Bone marrow transplantation. Extent of transplantation in Britain is overrepresented.
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Bone Marrow Transplantation↗
Biomedical subjects
J M Hows
Publications and source records attributed to J M Hows.
A survey of use of unrelated volunteer donor bone marrow transplantation at 46 centres worldwide, 1989-93. International Marrow Unrelated Search and Transplant (IMUST) Study.
Unrelated donor bone marrow transplantation is increasingly used to treat haemopoietic disorders where no HLA-identical sibling is available. The International Marrow Unrelated Search and Transplant Study has collected core data on consecutive unrelated donor BMT (UD-BMT) and HLA-identical sibling donor BMT (ID-BMT) performed in 46 participating centres world-wide between March 1989 and February 1993. Eighteen UD-BMT were performed in the first 6-month period in 14 participating centres, while in the last period there were 103 UD-BMT in 46 centres. The percentage of BMT recipients with the following diagnoses were: bone marrow failure UD-BMT 15% and ID-BMT 11%; AML 13% and 27%; ALL 18% and 17%; CML 48% and 31%; and other diseases 7% and 14%. Thirty-eight per cent of UD-BMT recipients had advanced disease compared with only 23% of ID-BMT recipients. Thirty six per cent of UD-BMT compared with 21% of ID-BMT recipients were under 16 years old. More extreme differences in pre-transplant clinical characteristics between UD and ID-BMT recipients were found when diagnosis and stage of disease were considered together. This survey indicates how UD and ID-BMT are currently used in the treatment of haematological disease; however, longer follow-up is required to assess the value of UD-BMT in the management of patients with bone marrow disorders.
Adolescent↗
Direct comparison by limiting dilution analysis of long-term culture-initiating cells in human bone marrow, umbilical cord blood, and blood stem cells.
Limiting-dilution analysis of long-term culture-initiating cells (LTCIC) is a quantitative method of estimating hematopoietic stem cell activity in clinical samples. We compared the numbers of LTCIC in bone marrow (BM), umbilical cord blood, and blood progenitor cells (obtained from patients with solid tumors at leukapheresis after mobilization with induction chemotherapy and filgrastim administration), using a two-stage long-term culture system and a limiting-dilution technique, scoring cobblestone areas of greater than 15 hematopoietic cells weekly for up to 8 weeks. Samples were obtained from 30 normal BMs, 20 human umbilical cords, and 32 leukapheresis products. Direct comparison of LTCIC in the three sources showed that the median proportions of cells generating hematopoietic foci from unfractionated mononuclear cells at 5 and 8 weeks, respectively, were 1:13,314 and 1:33,949 for BM, 1:12,506 and 1:34,546 for umbilical cord blood, and 1:10,302 and 1:12,891 for leukapheresis product. The estimated proportions of LTCIC from unfractionated mononuclear cells and CD34+ cells were similar in experiments with leukapheresis product. Leukapheresis product was superior to umbilical cord blood and cord blood to BM at 5 and 8 weeks of culture (P = .01). In two-stage long-term cultures, more colonies per flask and CD34+ cells were found in assays of leukapheresis product than in BM or umbilical cord blood cultures (P = .0005). Results obtained by this simplified limiting-dilution analysis correlated well with standard long-term cultures and can be used as a measure of the stem cell population. These data suggest that the incidence of putative stem cells in leukapheresis product and umbilical cord blood are at least comparable with that of BM.
Antigens, CD↗
Haemopoietic growth factors in aplastic anaemia: a cautionary note. European Bone Marrow Transplant Working Party for Severe Aplastic Anaemia.
We are concerned about the inappropriate use of haemopoietic growth factors in patients with severe aplastic anaemia (SAA). The treatment of choice for this disorder is bone-marrow transplantation from an HLA-identical sibling donor if the patient is younger than 45 years, but it must be done soon after onset before the patient becomes sensitised by multiple red-cell and platelet transfusions. Other patients should receive immunosuppressive therapy with antithymocyte globulin alone or with cyclosporin or oxymetholone. Haemopoietic growth factors may have a role in stimulation of granulopoiesis after immunosuppressive therapy, but there is no evidence that they can correct the underlying stem-cell defect in SAA, and therefore no justification for their use alone in newly diagnosed SAA. Such treatment is harmful because it delays bone-marrow transplantation, or immunosuppressive therapy in older patients and those without suitable donors, thus reducing the chances of a successful outcome.
