Treatment of severe aplastic anemia with antilymphocyte globulin and androgens.

The etiology of aplastic anemia is unknown. A stem cell lesion caused by a toxin, virus or microenvironment defect is the main hypothesis. An autoimmune origin has been recently suspected. In an attempt to demonstrate the autoimmune origin of the disease, 17 patients with severe aplastic anemia were treated with antilymphocyte globulin (ALG). Nine patients showed no improvement, developed infectious or hemorrhagic complications and died within 1 to 7 months. In contrast, eight patients had a prompt rise of granulocyte and reticulocyte counts. Although the hematological reconstitution is not complete, these eight patients are still alive between 11 months and 24 months after treatment. This study shows that ALG may have a beneficial effect in the treatment of patients with severe aplastic anemia.     

Treatment of severe aplastic anemia with antilymphocyte globulin and androgens: A report on 33 patients

Summary Thirty-three patients with severe aplastic anemia were treated with antilymphocyte globulin (ALG, Mérieux) and androgens (with or without corticosteroids) between 1981 and 1989; 24 patients (72.7%) were responders after one course of ALG, eight were nonresponders, and only one patient had an early death. Eighteen of the 24 responses occurred within 2 months of ALG treatment. Of note is the good response rate we obtained for very severe aplastic anemia (four responders of five evaluable patients). With a median follow-up of 36 months (range 1–97), a survival rate of 77.6%±1.2% was obtained at 30 months. No predictive factor of survival could be identified except response to treatment (p=0.0001). The duration of the disease before treatment was inversely related to survival, although this difference did not reach statistical significance (p=0.06). Four initial responders relapsed after 14, 24, 38, and 57 months. Three of these patients received a second course of ALG and two responded. In contrast, four of the nonresponders received a second course of ALG, with only one response. Toxicity of androgens was mild. No patient developed a PNH clone or myelodysplastic syndrome. Major toxicity of corticosteroids was femoral osteonecrosis in three patients. In our experience, the combination of ALG and androgens in SAA, with or without corticosteroids, was associated with a higher response rate and better survival than in many previously published reports. This could have been due to the intensive supportive care during the initial weeks of treatment. We suggest that it may also result from the addition of androgens to ALG, although this issue may only be resolved in a randomized study.     

Therapy of aplastic anemia with sequential antithymocyte globulin and cyclosporin

Five consecutive patients with severe aplastic anemia were treated with antithymocyte globulin followed by cyclosporin A. All received antithymocyte globulin initially, and because of lack of response within a 4 week period, cyclosporin was administered subsequently. Hematologic improvement occurred within four months of initiation of cyclosporin. Four patients no longer require blood product support, while one remains transfusion-dependent. In two patients, thrombocytopenia developed when the cyclosporin was tapered but re-institution of the drug resulted in a prompt improvement of counts. These observations indicate that the sequential use of antithymocyte globulin and cyclosporin may be an effective therapeutic approach in the treatment of severe aplastic anemia.     

Treatment of aplastic anemia with antithymocyte globulin, high-dose corticosteroids, and androgens

A total of 46 patients with aplastic anemia (34 severe; 12 moderate) were treated with antihuman thymocyte globulin (ATG), high-dose methylprednisolone, and oxymetholone. Early symptoms of ATG toxicity included fever, rash, and bronchospasm. Signs of serum sickness also developed in 23 patients. Complications associated with high doses of steroids were hyperglycemia, hypertension, fluid retention, gastrointestinal hemorrhage, and aseptic necrosis of the hip. Other morbidity possible associated with steroid administration included seizures, arrhythmias, and headache with papilledema. Studies of elevated liver function necessitated discontinuation of androgen therapy in eight patients. A complete or partial hematological response was noted in 19 patients (41%). Of these, three have had recurrent cytopenias, of whom one has developed a myelodysplastic syndrome. There are currently 34 patients surviving, and 12 who have died. Actuarial survival at three years is 65%. These response and survival data are comparable to those of previous trials using ATG and androgens without high-dose steroids. A prospective, randomized trial is needed to determine whether the addition of high-dose corticosteroids to ATG does significantly increase the rate and frequency of response in order to justify the toxicity of this additional immunosuppressive therapy in the treatment of aplastic anemia.     

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.     

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.     

