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TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS G.E. Janka Hamburg. Iran November 2018. HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Diagnostic criteria 1. Familial disease/known genetic defect

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TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

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  1. TREATMENT OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS G.E. Janka Hamburg Iran November 2018

  2. HAEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Diagnostic criteria1 Familial disease/known genetic defect Clinical and laboratory criteria (5 out of 8) Fever Splenomegaly Cytopenia of => 2/3 cell lines Hemoglobin <90g/l, platelets <100x109/l, ANC <1x109/l Hypertriglyceridemia and/or hypofibrinogenemia Fasting triglycerides =>3mmol/l, fibrinogen <1.5g/l Haemophagocytosis in bone marrow, CSF, lymphnodes Ferritin =>500µg/l sCD25 =>2400U/ml Decreased or absent natural killer cell activity Strong supportive evidence are cerebral symptoms with moderate pleocytosis and or elevated protein, elevated transaminases, bilirubin and LDH 1HLH Study Group of the Histiocyte Society, Henter et al. PBC 2007

  3. MAS - HLH New diagnosticcriteria • Multistepprocess: • Delphi surveytoidentify MAS featurespotentiallysuitable als criteria • Data collection on patientswithsJIA-associated MAS (362), patientswithsJIA not complicatedby MAS (404), andpatientswithsystemicinfections (345) • Selectionofcandidatecriteriafrompatientswithconsensus (391/428) in 28 • experts (cut-off valuescalculatedby ROC) • Selectionof final criteriabyconsensusconference Final criteria Ravelli 2016 MAS is diagnosed in a febrile patient with sJIA if the following criteria are met: Ferritin > 684ng/mL and any 2 of the following Platelet count ≤ 181 000/µL Aspartate aminotransferase (GOT) > 48 U/L Triglycerides > 156 mg/dL Fibrinogen ≤ 360 mg/dL

  4. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS MAS as first presentation of soJIA versus FHL/VA-HLH Retrospective analysis from German pediatric HLH database (Lehmberg J. Pediat 2013) pHLH = 90, VAHS = 42, MAS in soJIA= 27 Variables in favourof MAS ROC-AUC SensitivitySpecificity ANC ≥ 1.8 x 109/L 0.89 0.85 0.83 CRP ≥ 90mg/L 0.87 0.74 0.89 sCD25 ≤ 7900 U/L 0.79 0.79 0.76 pHLH: n = 258, MAS in soJIA: n = 362 (Minoia F, J Pediatr 2017) Development of „MH Score“ with 6 variables most closely associated with pHLH: Age ≤ 1.6 yearsPlatelets ≤ 78/nL ANC ≤ 1.4/nLHemoglobin ≤ 8.3g/L Fibrinogen ≤ 1.3g/L Splenomegalypresent Score assigned depending on statistical weight of each variable in multivariate analysis (median score: genetic HLH 97, MAS 12; best cut-off 59: sensitivity 91%, specificity 93%)

  5. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS How to differentiate between genetic and acquired HLH? Identification of an infectious agent not helpful severity of disease not helpful Age helpful ~90% of children below 1 year will have genetic HLH Do not forget: mutations in HLH-related genes are being increasingly identified in adolescents or adult patients Functional tests(degranulation, expression of perforin, SAP and XIAP) or mutation analysis allow differentiation between genetic and acquired forms, but are not widely available or still too expensive. The distinction between genetic and acquired HLH is not important for initial treatment which is guided mainly by the severity of the disease!

  6. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS General statement It is important to realize that HLH is a syndromewhere often an underlying trigger/condition can be identified. In children infections (mostly viral), autoinflammatory/ autoimmune diseases, malignant diseases and (rarely) metabolic diseases have to be considered. The search for a trigger is of utmost importance! Especially in adults and older children lymphomas (ultrasound, x-ray, CT, MRI) must be ruled out. Usually HLH-directed therapy is needed in addition to the specific treatment of the triggering condition (exceptions: leishmaniasis, tuberculosis).

  7. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Underlyingconditionsandclassification in children Genetic HLH Acquired HLH ● Familial HLH (FHL) („Farquhar`s disease“)● Infectious agents ● Endogenous products - tissue damage - radical stress - metabolic products ● Autoimmune/autoinflammatory ● Immune deficiency diseases(Macrophage activation syndromessyndrome; MAS) Chédiak-Higashi syndrome 1 Griscelli syndrome 2 Malignant diseases X-linked proliferative syndrome Other inborn immune deficiencies● Acquired immune defects Frequency ~ 1 : 5 bi-allelic mutations Perforin UNC13D Syntaxin11 UNC18B HLH

  8. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Principlesoftreatment Treatment for HLH depends on the underlying disease and severity of symptoms. Children with MAS are usually treated successfully with high-dose corticosteroids ± ciclosporin A. In non-responders anakinra is effective. HLH cases with less severe symptoms may only need corticosteroids ± immunoglobulins – but be aware of the dynamics of the disease!

