L4415: further characterization of the rat model for human acute lymphocytic leukemia.

The biological properties of a transplantable lymphocytic leukemia, L4415 in the WAG/Rij rat, are described. The radiation-induced L4415 leukemia is characterized as a relatively slowly growing, non-immunogenic, immature T-cell leukemia which shows a reproducible growth pattern upon intravenous (i.v.) transfer. Survival time following i.v. inoculation is inversely related to the number of leukemic cells in the inoculum, which allows a quantitative estimate in terms of log leukemic cell kill of the effect of treatment. The first signs of leukemic growth are found in the bone marrow, the spleen, and the liver. Leukemic cells can be detected in the peripheral blood 13 days after inoculation. Due to replacement of normal hemopoietic tissue by leukemic cells and their number increasing exponentially thereafter, normal hemopoiesis is inhibited in the later stages of the disease as indicated by severe thrombocytopenia and anemia. Death is caused by a combination of splenic rupture, gastrointestinal and pulmonary hemorrhage, and impaired functions of heavily infiltrated organs. Hepatosplenomegaly and lymphadenopathy are prominent features at autopsy. Cyclophosphamide- and radiosensitivity of the clonogenic leukemic cells have been determined, a 2.9 log cell kill could be induced by single dose cyclophosphamide inoculation and a dosage giving a surviving fraction of 0.37 (D0) of 0.99 Gy with an extrapolation number (N) of 8.5 were calculated. Based on these data, the L4415 rat leukemia may be regarded as a relevant model for human acute lymphocytic leukemia and may thus serve to explore new treatment strategies.

Quantitative studies on graft-versus-leukemia after allogeneic bone marrow transplantation in rat models for acute myelocytic and lymphocytic leukemia.

The major shortcoming of present day treatment of leukemia by bone marrow transplantation (BMT) remains leukemia relapse. It has become clear that a graft-versus-host reaction (GVHR) is accompanied by a graft-versus-leukemia reaction (GVLR) which may prevent leukemia relapse. In two non-immunogenic rat leukemia models, the Brown Norway acute myelocytic leukemia (BNML) and the WAG/Rij acute lymphocytic leukemia L4415, total body irradiation (TBI) was given to induce 'minimal residual disease' (MRD). Subsequently, it was attempted to evoke a GVLR by using syngeneic or allogeneic BMT, with or without addition of graded numbers of lymphocytes. In both leukemia models the addition of high numbers of syngeneic lymphocytes to the syngeneic graft had no antileukemic effect. Allogeneic marrow grafts, which contain at the most 8% lymphocytes, only resulted in a GVLR when splenocytes were added. The therapeutic window was found to be narrow, i.e. in fully mismatched BMT the number of allogeneic splenocytes resulting in a significant GVLR (2-3 log leukemic cell kill) without inducing (lethal) acute GVHD was critical. Increasing the number of allogeneic spleen cells added to the allogeneic BM graft induced lethal acute GVHD. To date, our data indicate that the GVLR is an allogeneic effect, inseparable from GVHD.