Successful engraftment of allogeneic CD34-enriched marrow cell transplantation from HLA-mismatched parental donors

The CD34 antigen is expressed on pluripotent stem cells and the CD34+ cell has been shown to be capable of hematopoietic reconstitution in animal and human autologous grafts. We asked if CD34+ cells could reconstitute hematopoiesis in human allogeneic transplantation from a HLA-mismatched donor. Three pediatric patients with advanced leukemia received allogeneic CD34-enriched marrow cell graft from HLA two (two patients) or three (one patient) loci-mismatched parental donors. CD34+ cell selection was performed with mouse anti-CD34 antibody 9C5 and magnetic beads coated sheep anti-mouse IgG1. 1.53 to 2.48 x 10(9) marrow cells were processed and 2.53 to 7.89 x 10(7) positively selected cells were recovered. The selected population showed 93.7 to 99.0% CD34+ cells and total recovery of CD34+ cells from the starting population was 54.6 to 62.3%. CD34+ cell selection resulted in more than 99.9% depletion of CD5+ cells from the bone marrow. The patients received 2.53 to 7.25 x 10(6) CD34-enriched cells/kg after myeloablative therapy. All patients achieved trilineage engraftment that was confirmed by various genetic markers. Acute graft-versus-host disease (GVHD) was grade 0 (two patients) or grade I (one patient), and hematological recovery was successfully achieved as follows; the days to reach granulocytes over 0.5 x 10(9)/I were 11 to 13 days, reticulocytes over 2% was 18 to 28 days, platelets over 50 x 10(9)/I was 33 to 58 days. One patient is surviving without relapse of leukemia and two patients died after either mixed hematopoietic chimerism or leukemia relapse was observed. These studies suggest that CD34+ marrow cells are capable of hematopoietic reconstitution from HLA two or three loci-mismatched donors even with the lowest dose of mature T cells.     

Effects of the intensity and timing of asbestos exposure on lung cancer risk at two mining areas in Quebec

BACKGROUND: Bone marrow transplantation (BMT) has been limited in the past by the availability of matched donors for patients. Over the past decade, the use of umbilical cord blood (UCB) as a source of hematopoietic stem cells has revolutionized the field of BMT, providing a source of hematopoietic stem cells for an increasing number of patients in need of a transplant. RESULTS: Umbilical cord blood transplantation (UCBT) appears to result in sustained engraftment of donor hematopoiesis similar to results achieved with marrow and peripheral blood hematopoietic stem cells. Early results indicate that UCBT is associated with a lower incidence and less severity of graft-versus-host disease than other sources of stem cells, potentially decreasing the morbidity and mortality of BMT. As the potential of UCBT has been realized, cord blood storage facilities have been established to provide UCB. The rapid emergence of UCBT has transformed a waste product of birth into a life-saving resource. Its use, however; has raised numerous ethical and medical concerns unique to this alternative source of stem cells. CONCLUSIONS: Umbilical cord blood transplantation represents a major advance in providing another stem cell source to patients in need of allogeneic hematopoietic stem cell transplantation. As with all new technologies, UCBT will have to be carefully studied over the next several years to determine its safety, efficacy, and precise indications in comparison with other sources of hematopoietic stem cells. The ethics of UCBT must properly respect the rights and needs of both donors and recipients.     

CD34 positive blood cells for allogeneic progenitor and stem cell transplantation

