Subcutaneous alemtuzumab plus cyclosporine for the treatment of aplastic anemia

Antithymocyte globulin (ATG) ؉ cyclosporine is effective in restoring hematopoiesis in severe aplastic anemia (SAA). We hypothesized that the humanized anti-CD52 mAb alemtuzumab might be active in SAA because of its lymphocytotoxic properties. We investigated alemtuzumab monotherapy from 2003-2010 in treatmentnaive, relapsed, and refractory SAA in 3 separate research protocols at the National Institutes of Health. Primary outcome was hematologic response at 6 months. For refractory disease, patients were randomized between rabbit ATG ؉ cyclosporine (n ‫؍‬ 27) and alemtuzumab (n ‫؍‬ 27); the response rate for alemtuzumab was 37% (95% confidence interval [CI], 18%-57%) and for rabbit ATG 33% (95% CI, 14%-52%; P ‫؍‬ .78). The 3-year survival was 83% (95% CI, 68%-99%) for alemtuzumab and 60% (95% CI, 43%-85%) for rabbit ATG (P ‫؍‬ .16). For relapsed disease (n ‫؍‬ 25), alemtuzumab was administered in a single-arm study; the response rate was 56% (95% CI, 35%-77%) and the 3-year survival was 86% (95% CI, 72%-100%). In treatment-naive patients (n ‫؍‬ 16), alemtuzumab was compared with horse and rabbit ATG in a 3-arm randomized study; the response rate was 19% (95% CI 0%-40%), and the alemtuzumab arm was discontinued early. We conclude that alemtuzumab is effective in SAA, but best results are obtained in the relapsed and refractory settings. The present trials were registered at www.clinicaltrials.gov as NCT00195624, NCT00260689, and NCT00065260. (Blood. 2012;119(2):345-354)

Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia

Scheinberg¹,

Núñez²,

Weinstein³

et al. 2012

“…Responses have been reported in several small series for untreated patients and nonresponders to ATG. [34][35][36] A large prospective study from the National Institutes of Health showed 37% response for refractory SAA and 56% for relapsed SAA. Patients with untreated SAA were randomized to alemtuzumab as part of the third arm of the prospective randomized study from the National Institutes of Health, the other 2 arms being hATG and rATG, respectively, as reported by Scheinberg et al 17 The third arm using alemtuzumab was closed prematurely because of 3 early deaths and a response rate of only 19%.…”

Section: Discussionmentioning

confidence: 99%

Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party

Marsh

Bacigalupo

Schrezenmeier

et al. 2012

151

136

Rabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age-and disease severitymatched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P ‫؍‬ .009). Transplant-free survival was 52% for rATG and 76% for hATG (P ‫؍‬ .002). On multivariate analysis, rATG (hazard ratio ‫؍‬ 3.9, P ‫؍‬ .003) and age more than 37 years (hazard ratio ‫؍‬ 4.7, P ‫؍‬ .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848. (Blood. 2012;119(23): 5391-5396) IntroductionHistorically, horse antithymocyte globulin (hATG) has been the preferred animal source of ATG as first-line treatment for acquired aplastic anemia (AA) patients who are ineligible for hematopoietic stem cell transplantation (HSCT). For severe AA (SAA), the combination of ATG and cyclosporine (CSA) results in a response rate of 60% to 75% of patients, and the response is superior to using either agent alone. [1][2][3][4][5] The addition of G-CSF to the combination of ATG and CSA has shown no significant benefit either in terms of response or survival, 6-8 although it may reduce infectious complications and duration of hospital admission. 6 For patients with nonsevere AA (NSAA) who are transfusion dependent, the combination of ATG and CSA is superior to CSA alone, with a higher response rate, higher blood counts, and improved disease-free survival. 9 Rabbit ATG (rATG) is more commonly used for a second course after relapse or lack of response to a first course of hATG. Response to a second course for nonresponse to a first course varies from 30% to 77% 10,11 and only 11% in children. 12 In contrast, in patients relapsing after a first course, the response to a second course is 65%. 11,13 Until 2007, there were 2 preparations of hATG, namely, lymphoglobulin (Genzyme) and ATGAM (Pfizer). The most commonly used preparation of rATG (thymoglobulin, Genzyme) uses the same immunogen as lymophoglobulin; horses or rabbits are immunized with human thymocytes obtained at the time of cardiac surgery from newborn infants. rATG is more immunosuppressive than hATG; it results in more prolonged lymphopenia, 14 and it is more effective at preventing and treating acute renal allograft rejection. 15 We undertook a European study conducted by th...

