title: Alemtuzumab in T-cell large granular lymphocytic leukaemia: interim results from a single-arm, open-label, phase 2 study.
abstract: BACKGROUND
  T-cell large granular lymphocytic leukaemia (T-LGL) is a lymphoproliferative disease that presents with immune-mediated cytopenias and is characterised by clonal expansion of cytotoxic CD3+ CD8+ lymphocytes. Use of methotrexate, ciclosporin, or cyclophosphamide as first therapy improves cytopenias in 50% of patients, but long-term use of these can lead to toxicity. We aimed to explore the activity and safety of alemtuzumab, an anti-CD52 monoclonal antibody, in patients with T-LGL.
  
  
  METHODS
  We did this single-arm, phase 2 trial in consecutively enrolled adults with T-LGL referred to the National Institutes of Health in Bethesda, MD, USA. Alemtuzumab was given intravenously at 10 mg per day for 10 days. The primary endpoint was haematological response at 3 months after infusion. A complete response was defined as normalisation of all affected lineages, and a partial response was defined in neutropenic patients as 100% increase in the absolute neutrophil count to more than 5 × 10(8) cells per L, and in those with anaemia, as any increase in haemoglobin of 20 g/L or higher observed in at least two serial measurements 1 week apart and sustained for 1 month or longer without exogenous growth factors support or transfusions. Analysis was by intention to treat. We report results from the first stage of this Simon two-stage design trial; enrolment into the second stage is continuing. This study is registered with ClinicalTrials.gov, number NCT00345345.
  
  
  RESULTS
  From Oct 1, 2006, to March 1, 2015, we enrolled 25 patients with T-LGL. 14 patients (56%; 95% CI 35-76) had a haematological response at 3 months. Four patients with associated myelodysplastic syndrome and two who had received haemopoietic stem cell transplantation had either no response or were not evaluable, meaning 14 (74% [49-91]) of the 19 patients with classic T-LGL responded. All patients had an infusion reaction (24 [96%] patients grade 1-2, one [4%] patient grade 3), which improved with symptomatic therapy. All patients developed lymphopenia, with 22 (88%) patients having grade 3 or 4 lymphopenia. The other most common grade 3 and 4 adverse events were leukopenia (eight [32%]) and neutropenic infections (five [20%]). Seven patients died; all were non-responders.
  
  
  CONCLUSIONS
  This is the largest and only prospective study of alemtuzumab in patients with T-LGL. The activity reported with a single course of a lymphocytotoxic drug in patients with mainly relapsed and refractory disease suggests that haematological response can be achieved without continued use of oral immunosuppression.
  
  
  BACKGROUND
  National Heart, Lung, and Blood Institute.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Sawa
authors.initials: S
authors.lastname: Ito
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Xingmin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Stephens
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Muharrem
authors.initials: M
authors.lastname: Yunce
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kajigaya
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Melenhorst
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Rios
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Priscila
authors.initials: P
authors.lastname: Scheinberg
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Fariba
authors.initials: F
authors.lastname: Chinian
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Minoo
authors.initials: M
authors.lastname: Battiwalla
authors.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Colin O
authors.initials: CO
authors.lastname: Wu
authors.affiliation: Department of Laboratory Medicine, Clinical Center, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Townsley
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, MD, USA.
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Barrett
authors.affiliation: Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa, São Paulo, SP, Brazil. Electronic address: phillip.scheinberg@hospitalsjose.org.br.
authors.forename: Phillip
authors.initials: P
authors.lastname: Scheinberg
mesh_terms: D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012074:Remission Induction; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074323:Alemtuzumab