The transplantation of allogeneic peripheral blood progenitor cells (PBPC) provides complete and sustained hematopoietic and lymphopoietic engraftment. In healthy donors, large amounts of PBPC can be mobilized with hematopoietic growth factors. However, the high content of immunocompetent T-cells in apheresis products may expose recipients of allogeneic PBPC to an elevated risk of acute and chronic graft-versus-host disease. Thus, the use of appropriate T-cell reduction, but not depletion might reduce this risk. The hazards of graft rejection and a higher relapse rate can be avoided by maintaining a portion of the T-cells in the graft. The positive selection of CD34+ cells from peripheral blood preparations simultaneously provides an approximately 1000-fold reduction of T-cells. These purified CD34+ cells containing committed and pluripotent stem cells are suitable for allogeneic transplantation and can be used in the following instances: 1. As hematopoietic stem and progenitor cell transplantation instead of bone marrow cells, from HLA-identical family donors; 2. for increasing the stem cell numbers from HLA-mismatched or three HLA-loci different family donors in order to reduce the incidence of rejection but without increasing the T-cell number; 3. boosting of poor marrow graft function with stem cells from the same family donors; 4. transplantation from volunteer matched unrelated donors; 5. split transplantation of CD34+ and T-cells; 6. addition of ex vivo expanded CD34+ cells to blood cell or bone marrow transplantation; 7. generation of antigen specific immune effector cells and antigen presenting cells for cell therapy.     

Identification of an immunoglobulin A binding motif located in the beta-antigen of the c protein complex of group B streptococci

Between September 1987 and December 1994, 80 patients with multiple myeloma (MM) received high-dose busulfan and cyclophosphamide without (n = 57) or with modified total body irradiation (n = 23) followed by marrow from allogeneic donors. At transplant, 71% of the patients had disease that was refractory to chemotherapy. Thirty-five patients died of transplant-related causes within 100 days and 11 deaths occurred later. The actuarial probabilities of survival and progression-free survival were .24 +/- 0.17 and .20 +/- 0.10 at 4.5 years. Complete remissions were obtained in 36% of patients who had actuarial probabilities of survival and event-free survival of .50 +/- 0.21 and .43 +/- 0.17 at 4.5 years. In a multivariate analysis, adverse risk factors for outcome endpoints included: transplantation greater than 1 year from diagnosis; beta-2 microglobulin > 2.5 at transplant; female patients transplanted from male donors; patients who had received greater than eight cycles of chemotherapy before transplant and Durie stage 3 disease at the time of transplant. These results indicate that allografting for patients with MM can result in long-term disease-free survival for a minority of patients. Efforts to reduce transplant-related mortality should focus on earlier transplantation, less toxic treatment regimens, better supportive care, and improved prevention and treatment of graft-versus-host disease (GVHD).     

Transplantation of hematopoietic stem cells. II: Indications for transplantation of hematopoietic stem cells after myeloablative therapy

The destruction of hematopoiesis and lymphopoiesis by total body irradiation or high dose chemotherapy for the treatment of malignancy can be reversed by the transplantation of allogeneic or autologous hematopoietic stem cells. In primary disorders of bone marrow or immune system, allogeneic stem cells replace deficient cells. Acute leukemias can be cured, with in 50 to 80% disease free survival after 5 to 8 years. The allogeneic graft versus leukemia effect by immunoreactive cells reduces the relapse rate in myeloid and lymphoid malignancies. 40 to 70% of patients with chronic myeloid leukemia remain disease free after more than 5 years. Patients with malignant lymphoma have a 40 to 70% chance of cure with autologous transplantation, which is not increased by allogeneic cells, because of a higher incidence of severe complications. An increasing number of patients without option for cure is treated with the aim of prolonging remission or retarding disease progression, such as in chronic myeloid leukemia, multiple myeloma and certain solid tumors. New studies suggest in breast cancer with axillary lymph node metastases, that adjuvant high dose chemotherapy with autologous stem cell support will significantly improve disease free survival from 30 to over 60% after 3 to 5 years. In congenital metabolic and storage diseases deficient enzymes are substituted by the allogeneic cells. Clinical trials explore the use of stem cell transplantation after myeloablative therapy in autoimmune disorders as well as in gene therapy with transfected hematopoietic stem cells.     

