Treatment of lymphohistiocytosis

In the vast majority of cases, the disease is fatal. One of the first reviews on hemophagocytic lymphohistiocytosis reported that the median survival from the onset of disease symptoms was approximately 6-8 weeks. Before the introduction of modern chemo- and immunosuppressive therapy protocols and BMT/HSCT, the median survival was 2-3 months.

According to G. Janka's data, presented in a literature review in 1983, 40 out of 101 patients died during the first month of illness, another 20 in the second month of illness, only 12% of patients lived more than six months, only 3 children survived.

The first real therapeutic success in hemophagocytic lymphohistiocytosis was the use of epipodophyllotoxin VP16-213 (VP-16) in 2 children, which allowed to achieve complete remission (1980). However, later both children developed a relapse with CNS damage, which ended in death 6 months and 2 years after diagnosis. Based on the fact that VP-16 does not penetrate the blood-brain barrier. A. Fischer et al. in 1985 conducted a combined treatment of four children with VP-16, steroids in combination with intrathecal methotrexate, or cranial irradiation. All four children were in remission at the time of publication with a follow-up of 13-27 months.

The use of high doses of epipodophyllotoxin derivatives due to the possibility of developing secondary tumors is a subject of discussion, but to date there is only one report in the literature on the development of myelodysplastic syndrome (MDS) in a child with primary hemophagocytic lymphohistiocytosis who received a total of 6.9 g / m2 of etoposide administered intravenously and 13.6 g / m2 orally, as well as 3.4 g / m ² of teniposide. In addition, the risk of dying from hemophagocytic lymphohistiocytosis is much higher than the possibility of developing a secondary tumor in the future, so etoposide remains the basic drug for the treatment of lymphohistiocytosis.

In 1993, JL Stephan reported the successful use of immunosuppressive drugs angiotensin-deficient globulin (ATG) and cyclosporine A in patients with primary lymphohistiocytosis. Remission was achieved in 5 of 6 children who received ATG and cyclosporine A, one patient died of severe progressive CNS damage. Further improvement of treatment protocols was associated with the inclusion of immunosuppressive drugs - cyclosporine A and ATG, including the latter - as one of the components (along with busulfan and cyclophosphamide) of the pretransplant conditioning regimen.

It should be noted that, despite the high probability of achieving clinical remission with the use of combined immunosuppressive therapy, individual clinical or biological signs of the disease always remain (hepato- or splenomegaly, anemia, hypertriglyceridemia, decreased activity of NK cells, increased level of activated lymphocytes in the blood, etc.), which does not allow us to talk about complete, but only partial remission of hemophagocytic lymphohistiocytosis. The only radical treatment method is bone marrow transplantation from an allogeneic donor.

Currently, two therapeutic options are proposed for induction of remission in primary hemophagocytic lymphohistiocytosis: the HLH-94 protocol, including etoposide, dexamethasone, cyclosporine A and intrathecal methotrexate, or the protocol proposed in 1997 by N. Oabado from the Necker Hospital, Paris (protocol recommended by the ESID / EBMT Working Party), including methylprednisolone, cyclosporine A, ATG and intrathecal methotrexate and depomedrol. Both protocols imply subsequent mandatory allogeneic BMT/HSCT from a related compatible or alternative - incompatible related or compatible unrelated - donor.

HLH Therapy Protocol (Nada Jabado, Hopital Necker - Enfants Halades), 1997

Since diagnosis:

1. Methylprednisolone:

• d 1 -» d 2: 5 mg/kg/day for 2 administrations (48 hours);
• d 3 -» d 4: 3 mg/kg/d (48 hours);
• d 4: 2 mg/kg/d,
• then gradual reduction until discontinuation if the disease is controlled (within 1 month).

2. ATG rabbit:

• 10 mg/kg/d daily for 5 days;
• as an intravenous infusion over 6-8 hours (50 ml of 5% glucose per 25 mg of ATG), starting on D1.

3. Cyclosporine A:

• onset 48-72 hours after the start of ATG;
• 3 mg/kg/day as a continuous intravenous infusion until a cyclosporinemia level of 200 ng/ml is achieved; oral treatment if possible.

4. Intrathecal MTX:

Doses: Age:

6 mg / 0-1 years

8 mg / 1-2 years

10 mg / 2-3 years

12 mg / 3 years

+ Depomedrol 20 mg or dexa in the appropriate dosage

4. Intrathecal therapy regimen:

• when the central nervous system is involved:
  • 2 times a week for 2 weeks
  • 1 time per week for 1 week
  • Next, adapt depending on the response: as a rule, once a week up until HSCT;
• in the absence of CNS involvement:
  • Once every 6 weeks, up to HSCT
  • Intrathecal therapy is discontinued if HSCT is not planned in the near future.
  • No more than 8 IT injections.

In 2002, the International Society for the Study of Histiocytic Diseases summarized the results of the protocol. In 88 of 113 analyzed patients, the therapy was effective: the patients survived until HSCT or remained in remission at the time of the last observation. Impressive data were published in 2006 by Chardin M et al. (a French group of researchers led by A. Fischer from the Necker-Enfants Malades hospital), concerning the analysis of the results of HSCT in 48 patients with HLH from both related and alternative donors, which were performed in their center. The overall survival was 58.5% (median follow-up 5.8 years, maximum follow-up period 20 years). According to the authors, patients in the active phase of the disease who receive HSCT from a haploidentical donor have a worse prognosis, since in these conditions HLH is associated with a higher frequency of transplant rejection. Twelve patients received 2 transplants each due to rejection (n = 7) or secondary graft loss leading to HLH relapse (n < 5). Stable remission was achieved in all patients with donor chimerism >20% (by leukocytes). It has also been repeatedly emphasized previously that for patients with HLH (unlike most other indications for HSCT), mixed chimerism is sufficient to maintain remission and prevent relapse of lymphocyte/macrophage activation syndrome. As for the late effects after HSCT, only 2 of 28 surviving patients (7%) had mild neurological disorders. This study confirms the opinion of doctors that HSCT is currently the only radical method of HLH therapy, regardless of the presence or absence of an “ideal”, i.e. HLA-compatible related donor.