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Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol

Helena Trottestam, AnnaCarin Horne, Maurizio Aricò, R. Maarten Egeler, Alexandra H. Filipovich, Helmut Gadner, Shinsaku Imashuku, Stephan Ladisch, David Webb, Gritta Janka, Jan-Inge Henter and for the Histiocyte Society

Data supplements

  • Supplemental materials for: Trottestam et al

    Members of the Histiocyte Society HLH-94 Clinical Study Group:
    Jan-Inge Henter, study coordinator
    Maurizio Aricò
    R. Maarten Egeler
    Göran Elinder
    Helmut Gadner
    Shinsaku Imashuku
    Gritta Janka
    Diane Komp
    Stephan Ladisch
    David Webb

    Files in this Data Supplement:

Article Figures & Data

Figures

  • Figure 1

    Overview of the HLH-94 treatment protocol. BMT: Patients with familial or persistent disease were recommended to go to HSCT as soon as an acceptable donor was available, preferably when the disease was nonactive. The patients without familial or persistent disease were recommended to stop therapy after the initial therapy, and restart in case of reactivation. Dexa: Daily dexamethasone (10 mg/m2 for 2 weeks followed by 5 mg/m2 for 2 weeks, 2.5 mg/m2 for 2 weeks, 1.25 mg/m2 for 1 week, and 1 week of tapering; pulses were 3 days, 10 mg/m2 daily). VP-16: Etoposide 150 mg/m2 IV. IT therapy: Intrathecal methotrexate in patients with progressive neurological symptoms and/or persisting abnormal cerebrospinal fluid findings. CSA: Cyclosporin A aiming at blood levels of 200 μg/L (trough value).

  • Figure 2

    Kaplan-Meier survival curves. (A) All eligible study patients treated with HLH-94 (n=249). (B) All patients with an affected sibling (n=60). (C) All patients who received transplants (n=124). (D) Survival related to HLH disease activity at HSCT (nonactive disease: black line; active disease: grey line; the time in both panels C and D is shown as the time from HSCT).

  • Figure 3

    Cause and time of deaths occurring in patients who did not receive transplantation within the first year of treatment (n=64). The majority of patients died with or from active HLH (Embedded Image). The causes of death in 4 patients who did not have active HLH at death (■) were: fatal bleeding following liver biopsy (n=1, 7th week); septicemia where HLH status at death is not known (n=1, 2nd week), and cause of death not stated (n=2, 1st and 38th weeks). One patient who died with or from active HLH is not represented in the graph, since the exact death date is missing.

Tables

  • Table 1

    Diagnostic criteria used in HLH-94

    Criteria
    Clinical
        Fever
        Splenomegaly
    Laboratory
        Cytopenias (affecting at least 2 of 3 lineages in the peripheral blood)
            Hemoglobin (< 90 g/L), platelets (< 100 × 109/L), neutrophils (< 1.0 × 109/L)
        Hypertriglyceridemia and/or hypofibrinogenemia
            Fasting triglycerides ≥ 2mM or ≥ 3 SDs of the normal value for age
            Fibrinogen ≤ 1.5 g/L or ≤ 3 SDs of the normal value for age
    Histopathologic
        Hemophagocytosis in the BM or spleen or lymph node
            No evidence of malignancy
  • Table 2

    Patient characteristics in history, clinical findings, and laboratory parameters before start of therapy in all patients

    Patient subgroupAll patients (N = 249)(1) Familial patients (n = 60)(2) Dead < 8 wk (n = 35)(3) HSCT (n = 124)(4) Off therapy, no HSCT (n = 49)
    General
        Mean/median age, mo (range)24/8 (0-184)16/2 (0-145) (↓*)23/4 (0-137)15/4 (0-150) (↓*)51/24 (2-184) (↑*)
        Male sex, %137, 5535, 5820, 5773, 5919, 39 (↓)
        Familial disease, %60/247, 2460, 1005/34, 1544/123, 36 (↑*)0 (↓*)
        Consanguinity, %50/240, 2118/56, 32 (↑)12/34, 35 (↑)26/119, 223/48, 6 (↓)
        Infectious history, %109/244, 4519/58, 33 (↓)15, 4347/120, 3925/48, 52
    Clinical parameters
        Hepatomegaly, %237, 952, 9734, 97119, 9643, 88 (↓)
        Lymphadenopathy, %80/244, 3312, 20 (↓)10/34, 2936/122, 3022, 45 (↑)
        Edema, %97/243, 4024/59, 4121/34, 62 (↑)36/121, 30 (↓)21, 43
        Jaundice, %84/244, 3421/58, 3620/34, 59 (↑)38/121, 3114, 29
        Rash, %77/246, 3120/59, 349/34, 2640/122, 3319, 39
        Neurological symptoms, %80/245, 3323, 3810/33, 3043, 358, 16 (↓)
        MRI or CT of brain pathological, %43/135, 325/26, 196/10, 60 (↑)22/75, 296/28, 21
    Laboratory findings
        ↑ Ferritin, %198/212, 9341/48, 85 (↓)26/29, 9096/102, 9444/47, 94
        ↑ LDH, %182/209, 8741/48, 8529/31, 9481/100, 81 (↓)42/44, 95
        ↑ SGOT, %164/216, 7637/53, 7025/30, 7180/107, 7538/45, 84
        ↑ SGPT, %181/237, 7641/55, 7527/34, 7988/118, 7541/47, 87
        ↑ Bilirubin, %123/239, 5132/57, 5623/34, 68 (↑)56/117, 4823/48, 48
        ↓ Albumin, %154/223, 6933/52, 6325/33, 7664/105, 61 (↓)36/46, 78
        Prolonged APTT, %127/227, 5629/54, 5421/32, 6656/109, 5129/48, 60
        ↓ Sodium, %119/234, 5131/57, 5413/33, 3953/115, 4633/47, 70 (↑)
        ↑ Creatinine, %21/242, 93/56, 58/35, 23 (↑)4/119, 3 (↓)7, 14
        ↑ Cerebrospinal fluid cells, %82/205, 4024/53, 4510/24, 4248/111, 436/40, 15 (↓*)
        ↑ Cerebrospinal fluid proteins, %80/197, 4122/48, 468/20, 4046/106, 439/40, 23 (↓)
    • Patient characteristics in history, clinical findings, and laboratory parameters before start of therapy in all patients, as well as in 4 different subgroups: (1) patients with an affected sibling; (2) patients who died within the first 8 weeks of therapy; (3) patients who underwent HSCT; and (4) patients who are alive and off all HLH therapy since ≥ 1 year without signs of disease activity or a HSCT. Patients could be included in several subgroups. Binary data have been used in the analyses (yes/no), and for laboratory data, standardized age-adjusted normal range values have been applied. Patients from a subgroup have been compared to the remaining patients. In the table body, numbers following commas are percentages.

    • HLH indicates hemophagocytic lymphohistiocytosis; MRI, magnetic resonance imaging; CT, computed tomography; LDH, lactate dehydrogenase; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; APTT, active partial thromboplastine time; ↑, an increased occurrence of the finding; and ↓, a decreased occurrence of the finding.

    • Symbols indicate statistical difference from other patients at the levels: *.001; †.05; or ‡.01.

  • Table 3

    Overall outcome, course of disease, survival, and sequelae in all patients and in familial patients

    All patients, n = 249 (%)Familial patients, n = 60 (%)
    Outcome
        Alive after HSCT82 (33)29 (48)
        Dead after HSCT42 (17)15 (25)
        Alive without HSCT53 (21)0
        Dead prior to HSCT72 (29)16 (27)
    Efficacy of HLH-94 pre-HSCT therapy
        Admitted to HSCT + alive without HSCT124 + 53 (71)44 + 0 (73)
        Dead during initial or continuation therapy72 (29)16 (27)
    Survival
        5-y cumulative survival, ± 95% CI54 ± 650 ± 13
        Alive at last follow-up135 (55)29 (48)
    Course
        Alive or HSCT at 2 mo214 (86)55 (92)
        Alive without HSCT at 2 mo212 (85)55 (92)
        NAD* at 2 mo (without HSCT)122/207 (59)37/54 (69)
        Alive or HSCT at 6 mo196/248 (79)50 (83)
        Alive without HSCT at 6 mo136/188 (72)30/40 (75)
    HSCT performed124 (50)44 (73)
        Off therapy, no HSCT49 (20)0
    Sequelae in survivors(n = 135)(n = 29)
        Neurological25 (19)9 (31)
        Non-neurological21/132 (16)8/27 (30)
    • CI indicates confidence interval; NAD, nonactive disease; HLH, hemophagocytic lymphohistiocytosis; and ADHD, attention-deficit/hyperactivity disorder.

    • * NAD, as stated by the treating clinician.

    • Off therapy: Alive without HSCT, no signs of HLH activity, and no HLH therapy for ≥ 1 year.

    • The most frequently reported neurological sequelae was epilepsy, in 9 patients. Other CNS sequelae ranged from severe mental retardation to speech delay, learning difficulties, motor dysfunctions, cranial nerve paresis and ADHD. Reported non-neurological sequelae included nutritional problems and/or growth retardation, hypertension, impaired renal function, obstructive bronchiolitis, and hearing impairment.