  9. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Principlesoftreatment HLH therapy is a two-sided sword On one hand hyperinflammation has to be suppressed to prevent the dangerous consequences of hyperinflammation; on the other hand immune- suppressive and cytostatic treatment may be counterproductive for control of infectious triggers and recovery of the bone marrow. In contrast to malignant diseases the aim is not to destroy as many cells as possible by intensive therapy but just to down-regulate the hyperactive immune response and to reduce the number of activated (infected) cells in the hope to achieve a new balance.

  10. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Principlesoftreatment Suppression of hyperinflammation corticosteroids immunoglobulins cyclosporin A anti-cytokine treatments antibodies Elimination of (infected) cells: APCs, lymphocytes etoposide, rituximab, corticosteroids antithymocyte globulin/alemtuzumab Treatment of the trigger Replacement of the defective immune system by stem cell transplantation in genetic cases

  11. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Treatment Immunosuppressive/immunomodulatory agents -Corticosteroids - Intravenous immunoglobulins - Cyclosporin A - Cytokine removal (plasmapheresis, cytokine-absorbers) - Antagonists of single cytokines: IL-1, IL-6, INFγ - Inhibition of Janus kinase 1/2: ruxolitinib - Antibody against IL-2 receptor: basiliximab Cytotoxic drugs - Corticosteroids - Etoposide (Ambruso 1980) - T-and B-cell antibodies (ATG, alemtuzumab, rituximab)

  12. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Founding of the Histiocyte Society in 1985 Founding of the HLH Study Group in 1989 Founding members Maurizio Aricò Jan-Inge Henter Blaise Favara Diane Komp Göran Elinder Christian Nezelof Gritta Janka Jon Pritchard

  13. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Two international studies: HLH-1994 and HLH-2004 Follow-up publication by Trottestam H, Blood 2011

  14. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS International treatment protocols for HLH A HLH-1994 B HLH-2004 CSA starts upfront Prednisolone is added to i.th. therapy

  15. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Treatment resultswithprotocol HLH-1994 and HLH-2004 Study HLH-1994 n = 232 33 (14%) died < 2 months 23 (10%) died >2 <12 months 7 ( 3%) died >12 months 40 (17%) died after HSCT Mortality after HSCT 40/118 (34%) Study HLH-2004 n = 369 50 (14%) died < 2 months 17 ( 6%) died >2 <12 months 8 ( 2%) died > 12 months 64 (17%) died after HSCT Mortality after HSCT 64/185 (35%) Trottestam H, Blood 2011; Bergsten E, Blood 2017

  16. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS n = 201 n = 201 n = 369 Results of HLH-2004 n = 369 n = 168 n = 240 n = 240 n = 168 Bergsten et al. Blood 2017 n = 232 n = 232

  17. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS HLH Steering Committee of the Histiocyte Society Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH Ehl S. et al. Journal of Allergy Clinical Immunology Practice 2018 Recommendation of HLH Study Group to use the HLH-94 protocol with HLH-2004 diagnostic criteria

  18. Authors of „Recommendations for use of protocol HLH-1994 AnnaCarin Horne Elena Sieni Michael Jordan Jan-Inge Henter Paul La Rosée Itziar Astigarraga Eiichi Ishii Melissa Hines Stephan Ehl Kim Nichols Tatiana Greenwood Kai Lehmberg Gritta Janka Rafal Machowicz Zhao Wang

  19. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Treatment resultswith T-cellantibodies Antithymocyte globulin (Mahloui N 2007) Results: 28 patients with FHL; 1-2 courses; CR 23/28; PR 5/28 22/28 HSCT; survival 17/22 (77%) HIT-HLH USA and EURO-HIT-HLH ATG instead of the first three doses of etoposide Results not better and not worse than HLH-1994; no publication yet

  20. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Treatment resultswith T-and B-cellantibodies Alemtuzumab Pilot study (2006-2015) (Moushous, HS meeting 2016) 23 patients with FHL, 1-3 courses Results: CR: 87%, PR 9%, 1 nonresponder; 22/23 patients HSCT Ongoing study (NCT02472954) (Moushous, HS meeting 2018) so far 20 patients with FHL; planned 30; Campath d1 0.5mg/kg; d 2+3 1mg/kg + Pred d 4-14 2mg/kg, then taper, + CSA same response rate; ~50% received haplo-BMT Rituximab(Chellapandian, Rituximab Study Group 2013) Retrospective survey; 42 patients with EBV-HLH; median 3 doses (2/3 within 1 mos after diagnosis; combination with other HLH drugs) Results: significant decrease in EBV load and ferritin; significant increase in platelets and SGOT.

