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Maddalena Mazzucchelli
Anna Maria Frustaci
Marina Deodato
Roberto Cairoli
Alessandra Tedeschi


Waldenstrom Macroglobulinemia, ibrutinib, chemoimmunotherapy, new agents


Waldenstrom Macroglobulinemia is a rare lymphoproliferative disorder with distinctive clinical features.

Diagnostic and prognostic charactrization in WM significantly changed with the discovery of two molecular markers: MYD88 and CXCR4. Mutational status of these latter influences both clinical presentation and prognosis and demonstrated therapeutic implications.

Treatment choice in Waldemstrom disease is strictly guided by patients age and characteristics, specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, disease characteristics, risk of immunosuppression or secondary malignancies and potential for future autologous stem cell transplantation.

Therapeutic landscape has expanded during the last years and the approval of ibrutinib, the first drug approved for Waldenstrom Macroglobulinemia, represents an important step forward for a better management of the disease. 


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[1] Owen RG, Treon SP, Al-Katib A, Fonseca R, G1reipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA. Clinicopathological definition of Waldenstro¨m’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol. 2003;30:110-5.
[2] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Vol 2. 4th Ed. Geneva, Switzerland: International Agency for Research on Cancer; 2008:441
[3] Sekhar J, Sanfilippo K, Zhang Q, Trinkaus K, Vij R, Morgensztern D. Waldenstrom macroglobulinemia: a Surveillance, Epidemiology, and End Results database review from 1988 to 2005. Leuk Lymphoma. 2012;53:1625-26.
[4] Dimopoulos MA, Panayiotidis P, Moulopoulos LA, Sfikakis P, Dalakas M. Waldenström's macroglobulinemia: clinical features, complications, and management. J Clin Oncol. 2000;18:214-26.
[5] Leblond V, Kastritis E, Advani R, Ansell SM, Buske C, Castillo JJ, García-Sanz R, Gertz M, Kimby E, Kyriakou C, Merlini G, Minnema MC, Morel P, Morra E, Rummel M, Wechalekar A, Patterson CJ, Treon S, Dimopoulos MA. Treatment recommendations from the Eighth International Workshop on Waldenström's Macroglobulinemia. Blood. 2016;128:1321-8.
[6] Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367:826-33.
[7] Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP. 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;123:1637-46.
[8] Dimopoulos MA, Kyle RA, Anagnostopoulos A, Treon SP. Diagnosis and management of Waldenstrom’s macroglobulinemia. J Clin Oncol. 2005;23:1564-77.
[9] Treon SP, Tripsas CK, Ciccarelli BT, Manning RJ, Patterson CJ, Sheehy P, Hunter ZR. Patients with Waldenström macroglobulinemia commonly present with iron deficiency and those with severely depressed transferrin saturation levels show response to parenteral iron administration. Clin Lymphoma Myeloma Leuk. 2013;13:241-3.
[10] Ciccarelli BT, Patterson CJ, Hunter ZR, Hanzis C, Ioakimidis L, Manning R, Yang G, Xu L, Zhou Y, Sun J, Liu X, Tseng H, Cao Y, Sheehy P, Rodig SJ, Treon SP. Hepcidin is produced by lymphoplasmacytic cells and is associated with anemia in Waldenström's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011;11:160-3.
[11] Kapoor P, Paludo J, Vallumsetla N, Greipp PR. Waldenström macroglobulinemia: What a hematologist needs to know. Blood Rev. 2015;29:301-19.
[12] García-Sanz R, Montoto S, Torrequebrada A, de Coca AG, Petit J, Sureda A, Rodríguez-García JA, Massó P, Pérez-Aliaga A, Monteagudo MD, Navarro I, Moreno G, Toledo C, Alonso A, Besses C, Besalduch J, Jarque I, Salama P, Rivas JA, Navarro B, Bladé J, Miguel JF. Waldenstrom macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br J Haematol. 2001;115:575-82.
[13] Mackenzie MR, Babcock J. Studies of the hyperviscosity syndrome. II. Macroglobulinemia. J Lab Clin Med. 1975;85:227-34.
[14] Fahey JL, Barth WF, Solomon A. Serum hyperviscosity syndrome. JAMA. 1965;192:120-3.
[15] Stone MJ, Bogen SA. Evidence-based focused review of management of hyperviscosity syndrome. Blood. 2012;119:2205-8.
[16] Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29:467-71.
[17] Gustine JN, Meid K, Dubeau T, Hunter ZR, Xu L, Yang G, Ghobrial IM, Treon SP, Castillo JJ. Serum IgM level as predictor of symptomatic hyperviscosity in patients with Waldenström macroglobulinaemia. Br J Haematol. 2017;177:717-25.
[18] Menke MN, Feke GT, McMeel JW, Branagan A, Hunter Z, Treon SP. Hyperviscosity-related retinopathy in Waldenström’s macroglobulinemia. Arch Ophthalmol. 2006;124:1601-6.
