Transplantation of T-lymphocyte-depleted bone marrow between HLA-mismatched individuals.

Four patients with acute leukemia received transplants from HLA-mismatched, related donors. Marrow cells that had been depleted of T lymphocytes using a monoclonal anti-T-lymphocyte antibody and rabbit complement were used. In vitro studies showed that 80-97% of the mature T lymphocytes were removed using this procedure. Infusion of the treated marrow was accomplished without complications, and engraftment occurred in each case. Graft-versus-host disease occurred in 3 of the 4 patients. These results show that additional manipulations of the marrow will be required to allow complete T lymphocyte removal from the marrow before the feasibility of this approach in HLA-mismatched patients can be determined.

Syngeneic bone marrow transplantation in a patient with metastatic neuroblastoma refractory to conventional therapy.

A child with metastatic neuroblastoma refractory to conventional chemotherapy was treated with lethal doses of chemotherapy and total body irradiation followed by syngeneic bone marrow transplantation. A complete remission was achieved. However, the tumor recurred after six months, and the patient succumbed to disseminated neuroblastoma nine months after marrow grafting.

Bone marrow transplantation. I. Use in neoplastic diseases.

Over the last decade, bone marrow transplantation has been employed with increasing frequency in an attempt to treat a variety of malignant processes--including acute and chronic leukemia, lymphomas, and a variety of solid tumors. This review attempts to summarize the progress that has been made over the last 10 years in applying bone marrow transplantation to the treatment of these diseases. Some of the limitations of the procedure will be discussed, as well as some of the possible techniques for overcoming these limitations. Future sections will deal with the application of bone marrow transplantation to nonmalignant disorders and to a general discussion of the complications of the procedure as it applies to both malignant and nonmalignant diseases. Some of the recent advances in marrow transplantation technology will also be reviewed.

Bone marrow transplantation. II. Use for aplastic anemia, hereditary diseases, and hemoglobinopathies.

Severe aplastic anemia has had a uniformly poor prognosis and is another area in which bone marrow transplantation has been performed in large numbers of patients. Graft rejection has proven to be a significant problem which has been successfully reduced by a variety of modalities which will be discussed. Over the past decade, clinical results have continued to improve, mostly as a result of the reduction in the rate of graft rejection. Immunotherapy with antithymocyte globulin, however, has recently been shown to be at least partially effective in this same group of patients. The clinical results and its role in the treatment of this disorder will also be discussed. A large number of congenital and hereditary disorders have been also successfully treated with bone marrow transplantation and, recently, severe beta thalassemia has been approached with this modality in a single patient. This is obviously an extremely large and heterogeneous group of disorders and few patients in any single category have been transplanted.

Bone marrow transplantation. III. Major problems and future directions.

In parts I and II, the applications of bone marrow transplantation to the treatment of neoplastic and non-neoplastic disorders have been discussed. In addition, problems which are unique to each of these areas have been presented. This final section addresses the problems that are common to both areas which include the problems of graft-versus-host disease and infection. Both experimental and clinical approaches to these areas will be presented and some of the newer approaches for controlling these problems will be discussed. Finally, the major challenges for the future will be presented.

Burkitt lymphoma in an American infant under one year of age, with electron microscopic examination of the tumor.

Burkitt lymphoma in the United States has not been reported in a child under the age of one year. We report here a nine-month-old child who had facial involvement and a rapidly downhill course. This occurred despite an early response to combination chemotherapy and vigorous supportive measures. Electron microscopic examination of the tumor is also presented.

Ovarian germ cell tumor evolving to myelodysplasia.

We present the case of a 14-year-old girl in whom a myelodysplastic syndrome was diagnosed 9 months after surgical resection and chemotherapy for an ovarian germ cell tumor. Cells from her marrow were characterized by trisomy 8 and an isochromosome 12p, a marker that appears to be unique to germ cell tumors. The presence of the same two anomalies in her original tumor was demonstrated by fluorescence in situ hybridization study of interphase cells in paraffin-embedded tissues and thus provided strong evidence that the two neoplasms had a common clonal origin.

Progressive ascending paralysis following administration of intrathecal and intravenous cytosine arabinoside. A Pediatric Oncology Group study.

Two childhood acute myelogenous leukemia (AML) patients receiving intrathecal (IT) and intravenous (IV) cytosine arabinoside (Ara-C) developed progressive ascending paralysis, resulting in death in one patient. Necropsy findings on this patient included spinal cord demyelination characteristic of Ara-C neurotoxicity. An unusual aspect of these two cases was the delay between cessation of IT therapy and the onset of neurologic symptoms. These patients received relatively low total doses of IT Ara-C and standard doses of IV Ara-C. Previous studies have shown that Ara-C equilibrates readily between serum and cerebrospinal fluid; this implies that total IV and IT doses of Ara-C may be additive in relation to development of neurotoxicity. For these reasons, use of IV and IT Ara-C in childhood AML must be approached with greater caution, especially if neurologic abnormalities develop during or after therapy.