Age Factors↗
Cord blood transplantation: a practical option?
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Blood Banks↗
A prospective study of factors determining the outcome of unrelated marrow donor searches: report from the International Marrow Unrelated Search and Transplant Study Working Group on behalf of collaborating centres.
Outcomes of searches for unrelated bone marrow donors were analysed to identify factors influencing the probability of identifying an HLA-matched donor and proceeding to an unrelated donor bone marrow transplant (UD-BMT). Between March 1989 and January 1991, 649 unrelated marrow donor searches were entered into the study. Searches were referred from transplant centres in Europe and North America to the Anthony Nolan Research Centre panel and/or the British Bone Marrow and Platelet Donor Panel, two predominantly Caucasian donor registries. Patient immunogenetic and clinical characteristics were documented on study search request forms and search outcomes were monitored at the donor registry. Data were analysed using proportional hazards regression. Major factors predicting favourable search outcomes were patient common Caucasian HLA phenotype and Caucasian ethnic group. Probability of search failure was increased by advanced disease, rare Caucasian HLA phenotype and referral to the smaller registry. Search failure frequently occurred at the mixed lymphocyte reaction stage. This study illustrates the relative roles of clinical, immunogenetic and registry factors in determining the outcome of searches. The information may be used to devise strategies to locate HLA-matched donors for a higher proportion of patients for whom UD-BMT is the preferred treatment.
Adult↗
Allogeneic bone marrow transplantation for chronic myeloid leukemia using sibling and volunteer unrelated donors. A comparison of complications in the first 2 years.
OBJECTIVE: To compare the short- and medium-term complications (particularly infection) of bone marrow transplantation for chronic myeloid leukemia in patients with HLA-identical sibling donors or volunteer unrelated donors. DESIGN: Retrospective review of two cohorts of patients. SETTING: Tertiary referral center. PATIENTS: One hundred three patients with chronic myeloid leukemia in first chronic phase. INTERVENTION: Patients were treated with bone marrow transplantation using marrow from HLA-identical siblings (n = 57) and volunteer donors (n = 46). MAIN RESULTS: In total, 68 patients survived a median of 22 months from bone marrow transplant (range, 7 to 81 months). The actuarial probabilities of overall survival and leukemia-free survival at 2 years for the sibling donor group were 73% (95% CI, 60% to 86%) and 72% (CI, 60% to 84%), respectively, and for the volunteer donor group, 47% (CI, 31% to 63%) and 42% (CI, 26% to 58%) (P = 0.07 and 0.05, respectively). However, after adjustment for duration of disease, overall and disease-free survival in the two donor groups did not differ significantly. A major problem was an increased incidence of severe viral infection in the volunteer unrelated donor group (19 episodes in 16 of 46 patients compared with 7 episodes in 7 of 57 sibling donor patients, P = 0.01). The actuarial incidence of chronic graft-versus-host disease (GVHD) was higher in volunteer unrelated donor patients (77% [CI, 63% to 91%] compared with 49% [CI, 35% to 63%]; P = 0.02) but that of acute GVHD was not. The median performance status of the survivors in the volunteer donor group is similar to that in the sibling donor group. The incidence of hematologic relapse in both groups so far is low. CONCLUSION: Results appear to justify the continued use of volunteer donors in chronic-phase chronic myeloid leukemia, but infection and chronic GVHD are still major problems.
Actuarial Analysis↗
Avascular necrosis after treatment of aplastic anaemia with antilymphocyte globulin and high-dose methylprednisolone.
Avascular necrosis of bone (AVN) occurring in patients with aplastic anaemia (AA) treated with antilymphocyte globulin (ALG) followed by high-dose methylprednisolone (HDMP) has been studied retrospectively. Out of 49 patients treated at two centres, seven have developed AVN at a median of 14 months (range 6-30) following treatment. The cumulative incidence of AVN is 21% (95% confidence intervals 7-35%). The hip was involved in six patients, bilaterally in five. Two patients had more than two joints affected. Surgical intervention was necessary in five patients, three of whom required total hip replacement. In contrast, there were no cases of AVN in a historical group of 61 patients with aplastic anaemia treated with an identical regimen of ALG but using a short course of low-dose prednisolone. Lack of convincing evidence for benefit, the considerable morbidity from AVN, and increased risk of early life-threatening infection, suggest that high-dose methyl prednisolone should be omitted from ALG treatment protocols for aplastic anaemia.
