Subcutaneous Alemtuzumab as Treatment Option for Patients with Severe Aplastic Anemia or Lineage-Restricted Aplasia.
Authors: Risitano Antonio M. , Selleri Carmine , Camera Andrea , Gallotta Giovanni , Perna Fabiana , Copeta Giampaolo , Rotoli Bruno 
Published: October 2019

Abstract
Severe aplastic anemia (SAA) is a typical acquired marrow failure syndrome, presenting with pancytopenia associated to an empty marrow. Less frequent forms of mono-lineage cytopenia may be due to selective aplasia, as in pure red cell aplasia (PRCA) or in agranulocytosis. The link among these conditions is their cellular immune-mediated pathophysiology, which is supported by many experimental data; for these conditions different immunosuppressive strategies have been employed. Here we report our preliminary experience with alemtuzumab as alternative immunosuppressive therapy in patients failing or not eligible for standard immunosuppression. Three patients have been treated: (i). a 39 year-old male affected by SAA, who had failed to respond to two lines of therapy; (ii). a 55 year-old female, suffering from recurrent agranulocytosis, responding to methylprednisone (MP) for 4 years but then refractory to MP, cyclosporine A (CsA) and G-CSF; (iii). a 60 year-old male affected by PRCA, who developed significant early toxicity by steroid treatment. All patients received alemtuzumab as subcutaneous injection, with a dose escalating schedule of 3–10–30–30–(30) mg in consecutive days; the total dose was 103 mg for SAA, and 73 for PRCA and agranulocytosis. The patients received MP 1 mg/kg in concomitance with alemtuzumab, with the exception of the PRCA patient, due to his previous steroid toxicity; all patients on day 7 started low dose CsA (1 mg/kg). Valgancyclovir 450 mg bi-daily and trimethoprim-sulphamethoxazole bidaily twice a week were administered as anti-CMV and anti-Pneumocystis Carinii prophylaxis, respectively. Two of the patients completed the treatment without any side effect, while the PRCA patient experienced injection-related febrile reactions, managed by doubling the dose interval. No significant abnormality of routine biochemical tests was reported. A complete lympho-ablation was observed in all patients within 3–4 days, which persisted for 3 months. No infectious event was observed at a median follow-up of 6 months, nor other medical complications. After 6 months, flow cytometry documented a partial T cell recovery, with persistence of CD4+ cells reduction. No GPI-anchored protein deficient clone was documented within each blood cell lineage. As efficacy of the treatment is concerned, the patients will be described individually. The SAA patient did not show any clinical improvement at +8 months from treatment, with persistent platelet and red cell transfusion requirement. In contrast, the women affected by agranulocytosis showed early and stable response, with absolute neutrophil counts raising from 0 to 3,000/uL (15,000/uL during G-CSF administration); at +6 months from treatment, she is well, free from any treatment, with the exception of a weekly dose of G-CSF. Finally, the PRCA patient did not show any improvement for 3 months, still requiring transfusions. In the fourth month, he suddenly showed a marked rise of reticulocyte count (130,000/uL), which leaded in few weeks to transfusion independence and hemoglobin stabilization; at +6 months, he is on low dose CsA with hemoglobin >12 g/dL. In conclusion, alemtuzumab administered as subcutaneous injection is a feasible and safe treatment which may be indicated for patients suffering from immune-mediated acquired marrow failure syndromes. Its positioning in the setting of immunosuppression is still to be established, and promises to be pivotal if the favourable risk-to-benefit profile shown in this preliminary experience will be confirmed.