Alemtuzumab treatment of intermediate-1 myelodysplasia patients is associated with sustained improvement in blood counts and cytogenetic remissions

Abstract

Purpose: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and progression to leukemia. Clinical and experimental evidence suggests an immune-mediated pathophysiology in some patients, in whom immunosuppressive therapy (IST) with horse antithymocyte globulin (h-ATG) and cyclosporine (CsA) can be effective. Because of the toxicities associated with h-ATG/CsA, we investigated an alternative regimen with alemtuzumab in MDS.

Patients and methods: We conducted a nonrandomized, off-label, pilot, phase I/II study of alemtuzumab monotherapy in patients with MDS who were judged likely to respond to IST based on the following criteria: HLA-DR15-negative patients whose age plus the number of months of RBC transfusion dependence (RCTD) was less than 58; and HLA-DR15-positive patients whose age plus RCTD was less than 72. In total, 121 patients with MDS were screened, of whom 32 met eligibility criteria to receive alemtuzumab 10 mg/d intravenously for 10 days. Primary end points were hematologic responses at 3, 6, and 12 months after alemtuzumab.

Results: Seventeen (77%) of 22 evaluable intermediate-1 patients and four (57%) of seven evaluable intermediate-2 patients responded to treatment with a median time to response of 3 months. Four of seven evaluable responders with cytogenetic abnormalities before treatment had normal cytogenetics by 1 year after treatment. Five (56%) of nine responding patients evaluable at 12 months had normal blood counts, and seven (78%) of nine patients were transfusion independent.

Conclusion: Alemtuzumab is safe and active in MDS and may be an attractive alternative to ATG in selected patients likely to respond to IST.

Trial registration: ClinicalTrials.gov NCT00217594.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Study design for alemtuzumab for myelodysplastic syndrome. Patients received a 10-day infusion of alemtuzumab as described in Patients and Methods. Follow-up visits and assessment for response were performed at 3, 6, and 12 months. IV, intravenous; CsA, cyclosporine.

Fig 2.

(A) Time to response after alemtuzumab. Patients receiving alemtuzumab had weekly blood counts for the first 3 months and every other week between 3 and 6 months. Response as a function of time was assessed using the Kaplan-Meier method. (B) Response duration in patients treated with alemtuzumab. Patients were monitored for evidence of relapse by routine blood counts as described in Patients and Methods. Relapse was defined as need for additional therapy including initiation of cyclosporine, growth factors, or androgens. Median duration of response has not yet been reached.

Fig A1.

Lymphocyte depletion after alemtuzumab treatment in patients with myelodysplastic syndrome. Absolute lymphocyte counts (cells/μL) from complete blood counts in patients at 0, 1, 3, 6, 12, and 24 months after the first dose of alemtuzumab. Each value represents the mean ± SE for all evaluable patients.

Fig A2.

Graphic representation of blood counts in all patients who achieved a complete response to alemtuzumab treatment. UPN, unique patient number; HGB, hemoglobin; ANC, absolute neutrophil count.

Fig A3.

Paroxysmal nocturnal hemoglobinuria (PNH) clone sizes in patients treated with alemtuzumab. Percentage of glycosylphosphatidylinositol (GPI) -linked anchored protein expression in peripheral blood neutrophils was determined by flow cytometry at 0, 3, 6, and 12 months after alemtuzumab treatment. Each line represents an individual patient.

Fig A4.

Overall survival after alemtuzumab. Kaplan-Meier survival curve is shown for all responders (R) and nonresponders (NR) to alemtuzumab.