[19] Ghobrial IM. Are you sure this is Waldenstrom macroglobulinemia? Hematology Am Soc Hematol Educ Program. 2012;2012:586-94.
[20] Kyle RA. Neuropathy associated with the monoclonal gammopathies. In: Noseworthy JH, ed. Neurologic therapeautics: principles and practice. London, New York. Martin Dunitz. 2003;2126-36.
[21] D'Sa S, Kersten MJ, Castillo JJ, Dimopoulos M, Kastritis E, Laane E, Leblond V, Merlini G, Treon SP, Vos JM, Lunn MP. Investigation and management of IgM and Waldenström-associated peripheral neuropathies: recommendations from the IWWM-8 consensus panel. Br J Haematol. 2017;176:728-42.
[22] Nobile-Orazio E, Meucci N, Baldini L, Di Troia A, Scarlato G. Long-term prognosis of neuropathy associated with anti-MAG IgM M-proteins and its relationship to immune therapies. Brain. 2000;123:710-17.
[23] Treon SP, Hanzis CA, Ioakimidis LI, Patterson CJ, Hunter ZR, Brodsky PS, Sheehy PS, Manning RJ. Clinical characteristics and treatment outcome of disease-related peripheral neuropathy in Waldenstrom’s macroglobulinemia (WM). J Clin Oncol. 2010;28:15s.
[24] Willison HJ, O’Leary CP, Veitch J, Blumhardt LD, Busby M, Donaghy M, Fuhr P, Ford H, Hahn A, Renaud S, Katifi HA, Ponsford S, Reuber M, Steck A, Sutton I, Schady W, Thomas PK, Thompson AJ, Vallat JM, Winer J. The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain. 2001;124: 1968-77.
[25] Rajkumar SV, Gertz MA, Kyle RA. Prognosis of patients with primary systemic amyloidosis who present with dominant neuropathy. Am J of Med. 1988;104:232-7.
[26] Themistocleous AC, Ramirez JD, Serra J, Bennett DL. The clinical approach to small fibre neuropathy and painful channelopathy. Prac Neur. 2014;14:368-79.
[27] Palladini G, Russo P, Bosoni T, Sarais G, Lavatelli F, Foli A, Bragotti LZ, Perfetti V, Obici L, Bergesio F, Albertini R, Moratti R, Merlini G. AL amyloidosis associated with IgM monoclonal protein: a distinct clinical entity. Clin Lymph Myel. 2009;9:80-3.
[28] Minnema MC, Kimby E, D'Sa S, Fornecker LM, Poulain S, Snijders TJ, Kastritis E, Kremer S, Fitsiori A, Simon L, Davi F, Lunn M, Castillo JJ, Patterson CJ, Le Garff-Tavernier M, Costopoulos M, Leblond V, Kersten MJ, Dimopoulos MA, Treon SP. Guideline for the diagnosis, treatment and response criteria for Bing-Neel syndrome. Haematologica. 2017;102:43-51.
[29] Lipsker D, Veran Y, Grunenberger F, Cribier B, Heid E, Grosshans E. The Schnitzler syndrome: four new cases and review of the literature. Medicine. 2001;80:37- 44.
[30] Ansell SM, Kyle RA, Reeder CB, Fonseca R, Mikhael JR, Morice WG, Bergsagel PL, Buadi FK, Colgan JP, Dingli D, Dispenzieri A, Greipp PR, Habermann TM, Hayman SR, Inwards DJ, Johnston PB, Kumar SK, Lacy MQ, Lust JA, Markovic SN, Micallef IN, Nowakowski GS, Porrata LF, Roy V, Russell SJ, Short KE, Stewart AK, Thompson CA, Witzig TE, Zeldenrust SR, Dalton RJ, Rajkumar SV, Gertz MA. Diagnosis and management of Waldenstrom macroglobulinemia: mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines. Mayo Clin Proc. 2010;85:824–33.
[31] Feiner HD, Rizk CC, Finfer MD, Bannan M, Gottesman SR, Chuba JV, Amorosi E. IgM monoclonal gammopathy/Waldenstrom’s macroglobulinemia: a morphological and immunophenotypic study of the bone marrow. Mod Pathol. 1990;3:348–56.
[32] San Miguel JF, Vidriales MB, Ocio E, Mateo G, Sánchez-Guijo F, Sánchez ML, Escribano L, Bárez A, Moro MJ, Hernández J, Aguilera C, Cuello R, García-Frade J, López R, Portero J, Orfao A. Immunophenotypic analysis of Waldenstrom’s macroglobulinemia. Semin Oncol. 2003;30:187–95.
[33] Hunter ZR, Branagan AR, Manning R, Patterson CJ, Santos DD, Tournilhac O, Dorfman DM, Treon SP. CD5, CD10, CD23 expression in Waldenstrom’s macroglobulinemia. Clin Lymph. 2005;5:246–9.