Adolescent↗
Matched unrelated donor bone marrow transplantation for chronic myeloid leukaemia in chronic phase: comparison of ex vivo and in vivo T-cell depletion.
Between January 1985 and March 1992, 48 patients with chronic phase CML underwent BMT from volunteer unrelated donors (MUD) serologically identical at HLA-A, B and DR loci. 19 patients received donor marrow ex vivo T-cell depleted (EX-TCD) with Campath monoclonal antibodies. 29 patients received unmanipulated donor marrow with CsA/MTX GVHD prophylaxis; 28 received additional intravenous antilymphocyte therapy from day +1 to +5 (IN-TCD). Overall 26 patients survive at median follow up of 362 days; actuarial survival at 3 years is 50%. 3 patients have sustained haematological relapse; actuarial leukaemia-free survival is 38%. There is no difference in overall survival between the EX-TCD and IN-TCD groups, but primary graft failure (n = 4) occurred only in the EX-TCD group, while GVHD (grade II or greater) occurred more frequently in the IN-TCD group (61% vs. 29%, p = 0.084). The optimum method for GVHD prophylaxis in MUD BMT remains uncertain.
Adolescent↗
Unrelated donor marrow transplantation: an interim report from the IMUST Study.
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Bone Marrow Transplantation↗
Growth of human umbilical-cord blood in longterm haemopoietic cultures.
Cryopreserved human umbilical-cord (HUC) blood is an alternative to bone marrow as a source of haemopoietic "stem" cells for HLA-identical transplantation of children with leukaemia or Fanconi's anaemia. We have studied the in-vitro growth potential of HUC blood in clonogenic assays and in longterm haemopoietic cultures. Clonogenic assays showed that HUC blood produced as many haemopoietic-cell colonies as normal adult bone marrow and a higher proportion of primitive-cell colonies. In longterm culture on preformed irradiated marrow stroma, both progenitor-cell production and lifespan of cultures were significantly greater in HUC blood than in normal bone marrow (p = 0.0007). Our findings indicate that the quality and quantity of HUC-blood-derived haemopoietic "stem" cells are better than those of normal bone marrow. Therefore, single HUC-blood donations are probably sufficient for adults requiring transplantation for leukaemia and other haemopoietic disorders. Banking of HLA-typed HUC blood to facilitate transplantation of patients who lack a family donor should be considered.
Blood Transfusion↗
"Stem cell" origin of the hematopoietic defect in dyskeratosis congenita.
We have used the long-term bone marrow culture (LTBMC) system to analyze hematopoiesis in three patients with dyskeratosis congenita (DC), two of whom had aplastic anemia, and the third had a normal blood count (apart from mild macrocytosis) and normal BM cellularity. Hematopoiesis was severely defective in all three patients, as measured by a low incidence of colony-forming cells and a low level of hematopoiesis in LTBMC. The function of the marrow stroma was normal in its ability to support the growth of hematopoietic progenitors from normal marrows seeded onto them in all three cases, but the generation of hematopoietic progenitors from patients marrow cells inoculated onto normal stromas was reduced, thus suggesting the defect to be of stem cell origin. The parents and unaffected brother of one of the families have also been studied in LTBMC and all showed normal hematopoietic and stromal cell function. From this study we speculate that there are some similarities between DC and the defect in the W/Wv mouse.
Adolescent↗
Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome.
Data for 595 patients with severe aplastic anemia receiving HLA-identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.
Adolescent↗
Autoimmune hemolytic anemia associated with anti-Sc1.
A case of autoimmune hemolytic anemia (AIHA) in a young child is described. The hemolysis was resistant to steroid therapy but responded to splenectomy and intravenous immunoglobulin. The autoantibody was shown to be anti-Sc1 by both serologic and immunoblotting techniques. This seems to be the first report of an autoanti-Sc1 detected by immunoblotting and the first example of AIHA in a child caused by autoanti-Sc1.
Anemia, Hemolytic, Autoimmune↗
Second transplants for patients with chronic myeloid leukaemia in relapse after original transplant with T-depleted donor marrow: feasibility of using busulphan alone for re-conditioning.
