Robert H. Rudolph

High‐dose cyclophosphamide therapy for malignant disease. Toxicity, tumor response, and the effects of stored autologous marrow

Twenty‐five patients with disseminated malignant disease received single or multiple courses of cyclophosphamide (CY) 60 to 120 mg/kg. Stored autologous marrow was infused following 120 mg/kg of CY in 6 instances. One patient received 240 mg/kg of CY over a 4‐day period followed by autologous marrow infusion. Patients receiving 60 mg/kg showed a moderate leukopenia (mean nadir of 500/mm3), anemia (mean hematocrit decline of 8.2 vol%) and variable thrombocytopenia that ranged from no change to 34,000/mm3 with a mean nadir of 127,000/mm3. Increasing the dose to 120 mg/kg produced leukopenia to below 500 cells/mm3 with a mean nadir of 120 cells/mm3. Thrombocytopenia was severe with a mean nadir of 37,000/mm3. Hematocrit values in this group fell by 15.2 vol%. Infectious complications occurred following 1 of 10 courses at 60 mg/kg and 18 of 35 courses at 120 mg/kg. In the latter group, there were 7 episodes of septicemia including one death from pseudomonas septicemia. A second patient, with cerebral metastases, died of a CNS hemorrhage. The patient receiving 240 mg/kg died as a consequence of myocardial necrosis. The infusion of autologous marrow had no apparent effect on hemopoietic recovery or infectious complications. Of the responding patients, 3 had ovarian carcinoma, 3 had testicular tumors, 1 had adenocarcinoma of the bowel, and 1 had an undifferentiated malignancy.

Marrow Grafts Between Dl-a-matched Canine Littermates

SUMMARY Three groups of recipient dogs were conditioned for transplantation by supralethal exposure to total body irradiation from dual 60Co sources and then given hemopoietic grafts from DL-A-matched littermates. Group 1 consisted of 17 dogs given marrow cells only and not treated with immunosuppressive therapy postgrafting. Group 2 was made up of 11 dogs given a combination of marrow and peripheral blood leukocytes and no postgrafting immunosuppression. Group 3 included 13 dogs given a combination of marrow and peripheral blood leukocytes and intermittent methotrexate (MTX) therapy for 102 days postgrafting. Nine of the 17 recipients in group 1 died between 30 and 230 days after grafting with graft-versus-host (GVH) disease. Eight recipients survived beyond 230 days without GVH disease. Seven of 11 recipients in group 2 died with GVH disease after 12–151 days and 4 survived beyond 200 days. One dog in group 3 died on day 61, and 12 survived beyond 200 days without evidence of GVH disease. Thus, fatal GVH disease was seen in a number of canine recipients not given postgrafting immunosuppression despite DL-A matching with their littermate donor. The addition of peripheral blood leukocytes to the marrow inoculum did not significantly change the overall survival but increased the severity of GVH disease. Therapy with intermittent MTX postgrafting significantly prolonged survival (P < 0.01) and resulted in the establishment of stable graft-host “tolerance” in most DL-A-matched recipients.

Allogeneic Marrow Engraftment Following Whole Body Irradiation in a Patient with Leukemia

A 46-year-old man with blastic crisis of chronic myelogenous leukemia was given 950 rads whole-body irradiation followed immediately by 17.6 x 109 marrow cells. The marrow donor was the patients sister who matched the patient in 11 of 12 HL-A groups and whose leukocytes reacted to the patients leukemic cells in mixed leukocyte culture. The patients white blood cell count began to go up on the 13th day and marrow engraftment was confirmed by repeated cytogenetic analyses. Secondary disease with skin rash and diarrhea was evident by the end of the second week but appeared to be controlled by methotrexate. The patient then developed fever, recurrent diarrhea and pneumonitis and died 56 days after irradiation. Autopsy showed inclusion bodies typical of cytomegalovirus. There was no histological evidence of acute secondary disease nor of leukemia.

Allogeneic canine bone marrow transplantation following cyclophosphamide

Allogeneic bone marrow transplantation following a lethal dose of cyclophosphamide was studied in 20 donor-recipient pairs of dogs. Eighteen of these were littermate pairs matched with four canine histocompatibility typing sera, and two were pairs of unrelated mismatched dogs. Ten dogs died in the 1st week from infection, bleeding, and nonhemopoietic drug toxicity. Their survival was too short to evaluate the success or failure of the marrow graft. Evidence for allogeneic bone marrow engraftment was demonstrated in 8 of the 10 recipients that lived beyond 7 days. Five of the dogs with marrow engraftment died within 36 days, 1 with evidence of graft-versus-host disease, 1 with pneumonia, and 3 after rejection of the marrow graft. Three of the 8 dogs with marrow grafts became long-term chimeras. Two are alive 350 and 450 days after transplantation. Peripheral blood, bone marrow, and lymph nodes in these 2 dogs showed a mixed population of host and donor cells. One additional dog survived over 8 months with evidence of a persistent change to donor red cell type and with prolonged survival of a skin graft from the marrow donor. In addition, this dog developed an isoantibody against the former host red cell type. It was concluded that persistent hemopoietic chimerism can be obtained in outbred animals following a lethal dose of cyclophosphamide.