[34] Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C, Santos DD, Hatjiharissi E, Xu L, Leleu X, Tournilhac O, Patterson CJ, Manning R, Branagan AR, Morton CC. Characterization of familial Waldenstrom's macroglobulinemia. Ann. Oncol. 2006;17:488–94
[35] Nguyen-Khac F, Lambert J, Chapiro E, Grelier A, Mould S, Barin C, Daudignon A, Gachard N, Struski S, Henry C, Penther D, Mossafa H, Andrieux J, Eclache V, Bilhou-Nabera C, Luquet I, Terre C, Baranger L, Mugneret F, Chiesa J, Mozziconacci MJ, Callet-Bauchu E, Veronese L, Blons H, Owen R, Lejeune J, Chevret S, Merle-Beral H, Leblondon V. Chromosomal aberrations and their prognostic value in a series of 174 untreated patients with Waldenström's macroglobulinemia Haematologica. 2013;98:649-54
[36] Nguyen-Khac F, Lejeune J, Chapiro E, Mould S, Barin C, Daudignon A. Cytogenetic abnormalities in a cohort of 171 patients with Waldenström macroglobulinemia before treatment: clinical and biological correlations. Blood. 2010;116:abstract 801
[37] Chang H, Qi C, Trieu Y, Jiang A, Young KH, Chesney A, Jani P, Wang C, Reece D, Chen C. Prognostic relevance of 6q deletion in Waldenstrom's macroglobulinemia: a multicenter study. Clin Lymph Myel. 2009;9:36–8
[38] Treon SP, Xu L, Zhou Y, Liu X, Yang G, Cao Y, Hanzis C, Sheehy P, Manning R, Patterson CJ, Laramie JM, Skifter DA, Lincoln SE, Hunter Z. Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in Waldenstrom’s macroglobulinemia. Blood. 2011;118:abstract 300.
[39] Xu L, Hunter ZR, Yang G, Zhou Y, Cao Y, Liu X, Morra E, Trojani A, Greco A, Arcaini L, Varettoni M, Brown JR, Tai YT, Anderson KC, Munshi NC, Patterson CJ, Manning RJ, Tripsas CK, Lindeman NI, Treon SP. MYD88 L265P in Waldenstrom macroglobulinemia, immunoglobulin M monoclonal gammopathy, and other B-cell lymphoproliferative disorders using conventional and quantitative allele-specific polymerase chain reaction. Blood. 2013;121:2051–8.
[40] Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP. 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;123:1637-46.
[41] Yang G, Zhou Y, Liu X, Xu L, Cao Y, Manning RJ, Patterson CJ, Buhrlage SJ, Gray N, Tai YT, Anderson KC, Hunter ZR, Treon SP. A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia. Blood. 2013;122:1222-32.
[42] Treon SP, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Sheehy P, Manning RJ, Patterson CJ, Tripsas C, Arcaini L, Pinkus GS, Rodig SJ, Sohani AR, Harris NL, Laramie JM, Skifter DA, Lincoln SE, Hunter ZR. MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med. 2012;367:826-33.
[43] Xu L, Hunter ZR, Yang G, Cao Y, Liu X, Manning R, Tripsas C, Chen J, Patterson CJ, Kluk M, Kanan S, Castillo J, Lindeman N, Treon SP. Detection of MYD88 L265P in peripheral blood of patients with Waldenstrom’s Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance. Leukemia. 2014;28:1698-704.
[44] Roccaro AM, Sacco A, Jimenez C, Maiso P, Moschetta M, Mishima Y, Aljawai Y, Sahin I, Kuhne M, Cardarelli P, Cohen L, San Miguel JF, Garcia-Sanz R, Ghobrial IM. C1013G/CXCR4 acts as a driver mutation of tumor progression and modulator of drug resistance in lymphoplasmacytic lymphoma. Blood. 2014;123:4120-31.
[45] Chakraborty R, Novak AJ, Ansell SM, Muchtar E, Kapoor P, Hayman SR, Dispenzieri A, Buadi FK, Lacy MQ, King RL, Gertz MA First report of MYD88 L265P somatic mutation in IgM-associated light-chain amyloidosis. Blood. 2016;127:2936-8.
[46] Gachard N, Parrens M, Soubeyran I, Petit B, Marfak A, Rizzo D, Devesa M, Delage-Corre M, Coste V, Laforêt MP, de Mascarel A, Merlio JP, Bouabdhalla K, Milpied N, Soubeyran P, Schmitt A, Bordessoule D, Cogné M, Feuillard J. IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenstrom macroglobulinemia/ lymphoplasmacytic lymphomas. Leukemia. 2013;27:183-9.
[47] Landgren O, Staudt L. MYD88 L265P somatic mutation in IgM MGUS. N Engl J Med. 2012;367:2255–6.
[48] Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood. 2014;123:2791-6.
[49] Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP. The genomic landscape of Waldenstom’s macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123:1637–46.
