hemophagocytic lymphohistiocytosis: when common things ... · hlh-94 vs. hlh-04 outcome hlh-94...

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Hemophagocytic Lymphohistiocytosis: When Common Things Aren’t Common Dylan M. Barth, Pharm.D.PGY-1 Pharmacy ResidentMayo Clinic


Objectives• Review diagnostic criteria for hemophagocytic

lymphohistiocytosis (HLH)• Evaluate current evidence for treatment of HLH• Recognize the future direction of clinical

research for HLH


Hemophagocytic Lymphohistiocytosis• Disorder of immune dysregulation

• Hyperinflammatory• Involves macrophages, natural killer (NK) cells,

and cytotoxic T-lymphocytes• May engage in hemophagocytosis

George, Melissa. Jour Blood Med 2014.Parikh S, et al. Mayo Clin Proc 2015.

Siddaiahgari SR, et al. J Blood Disord Transfus 2016.


Timeline

1952 • 1st described in publication form in 1952 by Farquhar and Claireaux

1985 • International workshop convened in Philadelphia initiated by Dr.

Giulio D’Angio• Led to foundation of the Histiocyte Society

1995• HLH-94 International Treatment Study opens for enrollment

2017• New data from HLH-04 trial published

Siddaiahgari SR, et al. J Blood Disord Transfus 2016, 7:4.


Types of HLH

Secondary HLH (sHLH)

Familial HLH (fHLH)

Tumor Associated

HLH

IdiopathicAutoimmune-Associated

Infection Associated


PathophysiologyPrecipitating Factor

Activation of Macrophages

Inability to Downregulate Macrophages

Cytokine Release

Cytokine Storm Hemophagocytosis Tissue Damage

1. Natural Killer cell deficiency

2. Lack of apoptosis


Diagnostic Criteria

Fever

Splenomegaly

Hypertriglyceridemia or

Hypofibrinogenemia

Hemophagocytosis**

Hyperferritinemia

Cytopenias*

Elevated Soluble CD25

Impaired NK Cell Function

Need 5 of 8 for diagnosis

*2 of 3 cell lines**Bone marrow, spleen, lymph nodes George M. Jour Blood Med 2014.

Parikh S, et al. Mayo Clin Proc 2015.


When Common Things Aren’t CommonClinical Manifestation Mechanism

Fever High interleukin levels

Hepatosplenomegaly Infiltration by lymphocytes and macrophages

Cytopenias Hemophagocytosis + elevated tissue necrosis factor-alpha (TNF-α)

Hypertriglyceridemia Decreased lipoprotein lipase activity initiated by high TNF-α

Hyperferritinemia Heme scavenging by CD163

Hypofibrinogenemia Hypersecretion of plasminogen activators by macrophages

George M. Journal of Blood Medicine 2014:5


IncidenceFinding fHLH (%) sHLH (%) Diagnostic

Fever 100 100 >37°

Hepatosplenomegaly 100 80-90 Physical Examination

Cytopenias 100 80 Hgb < 9 g/dL, Platelets < 100K, Neutrophils < 1000

Hypertriglyceridemia 70 40 > 3 265 mg/dL

Elevated ferritin 70 95 >500 mcg/L

Hemophagocytosis 85 Rare Bone Marrow

Elevated sCD25 90 Unreported, but occurs

> 2,400 U/mL

George M. Journal of Blood Medicine 2014.Pham A, et al. Ameri Socie Hematology 2015.


Ancillary Clinical Features

Prolonged Fever

Liver Disease

Skin Abnormalities

Pulmonary Dysfunction

Neurological Symptoms

Jordan M, et al. Blood 2011.


Diagnostic Algorithm

Unexplained cytopenias in at

least two cell lines HLH Unlikely

Ferritin >500 mcg/mL or elevated

sIL2r HLH Unlikely

Consider Hematology

Consult

Other Diagnostic Criteria Met HLH Confirmed

No

Yes

YesNo

Yes

Used with permission from Dr. Parikh. Do not redistribute.


