Clinical Management of Relapsed/Refractory Hemophagocytic Lymphohistiocytosis in Adult Patients: A Review of Current Strategies and Emerging Therapies

Figures & data

Table 1 Etiology of Secondary HLH in Adult Patients

Infection:  Virus:   Most frequent:    EBV, CMV (43% and 9% of cases respectively)    HIV  Less frequent:    Dengue, Hepatitis A, B, HSV-1 and 2, Influenza, Parvovirus, SFTS, VZV, Bk virus, Bunyavirus, Adenovirus, Hantavirus Bacteria: Most frequent:  TBC Less frequent:   Rickettsia, Coxiella burnetti, Brucellosis, Ehrlichia, Babesia, Bartonella henselae, Syphilis Enterococcus faecium, Klebsiella pneumoniae, Haemophilus influenzae, Group G streptococcal abiotrophia defectiva, Acinetobacter baummanii Fungi: Histoplasmosis, Candidiasis, Aspergillosis, Penicillium marneffei, Cunninghamela bertholletiae, Cryptococcus neoformansParasite: Leishmaniasis, Plasmodium, Toxoplasmosis

Malignancy:  Haematological disease: mainly lymphoma  Solid cancer Autoimmune disease:  Most frequent:   SLE, Still disease  Less frequent:   Rheumatoid arthritis, vasculitis, connectivitis   Antiphospholipid syndrome, Goodpasture syndrome   Kikuchi-Fujimoto disease, Inflammatory bowel disease Drug:  Chemotherapy: fludarabine and cyclophosphamide  Checkpoint inhibitors:   Pembrolizumab, Nivolumab, ipilimumab  Lamotrigine, Phenobarbital, Diaminophenylsulfone, BCG vaccination Other:  - Post-transplant (haematological, solid organ transplantation)  - Pregnancy

Abbreviations: HSV, herpes simplex virus; SFTS, severe fever with thrombocytopenia syndrome; VZV, varicella zoster virus; EBV, Epstein-Barr virus; CMV, cytomegalovirus; BK, polyomavirus BK; BCG, Bacille Calmette-Guérin; SLE, systemic lupus erythematosus.

Table 2 HLH-2004 Diagnostic Criteria and HScore for the Diagnosis of HLH

HLH-2004 Criteria*

HScore

A molecular diagnosis consistent with HLH Diagnostic criteria for HLH fulfilled (5 of the 8 criteria below) Fever Splenomegaly Ferritin ≥500 μg/L Cytopenias affecting ≥2 lineages: -Hemoglobin <9 g/dL -Platelet count <100x109/L -Absolute neutrophil count <1000/L Hypertriglyceridemia -Triglycerides ≥265 mg/dL (≥ 3 mmol/L) Hypofibrinogenemia -Fibrinogen ≤1.5 g/L Hemophagocytosis in bone marrow, spleen, or lymph nodes Low or absent NK cell activity sCD25 (sIL2Rα) ≥2400 U/mL

Presence of immunosuppression (No: 0 point; Yes: 18 points) Fever (<38.4: 0 pt; 38.4–39.4: 33 pt; >39.4: 49 pt) Organomegaly (No: 0 pt; splenomegaly or hepatomegaly: 23 pt; splenomegaly and hepatomegaly: 38 pt) Elevation in triglyceride levels (g/L) (<1.5: 0 pt; 1.5–4: 44 pt; >4: 64 pt) Elevation of ferritin levels (μg/L) (<2000: 0 pt; 2000–6000: 35 pt; >6000: 50 pt) Elevations of aspartate aminotransferase (U/L) (<30: 0 pt; ≥ 19 pt) Low fibrinogen levels (g/L) (>2.5: 0 pt; ≤ 2.5: 30 pt) Presence of cytopenias (1 lineage: 0 pt; 2 lineages: 24 pt; 3 lineages: 34 pt) ** Hemophagocytosis on bone marrow aspirate (No: 0 pt; Yes: 35 pt)

Notes: *The diagnosis of HLH can be established if criterion 1 or 2 is fulfilled. **Defined as hemoglobin level of 9.2 g/L and/or a leukocyte count ≤ 5 x10 9/L and/or a platelet count ≤ 110 x 10 9/L.

Table 3 Characteristics of Studies on Salvage Therapy for Refractory/Relapsed Adult HLH

Treatment	Number of Patients	Type of HLH	Complete Response/Partial Response	Overall Response	Number of Patients Who Achieved HSCT or Subsequent Chemotherapy	Rate of Survival
Alemtuzumab (Marsh, et al)^Citation45	22	8 F-HLH	0%/64%	64%	77%	64%
		5 EBV-HLH
		2 CMV-HLH
		7 I-HLH
DEP (Wang, et al)^Citation44	63	29 Mal-HLH	27%/49.2%	76.2%	13 (44.8%)	60.4%
		22 EBV-HLH
		4 F-HLH
		8 I-HLH
L-DEP (Wang, et al)^Citation53	28	EBV-HLH	32%/53.5%	85.7%	13 (54.1%)	76.9% (post HSCT)
Ruxolitinib (Ahmed, et al)^Citation60	5	Secondary HLH	100%	100%	NA	100%
Ruxolitinib (Boonstra, et al)^Citation61*	13	5 Infectious-HLH	38.4%/38.4%	77%	NA	76.9%
		4 MAS-HLH
		5 I-HLH
Ruxolitinib with and without glucocorticoids (Wang, et al)^Citation59	34	1 F-HLH	14.7%/58.8%	73.5	NA	55.9%
		25 EBV-HLH
		2 MAS
		6 I-HLH
DEP-Ru (Wang, et al)^Citation62	54	28 EBV-HLH	15.1%/58.5%	73.6%	32 (59.2%)	NA
		5 MAS
		3 Mal-HLH
		6 F-HLH
		1 Pregnancy-HLH
		1 Drug-HLH
		2 Infect-HLH
Emapalumab (Locatelli, et al)^Citation55	34	27 F-HLH	21%/32%	65%	22 (64.7%)	69% (90.9% post HSCT)
		7 I-HLH
Nivolumab (Liu, et al)^Citation64	7	EBV-HLH	71.4%/14.2%	85.6%	NA	71.4%

Note: *This study is an extension of Ahmed, et al study (Lancet Haematol 2019) but with data on longer follow-up and 7 more patients.

Abbreviations: NA, not available; DEP, doxorubicin, etoposide, methylprednisolone; L-DEP, DEP regimen with PEG aspargase; DEP-Ru, DEP-ruxolitinib; EBV, Epstein-Barr virus; CMV, cytomegalovirus; Mal-HLH, malignancy related HLH, I-HLH, idiopathic HLH; F-HLH, familial HLH; MAS, macrophage-activation syndrome; HSCT, hematopoietic stem-cell transplantation.

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