[50] Dotta L, Tassone L, Badolato R. Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) syndrome. Curr Mol Med. 2011;11:317–25.
[51] Braggio E, Keats JJ, Leleu X, Van Wier S, Jimenez-Zepeda VH, Valdez R, Schop RF, Price-Troska T, Henderson K, Sacco A, Azab F, Greipp P, Gertz M, Hayman S, Rajkumar SV, Carpten J, Chesi M, Barrett M, Stewart AK, Dogan A, Bergsagel PL, Ghobrial IM, Fonseca R. Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom’s macroglobulinemia. Cancer Res. 2009;69:3579–88.
[52] Poulain S, Roumier C, Galiègue-Zouitina S, Daudignon A, Herbaux C, Aiijou R, Lainelle A, Broucqsault N, Bertrand E, Manier S, Renneville A, Soenen V, Tricot S, Roche-Lestienne C, Duthilleul P, Preudhomme C, Quesnel B, Morel P, Leleu X. Genome Wide SNP Array identified multiple mechanisms of genetic changes in Waldenstrom macroglobulinemia. Am J Hematol. 2013;88:948–54.
[53] Facon T, Brouillard M, Duhamel A, Morel P, Simon M, Jouet JP, Bauters F, Fenaux P. Prognostic factors in Waldenstrom's macroglobulinemia: a report of 167 cases. J Clin Oncol. 1993;11:1553-8.
[54] Morel P, Monconduit M, Jacomy D, Lenain P, Grosbois B, Bateli C, Facon T, Dervite I, Bauters F, Najman A, De Gramont A, Wattel E. Prognostic factors in Waldenstrom's macroglobulinemia: a report on 232 patients with the description of a new scoring system and its validation on 253 other patients. Blood. 2000;96:852-8.
[55] Merlini G, Baldini L, Broglia C, Comelli M, Goldaniga M, Palladini G, Deliliers GL, Gobbi PG. Prognostic factors in symptomatic Waldenstrom's macroglobulinemia. Semin Oncol. 2003;30:211-5.
[56] García-Sanz R, Montoto S, Torrequebrada A, de Coca AG, Petit J, Sureda A, Rodríguez-García JA, Massó P, Pérez-Aliaga A, Monteagudo MD, Navarro I, Moreno G, Toledo C, Alonso A, Besses C, Besalduch J, Jarque I, Salama P, Rivas JA, Navarro B, Bladé J, Miguel JF. Waldenstrom macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br J Haematol. 2001;115:575-82.
[57] Owen RG, Barrans SL, Richards SJ, O'Connor SJ, Child JA, Parapia LA, Morgan GJ, Jack AS. Waldenstrom macroglobulinemia: development of diagnostic criteria and identification of prognostic factors. Am J Clin Pathol. 2001;116:420-8.
[58] Dimopoulos MA, Hamilos G, Zervas K, Symeonidis A, Kouvatseas G, Roussou P, Gika D, Karmiris T, Bourantas K, Zomas A, Mitsouli C, Xilouri I, Vervessou E, Matsis K, Anagnostopoulos N, Economopoulos T. Survival and prognostic factors after initiation of treatment in Waldenstrom's macroglobulinemia. Ann Oncol. 2003;14:1299-305.
[59] Ghobrial IM, Fonseca R, Gertz MA, Plevak MF, Larson DR, Therneau TM, Wolf RC, Hoffmann RJ, Lust JA, Witzig TE, Lacy MQ, Dispenzieri A, Vincent Rajkumar S, Zeldenrust SR, Greipp PR, Kyle RA. Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenstrom macroglobulinaemia. Br J Haematol. 2006;133:158-64.
[60] Gobbi PG, Bettini R, Montecucco C, Cavanna L, Morandi S, Pieresca C, Merlini G, Bertoloni D, Grignani G, Pozzetti U. Study of prognosis in Waldenstrom's macroglobulinemia: a proposal for a simple binary classification with clinical and investigational utility. Blood. 1994;83:2939-45.
[61] Dhodapkar MV, Jacobson JL, Gertz MA, Crowley JJ, Barlogie B. Prognostic factors and response to fludarabine therapy in Waldenstrom's macroglobulinemia: an update of a US intergroup trial (SW0G S9003). Semin Oncol. 2003;30:220-5.
[62] Kyrtsonis MC, Vassilakopoulos TP, Angelopoulou MK, Siakantaris P, Kontopidou FN, Dimopoulou MN, Boussiotis V, Gribabis A, Konstantopoulos K, Vaiopoulos GA, Fessas P, Kittas C, Pangalis GA. Waldenstrom's macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit. Ann Hematol. 2001;80:722-7.
[63] Morel P, Duhamel A, Gobbi P, Dimopoulos MA, Dhodapkar MV, McCoy J, Crowley J, Ocio EM, Garcia-Sanz R, Treon SP, Leblond V, Kyle RA, Barlogie B, Merlini G. International prognostic scoring system for Waldenstrom macroglobulinemia. Blood. 2009;113:4163-7.
