title: High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities.
abstract: Abnormalities of the p53 gene are known to confer detrimental effects in chronic lymphocytic leukaemia (CLL) and are associated with short survival. We have used high dose methylprednisolone (HDMP) to treat 25 patients with advanced refractory CLL of whom 45% had p53 abnormalities shown by one or more methods: flow cytometry, fluorescent in situ hybridisation and direct DNA sequencing. Fifteen were resistant to fludarabine and 16 were non-responders to their most recent therapy. Methylprednisolone had a cytotoxic effect on lymphocytes from 95% of cases assessed by an ex vivo apoptotic drug sensitivity index (DSI). HDMP was given alone or in combination with other drugs: vincristine, CCNU, Ara-C, doxorubicin, mitoxantrone and chlorambucil, according to the results of DSI. Three patients were treated twice and each treatment was analysed separately. The overall response rate was 77% with a median duration of 12 months (range 7 -23+). Responders included 5/10 with abnormal p53, of which two achieved nodular PR. Patients with p53 abnormalities fared worse than those with normal p53. There were no differences in response according to whether HDMP was used alone or in combination. Nine of the 22 evaluable patients (3 NR and 6 PR) have died from progressive disease or transformation. Main toxicity was infection in 7/25 patients. Event free and overall survival were significantly better in responders vs non-responders ( P>0.0001 and P=0.04 respectively). Patients with a DSI of 100% to steroids had a better overall and event free survival, but this was not statistically significant. This study demonstrates that HDMP alone or in combination with other agents is a useful treatment strategy in refractory CLL including patients with p53 abnormalities.
authors.affiliation: Academic Department of Haematology and Cytogenetics, The Royal Marsden NHS Trust, London, UK.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Thornton
authors.forename: Estella
authors.initials: E
authors.lastname: Matutes
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bosanquet
authors.forename: Anil K
authors.initials: AK
authors.lastname: Lakhani
authors.forename: Henri
authors.initials: H
authors.lastname: Grech
authors.forename: Janet E
authors.initials: JE
authors.lastname: Ropner
authors.forename: Rajeev
authors.initials: R
authors.lastname: Joshi
authors.forename: Peter H
authors.initials: PH
authors.lastname: Mackie
authors.forename: Ian D C
authors.initials: ID
authors.lastname: Douglas
authors.forename: Stella J
authors.initials: SJ
authors.lastname: Bowcock
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D009154:Mutation; D012074:Remission Induction; D014407:Tumor Cells, Cultured
chemical_list: D008775:Methylprednisolone