title: Lenalidomide and metronomic melphalan for CMML and higher risk MDS: a phase 2 clinical study with biomarkers of angiogenesis.
abstract: Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.
authors.affiliation: Department of Medical Oncology/Hematology, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada. Electronic address: rena.buckstein@sunnybrook.ca.
authors.forename: Rena
authors.initials: R
authors.lastname: Buckstein
authors.affiliation: Department of Medical Biophysics and Platform Biological Sciences, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Kerbel
authors.affiliation: Department of Medical Oncology/Hematology, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Department of Molecular Pharmacology, Rappaport Faculty of Medicine Technion - Israel Institute of Technology, Haifa, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.affiliation: Department of Medical Oncology/Hematology, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Chodirker
authors.affiliation: Department of Medical Biophysics and Platform Biological Sciences, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Lee
authors.affiliation: Department of Clinical Trials, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Martha
authors.initials: M
authors.lastname: Lenis
authors.affiliation: Department of Medical Oncology/Hematology, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Cindy
authors.initials: C
authors.lastname: Davidson
authors.affiliation: Department of Clinical Trials, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Cussen
authors.affiliation: Departments of Pathology and Laboratory Medicine, Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Marciano
authors.initials: M
authors.lastname: Reis
authors.affiliation: Departments of Pathology and Laboratory Medicine, Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Alden
authors.initials: A
authors.lastname: Chesney
authors.affiliation: Department of Clinical Trials, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Clinical Trials, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mamedov
authors.affiliation: Department of Medical Oncology/Hematology, Odette Cancer and Sunnybrook Health Sciences Center, Toronto, Canada; Department of Biological Sciences, Sunnybrook Research Institute, Toronto, Canada.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Wells
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D042783:Endothelial Cells / Q000502:physiology; D006801:Humans; D000077269:Lenalidomide; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011446:Prospective Studies; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide; D000077269:Lenalidomide; D008558:Melphalan
keywords: Angiogenesis; Biomarker; CMML; Circulating endothelial cells; MDS; VEGF