[64] Poulain S, Roumier C, Venet-Caillault A, Figeac M, Herbaux C, Marot G, Doye E, Bertrand E, Geffroy S, Lepretre F, Nibourel O, Decambron A, Boyle EM, Renneville A, Tricot S, Daudignon A, Quesnel B, Duthilleul P, Preudhomme C, Leleu X. Genomic Landscape of CXCR4 Mutations in Waldenström Macroglobulinemia. Clin Cancer Res. 2016;22:1480-8.
[65] Schmidt J, Federmann B, Schindler N, Steinhilber J, Bonzheim I, Fend F, Quintanilla-Martinez L. MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity.Br J Haematol. 2015;169:795-803.
[66] Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O. Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia patients: a population-based study in Sweden. Blood. 2008;112:3052–6.
[67] Hanzis C, Ojha RP, Hunter Z, Manning R, Lewicki M, Brodsky P, Ioakimidis L, Tripsas C, Patterson CJ, Sheehy P, Treon SP. Associated malignancies in patients with Waldenstro¨m’s macroglobulinemia and their kin. Clin Lymph Myel Leuk. 2011;11:88–92.
[68] Steingrímsson v, Lund SH, Turesson I, Goldin LR, Björkholm M, Landgren O, Kristinsson SY. Population-based study on the impact of the familial form of Waldenstrom macroglobulinemia on overall survival. Blood. 2015;125:2174–5.
[69] Treon SP, Hunter ZR, Aggarwal A, Ewen EP, Masota S, Lee C, Santos DD, Hatjiharissi E, Xu L, Leleu X, Tournilhac O, Patterson CJ, Manning R, Branagan AR, Morton CC. Characterization of familial Waldenstrom’s macroglobulinemia. Ann Oncol. 2006;17:488–94.
[70] Kristinsson SY, Goldin LR, Turesson I, Bjorkholm M, Landgren O. Familial aggregation of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia with solid tumors and myeloid malignancies. Acta Haematol. 2012;127:173–7.
[71] Treon SP, Tripsas C, Hanzis C, Ioakimidis L, Patterson CJ, Manning RJ, Sheehy P, Turnbull B, Hunter ZR. Familial disease predisposition impacts treatment outcome in patients with Waldenstrom macroglobulinemia. Clin Lymph Myel Leuk. 2012;12D6:433–7.
[72] Leblond V, Kastritis E, Advani R, Ansell SM, Buske C, Castillo JJ, García-Sanz R, Gertz M, Kimby E, Kyriakou C, Merlini G, Minnema MC, Morel P, Morra E, Rummel M, Wechalekar A, Patterson CJ, Treon SP, Dimopoulos MA. Treatment recommendations from the Eighth International Workshop on Waldenström's Macroglobulinemia. Blood. 2016;128:1321-8.
[73] Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol. 2007;44:3823–37.
[74] Dimopoulos MA, Zervas C, Zomas A, Kiamouris C, Viniou NA, Grigoraki V, Karkantaris C, Mitsouli C, Gika D, Christakis J, Anagnostopoulos N. Treatment of Waldenstrom’s macroglobulinemia with rituximab. J Clin Oncol. 2002;20:2327–33.
[75] Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter phase 2 trial of rituximab for Waldenstrom macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma. 2004;45:2047–55.
[76] Dimopoulos MA, Zervas C, Zomas A, Hamilos G, Gika D, Efstathiou E, Panayiotidis P, Vervessou E, Anagnostopoulos N, Christakis J. Extended rituximab therapy for previously untreated patients with Waldenstrom's macroglobulinemia. Clin Lymphoma. 2002;3:163-6.
[77] Treon SP, Emmanouilides C, Kimby E, Kelliher A, Preffer F, Branagan AR, Anderson KC, Frankel SR. Extended rituximab therapy in Waldenstro¨m’s macroglobulinemia. Ann Oncol. 2005;16:132–8.
[78] Kapoor P, Ansell SM, Fonseca R, Chanan-Khan A, Kyle RA, Kumar SK, Mikhael JR, Witzig TE, Mauermann M, Dispenzieri A, Ailawadhi S, Stewart AK, Lacy MQ, Thompson CA, Buadi FK, Dingli D, Morice WG, Go RS, Jevremovic D, Sher T, King RL, Braggio E, Novak A, Roy V, Ketterling RP, Greipp PT, Grogan M, Micallef IN, Bergsagel PL, Colgan JP, Leung N, Gonsalves WI, Lin Y, Inwards DJ, Hayman SR, Nowakowski GS, Johnston PB, Russell SJ, Markovic SN, Zeldenrust SR, Hwa YL, Lust JA, Porrata LF, Habermann TM, Rajkumar SV, Gertz MA, Reeder CB. Diagnosis and Management of Waldenström Macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. JAMA Oncol. 2017;3:1257-65.
