Treatment of lymphogystyocytosis

In the vast majority of cases, the disease is fatal. In one of the first reviews on hemophagocytic lymphogystyocytosis, it was reported that the average life expectancy from the onset of the first signs of the disease is approximately 6-8 weeks. Before the introduction of modern protocols of chemo- and immunosuppressive therapy and TCM / TSCA, the average life expectancy was 2-3 months.

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

The first real therapeutic success in hemophagocytic lymphogystyocytosis was the use of epipodophyllotoxin VP16-213 (VP-16) in 2 children, which allowed complete remission (1980). However, in the future, both children developed a relapse with CNS damage, which ended in a lethal outcome after 6 months and 2 years after the diagnosis. Proceeding from the fact that VP-16 does not penetrate the blood-brain barrier. A. Fischeretal. In 1985, combined treatment of four children VP-16, steroids in combination with intrathecal administration of methotrexate, or cranial irradiation. All four children at the time of publication were in remission with a catamnesis of 13-27 months.

The subject of discussion is the use of large doses of epipodophyllotoxin derivatives because of the possibility of developing secondary tumors, but to date there is only one report on the development of myelodysplastic syndrome (MDS) in a child with primary hemophagocytic lymphohistiocytosis who received a total of 6.9 g / m2 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 lymphogystyocytosis is much higher than the possibility of obtaining a secondary tumor in the future, so etoposide remains the base drug for the treatment of lymphogystiocytosis.

In 1993, JL Stephan reported on the successful use of immunosuppressive preparations of angiotymocyte globulin (ATG) and cyclosporin A - in patients with primary lymphohystiocytosis. In 5 of the 6 children who received ATG and cyclosporin A, a remission was obtained, one patient died of severe progressive CNS lesion. Further improvement of treatment protocols was associated with the inclusion of immunosuppressive drugs - cyclosporin A and ATG, including the latter as one of the components (along with busulfan and cyclophosphamide) of the pre-transplant conditioning regime.

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 (hepatoma or splenomegaly, anemia, hypertriglyceridemia, decreased activity of NK cells, increased level of activated lymphocytes in the blood, etc. .), which does not allow to talk about complete, but only partial remission of hemophagocytic lymphogystyocytosis. The only radical therapeutic method is a bone marrow transplant from an allogeneic donor.

Currently, two therapeutic options are proposed for the induction of remission of primary hemophagocytic lymphogystyocytosis: 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 ESID / EBMT Working Party), including methylprednieolone, cyclosporin A, ATG and intrathecal methotrexate and depomedrol. Both protocols imply the subsequent mandatory allogeneic TCM / HSC from a related compatible or alternative - an incompatible related or compatible unrelated donor.

Protocol for the therapy of HLG (Nada Jabado, Hopital Necker - Enfants Halades), 1997

From the moment of diagnosis:

1. Methylprednisolone:

• d 1 -> d 2: 5 mg / kg / d for 2 injections (48 hours);
• d 3 - »d 4: 3 mg / kg / d (48 hours);
• d 4: 2 mg / kg / d,
• then a gradual decrease until the cancellation if there is disease control (within 1 month).

2. ATG rabbit:

• 10 mg / kg / d daily for 5 days;
• in the form of IV infusion for 6-8 hours (50 ml of glucose 5% per 25 mg of ATG), beginning in D1.

3. Cyclosporin A:

• beginning 48-72 hours after the onset of ATG;
• 3 mg / kg / d in the form of long-term intravenous infusion before reaching the level of cyclosporinemia 200 ng / ml; treatment per os - whenever 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 as appropriate. Dosage

4. Mode of intrathecal therapy:

• with involvement of the central nervous system:
  • 2 times a week for 2 weeks
  • 1 time per week for 1 week
  • Further - to adapt depending on the answer: as a rule, 1 time a week up to TGSK;
• in the absence of CNS involvement:
  • 1 every 6 weeks, up to the TSCC
  • Intrathecal therapy is canceled if TSCC 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 out of 113 patients analyzed, therapy was effective: patients survived until TSCT was performed 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 TSCC in 48 patients with HLG both from the related and alternative donor who were conducted at their center. Overall survival was 58.5% (median follow-up of 5.8 years, maximum follow-up is 20 years). According to the authors, patients in the active phase of the disease who receive TSCS from a haploidentical donor have a worse prognosis, because under these conditions, GLG is associated with a higher incidence of graft rejection. Twelve patients received 2 transplantations due to rejection (n = 7), or a secondary loss of the graft, which resulted in a recurrence of GLH (n <5). Stable remission was achieved in all patients with donor chimerism> 20% (by leukocytes). Previously, it has also been repeatedly emphasized that for patients with HLG (unlike most other indications for HSCT) mixed chimerism is sufficient to maintain remission and the absence of a renewal of the lymphocyte / macrophage activation syndrome. With respect to long-term effects after TSCC, only 2 out of 28 surviving patients (7%) have neuronal neurological disorders. This study confirms the opinion of doctors that TSCC is by far the only radical method for the therapy of HLG, regardless of the presence or absence of an "ideal", that is, an HLA-compatible, related donor.