title: Ibrutinib in previously treated Waldenström's macroglobulinemia.
abstract: BACKGROUND
  MYD88(L265P) and CXCR4(WHIM) mutations are highly prevalent in Waldenström's macroglobulinemia. MYD88(L265P) triggers tumor-cell growth through Bruton's tyrosine kinase, a target of ibrutinib. CXCR4(WHIM) mutations confer in vitro resistance to ibrutinib.
  
  
  METHODS
  We performed a prospective study of ibrutinib in 63 symptomatic patients with Waldenström's macroglobulinemia who had received at least one previous treatment, and we investigated the effect of MYD88 and CXCR4 mutations on outcomes. Ibrutinib at a daily dose of 420 mg was administered orally until disease progression or the development of unacceptable toxic effects.
  
  
  RESULTS
  After the patients received ibrutinib, median serum IgM levels decreased from 3520 mg per deciliter to 880 mg per deciliter, median hemoglobin levels increased from 10.5 g per deciliter to 13.8 g per deciliter, and bone marrow involvement decreased from 60% to 25% (P<0.01 for all comparisons). The median time to at least a minor response was 4 weeks. The overall response rate was 90.5%, and the major response rate was 73.0%; these rates were highest among patients with MYD88(L265P)CXCR4(WT) (with WT indicating wild-type) (100% overall response rate and 91.2% major response rate), followed by patients with MYD88(L265P)CXCR4(WHIM) (85.7% and 61.9%, respectively) and patients with MYD88(WT)CXCR4(WT) (71.4% and 28.6%). The estimated 2-year progression-free and overall survival rates among all patients were 69.1% and 95.2%, respectively. Treatment-related toxic effects of grade 2 or higher included neutropenia (in 22% of the patients) and thrombocytopenia (in 14%), which were more common in heavily pretreated patients; postprocedural bleeding (in 3%); epistaxis associated with the use of fish-oil supplements (in 3%); and atrial fibrillation associated with a history of arrhythmia (5%).
  
  
  CONCLUSIONS
  Ibrutinib was highly active, associated with durable responses, and safe in pretreated patients with Waldenström's macroglobulinemia. MYD88 and CXCR4 mutation status affected responses to this drug. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01614821.).
authors: From the Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute (S.P.T., C.K.T., K.M., D.W., G.Y., Y.C., L.X., C.J.P., S.K., I.G., J.J.C., J.P.L., Z.R.H.), Harvard Medical School (S.P.T., G.Y., Y.C., S.R., J.C.A., N.L.H., I.G., J.J.C., J.P.L.), Department of Pathology, Brigham and Women's Hospital (S.R., J.C.A.), Department of Pathology, Massachusetts General Hospital (N.L.H.), and Department of Pathology, Boston University Medical Center (Z.R.H.) - all in Boston; Memorial Sloan Kettering Cancer Center, New York (R.G., K.V.A., M.L.P.); and Stanford University Medical Center, Stanford (G.V., J.L.Z., R.H.A.), and Pharmacyclics, Sunnyvale (Z.S., J.L., M.C., F.C., T.G.) - both in California.
authors: Steven P
authors: SP
authors: Treon
authors: Christina K
authors: CK
authors: Tripsas
authors: Kirsten
authors: K
authors: Meid
authors: Diane
authors: D
authors: Warren
authors: Gaurav
authors: G
authors: Varma
authors: Rebecca
authors: R
authors: Green
authors: Kimon V
authors: KV
authors: Argyropoulos
authors: Guang
authors: G
authors: Yang
authors: Yang
authors: Y
authors: Cao
authors: Lian
authors: L
authors: Xu
authors: Christopher J
authors: CJ
authors: Patterson
authors: Scott
authors: S
authors: Rodig
authors: James L
authors: JL
authors: Zehnder
authors: Jon C
authors: JC
authors: Aster
authors: Nancy Lee
authors: NL
authors: Harris
authors: Sandra
authors: S
authors: Kanan
authors: Irene
authors: I
authors: Ghobrial
authors: Jorge J
authors: JJ
authors: Castillo
authors: Jacob P
authors: JP
authors: Laubach
authors: Zachary R
authors: ZR
authors: Hunter
authors: Zeena
authors: Z
authors: Salman
authors: Jianling
authors: J
authors: Li
authors: Mei
authors: M
authors: Cheng
authors: Fong
authors: F
authors: Clow
authors: Thorsten
authors: T
authors: Graef
authors: M Lia
authors: ML
authors: Palomba
authors: Ranjana H
authors: RH
authors: Advani
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D018572:Disease-Free Survival; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D010880:Piperidines; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000235:genetics; D015996:Survival Rate; D008258:Waldenstrom Macroglobulinemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics
chemical_list: C527276:CXCR4 protein, human; D006454:Hemoglobins; D007075:Immunoglobulin M; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D019718:Receptors, CXCR4; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000225:Adenine