[79] Campagnolo M, Zambello R, Nobile-Orazio E, Benedetti L, Marfia GA, Riva N, Castellani F, Bianco M, Salvalaggio A, Garnero M, Ruiz M, Mataluni G, Fazio R, Ermani M, Briani C. IgM MGUS and Waldenstrom-associated anti-MAG neuropathies display similar response to rituximab therapy. J Neurol Neurosurg Psychiatry. 2017. Epub 2017 May 13.
[80] Teeling JL, French RR, Cragg MS, van den Brakel J, Pluyter M, Huang H, Chan C, Parren PW, Hack CE, Dechant M, Valerius T, van de Winkel JG, Glennie MJ. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004;104:1793-800.
[81] Furman RR, Eradat H, DiRienzo CG, Hayman SR, Hofmeister CC, Avignon NA, Leonard JP, Coleman M, Advani R, Switzky JC, Liao Q, Shah DN, Lisby S, Lin TS. A phase II trial of ofatumumab in subjects with Waldenstrom’s macroglobulinemia. Blood. 2011;118:abstract 3701.
[82] Kyle RA, Greipp PR, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Therneau TM. Waldenström's macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol. 2000;108:737-42.
[83] Leblond V, Johnson S, Chevret S, Copplestone A, Rule S, Tournilhac O, Seymour JF, Patmore RD, Wright D, Morel P, Dilhuydy MS, Willoughby S, Dartigeas C, Malphettes M, Royer B, Ewings M, Pratt G, Lejeune J, Nguyen-Khac F, Choquet S, Owen RG. Results of a randomized trial of chlorambucil versus fludarabine for patients with untreated Waldenström macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013;31:301-7.
[84] Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, Repoussis P, Symeonidis A, Delimpasi S, Katodritou E, Vervessou E, Michali E, Pouli A, Gika D, Vassou A, Terpos E, Anagnostopoulos N, Economopoulos T, Pangalis G. Primary treatment of Waldenstrom’s macroglobulinemia with dexamethasone, rituximab and cyclophosphamide. J Clin Oncol. 2007;25:3344–9.
[85] Kastritis E, Gavriatopoulou M, Kyrtsonis MC, Roussou M, Hadjiharissi E, Symeonidis A, Repoussis P, Michalis E, Delimpasi S, Tsatalas K, Tsirigotis P, Vassou A, Vervessou E, Katodritou E, Gika D, Terpos E, Dimopoulos MA. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final analysis of a phase 2 study. Blood. 2015;126:1392-4.
[86] Treon SP, Branagan AR, Ioakimidis L, Soumerai JD, Patterson CJ, Turnbull B, Wasi P, Emmanouilides C, Frankel SR, Lister A, Morel P, Matous J, Gregory SA, Kimby E. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood. 2009;113:3673-8.
[87] Tedeschi A, Benevolo G, Varettoni M, Battista ML, Zinzani PL, Visco C, Meneghini V, Pioltelli P, Sacchi S, Ricci F, Nichelatti M, Zaja F, Lazzarino M, Vitolo U, Morra E. Fludarabine plus cyclophosphamide and rituximab in Waldenstrom macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer. 2012;118:434-43.
[88] Souchet L, Levy V, Ouzegdouh M, Tamburini J, Delmer A, Dupuis J, Le Gouill S, Pégourié-Bandelier B, Tournilhac O, Boubaya M, Vargaftig J, Choquet S, Leblond V. Efficacy and long-term toxicity of the rituximab-fludarabine-cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia. Am J Hematol. 2016;91:782-6.
[89] Laszlo D, Andreola G, Rigacci L, Fabbri A, Rabascio C, Pinto A, Negri M, Martinelli G. Rituximab and subcutaneous 2-chloro-2'-deoxyadenosine as therapy in untreated and relapsed Waldenström's macroglobulinemia. Clin Lymp Myel Leuk. 2011;11:130-2.
[90] Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; Study group indolent Lymphomas (StiL). 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;381:1203–10.
[91] Castillo JJ, Olszewski AJ, Cronin AM, Hunter ZR, Treon SP. Survival trends in patients with Waldenstrom’s macroglobulinemia: an analysis of the Surveillance, Epidemiology, and End Results database. Blood. 2014;123:3999–4000.
[92] Treon SP, Ioakimidis L, Soumerai JD, Patterson CJ, Sheehy P, Nelson M, Willen M, Matous J, Mattern J 2nd, Diener JG, Keogh GP, Myers TJ, Boral A, Birner A, Esseltine DL, Ghobrial IM. Primary therapy of Waldenstrom’s macroglobulinemia with Bortezomib, Dexamethasone and Rituximab: results of WMCTG clinical trial 05-180. J Clin Oncol. 2009;27:3830–5.