Salvage therapy with whole‐abdominal irradiation in patients with advanced carcinoma of the ovary previously treated by combination chemotherapy

Whole‐abdominal irradiation was delivered to 22 patients with epithelial carcinoma of the ovary who had persistent disease after chemotherapy. Seventeen patients were treated with an open whole‐abdominal field and 5 with the moving‐field technique. Eleven of the 22 also received a pelvic boost. Two of nine patients with microscopic disease at second look are alive and disease‐free at 34 and 52 months, respectively. There were no salvages among the patient with macroscopic disease. Major complications included bowel obstruction in three patients and radiation enteritis in one patient. Whole‐abdominal irradiation is not an effective salvage regimen after multiagent chemotherapy.

Angioimmunoblastic lymphadenopathy: Clinical spectrum of disease

The clinical features of 13 patients with angioimmunoblastic lymphadenopathy were analyzed to determine prognostic factors and response to therapy. Eleven patients presented with sudden onset of fever, weight loss, generalized lymphadenopathy, and hepatosplenomegaly. Laboratory features included autoimmune hemolytic anemia and polyclonal hypergammaglobulinemia. Pulmonary involvement was seen in six cases and skin rash in four. Two patients had localized lymphadenopathy without systemic symptoms. Both are alive at 5.5 and 2.5 years, respectively, after diagnosis, although the latter patient has required intermittent prednisone for recurrent lymphadenopathy. An additional patient is alive on treatment four months following diagnosis. The remaining ten have died, nine of sepsis and one of cerebral hemorrhage. The immunosuppression and myelosuppression of combination chemotherapy may have hastened their deaths. An individualized, conservative treatment approach is recommended.

Mixed leukocyte reactivity and leukemia: study of identical siblings

This report describes a search for tumor-specific transplantation antigens in man by testing four sets of identical siblings using the mixed leukocyte transformation reaction. In each case, one member of the set had acute leukemia in relapse. In no instance did the leukemic cells of the patient stimulate the cells of the normal twin, nor did cells from the normal twin stimulate cells from the leukemic patient. Possible explanations for the failure to detect a leukemia-associated antigen in these studies are discussed.

CANINE MIXED LEUKOCYTE REACTIVITY AND TRANSPLANTATION ANTIGENS

SUMMARY A mixed leukocyte culture method was adapted for study of canine cells. The uptake of tritiated thymidine by reacting cells was measured following stimulation by cells inactivated by radiation. The results of histoeompatibility typing with this method bore a significant correlation (P < 0.01) to results obtained from typing with four cytotoxic antisera known to identify important transplantation antigens in this species.

Combined modality therapy for advanced, diffuse lymphocytic and histiocytic lymphomas

Forty‐six previously untreated patients with advanced aggressive non‐Hodgkins (34 poorly differentiated and mixed diffuse, 8 histiocytic and 4 undifferentiated) were treated with a 3 phase combined modality program employing cyclophosphamide (C), hydroxyl‐daunomycin (H), vincristine (O), prednisone (P), procarbazine (P) [CHOP(P)] combination chemotherapy in an initial induction phase, radiotherapy and nonmarrow toxic chemotherapy as a second consolidation phase, followed by a third phase of CHOP(P) chemotherapy for four more cycles. Long‐term maintenance therapy was not given. High dose involved field radiation in phase II was limited to volumes encompasing less than 50% of the marrow bearing skeleton. The large majority of patients (82%) had such widespread involvement that this limitation precluded the use of local radiation and were treated instead with a mean of 132 rad of fractionated total body irradiation (TBI). Thirty‐eight patients (83%) achieved complete remission. Twenty‐nine (66%) of the 44 patients evaluable for follow‐up, and 22 (61%) of the 36 patients receiving TBI, remain alive in complete remission for observation periods of up to 26 months. Cancer 42:1697–1704, 1978.

Histocompatibility studies in patients with trophoblastic tumors

Abstract The degree of histocompatibility of 3 women with trophoblastic tumors was evaluated with respect to 14 of their children. In one-way mixed leukocyte cultures, cells from all 14 of the children stimulated their mothers lymphocytes, indicating the presence of antigenic differences. However, leukocyte serotyping showed 6 children whose cells possessed only antigens that were present on their mothers leukocytes. Thus, in these 6 cases, there were antigenic differences between mother and child not detected with available antisera. The results of this study are not consistent with the hypothesis that the survival and dissemination of postgestational choriocarcinoma is dependent upon a high degree of histocompatibility between the malignant graft and the maternal host.