Efficacy of rabbit anti-thymocyte globulin in severe aplastic anemia

Background

A combination of horse anti-thymocyte globulin and cyclosporine produces responses in 60–70% of patients with severe aplastic anemia. We performed a phase II study of rabbit anti-thymocyte globulin and cyclosporine as first-line therapy for severe aplastic anemia.

Design and Methods

Twenty patients with severe aplastic anemia treated with rabbit anti-thymocyte globulin were compared to 67 historical control cases with matched clinical characteristics treated with horse anti-thymocyte globulin.

Results

Response rates at 3, 6 and 12 months were similar for patients treated with rabbit anti-thymocyte globulin or horse anti-thymocyte globulin: 40% versus 55% (P=0.43), 45% versus 58% (P=0.44) and 50% versus 58% (P=0.61), respectively. No differences in early mortality rates or overall survival were observed. We then performed multivariable analyses of response at 6 months and overall survival and identified the presence of a paroxysmal nocturnal hemoglobinuria clone (P=0.01) and a pretreatment absolute reticulocyte count greater than 30×10⁹/L (P=0.007) as independent predictors of response and younger age (P=0.003), higher pretreatment absolute neutrophil (P=0.02) and absolute lymphocyte counts (P=0.03) as independent predictors of overall survival. None of the immunogenetic polymorphisms studied was predictive of response to immunosupressive therapy.

Conclusions

Despite reports suggesting differences in biological activity of different anti-thymocyte globulin preparations, rabbit and horse anti-thymocyte globulin appear to have a similar efficacy for up-front treatment of severe aplastic anemia. Clinicaltrial.gov: {"type":"clinical-trial","attrs":{"text":"NCT01231841","term_id":"NCT01231841"}}NCT01231841)     

Morphology in patients with severe aplastic anemia treated with antilymphocyte globulin.

One hundred and seventeen patients with severe aplastic anemia (SAA) were treated at our institution between 1976 and 1990 with antilymphocyte globulin (ALG) therapy. Seventy-nine (68%) are alive and probability of survival at 14 years, according to Kaplan and Meier, is 62% +/- 12%. Twenty-six patients developed a late clonal complication: 11 had a myelodysplastic syndrome (MDS) and 17 had paroxysmal nocturnal hemoglobinuria (PNH); two patients had both. The cumulative risk at 10 years is 42%. The development of MDS/PNH after SAA directly affects survival. The probability of being alive at 14 years is 81% +/- 10% for patients with stable disease and 36% +/- 13% for those with clonal evolution (P = .001). To look for predictive signs, we reevaluated peripheral blood and bone marrow cytomorphology at presentation, during regeneration, and in remission. We examined the peripheral blood values for hemoglobin, reticulocytes, granulocytes, thrombocytes, mean corpuscular volume (MCV), and fetal hemoglobin, as well as bone marrow for cellularity, erythropoiesis, myelopoiesis, and megakaryopoiesis. ALG therapy induces slow and incomplete recovery. Although in "remission," ALG patients have lower hemoglobin values, higher reticulocyte counts, lower granulocyte and platelet values, and a higher MCV and fetal hemoglobin than normal controls. They retain a reduced number of megakaryocytes and a persistence of atypical monocytes in bone marrow morphology as stigmata of their disease. Patients with late clonal complications show distinct morphologic abnormalities: patients with PNH have higher MCVs, higher granulocyte and reticulocyte counts, and more dyserythropoiesis at diagnosis and a lower hemoglobin with an increased proportion of erythroblasts in the bone marrow in "remission." Patients who later developed MDS are not different from the total patient population at diagnosis. After therapy, these patients are characterized by the presence of ring sideroblasts and atypical monocytes during regeneration and by a persistent increase in MCV, a higher fetal hemoglobin, lower granulocyte values, and megakaryocytic dysplasia during "remission." Thus, routine morphologic follow-up examination of blood and bone marrow can discover patients at risk for late hematologic complications after ALG therapy.     

Antithymocyte globulin in the treatment of gold induced severe aplastic anemia

Severe aplastic anemia is the most serious complication of chrysotherapy. No treatment for this condition has been demonstrated effective. We report 3 patients with gold induced severe aplastic anemia treated with antithymocyte globulin. Complete marrow recovery was obtained in 1 case and a partial but satisfactory response in the other. All the patients remain alive without requiring blood transfusion after followup of longer than 16 months.     