  21. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Salvage therapy Patients with refractory/relapsed HLH, previously treated with steroids + etoposide or steroids + ATG. At least 2 patients treated. Literature survey by Working Group on Second-line Treatment in HLH (R. Marsh, PBC 2017) Anakinra: 3 patients with MAS (3 CR) (Behrens E, Miettunen PM ) ATG: 2 patients with FHL (2 CR) (Mahlaoui N) Alemtuzumab: 24 patients with HLH (16 PR, 8 NR) (Marsh R, Strout MP, Gerard LM) Liposomal doxorubin, etoposide and methyl-prednisolone Thirty-four adult patients without lymphoma: 12 CR, 14 PR, 8 NR (Wang Z)

  22. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS New drugs Interferon-γ antibody Emapalumab (NI-0501) NCT 01818492: phase II/III study, 20 countries, still recruiting Inclusion: children with primary HLH; reactivated disease, or unsatisfactory response, or intolerant to standard therapy Exclusion: secondary HLH, HLH in rheumatic or malignant diseases Treatment: antibody 1mg/kg every 3 days + dexamethasone Results: • Eleven of 13 patientsalive after 8 weeks (1 first-linetreatment) • Satisfactoryresponse in 9/13 patients (improvement in HLH parameters) • - Seven of 13 patientsproceededto HSCT • - Resolution of CNS symptoms in 2 evaluablepatients • - Reductionof DEX in 50% ofpatients in first 4 weeks. Update HS meeting 2016: 31 patients recruited, 25 with mutations; 5 first line-treatment Jordan M, Blood LBA 2015

  23. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS New drugs Ruxolitinib Ruxolitinib is an oral anti-inflammatory and immunosuppressive Janus kinase (JAK) inhibitor, approved for myelofibrosis. Activity has been shown in rheumatoid arthritis, GvHD, psoriasis, ulcerative colitis, and other diseases. JAK1 and JAK2 control signaling of many cytokines by transmitting cytokine-induced signals, notably from INF-γ, IL-2 and IL-6. Ruxolitinib is being evaluated in 2 ongoing clinical trial for HLH in adults).There are several recent case reports.

  24. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Ruxolitinib Das et al. (Kim Nichols` group) Blood 2016 Two mouse models for HLH: PRF1-/- mouse and CpG induced model for secondary HLH Preemptive treatment with ruxolitinib starting day 4 (to day 9) Prevention of HLH symptoms, hypercytokinemia and tissue inflammation, enhancement of survival Maschalidi et al. (Alain Fischer`s group) Blood 2016 Two mouse models for HLH: PRF1-/- mouse and RAB27a-/- Treatment of manifest HLH with ruxolitinib for 14 days starting day 7 (PRF1), or day 10 (RAB27A) post infection Enhancement of survival (comparable with INF-γ antibody treated mice) Correction of cytopenias, reduction of tissue inflammation, reversal of CNS symptoms (RAB27A-/- mouse)

  25. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Possibletherapeuticalgorithm Consider to wait for effect of antiinfectious therapy in mild disease Less severe cases: no prolonged neutropenia no organ failure no CNS symptoms no severe coagulopathy Functional studies Severe cases Steroids, IVIG EBV-HLH: + Rituximab good response 24-48 hrs. stop when CR and acquired HLH no response poor PR stop when CR and acquired HLH good response HLH-94 progressive Unsatisfactory response CSA Consider to add basiliximab/ daclizumab repeat IVIG alemtuzumab (INFγ antibody, ruxolitinib) cytokine absorption other cytostatics (e.g. DEP) salvage continuous poor response Consider early transplant

  26. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Stemcelltransplantation: Reducedintensityconditioning Author number conditioning regime survival Horne A, BJH 2005 86 BU, CYT, VP16 ± ATG 64% Cooper N BMT 200825 5-FU, MEL, alemtuzumab 84% (2-105 mos, med 36) Marsh R Blood 2010 26 5-FU, MEL, alemtuzumab pOS 92% (at 3 years) Lehmberg K Haemat.2013 19 5-FU, TREO, THIO (14), alemtu 100% (7-31,med 16mos) 60 manuscript in preparation 78% Allen C, Blood 2018 34 5-FU, MEL, alemtuzumab 68% at 18 mos RIC conditioningisassociatedwithlesstoxicityandbettersurvival, but a with a higherfrequencyofmixedchimerism, necessitating interventionwith DLIs orsecondtransplants

  27. HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Stemcelltransplantationwith RIC: mixeddonorchimerisms (DC) (Hartz B HS Blood 2016) 103 patientswith FHL from 7 countries, DC < 75%; overallsurvival 82% 17 (16%) reactivations (10 before d180); overallsurvival 9/17 18 pts. 2ndtransplants (9 withpreviousreactivations); mortality 33% Key messages: ● Patientswithreactivationsbefore d180 have variable DC and frequently viral triggers; underlyingimmunosuppressionplays a role. ● A DC of 20-30% protectsfromreactivation after d180 ● DC below 30% does not alwaysresult in reactivationof HLH ► 5 pts. line-specific DC (CD3) <10% 1.1.-10yrs (med. 5.1) withoutrelapse ● In patientswithlow DC, riskof 2nd HSCT must beweighedagainst riskofreactivation

  28. Thank you for your attention! Our HLH Team Hamburg: Kai Lehmberg Udo zur Stadt Ingo Müller Anke Clodius Manuela Adao Gritta Janka München: Karin Beutel Freiburg: Stephan Ehl Miriam Heizmann Carsten Speckmann Sandra Amman Ilka Fuchs

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