Candidates For Bone Marrow Transplantation Research Articles

Prognostic Discrimination Among Younger Patients With Chronic Granulocytic Leukemia: Relevance to Bone Marrow Transplantation

To obtain information relevant to the question of bone marrow transplantation, we examined the prognostic significance of disease features recorded at the time of diagnosis among 625 patients, aged 5 to 45, with Philadelphia chromosome-positive, nonblastic chronic granulocytic leukemia. The actuarial death rate for this population was 5% during the first year after diagnosis, 12% during the second year, and averaged 22.5% per year during the next eight years. Multivariable regression analysis of features recorded in nearly all cases indicated that sex, spleen size, hematocrit, platelet count, and percentage of circulating blasts were significant prognostic indicators. Analyses of additional data available in 113 to 421 cases suggested that serum lactic dehydrogenase activity, percentage of blasts in marrow, nucleated RBCs in blood, and percentage of basophils plus eosinophils might also provide useful prognostic information. A Cox model, generated with five variables representing features recorded regularly (the first five listed), permitted segregation of these patients into three groups with significantly different survival patterns. The high-risk group exhibited an actuarial mortality of 30% during the first two years after diagnosis and an annual risk of 30% thereafter. In contrast, the most favorable group had a two-year actuarial mortality of 9% and an average risk thereafter of 17% per year, with a median survival of 5 1/2 years. We conclude that it should be possible to classify potential candidates for bone marrow transplantation according to risk with conventional therapy. Such information may be useful in making decisions regarding early v deferred marrow transplantation.

Prognostic discrimination among younger patients with chronic granulocytic leukemia: relevance to bone marrow transplantation

To obtain information relevant to the question of bone marrow transplantation, we examined the prognostic significance of disease features recorded at the time of diagnosis among 625 patients, aged 5 to 45, with Philadelphia chromosome-positive, nonblastic chronic granulocytic leukemia. The actuarial death rate for this population was 5% during the first year after diagnosis, 12% during the second year, and averaged 22.5% per year during the next eight years. Multivariable regression analysis of features recorded in nearly all cases indicated that sex, spleen size, hematocrit, platelet count, and percentage of circulating blasts were significant prognostic indicators. Analyses of additional data available in 113 to 421 cases suggested that serum lactic dehydrogenase activity, percentage of blasts in marrow, nucleated RBCs in blood, and percentage of basophils plus eosinophils might also provide useful prognostic information. A Cox model, generated with five variables representing features recorded regularly (the first five listed), permitted segregation of these patients into three groups with significantly different survival patterns. The high- risk group exhibited an actuarial mortality of 30% during the first two years after diagnosis and an annual risk of 30% thereafter. In contrast, the most favorable group had a two-year actuarial mortality of 9% and an average risk thereafter of 17% per year, with a median survival of 5 1/2 years. We conclude that it should be possible to classify potential candidates for bone marrow transplantation according to risk with conventional therapy. Such information may be useful in making decisions regarding early v deferred marrow transplantation.

Sequential combination of methotrexate and vindesine in previously treated children with acute leukemia. A phase I-II study.

A therapeutic synergistic effect is seen in animal models when vinca alkaloids are administered after methotrexate. To examine further this interaction in clinical studies, a phase I-II trial was conducted in children with hematologic malignancies in the Department of Pediatrics at Memorial Sloan-Kettering Cancer Center. A schedule of sequential of methotrexate and vindesine was developed which showed effect in acute lymphoblastic leukemia in children in relapse and which was relatively nontoxic. The regimen has also been useful for reinduction for patients who are candidates for bone marrow transplant.

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.

The MHC in human bone marrow allotransplantation.