Cyclophosphamide/antithymocyte globulin conditioning of patients with severe aplastic anemia for marrow transplantation from HLA-matched siblings: Preliminary results

Many approaches have been taken to reducing the rate of graft failure and the incidence of graft-versus-host disease (GVHD) in bone marrow transplantation (BMT) of patients with severe aplastic anemia (SAA). The combination of cyclophosphamide with irradiation has had unequivocal success in reconstituting a sustained engraftment, but this procedure has severe associated risks such as second malignancies. Recently, cyclophosphamide (CYC) plus antithymocyte globulin (ATG) has been shown to be an effective alternative to irradiation-based programs in retransplants. Based on these experiences, the current clinical trial was started to prepare patients suffering from SAA for marrow transplantation from HLA-identical siblings with ATG plus CYC. Nine patients have been enrolled into the study so far. They received a total dose of 200 mg/kg CYC and concomitantly 120 mg/kg or 90 mg/kg ATG, followed by cyclosporine plus methotrexate as post-transplantation GVHD prophylaxis. Eight of nine patients survived without any transplant-associated complications; i.e., they had a documented stable engraftment without rejection and without acute or chronic GVHD. One patient died due to anAsper-gillus sepsis prior to a definite engraftment. Although our data are preliminary because of the small number of patients enrolled and a follow-up of only 30 months, CYC plus ATG appears to be an effective preparative regimen for BMT in patients with SAA, resulting in a favorable outcome.     

Bone marrow transplantation for patients with acquired severe aplastic anemia using cyclophosphamide and antithymocyte globulin: the experience from a single center

Between 1998 and 2001, 31 (24 male, 7 female) patients with severe aplastic anemia (SAA) and a median age of 19 years (range, 4-39 years) received an allogeneic bone marrow transplantation. Marrow donors were genotypically HLA-identical siblings in 30 cases and a monozygous twin in one case. The median time from diagnosis to bone marrow transplantation was 1 month (range, 0.5-5 months). Conditioning regimen consisted of cyclophosphamide (CY) combined with antithymocyte globulin (ATG), in all patients. For graft-versus-host disease (GvHD) prophylaxis, all patients received methotrexate and cyclosporin. A total of 84% of patients had sustained grafts, whereas 16% rejected grafts between 3 and 20 months after transplantation. Of the five rejecting patients, three are alive with successful second engraftments and two died from infections. Acute grade II-IV GvHD was seen in only 11% of patients. A limited chronic GvHD was seen in one patient. With a median follow-up of 18 months (range, 5-42 months), survival rate was 86% and Karnofsky score was at least 90%. This study confirms the high success rate of the CY/ATG regimen in SAA allografted from an HLA-identical sibling. Early and late graft failure remains a problem and may require modification of this regimen.     

Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia

Immunosuppressive therapy can produce hematologic improvement in a large proportion of patients with severe aplastic anemia. Antithymocyte globulin (ATG) is the current treatment of choice for patients who do not have histocompatible sibling donors or who are otherwise inegligible for allogeneic bone marrow transplantation. About 50% of patients respond to an initial course of ATG, and many nonresponders can be salvaged by subsequent treatment with cyclosporine (CsA). To determine whether simultaneous administration of these agents could further improve response rates, we enrolled 55 patients in a therapeutic trial of 4 days of ATG and 6 months of CsA. Among the 51 patients who had not received previous courses of ATG or CsA, 67% had responded by 3 months, and 78% had responded by 1 year (response was defined as an increase in peripheral blood counts sufficient that a patient no longer met the criteria for severe disease). There was a high incidence of relapse (36% actuarial risk at 2 years), but most relapsed patients responded to additional courses of immunosuppression, and relapse was not associated with a significant survival disadvantage. Evolution to myelodysplastic syndromes and acute leukemia was rare (1 of 51 patients), but the later appearance of paroxysmal nocturnal hemoglobinuria was more common (5 of 51 patients). Actuarial survival was 86% at 1 year and 72% at 2 years. These data support the use of a combination immunosuppressive regimen containing both ATG and CsA as first-line therapy for severe aplastic anemia.     

