title: Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial.
abstract: OBJECTIVE
  In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination.
  
  
  METHODS
  Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS).
  
  
  RESULTS
  The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%.
  
  
  CONCLUSIONS
  Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.
authors.affiliation: University of Liverpool, Liverpool, UK. arp@liverpool.ac.uk
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pettitt
authors.forename: Richard
authors.initials: R
authors.lastname: Jackson
authors.forename: Stacey
authors.initials: S
authors.lastname: Carruthers
authors.forename: James
authors.initials: J
authors.lastname: Dodd
authors.forename: Susanna
authors.initials: S
authors.lastname: Dodd
authors.forename: Melanie
authors.initials: M
authors.lastname: Oates
authors.forename: Gillian G
authors.initials: GG
authors.lastname: Johnson
authors.forename: Anna
authors.initials: A
authors.lastname: Schuh
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.forename: Claire E
authors.initials: CE
authors.lastname: Dearden
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.forename: John A
authors.initials: JA
authors.lastname: Radford
authors.forename: Adrian
authors.initials: A
authors.lastname: Bloor
authors.forename: George A
authors.initials: GA
authors.lastname: Follows
authors.forename: Stephen
authors.initials: S
authors.lastname: Devereux
authors.forename: Anton
authors.initials: A
authors.lastname: Kruger
authors.forename: Julie
authors.initials: J
authors.lastname: Blundell
authors.forename: Samir
authors.initials: S
authors.lastname: Agrawal
authors.forename: David
authors.initials: D
authors.lastname: Allsup
authors.forename: Stephen
authors.initials: S
authors.lastname: Proctor
authors.forename: Earnest
authors.initials: E
authors.lastname: Heartin
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Hamblin
authors.forename: Andrew
authors.initials: A
authors.lastname: Rawstron
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
mesh_terms: D000047:Academies and Institutes; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074323:Alemtuzumab; D019072:Antibiotic Prophylaxis / Q000379:methods; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D016015:Logistic Models; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012074:Remission Induction; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074323:Alemtuzumab; D008775:Methylprednisolone