title: Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases.
abstract: OBJECTIVE
  To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases.
  
  
  METHODS
  Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response.
  
  
  RESULTS
  Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response.
  
  
  CONCLUSIONS
  Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort.
authors.affiliation: Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy. Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Guidetti
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy. Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy. carmelo.carlostella@unimi.it.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
authors.affiliation: Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy. Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Locatelli
authors.affiliation: Istituto Superiore di Sanità, Roma, Italy. San Raffaele Institute, Sulmona, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Malorni
authors.affiliation: Human Tumors Immunobiology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mortarini
authors.affiliation: Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Viviani
authors.affiliation: Hematology and BMT Unit, University of Brescia, Brescia, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.affiliation: Radiology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Marchianò
authors.affiliation: Division of Hematology, S. Croce & Carle Hospital, Cuneo, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sorasio
authors.affiliation: Hematology and BMT Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Dodero
authors.affiliation: Hematology and BMT Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Farina
authors.affiliation: Biostatistic Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giordano
authors.affiliation: Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Di Nicola
authors.affiliation: Human Tumors Immunobiology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Anichini
authors.affiliation: Hematology and BMT Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy. Hematology, University of Milano, Milano, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Corradini
authors.affiliation: Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy. Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy.
authors.forename: Alessandro M
authors.initials: AM
authors.lastname: Gianni
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012008:Recurrence; D000077157:Sorafenib; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D010671:Phenylurea Compounds; D010767:Phosphorylcholine; D009536:Niacinamide; C105905:perifosine; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases