I. Diagnostic criteria
1.Molecular diagnosis
The diagnosis is confirmed by genetic alterations consistent with HLH. The main genetic abnormalities are: perforin gene mutation and hMunc13-4 gene mutation. The perforin gene is located at 10q21, and the mutation exists in 20-40% of FLH. hMunc13-4 gene is located at 17q25, and the mutation is also the cause of FLH.
2, clinical diagnosis (more than 5 of the following 8 items can be diagnosed)
Clinical manifestations
(1) Fever
(2) Splenomegaly
Laboratory tests
(3) Hematocrit (more than 2 lines)
Hb<90g/L (<100g/L in neonates)
Plt<100*109/L
ANC<1.0*109/L
(4) Hypertriglyceridemia or/and hypofibrinogenemia
TG≥3.0mmol/L
Fib≤1.5g/L
Histological findings
(5) Hemophilia in bone marrow, spleen or lymph nodes, except for malignant lesions.
New diagnostic criteria
(6) Reduced or absent NK cell activity
(7) Serum ferritin (Fer) ≥ 500ug/L
(8) Soluble CD25 (IL-2 receptor) ≥ 2400 U/ml
Second, chemotherapy
1, initial treatment (8 weeks)
VP16: 150mg/m2, 2/w, (1-2W)
150mg/m2, 1/w, (3-8W)
Dex: 10mg/m2/d, (1-2W)
5mg/m2/d, (3-4W)
2.5mg/m2/d, (5-6W)
1.25mg/m2/d, (7W)
tapered stop (8w)
CsA: Start at week 1 (6mg/kg to start), maintain blood concentration at 200ng/ml.
Sheath injection: MTX+Pred dose. CSF examination evaluation at diagnosis and at the 2nd week of treatment. If the patient has clinical symptoms or cerebrospinal fluid abnormalities after 2 weeks, sheath injection will be performed every 4 weeks.
2.Maintenance treatment (9-40 weeks)
VP16: 150mg/m2, 1/2w
Dex: 10mg/m2, 1/2w (for 3 days)
CsA: maintenance drug, maintain blood concentration of 200ng/ml.
III. Criteria for judging disease status
1. Chemotherapy is effective (judged at 2w and 4w after chemotherapy, respectively, to decide whether to continue chemotherapy or change the treatment plan)
(1) Fever subsides
(2) Spleen shrinkage
(3) Plt≥100*109/L
(4) Normal Fib
(5) Fer decreased ≥ 25%
2.Complete remission
(1) Fever remission
(2) No splenomegaly (some patients can be mildly enlarged)
(3) No hematocrit (Plt≥100*109/L, Hb≥90g/L, ANC≥0.5*109/L)
(4) TG<3mmol/L
(5) Fer<500ug/L
(6) CSF turns to normal (previously positive)
(7) Decrease in soluble CD25 (those who can be detected)
3.Disease activity
Those who do not meet the above criteria for complete remission
4.Recurrent disease
CR followed by 3 or more of the following 8 conditions
(1) Fever
(2) Splenomegaly
(3) Plt<100*109/L
(4) TG≥3mmol/L
(5) Fib≤1.5g/L
(6) Presence of hemophilia
(7) Soluble CD25 ≥ 2400 U/ml
(8) Fer level rises again
The presence of CNS symptoms can be used as a single indicator of recurrent disease!
IV. Transplantation treatment
1.Transplantation treatment indications: primary (familial) HLH, severe/continued non-remitting non-FHL, or non-FHL in remission with 8 weeks initial treatment and relapse during observation.
2.Transplantation treatment plan
(1) Donor: Sibling BMT/PBSCT, allogeneic unrelated donor, haploidentical donor, cord blood (non-depleted T)
(2) Pretreatment regimen: Bu/Cy+VP16
Bu: 2mg/kg,po; 1.6mg/kg,iv; bid, d-8~-5
VP16: 30mg/kg,iv, 6H(max1800mg), d-4
Cy: 60mg/kg,iv, 1H, d-3~-2
(3) GVHD prophylaxis: CsA+sMTX(+1, +3, +6)
For cord blood transplant recipients or those with abnormal liver function, replace MTX with MMF, 15mg/kg, bid; start application on day 0 and discontinue after 40 days.
For unrelated donor transplants, add ATG.