B Serio

Alemtuzumab is safe and effective as immunosuppressive treatment for aplastic anaemia and single-lineage marrow failure: a pilot study and a survey from the EBMT WPSAA.

An alemtuzumab‐based experimental immunosuppressive treatment (IST) regimen was investigated in 35 patients with severe aplastic anaemia (SAA), pure red cell (PRCA) or pure white cell aplasia (PWCA). Alemtuzumab total dose was 73–103u2003mgu2003s.c., followed by cyclosporine. No serious toxicity due to the regimen was observed. Adverse events were clinically irrelevant; infectious events were rare. The total response rate was 58%, 84% and 100% in SAA, PRCA and PWCA, respectively, with corresponding 6u2003months cumulative response probabilities of 84%, 84% and 100%. Subcutaneous alemtuzumab is a feasible and sufficiently safe IST regimen for patients suffering from immune‐mediated marrow failures.

High serum leptin in patients with chronic graft-versus-host disease after hematopoietic stem cell transplantation.

Background. Increased serum leptin has been described after various organ transplants, with a mechanism that is still unclear. Methods. We measured serum leptin in 60 patients before and after allogeneic (allo) or autologous (auto) stem cell transplant (SCT) and in 60 healthy controls, matched for age and body mass index (BMI). Results. Serum leptin was higher in patients after SCT than before and in controls. Leptin production was higher after allo- than after auto-SCT; the presence of chronic graft-versus-host disease (cGVHD) was associated with the highest values. The physiological correlation with BMI was lost in the allogeneic setting, indicating a strong influence of factors other than the nutritional status on circulating leptin. No relationship was found between serum leptin levels and time from transplant, age, cortisol, C-reactive protein, and T-lymphocyte CD4-to-CD8 ratio. Among the cytokines secreted by type-1/type-2 T-helper lymphocytes, only serum interferon-gamma significantly correlated with serum leptin levels. Anti-leptin blocking antibodies partially inhibited T-cell activation in mixed lymphocyte reaction, suggesting a link between leptin and T-lymphocyte activation in the allo-SCT setting. Conclusion. Taken together, these findings suggest that increased serum leptin concentrations may contribute to T-cell activation during development of cGVHD.

Valganciclovir as CMV reactivation prophylaxis in patients receiving alemtuzumab for marrow failure syndromes

Dear Editor, Elter et al. recently published in your journal a comprehensive report on the management of infectious risk during treatment by alemtuzumab [1]. Their paper referred exclusively to chronic lymphocytic leukemia patients. Marrow failure syndromes are a group of hematological disorders sharing an immune pathophysiology and may benefit from intense immunosuppressive treatment including antilymphocyte antibodies, such as heterologous antithymocyte globulin (ATG), and cyclosporine A (CyA) [2]. However, given its potent lympholytic effect, alemtuzumab may also be appropriate for patients requiring intense immunosuppression. We recently developed an alemtuzumab-based immunosuppressive treatment for patients suffering from aplastic anemia or singlelineage bone marrow failure disorders [3], with the aim of inducing a more potent and prolonged immunosuppression and allowing retreatment in case of relapse (retreatment is difficult to attempt when using heterologous antisera). We wish to add our own experience in this particular setting, with specific attention to prophylaxis of cytomegalovirus (CMV) reactivation, which remains a major problem limiting a broader use of alemtuzumab. A cohort of consecutive patients suffering from either severe aplastic anemia (SAA), pure red cell aplasia (PRCA) or pure white cell aplasia (PWCA) were enrolled in a prospective phase II clinical trial with alemtuzumabbased immunosuppression (EUDRACT number 2008001151-22). The drug was administered subcutaneously as a single course, at 3–10–30–30–(30) mg doses on four (five) consecutive days (non-SAA patients received the 4day dose), followed by low-dose (1 mg/kg) cyclosporine A starting from day 7; retreatment by alemtuzumab (as complete courses or single shoots) was allowed in case of relapse. Anti-CMV prophylaxis was administered per protocol to all seropositive patients starting day 7, using oral valganciclovir at the dose of 450 mg, bidaily. Initially, anti-CMV prophylaxis was scheduled until CD4+ T cells reached 250 per microliter; however, since after assessment of immune reconstitution performed in the first patients CD4+count sometimes remained below the planned cutoff for many months, the protocol was amended to withdraw valganciclovir at CD4+ levels above 100 per microliter, and in any case 3 months after treatment. All patients received also anti-Pneumocystisjiroveci prophylaxis by low-dose oral trimethoprimsulfamethoxazole (bidaily three times per week), as well as standard antibacterial and antifungal prophylaxis in case of severe (<500 per microliter) neutropenia. Twentythree consecutive patients were enrolled in the study (ten SAA, ten PRCA, and three PWCA) and received a total of 45 courses of alemtuzumab; additional courses were given in five SAA, four PRCA, and one PWCA patients who relapsed after responding to the initial treatment. All patients received prophylactic valganciclovir because they were CMV IgG seropositive. All patients showed complete lymphoablation within 2–3 days, which lasted several months. CMV antigenemia was monitored weekly by polymerase chain reaction (PCR), to be ready for preemptive therapy; CMV reactivation was defined as a positive PCR (detection limit 1,000 copies per milliliter) in two consecutive samples. After a cumulative follow-up Ann Hematol (2009) 88:1261–1262 DOI 10.1007/s00277-009-0749-z

Novel Immunosuppressive Strategies for Bone Marrow Failure Syndromes: A Focus on Alemtuzumab

Acquired bone marrow failure syndromes (BMFS) are a heterogeneous group of hematological disorders characterized by impaired bone marrow function and subsequent cytopenia of one or more blood cell lineages [1,2]. The well-accepted pathogenic mechanism of the typical bone marrow failure - aplastic anemia (AA)- is a T cell mediated immune attack targeting the hematopoietic tissue [3]. This pathogenic mechanism is at least partially shared by other bone marrow failure syndromes, such as lineage-restricted aplasias and some myelodysplastic syndromes. Thus, for these disorders immunosuppression (IS) is the pivotal etiologic treatment. While the standard IS regimen include the heterologous anti-thymocyte globulin [4], here we review the recent data on the anti-CD52 monoclonal antibody alemtuzumab as a novel IS agent for marrow failures. Alemtuzumab led to objective responses in aplastic anemia patients in 3 recent prospective studies, with overall response rates ranging between 37% and 72%. Adverse events were irrelevant, ruling out even the concerns about the risk of infectious complications. Alemtuzumab was effective even for the treatment of lineage-restricted marrow failure, with very acceptable toxicity and excellent response rates (as high as 80%). More recently, even patients suffering from myelodysplastic syndromes showed a remarkable hematological response to alemtuzumab-based IS treatment. Thus, alemtuzumab is a novel IS agent representing an excellent alternative to ATG for all immune-mediated marrow failure syndromes. Even if the dose and the schedule may still require further refining, the available data support the need of large prospective trials comparing alemtuzumab to current standard IS regimens.