title: Alemtuzumab and CHOP Chemotherapy for the Treatment of Aggressive Histology Peripheral T Cell Lymphomas: A Multi-Center Phase I Study.
abstract: BACKGROUND
  Alemtuzumab has single-agent activity in relapsed peripheral T cell lymphoma (PTL), but the optimal dose and/or schedule in combination with chemotherapy for first-line use is unknown. The primary objectives were to establish the maximally tolerated dose and pharmacokinetics (PK) of alemtuzumab combined in this way.
  
  
  METHODS
  Adult patients with untreated CD52-positive (CD52(+)) PTL were enrolled in a phase I trial. Alemtuzumab was given subcutaneously in escalating doses and/or schedules in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) using a 3+3 design. Trough PK of alemtuzumab were measured on day 1 of each 21-day cycle and B and T cell subsets were serially measured.
  
  
  RESULTS
  Twenty patients were enrolled across 4 dose levels. Dose-limiting toxicities necessitated expansion at 10 mg weekly (fatal tuberculosis reactivation) and 60 mg every 3 weeks (grade 4 thrombocytopenia) dose levels. Maximally tolerated dose was not reached. Ten patients developed asymptomatic cytomegalovirus reactivations at a median of 39 days (range, 4-99 days). Two patients developed fungal pneumonias. The overall and complete response rates were 68% and 37%, respectively. Highest day 1 alemtuzumab trough levels were achieved at 60 mg (1973 ng/mL), but with significant inter- and intradose variability. Lymphopenia at baseline was common and T cell recovery was significantly delayed.
  
  
  CONCLUSIONS
  With monitoring and prophylaxis, alemtuzumab 60 mg combined with CHOP showed activity in CD52(+) PTL and achieved the highest drug levels.
authors.affiliation: Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada. Electronic address: Rena.buckstein@sunnybrook.ca.
authors.forename: Rena
authors.initials: R
authors.lastname: Buckstein
authors.affiliation: Juravinski Hospital and Cancer Center and McMaster University, Hamilton, Ontario, Canada.
authors.forename: Graeme
authors.initials: G
authors.lastname: Fraser
authors.affiliation: Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cheung
authors.affiliation: University Health Network-Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Vishal
authors.initials: V
authors.lastname: Kukreti
authors.affiliation: University Health Network-Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Kuruvilla
authors.affiliation: Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Imrie
authors.affiliation: Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Piliotis
authors.affiliation: Ontario Clinical Oncology Group (OCOG), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Gregory
authors.initials: G
authors.lastname: Pond
authors.affiliation: Ontario Clinical Oncology Group (OCOG), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Windsor
authors.affiliation: Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Zeina
authors.initials: Z
authors.lastname: Ghorab
authors.affiliation: Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shuoprasad
authors.affiliation: University Health Network-Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Turner
authors.affiliation: Juravinski Hospital and Cancer Center and McMaster University, Hamilton, Ontario, Canada.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Meyer
authors.affiliation: Odette Cancer Center, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard
authors.affiliation: Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Walker
authors.affiliation: Ontario Clinical Oncology Group (OCOG), McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
authors.affiliation: University Health Network-Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Crump
mesh_terms: D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000074301:CD52 Antigen; D003520:Cyclophosphamide / Q000627:therapeutic use; D003587:Cytomegalovirus / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000097:blood / Q000517:prevention & control; D004317:Doxorubicin / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011241:Prednisone / Q000627:therapeutic use; D014750:Vincristine / Q000627:therapeutic use; D014775:Virus Activation; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000074301:CD52 Antigen; C000613862:CD52 protein, human; D006023:Glycoproteins; D000074323:Alemtuzumab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone
keywords: CD52(+); Immune reconstitution; PTL; Pharmacokinetics; Phase 1