Search

Familial hemophagocytic lymphohistiocytosis (FHL) is a potentially fatal disease characterized by diffuse infiltration by histiocytes and T lymphocytes. Treatment with myelotoxic drugs, such as etoposide, brings about remission in most patients, but problems of toxicity remain, and the development of disease resistance can cause secondary relapses. We have used an alternative approach, based on the suggested primary role of T-cell activation in FHL, comprising combined treatment with steroids (2 to 5 mg/kg/d methylprednisolone intravenously, followed by progressive tapering) and rabbit antithymocyte globulins (10 mg/kg/d for 5 days), followed by maintenance therapy with cyclosporine A (CSA). In a pilot study of six patients (four with a family history of FHL), all showed systemic remission within 7 days, which was complete in five cases; despite treatment with intrathecal methotrexate, one patient died of severe brain involvement. Two patients received T-cell--depleted HLA--non-identical bone marrow transplants, which was successful in one case. The other three patients, who have been on CSA maintenance therapy for periods of 6 to 24 months, are in complete remission. We have observed no side-effects (there has been no persisting T-cell immunodeficiency). These results suggest that nonmyelotoxic treatments for FHL may be safe, effective, and worthy of further investigation; they also support the key role of T lymphocytes in the disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematological malignancies or inherited disorders. In the partially incompatible HLA setting, ex vivo T-cell depletion of the graft and post-transplantation immunosuppression effectively prevent development of graft-versus-host-disease (GVHD), but lead, in turn, to a delay in immune reconstitution and a concordant increase in the rate of incidence of opportunistic infections and disease relapse. In order to selectively deplete T cells responsible for GVHD, we have designed an ex vivo procedure to eliminate CD25 expressing alloactivated donor T cells. In a first phase I/II study based on the use of an anti-CD25 immunotoxin (IT) 15 pediatric patients with acquired or congenital hematopoietic disorders who had received HSCT were infused with 1 to 8x105 allodepleted T cells/kg. No cases of severe acute (>grade II) GVHD occurred. aGVHD of grade I or II, which developed in four patients, correlated with anti-host residual proliferation above 1% in a mixed lymphocyte reaction. Evidence for early T cell expansion was shown in 3 patients with ongoing viral infections. In an attempt to improve allo-depletion and infuse larger numbers of cells, we have developed a new method based on immuno-magnetical depletion of CD25 expressing cells. In pre-clinical tests, this method lead to a more specific and efficient allo-depletion than that obtained with IT. This new procedure is currently used in a phase I/II clinical trial that will include 25 pediatric patients with inherited disorders of the immune system. 3x105 to 5x106 allo-depleted donor T cells/kg will be infused, with three to five patients per dose. Allodepleted donor T cells are cryopreserved until the obtention of quality control results Inclusion, i.e. infusion of allodepleted T cells is performed only if:1) engraftment is proven, 2) absence of GVHD 3)residual antithymoglobulin <0.2microg/ml,4) allodepletion inhibition more than 99% of residual proliferation against host cells in a mixed lymphocyte reaction. Included patients will be stratified in two groups depending on the presence or absence of a viral infection with clinical symptoms. Toxicity is evaluated by occurrence of aGVHD above grade II. Efficacy is measured by CD4+CD3+ T cell counts in the blood two months post HSCT. A real time bayesian statistical approach will allow to test both criteria as primary objectives and to increase or decrease the dose according to the results obtained. Two patients have been so far included in the “infected” group and infused with 3x105 allodepleted T cells/kg. One patient developed grade II cutaneus GVHD. For both, efficacy was reached, since they presented more than 200 CD4+CD3+ T cells /mm3 as early as 60 days post HSCT. These preliminary results are encouraging but need to be further confirmed.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematological malignancies or inherited disorders. In the partially incompatible HLA setting, ex vivo T-cell depletion of the graft and post-transplantation immunosuppression effectively prevent development of graft-versus-host-disease (GVHD), but lead, in turn, to a delay in immune reconstitution and a concordant increase in the rate of incidence of opportunistic infections and disease relapse. In order to selectively deplete T cells responsible for GVHD, we have designed an ex vivo procedure to eliminate CD25 expressing alloactivated donor T cells. In a first phase I/II study based on the use of an anti-CD25 immunotoxin (IT) 15 pediatric patients with acquired or congenital hematopoietic disorders who had received HSCT were infused with 1 to 8x105allodepleted T cells/kg. No cases of severe acute (>grade II) GVHD occurred. aGVHD of grade I or II, which developed in four patients, correlated with anti-host residual proliferation above 1% in a mixed lymphocyte reaction. Evidence for early T cell expansion was shown in 3 patients with ongoing viral infections. In an attempt to improve allo-depletion and infuse larger numbers of cells, we have developed a new method based on immuno-magnetical depletion of CD25 expressing cells. In pre-clinical tests, this method lead to a more specific and efficient allo-depletion than that obtained with IT. This new procedure is currently used in a phase I/II clinical trial that will include 25 pediatric patients with inherited disorders of the immune system. 3x105to 5x106allo-depleted donor T cells/kg will be infused, with three to five patients per dose. Allodepleted donor T cells are cryopreserved until the obtention of quality control results Inclusion, i.e. infusion of allodepleted T cells is performed only if:1) engraftment is proven, 2) absence of GVHD 3)residual antithymoglobulin <0.2microg/ml,4) allodepletion inhibition more than 99% of residual proliferation against host cells in a mixed lymphocyte reaction. Included patients will be stratified in two groups depending on the presence or absence of a viral infection with clinical symptoms. Toxicity is evaluated by occurrence of aGVHD above grade II. Efficacy is measured by CD4+CD3+ T cell counts in the blood two months post HSCT. A real time bayesian statistical approach will allow to test both criteria as primary objectives and to increase or decrease the dose according to the results obtained. Two patients have been so far included in the “infected” group and infused with 3x105allodepleted T cells/kg. One patient developed grade II cutaneus GVHD. For both, efficacy was reached, since they presented more than 200 CD4+CD3+ T cells /mm3as early as 60 days post HSCT. These preliminary results are encouraging but need to be further confirmed.