Therapy For Severe Aplastic Anemia Research Articles

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Hypocalcemia, and Hypomagnesemia

Excerpt To the Editor:Granulocyte-macrophage colony-stimulating factor (GM-CSF) is currently being studied as a possible therapy for severe aplastic anemia, although the myelopoietic response to su...

Changes in Peripheral Blood Mononuclear Cell Subpopulations during Antithymocyte Globulin Therapy for Severe Aplastic Anemia

The short-term effect of a domestically produced equine antithymocyte globulin (ATG) was analyzed in 6 patients with acquired severe aplastic anemia (AA). All patients received 5 doses of ATG every other day in a 60-min intravenous infusion. Five peripheral blood immunoregulatory mononuclear cell (MNC) subsets, defined by monoclonal antibodies, were enumerated before and 24 h after each application of ATG. Following the first dose of ATG there was a significant and transient reduction in the absolute number of helper T lymphocytes. There was no statistically significant difference pre-ATG to post-ATG in the absolute number of MNC expressing activation antigen Tac (interleukin-2 receptor). However, Tac+ cells, which were significantly increased before ATG therapy, decreased to nearly normal levels after the fourth dose of ATG. A significant and sustained increment in the absolute number of monocytes (CD14+ cells) occurred following the third dose of ATG. The absolute numbers of MNC, suppressor T lymphocytes and cells bearing HLA-DR antigen remain without significant change along ATG treatment. These results suggest that: (a) Tac+ cells are probably involved in the pathogenesis of AA; (b) the target of ATG may be a Tac+ cell, and (c) ATG may stimulate monopoiesis.

Therapy of severe aplastic anemia in young adults and children with allogeneic bone marrow transplantation

During an 8-year period, 28 young adults (median age 27 years) and 30 children (median age 10 years) with severe aplastic anemia have received allogeneic bone marrow transplantation (BMT) from major histocompatibility locimatched sibling donors after preparation with cyclophosphamide and total lymphoid irradiation (TLI). All recipients were previously transfused. Comparison of post-bone marrow transplantation events in adults and children reveals equivalent median time to engraftment, median duration of hospitalization, median Karnofsky assessment of activity, and equivalent low rejection rate. Although the incidence of moderate and severe acute graft-v-host disease (GVHD) and of extensive chronic GVHD was greater in adults than in children, the projected survival at 4 years of adults (67%; 95% confidence interval [CI] 49% to 85%) and of children (73%; 95% CI 57% to 89%) was equivalent. All survivors are transfusion-free and have normal peripheral blood counts. One of 28 adults and 2 of 30 children have experienced rejection, and 1 of these patients survives after a second transplant. No malignancies have been identified following transplantation. An unexpectedly high incidence of hypothyroidism has been detected and may be attributable to preparation of recipients with TLI. Therapy of severe aplastic anemia with allogeneic BMT after preparation with cyclophosphamide and TLI offers a high rate of transfusion-free survival and a low rejection rate in previously transfused young adults and children.

Therapy of Severe Aplastic Anemia in Young Adults and Children With Allogeneic Bone Marrow Transplantation

Abstract During an 8-year period, 28 young adults (median age 27 years) and 30 children (median age 10 years) with severe aplastic anemia have received allogeneic bone marrow transplantation (BMT) from major histocompatibility locimatched sibling donors after preparation with cyclophosphamide and total lymphoid irradiation (TLI). All recipients were previously transfused. Comparison of post-bone marrow transplantation events in adults and children reveals equivalent median time to engraftment, median duration of hospitalization, median Karnofsky assessment of activity, and equivalent low rejection rate. Although the incidence of moderate and severe acute graft-v-host disease (GVHD) and of extensive chronic GVHD was greater in adults than in children, the projected survival at 4 years of adults (67%; 95% confidence interval [CI] 49% to 85%) and of children (73%; 95% CI 57% to 89%) was equivalent. All survivors are transfusion-free and have normal peripheral blood counts. One of 28 adults and 2 of 30 children have experienced rejection, and 1 of these patients survives after a second transplant. No malignancies have been identified following transplantation. An unexpectedly high incidence of hypothyroidism has been detected and may be attributable to preparation of recipients with TLI. Therapy of severe aplastic anemia with allogeneic BMT after preparation with cyclophosphamide and TLI offers a high rate of transfusion-free survival and a low rejection rate in previously transfused young adults and children.

Therapy of severe aplastic anemia with anti-human thymocyte globulin (ATGAM) with and without HLA-haploidentical bone-marrow infusion.