Indications and donor source of hematopoietic stem cell transplants in Europe 1993: report from the European Group for Blood and Marrow Transplantation (EBMT)

This report details the evolution of bone marrow transplantation in Europe over a 20-year period. In 1973, 8 teams undertook a total of 16 allogeneic bone marrow transplants; in 1983, 97 teams performed 1353 transplants. In 1993, the numbers had risen to 260 teams and 7737 transplants. Donor source in 3092 cases was an allogeneic donor (2464 HLA-identical sibling transplants, 147 non-identical family donor transplants, 25 twin donor transplants and 456 unrelated donor transplants). For 4645 patients the transplant was autologous (2450 autologous bone marrow transplants, 1830 autologous peripheral blood stem cell transplants and 365 combined autologous peripheral blood and bone marrow transplants). Indications for transplants in 1993 were leukemias in 3419 patients (44%; 2332 allogeneic, 1087 autologous), lymphoproliferative disorders in 2666 patients (34%; 197 allogeneic, 2469 autologous), solid tumors in 1077 patients (14%; 9 allogeneic, 1068 autologous), aplastic anemia in 251 patients (3%; 250 allogeneic, 1 autologous), inborn errors in 244 patients (3%; 242 allogeneic, 2 autologous) and miscellaneous disorders in 80 patients (1%; 62 allogeneic, 18 autologous). These data illustrate the increase of hematopoietic stem cell transplants as a therapeutic modality over the last 20 years in Europe.     

Changes in lung and chest wall properties with abdominal insufflation of carbon dioxide are immediately reversible

There is increasing interest in blood cell transplants (BCT) from normal donors as an alternative to BMT. Ten patients with relapsed or persistent leukemia after BMT received intensive cytotoxic conditioning followed by allogeneic BCT. Three BCT were from single-antigen mismatched donors; two of the corresponding recipients had rejected a BMT from the same donor. Two patients received BCT from a different donor (one matched, one single-antigen mismatched). The other six BCT were from the same, fully matched, bone marrow donors. Donors were given G-CSF to mobilize progenitor cells which were collected by a single 2-4 h leukapheresis. Methotrexate, CsA and folinic acid were used for GVHD prophylaxis for all transplants but CsA was discontinued sooner after BCT than after BMT. One patient died without engraftment having rejected a BMT from the same single-antigen mismatched donor 4 years previously. Nine patients had granulocyte recovery at a median of 14 days, up to 6 days faster than with their previous BMT. Platelet recovery was also 2-6 days faster than with BMT in four previously engrafting patients. Four patients died without platelet recovery after BCT within a year of BMT, three of treatment-related toxicity and one of relapse. Two patients developed grade II acute GVHD. Of six patients given BCT more than a year from BMT, four, all with acute leukemia, survive 7, 14, 29 and 29 months after BCT and one relapsed at 7 months. All four survivors developed chronic GVHD. These results indicate that BCT may be useful therapy for relapse occurring more than a year after BMT.     

Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.     

Thymus transplantation, a critical factor for correction of autoimmune disease in aging MRL/+mice

MRL/MP-+/+ (MRL/+) mice develop pancreatitis and sialoadenitis after they reach 7 months of age. Conventional bone marrow transplantation has been found to be ineffective in the treatment of these forms of apparent autoimmune disease. Old MRL/+ mice show a dramatic thymic involution with age. Hematolymphoid reconstitution is incomplete when fetal liver cells (as a source of hemopoietic stem cells) plus fetal bone (FB; which is used to recruit stromal cells) are transplanted from immunologically normal C57BL/6 donor mice to MRL/+ female recipients. Embryonic thymus from allogeneic C57BL/6 donors was therefore engrafted along with either bone marrow or fetal hematopoietic cells (FHCs) plus fragments of adult or fetal bone. More than seventy percent of old MRL/+ mice (> 7 months) that had been given a fetal thymus (FT) transplant plus either bone marrow or FHCs and also bone fragments survived more than 100 days after treatment. The mice that received FHCs, FB, plus FT from allogeneic donors developed normal T cell and B cell functions. Serum amylase levels decreased in these mice whereas they increased in the mice that received FHCs and FB but not FT. The pancreatitis and sialoadenitis already present at the time of transplantations were fully corrected according to histological analysis by transplants of allogeneic FHCs, FB and FT in the MRL/+ mice. These findings are taken as an experimental indication that perhaps stem cell transplants along with FT grafts might represent a useful strategy for treatment of autoimmune diseases in aged humans.     