In this chapter, we have considered the theoretical and practical background of bone marrow transplantation. The immune response and its regulation by genes within the major histocompatibility complex, particularly of the I region of the mouse and of the HLA-D/DR region in man, is of central importance in both graft acceptance (rejection) and graft-versus-host disease. Methods which are available for typing alleles at the HLA-A, -C, -B, -DR and complotype (BF, C2, C4A, C4B) loci, have been considered in detail. The extent to which recombination affects specific alleles on haplotypes within families is discussed, as is the occurrence of linkage disequilibrium and extended haplotypes in populations of unrelated individuals. Because the HLA-DR and complotype region in man is thought to be critical for the success of bone marrow transplantation, methods for typing of HLA-D by both the HTC and PLT approaches have been examined. Although HLA-D/DR assignments are easily made in normal subjects, they are ambiguous in about 50 per cent of candidates for bone marrow transplantation, including, particularly, patients with aplastic anaemia, leukaemia, and severe combined immunodeficiency. In this setting, it is particularly important to obtain additional information by modification of HLA-D typing procedures and through complotype and GLO allele determinations in all family members. Finally, we can hope that there will be an increased possibility of using non-family donors through methods for removing cytotoxic T cells from donor marrow and through the identification, in the general population, of individuals who are genotypically similar or identical to the recipient. In this regard, the recognition that some 30 per cent of chromosome 6 in caucasians (50 per cent of individuals) bear extended haplotypes, which include a relatively fixed set of alleles particularly in the HLA-B, -DR, complotype and GLO regions, offers considerable promise.

Anti-thymocyte globulin treatment for aplastic anemia.

20 patients with severe aplastic anemia were treated with anti-thymocyte globulin (ATG), 6 of them in combination with haplo-identical bone marrow. 7 patients (35%) showed a good clinical response within 6 months; they were off transfusions and had greater than or equal to 0.8 x 10(9)/l neutrophils. ATG had the greatest effect on red-cell production and the least on platelet production. The hematological recovery with ATG could not be predicted from the bone-marrow histology, CFU-c growth, or clinical data. However, patients with strong HLA antibodies seemed to respond more often. The actuarial survival was 55% at 5 years. Under intensive supportive care, even 7 out of 12 non-responders were alive after 1 year. ATG appears to be a useful form of therapy for patients with severe aplastic anemia who are not candidates for bone-marrow transplantation.

Prognosis in acquired aplastic anemia. An approach in the selection of patients for allogeneic bone marrow Ttransplantation

In a retrospective study, factors influencing the eventual course and outcome of patients suffering from aplastic anaemia were analysed. Of the 62 patients with pancytopenia concomitant with an aplastic or hypoplastic bone marrow, 36 have died during the first 24 months following diagnosis, 27 of these 36 cases within the first six months. 26 patients survived more than two years after presentation, but a further six of these cases succumbed during the following months. Of the 62 cases, 46 had neutrophil counts under 1 X 10(9)/l and platelet counts under 20 X 10(9)/l. These cases were subdivided according to their reticulocyte levels. In the age group of patients between 10 and 35 years, all those patients having more than 10,000/mul reticulocytes survived more than two years with only one exception, whereas only one of the 11 patients having reticulocyte counts below 10,000/mul has survived. In our series, the initial neutrophil and platelet counts were not of predictive value in identifying poor prognosis patients. The initial reticulocyte counts, however, appear to be a valid parameter for selecting patients in two groups, one with a favorable, and the other with an extremely unfavorable prognosis on conservative treatment. Young individuals with a poor predicted prognosis could thus be defined as possible candidates for bone marrow transplantation.

IDENTIFICATION OF HIGH-RISK PATIENTS WITH APLASTIC ANÆMIA IN SELECTION FOR ALLOGENEIC BONE-MARROW TRANSPLANTATION

Of 75 patients with aplastic anæmia treated between 1968 and 1975, 33 were retrospectively considered as potential candidates for allogeneic bone-marrow transplantation on the basis of their age and severity of marrow failure. The prognosis of these patients with conservative treatment was assessed from parameters obtained at the time of the initial diagnosis. Initial peripheral-blood granulocyte or platelet concentrations were not of prognostic value. In contrast, initial reticulocyte concentrations, allowed separation of the patients into two groups with poor and good prognosis. Low initial reticulocyte concentrations (less than 10 000/μl) indicated those patients at extremely high risk of succumbing to their marrow aplasia (there were no survivors 36 months after diagnosis). In contrast, 75% of those patients with more than 10 000 reticulocytes per μl at diagnosis survived for 3 years. Initial peripheral-blood reticulocyte concentrations thus appear to indicate the extent of the marrow failure in aplastic anæmia more accurately than granulocytes or platelets. Low initial reticulocyte concentrations may indicate, among patients with severe aplastic anæmia, those for whom allogeneic bone-marrow transplanation should be seriously considered; patients with higher initial reticulocyte concentrations may benefit from conservative treatment.