Treatment of canine malignancies by 1200 R total body irradiation and autologous marrow grafts.

Twenty-five dogs with malignant lymphoma (L) and 18 dogs with solid, nonhematologic tumors (ST) were treated with 1200 R total body irradiation (TBI). Rescue from the otherwise lethal hemopoietic toxicity by infusion of autologous marrow aspirated before TBI was attempted, and survival, response to TBI, and immune reactivity post-grafting were determined. Eight L dogs survived more than 14 days post TBI and marrow grafting, and 12 out of 19 evaluable dogs showed a decrease of 75 per cent or more in clinically detectable tumor. There was no evident relationship between clinical status or marrow status before TBI and survival of more than 14 days or tumor response to TBI. Seven of the 8 survivors ultimately developed recurrent tumor. Eight ST dogs survived more than 14 days. Only 4 of 14 evaluable ST dogs showed significant clinical response of their tumor to TBI. Humoral and cellular immune reactivity were significantly impaired during the 10-week period following TBI and marrow grafting in all dogs studied. These results indicate that therapy in addition to lethal doses of TBI is necessary to cure spontaneous L or to significantly affect ST in dogs. They also provide baseline data which are necessary to assess the immunotherapeutic effectiveness of allogeneic marrow grafts.

Marrow grafts between DLA-identical and homozygous unrelated dogs: evidence for an additional locus involved in graft-versus-host disease.

Marrow transplants were carried out between unrelated donor-recipient pairs of dogs that were homozygous and identical for DLA-A, B, C, and D, i.e., mutually nonreactive in mixed leukocyte culture. Recipients were conditioned for transplantation by 1,200 R of total body irradiation and then treated with intermittent methotrexate for 102 days in order to prevent or delay graft-versus-host disease (GVHD). Of 13 dogs that received transplants, 4 are surviving with good grafts and no GVHD for more than 12 to 20 minutes. Nine died, 6 with GVHD between days 26 and 141, 1 with wasting on day 65, 1 with interstitial pneumonia on day 83, and 1 with graft rejection on day 23. In comparison, the survival of 17 DLA-identical littermates treated in the same manner was significantly better with 16 surviving without GVHD (P less than 0.01), while the survival of 54 DLA-nonidentical littermates was significantly worse with only two surviving without GVHD (P less than 0.025). These results are incompatible with the concept that solely the loci detected by mixed leukocyte culture and serotyping are responsible for GVHD. One or more additional loci appear to be involved. Knowledg e of this locus (loci) is important if marrow grafting between unrelated individuals is to be successful. However, results also indicate that an unrelated "compatible" marrow graft is more likely to succeed than a graft from an incompatible littermate.

Marrow grafts between canine litter-mates homozygous or heterozygous for lymphocyte-defined histocompatibility antigens.

Hemopoietic grafts following 1,200 R of total body irradiation were carried out between canine littermates homozygous or heterozygous for lymphocyte defined (LD) antigens of the major histocompatibility complex (MHC). In all but five of the 25 pairs studied, LD homozygous dogs were also homozygous for serologically defined (SD) antigens of the MHC. Results of transplants were compared with previous results obtained in littermate pairs matched or mismatched for the MHC. Two groups of recipients were studied. Of 14 LD homozygous recipients in group 1 given grafts from LD heterozygous donors, 12 died between 8 and 193 days and two survived more than 238 and 627 days. The most frequent cause of death was graft-versus-host disease (GVHD). Survival was significantly shorter (P less than 0.005) than that of dogs given grafts from matched littermates and not different (P congruent to 0.5) from that of dogs given grafts from mismatched littermates. Survival of 11 LD heterozygous recipients in group 2 given grafts from LD homozygous donors was not different from that of dogs in group 1 (P congruent to 0.5). The results indicate that the LD loci detected by mixed leukocyte culture are not the principal determinants within the MHC that are responsible for GVHD.

Intensive chemotherapy and autologous peripheral blood stem cell transplantation in a patient with persistent marrow involvement with Hodgkin's disease.

A patient with refractory Hodgkin's disease whose persistent, dense marrow infiltration precluded autologous marrow harvest underwent peripheral blood stem cell harvest followed by intensive chemotherapy and re-infusion of the peripheral blood stem cells. Complete remission was followed by relapse 6 months later and death 13 months post-transplant. However, at no time post-transplant was evidence of marrow recurrence demonstrated. This case indicates that remission can be achieved using peripheral blood stem cell transplants despite persistent marrow involvement with Hodgkin's disease.

Multiple tumors after androgen therapy.

A case of multiple small well-differentiated hepatomas with early peliosis hepatis, multiple pancreatic islet cell tumors, and a renal medullary interstitial cell tumor following five years of androgen and prednisone therapy for idiopathic aplastic anemia is reported in a patient who died shortly after allogeneic bone marrow transplantation. The hepatic tumors were well differentiated, and the pancreatic tumors were of mixed ribbon and islet cell pattern. Therapeutic and experimental implications and the relevant literature are briefly summarized.

Marrow transplantation in aplastic anemia and leukemia.

Human marrow transplantation has resulted in observations of fundamental significance in understanding both aplastic anemia and acute leukemia. For example, the observation that transplanted marrow can grow successfully in patients with aplastic anemia indicates that the disease is due to a defect in the marrow precursor cells and not in the marrow microenvironment. Similarly, the observation of recurrent leukemia in donor cells has important implications. Nonetheless, marrow transplantation is sufficiently established therapeutically to be considered the treatment of choice for patients with severe aplastic anemia, and a realistic alternative for patients with recurrent acute leukemia. We suggest that patients be managed with regard to marrow transplantation according to the general approach outlined in Table 3. Marrow transplantation and histocompatibility typing are available at increasing numbers of institutions throughout the world. More and more patients with either severe aplastic anemia or recurrent acute leukemia should have marrow transplantation available to them when it is indicated as part of optimal management of these no longer hopeless diseases.