Six patients with severe aplastic anemia treated with horse anti-human thymocyte globulin (ATG) and androgen. Four of these patients were only given ATG (ATGAMR), 16 mg/Kg/dose x 10 doses. The remaining two cases received an infusion of maternal HLA-haploidentical marrow cells following ATG therapy. One patient had a complete response, three had a partial response, one showed minimal improvement and two were non-responders. The two patients who received the additional haploidentical marrow cells showed a hematologic recovery sooner than the ATG alone cases. The toxicity of the ATG therapy was tolerable. Long term follow up of there patients and further studies of this treatment in aplastic anemia with pediatric age group are under way.

Anti-thymocyte globulin therapy in severe aplastic anemia: an alternative to bone marrow transplantation

Eight patients with severe aplastic anemia (SAA) and two patients with congenital hypoplastic anemia (CHA) were treated with absorbed samples of rabbit anti-thymocyte globulin (ATG) at a total dose of 50-75 mg/kg body weight intravenously over 5 days. Duration of the disease was 1-14 years. Median age of the ten patients was 11 (4-15) years. Four of the eight patients with SAA were responders and transfusion independent for a follow up of 11 to 50 months. In two cases thrombocytopenia of about 100 000/mm3 is present. Four patients were non-responders three of them died in the meantime by the underlining disease. Two patients with CHA did not respond to ATG treatment. The CFU-C level of all eight patients with SAA before treatment was severely decreased. In co-culture studies with normal bone marrow no growth inhibition of normal bone marrow could be demonstrated. Also 20% patients serum did not inhibit normal bone marrow growth. The results are compared with data from literature and discussed in respect to alternative therapies.

Comparison between bone marrow transplantation and antithymocyte globulin in treatment of young patients with severe aplastic anemia

Fifty-seven patients younger than 25 years with severe aplastic anemia underwent either bone marrow transplantation or antithymocyte globulin therapy (ATG) to ascertain which approach should be used in young patients. Thirty-five patients who had an HLA-identical sibling donor underwent bone marrow transplantation after conditioning with cyclophosphamide and low-dose total-body radiation. Twenty-two patients who did not have an HLA-identical donor received ATG. The 2-year actuarial survival of patients after transplant is 72% (95%, CI 64% to 80%), versus 45% (95%, CI 29% to 61%) in those given ATG therapy (P = 0.18). In those patients surviving 6 months after treatment, return of peripheral blood counts to normal values was more common in patients who received marrow transplant compared with those given ATG therapy (P less than 0.001). Furthermore, 24 of 26 transplant survivors had Karnofsky performance scores greater than 90%, compared with only five of 13 ATG survivors. These data suggest that bone marrow transplantation is the preferred therapy for severe aplastic anemia in young patients who have an HLA-identical sibling donor. ATG should be reversed for those young patients with severe aplastic anemia who do not have a histocompatible marrow donor.

Therapy of Severe Aplastic Anemia With Anti-Human Thymocyte Globulin and Androgens: The Effect of HLA-Haploidentical Marrow Infusion

Fifty-four patients with severe aplastic anemia were treated with horse anti-human thymocyte globulin (ATG) and androgens. Thirty of these patients also received an infusion of HLA-haploidentical marrow cells. Only those patients having evidence of hematologic recovery within 3 mo after ATG therapy were considered responders to the immunosuppressive regimen. Of 53 patients evaluable for response, 21 had complete or partial responses and 7 had minimal improvement by defined criteria. The remaining patients did not respond or died. Factors correlated with response to therapy included a short duration of aplasia and a high admission granulocyte count. Thirty-six patients (66.7%) are surviving between 18 and 43 mo, and 18 have died. Deaths were due to hemorrhage and/or infection. Short duration of aplasia and high granulocyte counts also correlated with survival, as did younger age. Four patients with complete or partial responses had a recurrence of severe aplasia 6-17 mo after their first course of ATG. Three of these patients were retreated with ATG (and oxymetholone in two cases). All three had second responses to therapy, but two of the three have had second relapses. The fourth patient responded to oxymetholone alone, but died after a second relapse. Mismatched marrow infusion had no effect on the incidence of response or survival.

