Prolonged Severe Pancytopenia and Myelodysplastic Features Following Alemtuzumab Therapy in Patients with Cutaneous T-Cell Lymphomas.
Authors: Gibbs Simon D. , Westerman David Alan , Seymour John Francis , Prince Miles 
Published: April 2020

Background. Alemtuzumab is an increasingly utilized salvage therapy for refractory and/or relapsed B- and T-cell lymphoproliferative disorders with response rates of ~35%. Therapy has been associated with significant infectious and haematologic toxicity. Multilineage cytopenias are a recognised complication, but have been described mostly among patients with CLL and are transient. We report four of twelve (33%) patients treated with alemtuzumab for T-cell lymphoproliferative disorders with unexpectedly prolonged multilineage cytopenias (4 - 11+ months) including two cases of marrow aplasia and one of definitive clonal myelodysplasia.

Methods. Patients received the standard alemtuzumab schedule (Eur J Haematol71:250, 2003) of one dose of 3mg IV on d1,10mg on d3 and 30mg on d5, then 30 mg thrice weekly for 12 weeks. Cytomegalovirus (CMV) PCR was performed in all cases of fever, or pancytopenia. Haematologic toxicity was graded according to the NCI Common Toxicity Criteria.

Results. 11 patients with advanced (IIB-IV) relapsed and/or refractory cutaneous T-cell lymphomas and one with T-cell PLL were treated. The median age was 55 years (range 29 – 69) and the median number of previous treatments was 4 (range 0 – 17). The median cumulative dose of alemtuzumab was 333mg (range 98–1056). Five patients (42%) experienced grade IV (&lt;0.5 x 109/L) neutropenia and thrombocytopenia (&lt;25 x 109/L). In 4 cases this severity of cytopenias lasted &gt; 2 months, some never recovering before their death, or with persisting cytopenias during follow-up. The fifth patient died five weeks after starting alemtuzumab with pancytopenia and progressive disease. Four had confirmed CMV reactivation. Neutropenia occurred within 2 weeks of reactivation and in 2 patients, pancytopenia occurred before ganciclovir commenced. One patient who did not experience prolonged pancytopenia had CMV reactivation. One had evidence of chronic parvovirus P19 infection and none had evidence of haemophagocytosis.

Discussion. In our series, the alemtuzumab-associated cytopenias were more prolonged than previously described. In four patients, recovery occurred well after the expected two weeks. Two had evidence of marrow aplasia, one of whom died soon after this diagnosis; the other is alive, remaining pancytopenic and transfusion dependent at 14+ weeks after treatment. A third patient was diagnosed with myelodysplasia (cytogenetics: 45X, Y(8)/46, XY (12)), never recovering normal counts, now 12 months post treatment. There was no difference in the liklihood of developing cytopenias in terms of age, sex or dose of alemtuzumab and the pancytopenia never heralded disease recurrence. The exact mechanism of alemtuzumab-associated haematologic toxicity remains elusive. While prolonged lymphopenia is expected, pancytopenia is unexpected since neither haematopoietic stem cells (CD34+) nor more mature myeloid or erythroid cells or megakaryocytes express CD52. We believe the prolonged cytopenias observed were partially a direct effect of alemtuzumab as we excluded infective causes such as parvovirus P19 in four of the five patients and haemophagocytosis in all. Whether the CMV reactivation is involved in the development of, or prolongs the duration of the cytopenias is unknown and further study into the link between CMV and alemtuzumab in the advent of cytopenias in T-cell lymphoproliferative disorders is warranted.