The use of lymphocyte phosphoglucomutase as a genetic marker in bone marrow transplant recipients.

Lymphocyte phosphoglucomutase can be used as a genetic marker to document successful engraftment in bone marrow transplant recipients. Two patients who underwent marrow transplantation as a treatment for acute leukemia showed a change into donor-type isozyme pattern.

Genetic markers in human bone marrow transplantation.

Blood cell isozymes, red cell antigens, immunoglobulin allotypes, and marker chromosomes are suitable tools to monitor bone marrow engraftment and marrow graft quality. Data on genetic markers from 26 patients who underwent bone marrow transplantation as a treatment for acute leukemia are presented here.

Successful second bone marrow transplantation in a patient with myositis ossificans progressiva and aplastic anemia.

Bone marrow transplantation has become the treatment of choice for patients with severe aplastic anemia who are fortunate enough to have allogeneic sibling donors. As patients have been transplanted earlier in the course of their disease, significant improvements have been obtained in long-term survival. However, in patients who have been sensitized by previous blood product transfusions, graft rejection continues to be a significant problem and second transplants when performed are frequently unsuccessful. This case report deals with a patient with myositis ossificans progressiva (MOP) who developed severe idiopathic aplastic anemia. He rejected his first graft after 160 days. However, he was successfully reingrafted with marrow from the same donor using a different conditioning regimen.

Human cyclic neutropenia transferred by allogeneic bone marrow grafting.

Human cyclic neutropenia shows many features in common with the animal model of cyclic neutropenia in grey collie dogs. Until now, however, evidence was lacking that cyclic neutropenia in man as in the dog is caused by a defect in a transplantable hematopoietic stem cell. A patient is presented who, while undergoing bone marrow transplantation as treatment for acute lymphoblastic leukemia in relapse, acquired cyclic neutropenia from her histocompatible sibling donor.

Bone marrow ablation followed by allogeneic marrow grafting during first complete remission of acute nonlymphocytic leukemia.

Of 33 patients who had undergone allogeneic bone marrow transplantation during first complete remission of acute nonlymphocytic leukemia, 21 patients have now been followed in continued complete remission for 6-64 mo (median greater than 18 mo) without maintenance chemotherapy. The median age of the surviving patients is 27 yr. Transplant-related complications occurring throughout the first year after marrow grafting were fatal in 7 patients, and leukemic recurrence led to the death of 5 patients. The actuarial long-term disease-free survival is 60% and the actuarial remission rate is 79%.

Outcome of bone marrow transplantation in patients with extramedullary involvement of acute leukemia.

Infiltration of extrahemopoietic tissue with leukemic cells was evaluated as a prognostic indicator in 18 patients with acute leukemia undergoing bone marrow transplantation. When compared to 107 patients who did not have extramedullary leukemia at any time prior to marrow grafting, the patients with leukemic invasion into organs outside the hemopoietic system had a significant increase of leukemic recurrence and a significant decrease in survival after marrow transplantation. Extramedullary leukemia may be a negative prognostic indicator for bone marrow transplantation candidates.

Reversal of acute ("malignant") myelosclerosis by allogeneic bone marrow transplantation.

A 28-yr-old woman with acute malignant myelosclerosis received, as primary treatment, ablative chemotherapy and total body radiation therapy followed by bone marrow transplantation from her histocompatible brother. The patient is now well more than 15 mo after bone marrow transplantation, with normal peripheral blood counts, a normal bone marrow, no evidence of graft-versus-host disease, and is on no therapy. In light of the poor results obtained with conventional chemotherapy in this disease, bone marrow transplantation may represent the treatment of choice for patients who have an appropriate donor.

Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia.

Thirty-three patients with acute leukemia (15 with lymphoblastic leukemia and 18 with myeloblastic leukemia) were entered into a program of high-dose radiochemotherapy followed by allogeneic bone-marrow transplantation. These patients were in various clinical stages of disease. Of 10 in complete hematologic remission at the time of transplantation, seven were alive without maintenance therapy at the time of evaluation, eight to 35 months after grafting; one was in relapse. Of 11 who received transplants during partial remission, six were in remission without further treatment eight to 33 months after transplantation. In 12 the disease was refractory to chemotherapy when preparation for transplantation was started, and only one of them was alive and free of disease after 10 months. Recurrent leukemia, graft-versus-host disease, viral pneumonia, and early therapy-related toxicity were the major causes of failure. High-dose chemotherapy and total-body irradiation followed by allogeneic marrow transplantation performed during complete or partial remission can produce long-term remission of acute leukemia.