^3/µL.
Neutrophils
90%,
Lymphocytes
5%
Monocytes 5%
PB (outside, 1/4/2017)

33. BM (outside, 1/4/2017)

34. BM core touch

35. BM core

36. Hemophagocytosis
(green arrows)
BM core

37. Hemophagocytosis
(green arrows)
BM core, CD163

38. BM DIAGNOSIS:
PERIPHERAL BLOOD, BONE MARROW ASPIRATE, BONE
MARROW CORE BIOPSY (1/4/2017):
- PANCYTOPENIA IN A NORMOCELLULAR BONE
MARROW WITH TRILINEAGE HEMATOPOIESIS
- FOCAL SIGNIFICANT HEMOPHAGOCYTOSIS
- No evidence of lymphoma

39. LN

40. LN

41. LN

42. CD3 CD5
LN

43. CD20 Ki-67
LN

44. Summary of IHC on lymphoma cells
Negative
for
CD5
PAX-5
CD20
CD30
ALK-1
Positive for
CD2
CD3
CD7
PD-1
Ki-67:90-
100%
DIAGNOSIS
Peripheral T-cell Lymphoma, NOS

45. CG Result:
46,X,-X,del(6)(q13q21),add(11)(q21),+del(12)(p15q24.3),
add(15)(p11.2)[cp3]/46,idem,-del(6),+del(6)(q12q27),
add(17)(p13)[cp2]/46,idem,add(17)(p11.2)[cp8]/46,idem,-
del(6),+6,-13,der(17)t(13;17)(p11.2;p13)[cp7]
Impression:
Abnormal female karyotype with four related clones containing
multiple numerical and structural abnormalities

46. 71% medium-sized to large cells: CD1a (-), CD2(+), surface CD3(+),
CD4(small subset +), CD5(-), CD7(+), CD8(- to dim +), CD10(-), CD30(-),
CD34(-), CD45(+), CD56(-), TCR ab(+), TCR gd(-).
Flow IP2017-154 (LN)
CD8 APC-H7
CD7 BV605TCR ab
TCRgd
CD5 PerCP-Cy5.5FSC
SSC
CD2FITC
CD4APC
CD3PE
CD30 BV421
CD45V500

47. DIAGNOSIS
LN: Peripheral T-cell Lymphoma, NOS
BM: Hemophagocytic Lymphohistiocytosis

48. Case Wrap-up:
Peripheral T cell Lymphoma-driven HLH.
Unfortunately, patient expired as treatment was getting started.
Poor prognostic factors:
- T cell lymphoma driven
- Older age
- Very low platelets
- Shock in ICU
- Long delay between symptom onset, diagnosis and start of etoposide (>4 weeks)
Cases always confusing, diagnostic markers non-specific, treatment approaches
variable, leads to uncertainty
We are working to optimize diagnosis and treatment!!

49. UT SOUTHWESTERN HLH/MAS TASK FORCE:
Chris Wysocki Immunology
Sri Nagalla Heme/Onc
Bonnie Prokesch Infectious disease
Fatemeh Ezzati Rheumatology
Shannan Tujios Hepatology
Corey Kershaw Pulmonary Critical Care
Arturo Dominguez Dermatology
Prapti Patel Bone Marrow Transplant
Goals:
• Improve multidisciplinary care of adult patients with HLH/MAS
• Minimize diagnostic delays and improve time to treatment
• Improve patient outcomes
• Facilitate clinical and translational research
Please contact any of us if you are suspicious of HLH/MAS….or email:
adult-hlh-mas@lists.utsouthwestern.edu