Between July 1986 and March 1991, 16 patients who had relapsed after T-lymphocyte depleted bone marrow transplantation (BMT) for chronic myeloid leukaemia (CML) received a second transplant using unmanipulated marrow cells from the same HLA-identical sibling donor. The median numbers of days from first BMT to haematological relapse and to second BMT were 557 (range 273-1543) and 1211 (range 476-2310) respectively. 11 patients were in uncomplicated chronic phase at time of second BMT, and five had more advanced disease. As conditioning for second BMT, eight patients received various combinations of cytotoxic drugs, and eight received high-dose busulphan alone. Eight (50%) patients survive at a median of 424 d post-second BMT (range 158-1789) and all are free of leukaemia by conventional criteria: five had been conditioned with high-dose busulphan alone. Causes of death in the eight patients who died included relapse (n = 2), graft-versus-host disease (n = 2), interstitial pneumonitis (n = 2), and infection (n = 2). We conclude that patients relapsing into chronic phase after BMT with T-lymphocyte depleted donor marrow may be offered the option of second BMT with unmanipulated marrow from the original donor. Conditioning with high-dose busulphan alone may be safer than use of more intensive schedules.
Adolescent↗
Two distinct patterns of glycosylphosphatidylinositol (GPI) linked protein deficiency in the red cells of patients with paroxysmal nocturnal haemoglobinuria.
We have studied three glycosylphosphatidylinositol (GPI) linked proteins on the erythrocytes of 14 patients with paroxysmal nocturnal haemoglobinuria (PNH). The pattern observed was bimodal in 12 of the patients and trimodal in two. Ten patients had a red cell population with normal CD59 antigen (membrane inhibitor of reactive lysis, MIRL), decay accelerating factor (DAF or CD55) and lymphocyte function-associated antigen (LFA-3 or CD58) and a second abnormal PNH population with absent CD59 antigen, DAF and LFA-3. The other two patients with a bimodal pattern had a red cell population with normal CD59 antigen, DAF and LFA-3 and an abnormal population with reduced, but not absent, CD59 antigen and DAF. The LFA-3 on the abnormal red cells in these two patients appeared to be only slightly reduced. The two patients with a trimodal pattern had a normal population, a population with reduced, not absent, CD59 antigen and DAF, and a population with complete absence of CD59 antigen, DAF and LFA-3. The accuracy of the Ham test in estimating the proportion of red cells with the PNH defect in the two types of PNH was assessed. The case of one patient who appeared to be 'rescued' from severe aplastic anaemia by the development of PNH is described.
Adult↗
Lymphocytes from multi-transfused patients exhibit cytotoxicity against autologous cells.
We previously demonstrated that multitransfused patients with severe aplastic anaemia (SAA) exhibit high numbers of alloreactive cytotoxic T lymphocyte precursors directed against their HLA identical siblings. In this study a group of patients who had received multiple blood transfusions for SAA, other haematological diseases or acute blood loss were tested for autocytotoxicity and the results compared with those of untransfused controls. These controls consisted of normal individuals, patients with chronic myeloid leukaemia (CML) or untransfused patients with SAA. There was a significantly higher degree of autocytotoxicity in multitransfused patients, than in the untransfused controls, including untransfused patients with SAA (P = 0.0001). These results suggest that blood transfusion is responsible for inducing autoreactivity. In one patient, in whom both alloreactive anti-non-MHC and autoreactive cytotoxic T lymphocytes (CTL) had been detected, it was demonstrated that there was no crossreactivity between the alloreactive and autoreactive CTL responses. Inhibition studies using monoclonal antibodies revealed the effector cells to be T lymphocytes and the restricting determinants to be both HLA class I and II molecules.
Anemia, Aplastic↗
Relapse into blast crisis following bone marrow transplantation for chronic phase chronic myeloid leukaemia: a report of five cases.
A proportion of patients receiving allogeneic bone marrow transplants (BMT) for chronic myeloid leukaemia (CML) in first chronic phase relapse; most of these relapses show features of chronic phase disease. We report here a series of five patients seen at a single institution over a 10 year period who developed blast crisis as the first sign of relapse after BMT for CML in chronic phase. The blast cells were myeloid in three cases and lymphoid in two. In one case the relapse may have occurred in cells of donor origin. The possible explanations for this unusual sequence of events include incipient transformation that was not detected before BMT, undetected relapse into chronic phase proceeding into transformation post-BMT, and transformation occurring de novo post-BMT in small numbers of residual leukaemic stem cells.
Adult↗