Clinical Case• DMB is a 52 year old previous Mayo Clinic

Pharmacy Practice Resident transferred to Mayo for fever of unknown origin.

• Extensive work-up is unrevealing• Temp: 38.7; Ferritin 5485 mcg/L

137

4.2

107 27

19 1.5 (BL 1.1)

7.8

1.5 7523


Which of the following is NOT a diagnostic criterion of HLH?A. HyperferritinemiaB. Acute Kidney InjuryC. FeverD. Thrombocytopenia


HLH-94• Largest study had 249 patients

• 5-year probability of survival of 54% +/- 6%• Immunosuppressive and cytotoxic therapy

• Etoposide, Dexamethasone, Methotrexate*, and Cyclosporine**

• Only data in familial HLH• Goal is stem cell transplant (SCT)

*Progressive neurologic symptoms or persistent cerebrospinal fluid findings**Starts after week 8

Trottestam H, et al. Blood 2011; 118(17)


Evaluate current evidence for treatment of HLH


HLH Treatment Algorithm

Infection associated

Autoimmune associated

Malignancy associated

Idiopathic

Treat underlying condition

HLH-04 Protocol

Used with permission from Dr. Parikh. Do not redistribute.


HLH-04• < 18-years meeting 5/8 diagnostic

criteria, affected siblings, and/or molecular diagnosis in fHLH-causative genes

Population

• No prior cytotoxic or cyclosporine treatment

• No underlying disease

Inclusion Criteria

• Other malignancies, systemic rheumatic diseases, Langerhans cell histiocytosis, Kawasaki disease, or Leishmaniasis

Exclusion Criteria

• Survival, time to transplant, neurological sequelae Outcomes

Bergsten E, et al. Blood. Online. 2017.


HLH Initial Therapy

HLH-94 HLH-04

Etoposide Etoposide

Dexamethasone Dexamethasone

Methotrexate Methotrexate

- Cyclosporine

- Hydrocortisone



HLH-2004 Results

0

10

20

30

40

50

60

70

80

90

100

5- year probability ofsurvival

SCT Alive at 5-years andreceived SCT


%


HLH-94 vs. HLH-04

Outcome HLH-94 HLH-04 P-value5-year survival 54% 61% -

Mortality prior to HSCT 27% 19% 0.064*Neurologic Alterations at

HSCT22% 17% 0.26

Time to HSCT (Days) 180 154 0.020*

Conclusion

• No statistical evidence showing HLH-2004 is better than HLH-94• HLH-94 protocol with HLH-2004 diagnostic criteria• Need trial comparing novel therapeutic approaches to HLH concepts

* Adjusted for age and gender Bergsten E, et al. Blood 2017.


Secondary HLH at Mayo Clinic• Retrospective analysis of adult patients

treated at Mayo Clinic from January 1996 through December 2011

Population

• All patients who satisfied HLH-2004 criteria during study period

Inclusion Criteria

• Familial HLHExclusion Criteria

• Overall survival (OS)OutcomesParikh S, et al. Mayo Clin Proc 2014.


Cause of HLH

52%

34%

8%6%

Malignant TumorInfectionAutoimmuneIdiopathic

N=62



Mortality• 41 of 62 patients had died at median follow-up

of 42 months• 30 day mortality 44%

• Median OS: 2.1 months• OS Tumor vs. Non-tumor

• 1.4 vs. 22.8 months (p=0.01)• Cause of death: Multi-organ failure, infection,

progressive disease



Other Clinical Considerations• Less than 50% of adults with malignant HLH

receive HLH-directed therapy• Lack of awareness and missed diagnosis

• Delay in consultation of hematology• Dose adjustment of drug therapies• Immunocompromised• Unfit for transplant

Daver N, et al. Cancer 2017;123.


Conclusion

Poor detection

Rapid Progression

High Mortality


Based on the results of HLH-04, HLH algorithms will likely include which of the following?A. Cyclosporine and Hydrocortisone in first 8

weeks of therapyB. Cyclosporine and Hydrocortisone after the

initial 8 weeks of therapy


Recognize the future direction of clinical research for HLH


Now what?

Salvage vs Future

Emapalumab

RuxolotinibDEP

DEP = Doxorubicin, Etoposide, Methylprednisolone


DEP Salvage Therapy

• 63 adult patients who did not achieve partial response 2 weeks after initial HLH-94 therapyPopulation

• >18 year old patients that met HLH-2004 diagnostic criteria

• No GI bleed, and LVEF > 50% at time of enrollment

Inclusion Criteria

• Liposomal doxorubicin 25 mg/m2 day 1 • Etoposide 100 mg/m2 weekly x4 weeks• Methylprednisolone 15 mg/kg day 1, then taper

Intervention

• Survival and Response (Partial and Complete)EndpointsGI: Gastrointestinal LVEF: Left Ventricular Ejection Fraction

Wang Y, et al. Blood 2015; 126.


Results (N=63)

Endpoint Responders (%)Overall Response 48 (76)Partial Response 31 (49)

Complete Response 17 (27)

Type of HLH

EBV-HLH

LymphomaAssociatedFamilial

Idiopathic

Wang Y, et al. Blood 2015; 126.


Abbreviated Results and ConclusionParameter At HLH

DiagnosisBefore DEP

Regimen2 weeks

after DEP4 weeks

after DEPFerritin (mcg/L) 3386 6786 2339 1119sCD25 (pg/mL) 22435 39285 16100 6878

ALT (U/L) 104 95 69 37Platelets (x109/L) 52 61 88 115

WBC (x109/L) 2 2 3 4

Wang Y, et al. Blood 2015; 126.Daver N, et al. Cancer 2017;123.

Conclusion

• Encouraging results for refractory HLH• May be difficult to use in already myelosuppressed individuals • Bridge to etiology therapy?


Ruxolitinib

What we know

• Janus Kinase 1 (JAK1)/JAK2 Inhibitor

• Utility in other inflammatory conditions

• Prolonged survival in murine models with HLH

• Suppressed CD8 positive T-Cell activation

• Positive case report results

Possibilities

• Monotherapy?

• Concerns for immunosuppression?

• Combination with standard therapy?

• Maintenance?

• NCT02400463

Daver N, et al. Cancer 2017;123.Das R, et al. Blood 2016; 127.Maschalidi S, et al. Blood 2016; 128.


Emapalumab (NI-501)• First targeted treatment for fHLH• Humanized anti-interferon-gamma monoclonal

antibody• 13 patients treated

• 85% alive at 8 weeks• 7 proceeded to allogeneic stem cell

transplantation• Significant improvement in neutrophils,

platelets, ferritin, and glucocorticoid tapering

Jordan M, et al. Blood. 2015.


Other Therapies• Alemtuzumab

• T and B lymphocyte depletion• Antithymocyte Globulin

• Suppression of macrophages and CD8 t- lymphocytes

• Anakinra• Interleukin-1 Inhibitor

• Over 30 trials on clinicaltrials.gov

Daver N, et al. Cancer 2017;123.


DEP therapy causes worsening of which of the following after four weeks?• Hyperferritinemia• Leukopenia• Thrombocytopenia• None of the above

DEP = Doxorubicin, Etoposide, Methylprednisolone


Conclusion• Hemophagocytic lymphohistiocytosis is a

complex disease that requires early diagnosis and treatment to improve patient outcomes

• New data call for new guidance on the use of therapeutic agents

• Studies of novel therapies against traditional regimens are on the horizon


Hemophagocytic Lymphohistiocytosis: When Common Things Aren’t Common Dylan M. Barth, Pharm.D.PGY-1 Pharmacy ResidentMayo Clinic

hemophagocytic lymphohistiocytosis: when common things ... · hlh-94 vs. hlh-04 outcome hlh-94...

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