[93] Treon SP, Meid K, Gustine J, Patterson CJ, Matous JV, Ghobrial IM, Castillo JJ. Long-term outcome of a prospective study of bortezomib, dexamethasone and rituximab (BDR) in previously untreated, symptomatic patients with Waldenstrom’s macroglobulinemia. Blood. 2015; abstract 1833.
[94] Ghobrial IM, Xie W, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Poon T, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenstrom macroglobulinemia. Am J Hematol. 2010;85:670–4.
[95] Dimopoulos MA, García-Sanz R, Gavriatopoulou M, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Kastritis E, Sonneveld P. 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;122:3276–82.
[96] Gavriatopoulou M, García-Sanz R, Kastritis E, Morel P, Kyrtsonis MC, Michalis E, Kartasis Z, Leleu X, Palladini G, Tedeschi A, Gika D, Merlini G, Sonneveld P, Dimopoulos MA. BDR in newly diagnosed patients with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years. Blood. 2017;129:456-9.
[97] Treon SP, Hanzis C, Manning RJ, Ioakimidis L, Patterson CJ, Hunter ZR, Sheehy P, Turnbull B. Maintenance rituximab is associated with improved clinical outcome in rituximab na?¨ve patients with Waldenstrom’s macroglobulinemia who respond to a rituximab containing regimen. Br J Haematol. 2011;154:357–62.
[98] Treon SP, Agus TB, Link B, Rodrigues G, Molina A, Lacy MQ, Fisher DC, Emmanouilides C, Richards AI, Clark B, Lucas MS, Schlossman R, Schenkein D, Lin B, Kimby E, Anderson KC, Byrd JC. CD20-Directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom’s macroglobulinemia. J Immunother. 2001;24:272–9.
[99] Treon SP, Hanzis C, Tripsas C, Ioakimidis L, Patterson CJ, Manning RJ, Sheehy P. Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia. Clin Lymph Myel Leuk. 2011;11:133-5.
[100] Tedeschi A, Picardi P, Ferrero S, Benevolo G, Margiotta Casaluci G, Varettoni M, Baratè C, Motta M, Gini G, Goldaniga MC, Visco C, Zaja F, Belsito Petrizi V, Ravelli E, Gentile M, Urbano MA, Franceschetti S, Ghione P, Orsucci L, Frustaci AM, Gaidano G, Vitolo U, Morra E. Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenström macroglobulinemia. Leuk Lymphoma. 2015;56:2637-42.
[101] Tedeschi A, Ricci F, Goldaniga MC, Benevolo G, Varettoni M, Motta M, Pioltelli P, Gini G, Barate' C, Luraschi A, Vismara E, Frustaci AM, Nichelatti M, Vitolo U, Baldini L, Morra E. Fludarabine, cyclophosphamide, and rituximab in salvage therapy of Waldenström's macroglobulinemia. Clin Lymph Myel Leuk. 2013;13:231-4.
[102] Tedeschi A, Picardi P, Goldaniga MC, Margiotta Casaluci G, Benevolo G, Ferrero S, Varettoni M, Baratè C, Gini G, Visco C, Motta M, Belsito Petrizzi V, Zaja F, Ravelli E, Gentile M, Frustaci AM, Orsucci L, Morra E, Gaidano G, Cairoli R. Long Term Toxicity and Follow-up of Waldenstrom´s Macroglobulinemia Patients after Salvage Treatment with Fludarabine Cyclophosphamide Rituximab or Bendamustine and Rituximab. Blood ASH Annual Meet. 2015;623:abstract 3958.
[103] Paludo J, Abeykoon JP, Kumar S, Shreders A, Ailawadhi S, Gertz MA, Kourelis T, King RL, Reeder CB, Leung N, Kyle RA, Buadi FK, Habermann TM, Dingli D, Witzig TE, Dispenzieri A, Lacy MQ, Go RS, Lin Y, Gonsalves WI, Warsame R, Lust JA, Rajkumar SV, Ansell SM, Kapoor P. Dexamethasone, rituximab and cyclophosphamide for relapsed and/or refractory and treatment-naïve patients with Waldenstrom macroglobulinemia. Br J Haematol. 2017;179:98-105.
[104] Ghobrial IM, Hong F, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol. 2010;28:1422-8.
[105] IMBRUVICA™ (ibrutinib). US Prescribing Information. Pharmacyclics, Inc; 2015 Jan
[106] IMBRUVICA™ (ibrutinib). European Medical Agency. EMEA/H/C/003791. Pharmacyclics, Inc; 2015 Jul
[107] Treon SP, Hunter ZR, Castillo JJ, Merlini G. Waldenstrom Macroglobulinemia. Hematol Oncol Clin North Am. 2014;28:945-7.
[108] Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NL, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba ML, Advani RH. Ibrutinib in previously treated Waldenström’s macroglobulinemia. N Engl J Med. 2015;372:1430–40.
[109] Palomba ML, Bantilan K, Meid K, Tripsas CK, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Advani RH and Treon SP. Long-term follow-up of a pivotal phase II trial of ibrutinib for relapsed Waldenström's Macroglobulinemia. IWWM-9 Session 9, October 7, 2016.
