title: Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia.
abstract: We examined the combination of the mammalian target of rapamycin inhibitor everolimus with bortezomib and rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM) in a phase I/II study. All patients received six cycles of the combination of everolimus/rituximab or everolimus/bortezomib/rituximab followed by maintenance with everolimus until progression. Forty-six patients were treated; 98% received prior rituximab and 57% received prior bortezomib. No dose-limiting toxicities were observed in the phase I. The most common treatment-related toxicities of all grades were fatigue (63%), anemia (54%), leucopenia (52%), neutropenia (48%) and diarrhea (43%). Thirty-six (78%) of the 46 patients received full dose therapy (FDT) of the three drugs. Of these 36, 2 (6%) had complete response (90% confidence interval (CI): 1-16). In all, 32/36 (89%) of patients experienced at least a minimal response (90% CI: 76-96%). The observed partial response or better response rate was 19/36 (53, 90 CI: 38-67%). For the 36 FDT patients, the median progression-free survival was 21 months (95% CI: 12-not estimable). In summary, this study demonstrates that the combination of everolimus, bortezomib and rituximab is well tolerated and achieved 89% response rate even in patients previously treated, making it a possible model of non-chemotherapeutic-based combination therapy in WM.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Ghobrial
authors.affiliation: Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Redd
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Armand
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Banwait
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Boswell
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chuma
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Huynh
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Roccaro
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Perilla-Glen
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Noonan
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: MacNabb
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Leblebjian
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Warren
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Henrick
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Castillo
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Colorado Blood Cancer Institute, Denver, CO, USA.
authors.forename: J
authors.initials: J
authors.lastname: Matous
authors.affiliation: Department of Biostatistics, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Weller
authors.affiliation: Medical Oncology, Dana-Farber Cancer Center, Boston, MA, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Treon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000069286:Bortezomib / Q000008:administration & dosage / Q000009:adverse effects; D004359:Drug Therapy, Combination; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D012008:Recurrence; D000069283:Rituximab / Q000008:administration & dosage / Q000009:adverse effects; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy*
chemical_list: C527276:CXCR4 protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D019718:Receptors, CXCR4; D000069283:Rituximab; D000069286:Bortezomib; D000068338:Everolimus