Therapy of severe aplastic anemia with anti-human thymocyte globulin and androgens: the effect of HLA-haploidentical marrow infusion

Fifty-four patients with severe aplastic anemia were treated with horse anti-human thymocyte globulin (ATG) and androgens. Thirty of these patients also received an infusion of HLA-haploidentical marrow cells. Only those patients having evidence of hematologic recovery within 3 mo after ATG therapy were considered responders to the immunosuppressive regimen. Of 53 patients evaluable for response, 21 had complete or partial responses and 7 had minimal improvement by defined criteria. The remaining patients did not respond or died. Factors correlated with response to therapy included a short duration of aplasia and a high admission granulocyte count. Thirty-six patients (66.7%) are surviving between 18 and 43 mo, and 18 have died. Deaths were due to hemorrhage and/or infection. Short duration of aplasia and high granulocyte counts also correlated with survival, as did younger age. Four patients with complete or partial responses had a recurrence of severe aplasia 6–17 mo after their first course of ATG. Three of these patients were retreated with ATG (and oxymetholone in two cases). All three had second responses to therapy, but two of the three have had second relapses. The fourth patient responded to oxymetholone alone, but died after a second relapse. Mismatched marrow infusion had no effect on the incidence of response or survival.

Antithoracic duct lymphocyte globulin therapy of severe aplastic anemia

We performed a prospective randomized trial of antithoracic duct lymphocyte globulin (ATDLG), HLA-haploidentical marrow, and androgen (regimen ABA) versus androgen alone (concurrent STANDARD care controls) in 42 newly diagnosed individuals with severe aplastic anemia. ABA patients also were matched with patients from our preceding study (historical STANDARD care controls). Supportive care and pretreatment patient characteristics were the same in all groups. By life table analysis, 76% of patients receiving ABA are alive at 2 yr compared to 31% of the concurrent control group (p less than 0.002 versus ABA) and 19% of the historical controls (p less than 0.0001 versus ABA) given STANDARD care. ABA patients had greater hematologic improvement than either control group (p less than 0.001). However, improvement with ABA was often incomplete. Toxicity of ATDLG was considerable but manageable. Further studies to determine the mechanism of action and active component(s) of ABA are indicated.

Hla-matched platelet transfusion therapy of severe aplastic anemia [letter

Hla-matched platelet transfusion therapy of severe aplastic anemia [letter

HLA-matched Platelet Transfusion Therapy of Severe Aplastic Anemia

HLA-matched Platelet Transfusion Therapy of Severe Aplastic Anemia

HLA-matched platelet transfusion therapy of severe aplastic anemia

In order to define more clearly the importance of the degree of HLA compatibility in the hematologic support of patients refractory to random-donor platelets, we retrospectively analyzed over 1000 platelet transfusions given during stable periods of their disease to 11 thrombocytopenic, severely alloimmunized patients with aplastic anemia: 28% of the donors fully matched with the recipient for HLA A and B loci (A-matched) and 17% of the donors mismatched with the recipient for two or more HLA antigens (D-matched) provided excellent responses, and 18% of A-matched and 46% of D-matched donors provided poor posttransfusion increments. Among all groups analyzed only A-matched donor-recipient pairs had higher increments than predicted by chance (p

Severe Aplastic Anemia: A Prospective Study of the Effect of Early Marrow Transplantation on Acute Mortality

A prospective randomized trial of therapy for severe aplastic anemia was designed to compare early bone marrow transplantation with conventional treatments. All patients with a sibling matched at the major histocompatibility region were transplanted. Transplantation was performed with 17-100 (median 33) days of original diagnosis. Conventional treatments included transfusion support with or without androgens. Twenty-four of 36 patients intered on the transplant arm are alive after 4-20 (median 9) mo with full marrow reconstitution. Only two are limited by chronic graft-versus-host disease. In contrast only 12 of 31 conventionally treated patients are alive. Six of these survivors have improved, five incompletely. The 19 nontransplant deaths have occurred within 1-11 (median 3) mo of diagnosis. Compared to nontransplant regimens, early transplantation more effectively restores normal marrow function and decreases the acute mortality of severe marrow aplasia (p = 0.006). Pending longer follow-up, early marrow transplantation appears to be the most effective available treatment for severe aplastic anemia.

Severe aplastic anemia: a prospective study of the effect of early marrow transplantation on acute mortality

A prospective randomized trial of therapy for severe aplastic anemia was designed to compare early bone marrow transplantation with conventional treatments. All patients with a sibling matched at the major histocompatibility region were transplanted. Transplantation was performed with 17–100 (median 33) days of original diagnosis. Conventional treatments included transfusion support with or without androgens. Twenty-four of 36 patients intered on the transplant arm are alive after 4–20 (median 9) mo with full marrow reconstitution. Only two are limited by chronic graft-versus-host disease. In contrast only 12 of 31 conventionally treated patients are alive. Six of these survivors have improved, five incompletely. The 19 nontransplant deaths have occurred within 1–11 (median 3) mo of diagnosis. Compared to nontransplant regimens, early transplantation more effectively restores normal marrow function and decreases the acute mortality of severe marrow aplasia (p = 0.006). Pending longer follow-up, early marrow transplantation appears to be the most effective available treatment for severe aplastic anemia.