{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:53:37Z","timestamp":1790963617448,"version":"4.1.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420\u2009mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without <jats:italic>CXCR4<\/jats:italic> mutations (14% vs. 44%; <jats:italic>p<\/jats:italic>\u2009=\u20090.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated <jats:italic>CXCR4<\/jats:italic> at 1.7 months (<jats:italic>p<\/jats:italic>\u2009=\u20090.07) and 7.3 months (<jats:italic>p<\/jats:italic>\u2009=\u20090.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without <jats:italic>CXCR4<\/jats:italic> mutations (59% vs. 92%; <jats:italic>p<\/jats:italic>\u2009=\u20090.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. <jats:italic>CXCR4<\/jats:italic> mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.<\/jats:p>","DOI":"10.1038\/s41375-021-01417-9","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T13:04:38Z","timestamp":1631797478000},"page":"532-539","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia"],"prefix":"10.1038","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-7532","authenticated-orcid":false,"given":"Jorge J.","family":"Castillo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Meid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6717-7669","authenticated-orcid":false,"given":"Joshua N.","family":"Gustine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carly","family":"Leventoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine A.","family":"Flynn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0075-6735","authenticated-orcid":false,"given":"Shayna","family":"Sarosiek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria G.","family":"Demos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Guerrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Kofides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manit","family":"Munshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Tsakmaklis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3049-4200","authenticated-orcid":false,"given":"Guang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3868-9267","authenticated-orcid":false,"given":"Andrew R.","family":"Branagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"O\u2019Donnell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noopur","family":"Raje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3623-7491","authenticated-orcid":false,"given":"Andrew J.","family":"Yee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Patterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1689-1691","authenticated-orcid":false,"given":"Zachary R.","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6393-6154","authenticated-orcid":false,"given":"Steven P.","family":"Treon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"1417_CR1","doi-asserted-by":"publisher","first-page":"1637","DOI":"10.1182\/blood-2013-09-525808","volume":"123","author":"ZR Hunter","year":"2014","unstructured":"Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123:1637\u201346.","journal-title":"Blood."},{"key":"1417_CR2","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1056\/NEJMoa1200710","volume":"367","author":"SP Treon","year":"2012","unstructured":"Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, et al. MYD88 L265P somatic mutation in Waldenstrom\u2019s macroglobulinemia. N Engl J Med. 2012;367:826\u201333.","journal-title":"N Engl J Med"},{"key":"1417_CR3","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1182\/blood-2012-12-475111","volume":"122","author":"G Yang","year":"2013","unstructured":"Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, et al. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia. Blood. 2013;122:1222\u201332.","journal-title":"Blood."},{"key":"1417_CR4","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1111\/bjh.13200","volume":"168","author":"Y Cao","year":"2015","unstructured":"Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, et al. CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P) -directed survival signalling in Waldenstrom macroglobulinaemia cells. Br J Haematol. 