Haemopoietic cell transplantation in children with juvenile myelomonocytic leukaemia

Seven children, 11 months to 5.9 years of age, with juvenile myelomonocytic leukaemia (JMML) underwent allogeneic haemopoietic cell transplantation (HCT) using related or unrelated donor bone marrow or umbilical cord blood. All patients had active disease at time of transplant despite chemotherapy in five patients and chemotherapy and splenectomy in one patient prior to HCT conditioning. All patients received cyclophosphamide and TBI, with the addition of busulphan in two cases. Engraftment was documented in all cases. Notably, six of seven patients relapsed after allogeneic HCT with one achieving a return to full donor chimaerism after cyclosporin A (CSA) withdrawal. Two patients are alive in remission, 23+ and 30+ months after transplant. The role of allogeneic HCT in patients with JMML is discussed. A cooperative multicentre trial is needed to establish the optimal therapy for these patients.     

Transplant of hematopoietic stem cells in childhood: where we are and where we are going

Over the past decade, relevant improvements and refinements have significantly changed the indications, technique and results obtained with allogeneic transplantation of hematopoietic stem cells (HSC) in childhood. In this review the most important innovations that have characterized the practice of HSC transplantation in childhood during this decade will be discussed. We will analyze the clinical and biological advantages or disadvantages which characterize most typically HSC transplantation procedure in terms of the source of these cells (bone marrow, peripheral blood, placental blood). A fundamental turning point in the history of allogeneic transplantation of HSC is represented by the use of placental blood, which was first employed in 1988. Autologous, peripheral blood progenitor cells are increasingly being used as a source of HSC following high-dose therapy for malignant disease, because of the ease of collection and the markedly faster kinetics of engraftment in comparison with bone marrow. In particular, over the past decade, due to the much faster recovery of all hematopoietic lineages in comparison with bone marrow and due to the short duration of antibiotic therapy and hospitalization, also in pediatric patients, auto-transfusion of circulating hematopoietic progenitors is rapidly replacing autologous bone marrow transplantation after high-dose chemotherapy for lymphomas and solid tumors. On the contrary, due to concerns in pediatric patients related to the use of hematopoietic growth factors in a healthy donor, allograft of peripheral blood progenitor cells is not routinely used. Since indications for allogeneic HSC transplantation that had already been well established in the recent past have been complemented by others and a relevant number of disorders are no longer considered to be eligible for allograft, the evolution in the indications for allogeneic transplant of HSC in childhood will be discussed. Likewise, biotechnological, social and organizational refinements which have allowed the greatest advances of allogeneic HSC transplantation in this decade will be analyzed, as well as some still open bioethical question regarding this procedure.     

Empirically supported comprehensive treatments for young children with autism

Aplastic anemia can be either acquired or congenital. The paradigm for the congenital form is Fanconi's anemia (FA). FA is an autosomal recessive, genetic syndrome characterized by progressive bone marrow failure, developmental abnormalities, and a predisposition to malignancy. The clinical manifestations of FA are heterogeneous, but one common outcome in the majority of patients is the development of life-threatening hematologic disease. FA is thought to affect the hematopoietic stem cell, and the hematologic consequences of FA can be effectively treated by complete replacement of patient stem cells by those from a histocompatible donor. Unfortunately, allogeneic stem cell transplantation is currently limited to patients with an unaffected matched sibling donor. Transplantation from alternative donors, while successful in selected cases, is associated with a high risk of graft failure and must be carefully considered in terms of risk and benefit for each individual. For FA patients lacking an appropriate donor, new therapies need to be devised. This review summarizes both the scientific rationale and the progress of gene therapy strategies aimed at correcting the hematopoietic defect of FA.     

Allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) after high-dose, marrow-ablative chemoradiotherapy has been established as the treatment of choice for various hematologic, neoplastic, and congenital disorders. The most common type of marrow graft is an allogeneic one from a sibling donor who has compatible human leukocyte antigen (HLA). Only 30% of patients requiring allogeneic BMT have an HLA-compatible sibling donor. Over the past few years, marrows from unrelated HLA-compatible donors have been used with increasing frequency and promising outcome in certain hematologic malignancies. Despite the morbidity and mortality associated with this treatment modality, allogeneic BMT may provide a 20% to 90% chance of long-term, disease-free survival to patients with a wide variety of neoplastic and abnormal marrow disorders.     

Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy

BACKGROUND: Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease. METHODS: Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years. RESULTS: Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form. CONCLUSIONS:Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.     

The success of lymphocyte infusion as treatment of leukemia recurrence following allogeneic bone marrow transplantation depends on low percentage of patient's own lymphocytes

OBJECTIVE: Evaluation of induction of complete remission with infusion of lymphocytes from the original bone marrow donor in patients with leukaemia which relapsed after allogeneic bone marrow transplantation. SETTING: Division of Haematology, University Hospital Nijmegen and the Red Cross Blood Bank Nijmegen, the Netherlands. DESIGN: Prospective, non-randomized study. METHODS: Twenty-eight patients who relapsed after allogeneic bone marrow transplantation were treated with infusion of lymphocytes from the original bone marrow donor. Lymphocytes were collected by means of leukapheresis. Follow-up was done by frequent checks at the outpatient clinic. RESULTS: Eleven of 15 (73%) patients with relapsed chronic myeloid leukaemia (CML) and only one of 13 patients (8%) with a relapse of acute leukaemia went into complete remission (p < 0.001). Entering complete remission was always preceded by acute or chronic graft-versus-host disease (GVHD). The development of acute and/or chronic GVHD was significantly associated with the origin of T-lymphocytes in the blood of the recipient at the time of infusion. If the T-lymphocytes came mostly from the patient himself, the infusion remained usually without effect. If the T-lymphocytes came mostly from the donor, the patients went into complete remission. CONCLUSION: Patients with a relapse of leukaemia after allogeneic bone marrow transplantation may enter complete remission after infusion of lymphocytes from the original marrow donor. This form of immunotherapy can be successful especially in patients with a relapsed CML with a relatively low percentage of autologous T-lymphocytes at the time of infusion.     

Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia

BACKGROUND: Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. METHODS: Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. RESULTS: The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. CONCLUSIONS: Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.     

Single-species infections of Echinostoma caproni cercariae in pulmonate snails and concurrent infections of E. caproni and Echinostoma trivolvis cercariae in Biomphalaria glabrata

Secondary malignancies (lymphomas, leukemias, and solid tumors) occurring after bone marrow transplantation are now more frequently reported, as the patients surviving the early phase of the graft and remaining free of their original disease are more numerous. Besides early Epstein-Barr virus-associated B-cell lymphoproliferative diseases, which are the most common type and most often of donor origin, few late-occurring lymphomas have been described that might represent a distinct entity. We report here a case of Hodgkin's disease developing 8 years after allogeneic bone marrow transplantation for chronic myelogeneous leukemia. Only two Hodgkin's diseases after allogeneic bone marrow transplantation have been reported in the literature so far. The case we report is of interest because of its donor origin and its association with Epstein-Barr virus infection.     

Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program

BACKGROUND AND METHODS: Allogeneic bone marrow transplantation is curative in a substantial number of patients with hematologic cancers, marrow-failure disorders, immunodeficiency syndromes, and certain metabolic diseases. Unfortunately, only 25 to 30 percent of potential recipients have HLA-identical siblings who can act as donors. In 1986 the National Marrow Donor Program was created in the United States to facilitate the finding and procurement of suitable marrow from unrelated donors for patients lacking related donors. RESULTS: During the first four years of the program, 462 patients with acquired and congenital lymphohematopoietic disorders or metabolic diseases received marrow transplants from unrelated donors. The probability of engraftment by 100 days after transplantation was 94 percent, although 8 percent of patients later had secondary graft failure. The probability of grade II, III, or IV acute graft-versus-host disease was 64 percent, and the probability of chronic graft-versus-host disease at one year was 55 percent. The rate of disease-free survival at two years among patients with leukemia and good prognostic factors was 40 percent and among patients at higher risk, 19 percent. Twenty-nine percent of the patients with aplastic anemia were alive at two years, and the rate of two-year disease-free survival among patients with myelodysplasia was 18 percent. For patients with congenital immunologic or nonimmunologic disorders, the probability of survival was 52 percent. CONCLUSIONS: The National Marrow Donor Program has benefited a substantial number of patients in need of marrow transplants from closely HLA-matched unrelated donors and has facilitated the recruitment of unrelated donors into the donor pool and the access to suitable marrow.     

The use of umbilical cord blood in mismatched related and unrelated hemopoietic stem cell transplantation

Over the past 6 years, umbilical cord blood has emerged as an efficacious alternative source of hematopoietic stem cells in related bone marrow transplantation. These encouraging results led us to extend this technology to the mismatched related and unrelated settings in three high-risk leukemic children lacking a matched-related donor for transplantation. Two of the three children also lacked identifiable donors through the National Marrow Donor Program, while the third was in relapse and did not have time to wait for completion of a search. The first child was transplanted with haploidentical umbilical cord blood-derived mononuclear cells from his sister, while the remaining two children were transplanted with partially mismatched, unseparated, unrelated umbilical cord blood banked through the Placental Blood Project at the New York Blood Center. All three children demonstrated trilineage engraftment with donor cells within 6 weeks of transplantation. The patient transplanted with haploidentical marrow developed grade 2 graft vs. host disease (GVHD), which was controlled with steroid and anti-thymocyte globulin (ATG) therapy. One of the two patients grafted with unrelated umbilical cord blood developed mild grade 1 GVHD of the skin, which rapidly cleared with steroid therapy. One patient remains alive, in good health and disease-free 12 months from transplantation.     

Allogeneic transplantation combining mobilized blood and bone marrow in patients with refractory hematologic malignancies

BACKGROUND: Mobilized blood stem cells have been used successfully in autologous transplant recipients to reduce the complications of pancytopenia due to dose-intensive chemotherapy. Reports of cytokine-mobilized blood progenitor cells in allogeneic transplant recipients are rare. STUDY DESIGN AND METHODS: This is a pilot trial of six patients. Patients with advanced hematologic malignancy received bone marrow (median total 2.6 x 10(8) mononuclear cells/kg) followed by four daily transfusions of blood (median total 9.5 x 10(8) mononuclear cells/kg) from HLA-matched sibling donors who were mobilized with recombinant human granulocyte-colony-stimulating factor (5 micrograms/kg/day subcutaneously for 5 days). All patients received cyclosporine and prednisone for graft-versus-host disease (GVHD) prophylaxis. RESULTS: An absolute neutrophil count greater than 500 per mm3 was achieved on Day 12, and platelet transfusion independence was achieved on Day 16. The median day of hospital discharge was Day 23 after transplant. All patients achieved 100-percent donor cell engraftment. Acute > or = Grade III GVHD did not develop in any patients, but all patients developed Grade I (n = 4) or Grade II (n = 2) acute GVHD. Chronic extensive GVHD developed in four of six patients. One patient died of pneumonia 263 days after transplant while undergoing immune-suppressive therapy for chronic GVHD. CONCLUSION: The transfusion of blood stem cells in patients undergoing allogeneic bone marrow transplant is well tolerated soon after transplant, but the development of chronic GVHD may limit the general usage of unmanipulated blood stem cells.