E. Donnall Thomas

SUPRALETHAL WHOLE BODY IRRADIATION AND ISOLOGOUS MARROW TRANSPLANTATION IN MAN

Leukemia has been studied in two sets of identical two. One leukemic twin was irradiated with 850 r and the other with 1,140 r from Co/sup 60/ sources. Each was then given bone marrow from the respective normal twin. Successful transplantation of this isologous marrow was determined by the return of morrow function, evident after less than two weeks, and by a benign clinical course following radiation. Leukemia recurred after remissions of seven weeks in one case and 12 weeks in the other. From these two patients it was concluded that transplants of isopogous marrow are readily achieved in man; one thousand r of whole-body radiation does not produce troublesome acute radiation sickness in man when given at a rate of 20 to 40 r per hour; whole-body irradiation at the 1,000 r level produces a remission but not a cure of leukemia when followed by isologous marrow. (auth)

Transplantation of Marrow from an Unrelated Donor to a Patient with Acute Leukemia

MARROW transplantation between genotypically HLA-identical siblings has an established and expanding place in the management of leukemia and aplastic anemia.1 2 3 The majority of patients, unfortun...

A Comparison of Marrow Transplantation with Chemotherapy for Children with Acute Lymphoblastic Leukemia in Second or Subsequent Remission

The progress of 24 children with acute lymphoblastic leukemia treated with cyclophosphamide, total-body irradiation, and marrow transplantation during a second or subsequent remission was compared with that of 21 children treated with conventional chemotherapy after they had entered a second remission. Eleven of the transplantation group are alive, including nine in continuing complete remission for 17 to 55 months; only two of the chemotherapy group are alive, one in complete remission after 20 months. Relapse was the major cause of failure in both groups. Acute and chronic graft-versus-host disease in the transplantation group and leukoencephalopathy in both groups were the other major causes of morbidity and mortality. This study demonstrates that marrow transplantation currently offers the best chance of long-term remission and potential cure after a child with acute lymphoblastic leukemia has had a relapse in the marrow.

The Effect of Granulocyte Transfusions on the Incidence of Cytomegalovirus Infection After Allogeneic Marrow Transplantation

The association of granulocyte transfusions with cytomegalovirus infection and interstitial pneumonitis in allogeneic marrow transplant recipients was reviewed. Data from 387 patients with aplastic anemia or acute leukemia receiving transplants from human leukocyte antigen-matched siblings were analyzed. Acquisition of cytomegalovirus infection was higher in recipients of prophylactic and therapeutic granulocytes than in control subjects. The incidence was significantly different, however, only in cytomegalovirus seronegative patients who received granulocytes from seropositive granulocyte donors. There was no significant increase in the total incidence of or mortality from all forms of interstitial pneumonitis.

Cytomegalovirus Pneumonia After Human Marrow Transplantation

Thirty-three of 85 patients undergoing marrow transplantation between 1969 and 1973 developed interstitial pneumonia; 23 died. The clinical syndrome consisted of tachypnea, cough, fever, rales, and hypoxemia; the radiologic findings were variable. The development of interstitial pneumonia was significantly associated with graft-versus-host disease and allogenic grafting; patients with isogenic grafts were relatively spared. The increased attack rate between 1969-71 (20%) and 1972-73 (49%) was not fully explained by improved long-term survival, by an increased proportion of allogenic transplants, or by an increased incidence of graft-versus-host disease. Intranuclear inclusions typical of cytomegalovirus were identified in 9 of 17 autopsy-confirmed cases, and patients whose marrow donors had positive cytomegalovirus antibody titers developed interstitial pneumonia more often than patients whose donor had negative titers. Interstitial pneumonia is an important cause of morbidity and mortality after human marrow transplantation. No effective treatment is presently available.

Infection Due to Corynebacterium Species in Marrow Transplant Patients

A Corynebacterium species consistently resistant to all antibiotic therapy except vancomycin caused bacteremia in 32 of 284 (11%) marrow transplant patients. Twenty-one patients had colonization or infection before bacteremia. Twenty-six of the 32 patients were males, and males older than 16 years were infected significantly more often than females over 16, or than all patient under 16. A case-control study showed that infected patients had greater exposure to antibiotics; more often had failure of engraftment and persistent granulocytopenia; were in laminar air-flow rooms less often; and had greater inhospital mortality. Cultural surveillance showed that 17 of 42 marrow transplant patients were colonized with Corynebacterium species. Likelihood of colonization appeared related to age, sex, and duration of hospitalization. Prevalence of colonization in other populations was 1% in nonhospitalized healthy adults and 13% in adults in a general hospital. Corynebacterium species infections occur primarily in adult males with granulocytopenia, mucocutaneous defects, and receiving intensive antibiotic therapy.

Diffuse intestinal ulceration after marrow transplantation: A clinicopathologic study of 13 patients*

The cases of 13 allogeneic marrow transplant recipients who had undergone laparotomy for manifestations of severe enteritis were reviewed to determine the causes of the severe intestinal disease and to assess the relation between clinical, histologic, and microbiologic findings. Laparotomies were performed a median of 63 days (range, 11 to 273 days) after transplantation for suspected peritonitis, intestinal obstruction, or bleeding. Intestinal tissue was available from small bowel resections in nine patients, intraoperative biopsies in one, and from autopsies in three patients who died shortly after laparotomy. Widespread small bowel ulceration was present in all 13 cases. Four causes of ulceration were identified: chemoradiation toxicity (n = 2), acute graft-versus-host disease (GVHD) (n = 5), opportunistic infections superimposed on either GVHD or toxicity from chemotherapy (n = 4), and Epstein-Barr virus-associated lymphoproliferative disorder (n = 2). Intestinal infections, unrecognized before laparotomy, were due to cytomegalovirus (CMV), herpes simplex virus (HSV), adenovirus, and Torulopsis glabrata. CMV- and HSV-infected cells, often lacking diagnostic inclusions, were identified in the intestine by in situ hybridization with biotinylated DNA probes. Eleven patients died in the perioperative period, and two died 452 and 558 days after surgery of complications of chronic GVHD. Poor outcomes were related to extensive intestinal involvement, which was commonly underestimated before surgery, failure to diagnose intestinal infections early, poor marrow function, impaired immunity, and refractoriness of severe GVHD.

Bone-Marrow Transplantation for Hematologic Neoplasia in 16 Patients with Identical Twins

Abstract Sixteen patients (11 years to 67 years of age) with hematologic neoplasia refractory to conventional therapy were treated with cyclophosphamide (60 mg per kilogram per day on two occasions), a supralethal dose of total-body irradiation (1000 rads) and a bone-marrow transplant from a normal identical twin. Twelve patients also received immunotherapy consisting of subcutaneous injections of the patients own leukemia cells lethally irradiated with 10,000 rads and intravenous infusions of peripheral blood lymphocytes from the normal twin. Fourteen patients experienced complete remissions. Six patients (two with acute lymphoblastic leukemia, three with acute myelogenous leukemia, and one with lymphosarcoma-leukemia) remained in complete remission at 11 to 44 months without any maintenance chemotherapy, and two others with acute myelogenous leukemia were in complete remission at two and three months. One patient died of viral hepatitis without leukemia. Five patients relapsed at three to seven months....

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.

Cure of Hematologic Neoplasia with Transplantation of Marrow from Identical Twins

IN 1974, we reported1 on 16 patients with refractory hematologic neoplasia who were treated with high-dose cyclophosphamide, supralethal total-body irradiation, bone-marrow transplantation from a n...