“…Small series of patients indicate that alemtuzumab at conventional doses [15][16][17][18] may induce responses in severe AIHA cases, and lower doses have been also effective in other immunologic diseases. 22,23 In our study, 3 of 8 patients with AIHA maintained CR at 33, 46, and 89 weeks. One TT indicates time to treatment; PR, partial response; CR, complete response; P, prednisone; S, splenectomy; D, danazol; Cy, cyclophosphamide; IVIG, intravenous immunoglobulin; MP, methylprednisolone; and Dex, dexamethasone.…”

Section: Resultsmentioning

confidence: 46%

Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias

Gómez‐Almaguer

Solano-Genesta

Tarín‐Arzaga

et al. 2010

Self Cite

Treatment of autoimmune cytopenias remains unsatisfactory for patients refractory to first-line management. We evaluated the safety and efficacy of low-dose rituximab plus alemtuzumab in patients with steroidrefractory autoimmune hemolytic anemia and immune thrombocytopenic purpura. Nineteen of 21 included patients were assessable for response (11 with immune thrombocytopenic purpura, 8 with autoimmune hemolytic anemia). Treatment with 10 mg of alemtuzumab subcutaneously on days 1 to 3, plus 100 mg of rituximab intravenously weekly in 4 doses, was administered. The overall response rate was 100%, with complete response in 58%. IntroductionAutoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) are characterized by antibody-mediated destruction of red blood cells and platelets; as in other autoimmune disorders, B and T lymphocytes have important roles in their pathogenesis. 1 Corticosteroids are the standard initial treatment, with a 60% response rate. Patients unresponsive to corticosteroids usually experience a complicated course and show increased morbidity and mortality rates. Splenectomy and a large number of drugs have been used as second-line therapies with variable success, without evidence that any single agent is more effective than another. 2 Rituximab effectively depletes B cells involved in the production of antibodies and has been studied as a second-line treatment for ITP at full 3-10 and low doses 11,12 ; its use in ITP has led to a median overall response rate of approximately 60%. 7,9 Alemtuzumab, a humanized IgG monoclonal antibody specific for the CD52 antigen, expressed on lymphocytes, has been used in the treatment of lymphoproliferative disorders and recently for autoimmune diseases. 13,14 Preliminary results indicate that alemtuzumab may induce responses in patients with autoimmune cytopenias. [15][16][17][18] We evaluated the safety and efficacy of low-dose rituximab plus alemtuzumab in combination therapy in patients with steroidrefractory AIHA and ITP. The rationale for combining the 2 monoclonal antibodies was their reported single-agent activity, and the possibility of a synergistic effect, based on the fact that T lymphocytes are involved in the control of expansion of immunoglobulinproducing, autoreactive B-lymphocyte clones. MethodsApproval for the study was obtained from the Ethics Committee of the School of Medicine and University Hospital of the Universidad Autónoma de Nuevo León. Eligible patients were adults with active symptomatic ITP or AIHA, who had previously received treatment with at least one line of therapy, or followed a chronic relapsing course, and who provided written informed consent. Patients were excluded if they had active bacterial or viral infection, HIV, hepatitis C virus, cytomegalovirus immunoglobulin M (CMV-IgM)-positive serology, hepatitis B surface antigen positivity, pregnancy, or concomitant malignant disease. Pretreatment assessment included complete blood, reticulocyte, lymphocyte subset counts, serum immunoglobulins, direct an...