Do androgens enhance the response to antithymocyte globulin in patients with aplastic anemia? A prospective randomized trial

We analyzed the effect of antithymocyte globulin (ATG) with or without androgens in 121 patients with aplastic anemia. Fifty-three patients with moderate to severe aplastic anemia were prospectively randomized to receive ATG with or without oral androgens. Eleven of 26 patients (42%) receiving ATG plus androgen responded, including three complete and eight partial responses. Twelve of 27 patients (44%) receiving ATG plus placebo responded, including five complete and seven partial responses. The difference in response rates was not significant (P greater than .9). Survival was also comparable in the two groups; for patients with severe aplastic anemia, actuarial survival at two years was 55% +/- 24% (95% confidence interval) in patients receiving ATG plus androgen compared with 50% +/- 24% in the ATG plus placebo group (P = .65). Furthermore, results in both groups were indistinguishable from those obtained in 68 historical controls receiving ATG without androgens. These data indicate that androgens are not required in order to respond to antithymocyte globulin and the addition of androgens, as used in this trial, did not significantly improve response rates to ATG treatment.     

Long-term outcome of aplastic anemia in adults treated with antithymocyte globulin: comparison with bone marrow transplantation

The outcome of 155 adult aplastic anemia (AA) patients treated with antithymocyte globulin (ATG, Upjohn, Kalamazoo, MI) at University of California, Los Angeles from 1977 to 1988 was evaluated. The median survival of the 146 patients who did not undergo bone marrow transplantation was 5.6 years, with 49% +/- 4% surviving more than 6 years. The most important predictor of survival was positive response to ATG (P < 0.001), which was observed in 48% of patients. Among pretreatment variables, disease severity was the best predictor of survival. Patients with moderate AA (MAA) had significantly better survival than those with severe (SAA) or very severe (VSAA) disease (P = 0.04). The 6-year actuarial survival rates of the three groups were 71% +/- 9%, 48% +/- 7% and 38% +/- 7%, respectively. Cox regression analysis found disease severity to be the only pretreatment variable significantly associated with survival (P = .02). Patient age, sex, disease etiology, concurrent treatment with androgens, or duration of ATG therapy were not associated with differences in survival or response to ATG. Late clonal hematologic complications (ie, myelodysplasia, acute myelogenous leukemia) were observed in 5 of the 77 patients followed for more than 2 years after ATG treatment. In addition, one case of non-Hodgkin's lymphoma and three solid tumors occurred in the ATG-treated patients. The survival of 56 ATG-treated patients with SAA or VSAA between the ages of 16 and 43 did not differ significantly from that of 55 adult AA patients who underwent bone marrow transplant (BMT) during the same time period (P = 0.6). However, 6-year survival rates improved from 43% for patients transplanted before 1984, to 72% for those who underwent BMT between 1984 and 1989. In contrast, there was no difference in the survival rates of patients treated with ATG during these two time periods (46% v 45%, respectively). The results suggest a superior long-term outcome for adult patients with SAA treated with BMT rather than with ATG alone, using current protocols.     

In vivo effects of horse and rabbit antithymocyte globulin in patients with severe aplastic anemia

We recently reported that rabbit antithymocyte globulin was markedly inferior to horse antithymocyte globulin as a primary treatment for severe aplastic anemia. Here we expand on our findings in this unique cohort of patients. Rabbit antithymocyte globulin was detectable in plasma for longer periods than horse antithymocyte globulin; rabbit antithymocyte globulin in plasma retained functional capacity to bind to lymphocytes for up to 1 month, horse antithymocyte globulin for only about 2 weeks. In the first week after treatment there were much lower numbers of neutrophils in patients treated with rabbit antithymocyte globulin than in patients receiving horse antithymocyte globulin. Both antithymocyte globulins induced a “cytokine storm” in the first 2 days after administration. Compared with horse antithymocyte globulin, rabbit antithymocyte globulin was associated with higher levels of chemokine (C-C motif) ligand 4 during the first 3 weeks. Besides a much lower absolute number and a lower relative frequency of CD4⁺ T cells, rabbit antithymocyte globulin induced higher frequencies of CD4⁺CD38⁺, CD3⁺CD4⁻CD8⁻ T cells, and B cells than did horse antithymocyte globulin. Serum sickness occurred around 2 weeks after infusion of both types of antithymocyte globulin. Human anti-antithymocyte globulin antibodies, especially of the IgM subtype, correlated with serum sickness, which appeared concurrently with clearance of antithymocyte globulin in blood and with the production of cytokines. In conclusion, rabbit and horse antithymocyte globulins have very different pharmacokinetics and effects on neutrophils, lymphocyte subsets, and cytokine release. These differences may be related to their efficacy in suppressing the immune system and restoring hematopoiesis in bone marrow failure. Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00260689","term_id":"NCT00260689"}}NCT00260689.