2015;168:701\u20137.","journal-title":"Br J Haematol"},{"key":"1417_CR5","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1056\/NEJMoa1501548","volume":"372","author":"SP Treon","year":"2015","unstructured":"Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenstrom\u2019s macroglobulinemia. N Engl J Med. 2015;372:1430\u201340.","journal-title":"N Engl J Med"},{"key":"1417_CR6","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1200\/JCO.20.00555","volume":"39","author":"SP Treon","year":"2021","unstructured":"Treon SP, Meid K, Gustine J, Yang G, Xu L, Liu X, et al. Long-term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenstrom macroglobulinemia. J Clin Oncol. 2021;39:565\u201375.","journal-title":"J Clin Oncol"},{"key":"1417_CR7","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1200\/JCO.2018.78.6426","volume":"36","author":"SP Treon","year":"2018","unstructured":"Treon SP, Gustine J, Meid K, Yang G, Xu L, Liu X, et al. Ibrutinib monotherapy in symptomatic, treatment-naive patients with Waldenstrom macroglobulinemia. J Clin Oncol. 2018;36:2755\u201361.","journal-title":"J Clin Oncol"},{"key":"1417_CR8","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1053\/sonc.2003.50038","volume":"30","author":"RA Kyle","year":"2003","unstructured":"Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhodapkar M, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom\u2019s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom\u2019s macroglobulinemia. Semin Oncol. 2003;30:116\u201320.","journal-title":"Semin Oncol"},{"key":"1417_CR9","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1053\/sonc.2003.50082","volume":"30","author":"RG Owen","year":"2003","unstructured":"Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al. Clinicopathological definition of Waldenstrom\u2019s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom\u2019s Macroglobulinemia. Semin Oncol. 2003;30:110\u20135.","journal-title":"Semin Oncol"},{"key":"1417_CR10","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1111\/bjh.12102","volume":"160","author":"RG Owen","year":"2013","unstructured":"Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, et al. Response assessment in Waldenstrom macroglobulinaemia: update from the VIth International Workshop. Br J Haematol. 2013;160:171\u20136.","journal-title":"Br J Haematol"},{"key":"1417_CR11","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/S1470-2045(16)30632-5","volume":"18","author":"MA Dimopoulos","year":"2017","unstructured":"Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, et al. Ibrutinib for patients with rituximab-refractory Waldenstrom\u2019s macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18:241\u201350.","journal-title":"Lancet Oncol"},{"key":"1417_CR12","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1182\/blood-2020-133916","volume":"136","author":"J Trotman","year":"2020","unstructured":"Trotman J, Buske C, Tedeschi A, Matous JV, MacDonald D, Tam C, et al. Long-term follow-up of ibrutinib treatment for rituximab-refractory Waldenstr\u00f6m\u2019s macroglobulinemia: final analysis of the open-label substudy of the Phase 3 iNNOVATETM Trial. Blood. 2020;136:38\u20139.","journal-title":"Blood."},{"key":"1417_CR13","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1182\/blood-2020-134460","volume":"136","author":"C Buske","year":"2020","unstructured":"Buske C, Tedeschi A, Trotman J, Garc\u00eda-Sanz R, MacDonald D, Leblond V, et al. Five-year follow-up of ibrutinib plus rituximab vs placebo plus rituximab for Waldenstrom\u2019s macroglobulinemia: final analysis from the randomized Phase 3 iNNOVATETM Study. Blood. 2020;136:24\u20136.","journal-title":"Blood."},{"key":"1417_CR14","doi-asserted-by":"publisher","first-page":"e452","DOI":"10.3324\/haematol.2017.172627","volume":"102","author":"JM Vos","year":"2017","unstructured":"Vos JM, Tsakmaklis N, Patterson CJ, Meid K, Castillo JJ, Brodsky P, et al. CXCL13 levels are elevated in patients with Waldenstrom macroglobulinemia, and are predictive of major response to ibrutinib. Haematologica. 2017;102:e452\u2013e455.","journal-title":"Haematologica."},{"key":"1417_CR15","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1111\/bjh.15200","volume":"184","author":"JJ Castillo","year":"2018","unstructured":"Castillo JJ, Gustine JN, Meid K, Dubeau T, Severns P, Xu L, et al. Low levels of von Willebrand markers associate with high serum IgM levels and improve with response to therapy, in patients with Waldenstrom macroglobulinaemia. Br J Haematol. 2018;184:1011\u20134.","journal-title":"Br J Haematol"},{"key":"1417_CR16","doi-asserted-by":"publisher","first-page":"3276","DOI":"10.1182\/blood-2013-05-503862","volume":"122","author":"MA Dimopoulos","year":"2013","unstructured":"Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, et al. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood. 2013;122:3276\u201382.","journal-title":"Blood."},{"key":"1417_CR17","doi-asserted-by":"publisher","first-page":"3830","DOI":"10.1200\/JCO.2008.20.4677","volume":"27","author":"SP Treon","year":"2009","unstructured":"Treon SP, Ioakimidis L, Soumerai JD, Patterson CJ, Sheehy P, Nelson M, et al. Primary therapy of Waldenstrom macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol. 2009;27:3830\u20135.","journal-title":"J Clin Oncol"},{"key":"1417_CR18","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1016\/S0140-6736(12)61763-2","volume":"381","author":"MJ Rummel","year":"2013","unstructured":"Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381:1203\u201310.","journal-title":"Lancet."},{"key":"1417_CR19","doi-asserted-by":"publisher","first-page":"2399","DOI":"10.1056\/NEJMoa1802917","volume":"378","author":"MA Dimopoulos","year":"2018","unstructured":"Dimopoulos MA, Tedeschi A, Trotman J, Garcia-Sanz R, Macdonald D, Leblond V, et al. Phase 3 trial of ibrutinib plus rituximab in Waldenstrom\u2019s macroglobulinemia. N Engl J Med. 2018;378:2399\u2013410.","journal-title":"N Engl J Med"},{"key":"1417_CR20","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1111\/bjh.13897","volume":"172","author":"L Xu","year":"2016","unstructured":"Xu L, Hunter ZR, Tsakmaklis N, Cao Y, Yang G, Chen J, et al. Clonal architecture of CXCR4 WHIM-like mutations in Waldenstrom Macroglobulinaemia. Br J Haematol. 2016;172:735\u201344.","journal-title":"Br J Haematol"},{"key":"1417_CR21","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1111\/bjh.16088","volume":"187","author":"JJ Castillo","year":"2019","unstructured":"Castillo JJ, Xu L, Gustine JN, Keezer A, Meid K, Dubeau TE, et al. CXCR4 mutation subtypes impact response and survival outcomes in patients with Waldenstrom macroglobulinaemia treated with ibrutinib. Br J Haematol. 2019;187:356\u201363.","journal-title":"Br J Haematol"},{"key":"1417_CR22","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1182\/blood.2020006844","volume":"136","author":"CS Tam","year":"2020","unstructured":"Tam CS, Opat S, D\u2019Sa S, Jurczak W, Lee HP, Cull G, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstr\u00f6m macroglobulinemia: the ASPEN study. Blood. 2020;136:2038\u201350.","journal-title":"Blood"},{"key":"1417_CR23","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.jacc.2018.06.002","volume":"72","author":"A Guha","year":"2018","unstructured":"Guha A, Derbala MH, Zhao Q, Wiczer TE, Woyach JA, Byrd JC, et al. Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies. J Am Coll Cardiol. 2018;72:697\u20138.","journal-title":"J Am Coll Cardiol"},{"key":"1417_CR24","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.1182\/blood-2016-10-742437","volume":"129","author":"BL Lampson","year":"2017","unstructured":"Lampson BL, Yu L, Glynn RJ, Barrientos JC, Jacobsen ED, Banerji V, et al. Ventricular arrhythmias and sudden death in patients taking ibrutinib. Blood. 2017;129:2581\u20134.","journal-title":"Blood."}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-021-01417-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-021-01417-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-021-01417-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,1]],"date-time":"2022-02-01T09:07:32Z","timestamp":1643706452000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-021-01417-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,16]]},"references-count":24,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,2]]}},"alternative-id":["1417"],"URL":"https:\/\/doi.org\/10.1038\/s41375-021-01417-9","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,16]]},"assertion":[{"value":"11 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 August 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"JJC received research funds and\/or honoraria from Abbvie, Beigene, Janssen, Pharmacyclics, Roche, and TG Therapeutics. ARB received research funds and\/or honoraria from Adaptive, Beigene, CSL Behring, Genzyme, Karyopharm, Pharmacyclics, and Sanofi. AJY received research funds and\/or honoraria from Adaptive, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Sanofi, Takeda. SPT received research funds and\/or honoraria from Abbvie, Beigene, BMS, Pharmacyclics, and X4. All other authors have no conflicts of interest to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}