Upload
others
View
6
Download
0
Embed Size (px)
Citation preview
©2018 MFMER | slide-1
Hemophagocytic Lymphohistiocytosis: When Common Things Aren’t Common Dylan M. Barth, Pharm.D.PGY-1 Pharmacy ResidentMayo Clinic
©2018 MFMER | slide-2
Objectives• Review diagnostic criteria for hemophagocytic
lymphohistiocytosis (HLH)• Evaluate current evidence for treatment of HLH• Recognize the future direction of clinical
research for HLH
©2018 MFMER | slide-3
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.
©2018 MFMER | slide-4
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.
©2018 MFMER | slide-5
Types of HLH
Secondary HLH (sHLH)
Familial HLH (fHLH)
Tumor Associated
HLH
IdiopathicAutoimmune-Associated
Infection Associated
©2018 MFMER | slide-6
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
©2018 MFMER | slide-7
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.
©2018 MFMER | slide-8
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
©2018 MFMER | slide-9
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.
©2018 MFMER | slide-10
Ancillary Clinical Features
Prolonged Fever
Liver Disease
Skin Abnormalities
Pulmonary Dysfunction
Neurological Symptoms
Jordan M, et al. Blood 2011.
©2018 MFMER | slide-11
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.
©2018 MFMER | slide-12
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
©2018 MFMER | slide-13
Which of the following is NOT a diagnostic criterion of HLH?A. HyperferritinemiaB. Acute Kidney InjuryC. FeverD. Thrombocytopenia
©2018 MFMER | slide-14
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)
©2018 MFMER | slide-15
Evaluate current evidence for treatment of HLH
©2018 MFMER | slide-16
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.
©2018 MFMER | slide-17
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.
©2018 MFMER | slide-18
HLH Initial Therapy
HLH-94 HLH-04
Etoposide Etoposide
Dexamethasone Dexamethasone
Methotrexate Methotrexate
- Cyclosporine
- Hydrocortisone
Bergsten E, et al. Blood. Online. 2017.
©2018 MFMER | slide-19
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
Bergsten E, et al. Blood. Online. 2017.
%
©2018 MFMER | slide-20
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.
©2018 MFMER | slide-21
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.
©2018 MFMER | slide-22
Cause of HLH
52%
34%
8%6%
Malignant TumorInfectionAutoimmuneIdiopathic
N=62
Parikh S, et al. Mayo Clin Proc 2014.
©2018 MFMER | slide-23
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
Parikh S, et al. Mayo Clin Proc 2014.
©2018 MFMER | slide-24
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.
©2018 MFMER | slide-25
Conclusion
Poor detection
Rapid Progression
High Mortality
©2018 MFMER | slide-26
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
©2018 MFMER | slide-27
Recognize the future direction of clinical research for HLH
©2018 MFMER | slide-28
Now what?
Salvage vs Future
Emapalumab
RuxolotinibDEP
DEP = Doxorubicin, Etoposide, Methylprednisolone
©2018 MFMER | slide-29
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.
©2018 MFMER | slide-30
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.
©2018 MFMER | slide-31
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?
©2018 MFMER | slide-32
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.
©2018 MFMER | slide-33
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.
©2018 MFMER | slide-34
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.
©2018 MFMER | slide-35
DEP therapy causes worsening of which of the following after four weeks?• Hyperferritinemia• Leukopenia• Thrombocytopenia• None of the above
DEP = Doxorubicin, Etoposide, Methylprednisolone
©2018 MFMER | slide-36
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
©2018 MFMER | slide-37
Hemophagocytic Lymphohistiocytosis: When Common Things Aren’t Common Dylan M. Barth, Pharm.D.PGY-1 Pharmacy ResidentMayo Clinic