Prospective, Multicenter Clinical Trial of Everolimus as Primary Therapy in Waldenstrom Macroglobulinemia (WMCTG 09-214).
Purpose:Everolimus inhibits mTOR, a component of PI3K/AKT prosurvival signaling triggered by MYD88 and CXCR4-activating mutations in Waldenstrom macroglobulinemia.Experimental design:We evaluated everolimus in a prospective, multicenter study of 33 symptomatic, previously untreated Waldenstrom macroglobulinemia patients. Intended therapy consisted of everolimus (10 mg/day) until progression or unacceptable toxicity. Dose deescalation was permitted. The study was registered at www.clinicaltrials.gov (NCT00976248).Results:At best response, median serum IgM levels declined from 4,440 to 1,360 mg/dL (P< 0.0001), median hemoglobin rose from 10.8 to 12 g/dL (P= 0.001), and median bone marrow disease burden declined from 75% to 52.5% in serially biopsied patients. The ORR and major response rates were 72.7% and 60.6%, respectively. Among genotyped patients, nonresponders associated with wild-type MYD88 and mutated CXCR4 status. Median time to response was 4 weeks. Discordance between serum IgM levels and bone marrow disease burden was remarkable. With a median follow-up of 13.1 (range, 1.6-64.6 months), the median time to progression was 21 months for all patients and 33 months for major responders. Discontinuation of everolimus led to rapid serum IgM rebound in 7 patients and symptomatic hyperviscosity in 2 patients. Toxicity led to treatment discontinuation in 27% of patients, including 18% for pneumonitis.Conclusions:Everolimus is active in previously untreated Waldenstrom macroglobulinemia. IgM discordance is common, and treatment cessation can often lead to rapid serum IgM rebound. Pneumonitis also appears more pronounced in untreated versus previously treated Waldenstrom macroglobulinemia patients. The risks and benefits of everolimus should be carefully weighed against other primary Waldenstrom macroglobulinemia therapy options.Clin Cancer Res; 23(10); 2400-4. ©2016 AACR.
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts. steven_treon@dfci.harvard.edu.
Steven P
SP
Treon
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Kirsten
K
Meid
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Christina
C
Tripsas
Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.
Leonard T
LT
Heffner
Jonsson Comprehensive Cancer Center, UCLA School of Medicine, Los Angeles, California.
Herbert
H
Eradat
Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland.
Ashraf Z
AZ
Badros
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Lian
L
Xu
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Zachary R
ZR
Hunter
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Guang
G
Yang
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Christopher J
CJ
Patterson
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Joshua
J
Gustine
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Jorge J
JJ
Castillo
Rocky Mountain Cancer Center, Denver, Colorado.
Jeffrey
J
Matous
Bing Center for Waldenstrom's Macroglobulinemia at the Dana-Farber Cancer Institute; and Harvard Medical School, Boston, Massachusetts.
Irene M
IM
Ghobrial
D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000473:pathology; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D005838:Genotype; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D008258:Waldenstrom Macroglobulinemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
C527276:CXCR4 protein, human; D007075:Immunoglobulin M; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D019718:Receptors, CXCR4; D000068338:Everolimus