[110] Dimopoulos MA, Trotman J, Tedeschi A, Matous JV, Macdonald D, Tam C, Tournilhac O, Ma S, Oriol A, Heffner LT, Shustik C, García-Sanz R, Cornell RF, de Larrea CF, Castillo JJ, Granell M, Kyrtsonis MC, Leblond V, Symeonidis A, Kastritis E, Singh P, Li J, Graef T, Bilotti E, Treon S, Buske C; iNNOVATE Study Group and the European Consortium for Waldenström's Macroglobulinemia. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial. Lancet Oncol. 2017;18:241-50.
[111] Cao Y, Hunter ZR, Liu X, Xu L, Yang G, Chen J, Patterson CJ, Tsakmaklis N, Kanan S, Rodig S, Castillo JJ, Treon SP. The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK, and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom's Macroglobulinemia. Leukemia. 2015;29:169-76.
[112] Xu L, Tsakmaklis N, Yang G, Chen JG, Liu X, Demos M, Kofides A, Patterson CJ, Meid K, Gustine J, Dubeau T, Palomba ML, Advani R, Castillo JJ, Furman RR, Hunter ZR, Treon SP. Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017;129:2519-25.
[113] Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, Briccetti FM, Pasmantier M, Zimbler H, Cooper RB, Moore M, Hill J 2nd, Rauch A, Garbo L, Chu L, Chua C, Nantel SH, Lovett DR, Boedeker H, Sonneborn H, Howard J, Musto P, Ciccarelli BT, Hatjiharissi E, Anderson KC. Thalidomide and rituximab in Waldenstrom’s macroglobulinemia. Blood. 2008;112:4452–7.
[114] Treon SP, Soumerai JD, Branagan AR, Hunter ZR, Patterson CJ, Ioakimidis L, Chu L, Musto P, Baron AD, Nunnink JC, Kash JJ, Terjanian TO, Hyman PM, Nawfel EL, Sharon DJ, Munshi NC, Anderson KC. Lenalidomide and rituximab in Waldenstrom’s macroglobulinemia. Clin Cancer Res. 2008;15:355–60.
[115] Treon SP, Tripsas CK, Meid K, Kanan S, Sheehy P, Chuma S, Xu L, Cao Y, Yang G, Liu X, Patterson CJ, Warren D, Hunter ZR, Turnbull B, Ghobrial IM, Castillo JJ. Carfilzomib, rituximab and dexamethasone (CaRD) is active and offers a neuropathy-sparing approach for proteasomeinhibitor based therapy in Waldenstrom’s macroglobulinemia. Blood. 2014;124:503–10.
[116] Leleu X, Jia X, Runnels J, Ngo HT, Moreau AS, Farag M, Spencer JA, Pitsillides CM, Hatjiharissi E, Roccaro A, O'Sullivan G, McMillin DW, Moreno D, Kiziltepe T, Carrasco R, Treon SP, Hideshima T, Anderson KC, Lin CP, Ghobrial IM. The Akt pathway regulates survival and homing in Waldenstrom macroglobulinemia. Blood. 2007;110:4417–26.
[117] Ghobrial IM, Gertz M, Laplant B, Camoriano J, Hayman S, Lacy M, Chuma S, Harris B, Leduc R, Rourke M, Ansell SM, Deangelo D, Dispenzieri A, Bergsagel L, Reeder C, Anderson KC, Richardson PG, Treon SP, Witzig TE. Phase II Trial of the Oral Mammalian Target of Rapamycin Inhibitor Everolimus in Relapsed or Refractory Waldenstrom Macroglobulinemia. J Clin Oncol. 2010;28:1408–14.
[118] Ghobrial IM, Witzig TE, Gertz M, LaPlant B, Hayman S, Camoriano J, Lacy M, Bergsagel PL, Chuma S, DeAngelo D, Treon SP. Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom macroglobulinemia. Am J Hematol. 2014;89:237–42.
[119] Ghobrial IM, Redd R, Armand P, Banwait R, Boswell E, Chuma S, Huynh D, Sacco A, Roccaro AM, Perilla-Glen A, Noonan K, MacNabb M, Leblebjian H, Warren D, Henrick P, Castillo JJ, Richardson PG, Matous J, Weller E, Treon SP. Phase I/II trial of everolimus in combination with bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. Leukemia. 2015;29:2338- 46.
[120] Ghobrial IM, Roccaro A, Hong F, Weller E, Rubin N, Leduc R, Rourke M, Chuma S, Sacco A, Jia X, Azab F, Azab AK, Rodig S, Warren D, Harris B, Varticovski L, Sportelli P, Leleu X, Anderson KC, Richardson PG. Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia. Clin Cancer Res. 2010;16:1033-41.
[121] Ghobrial IM, Moreau P, Harris B, Poon T, Jourdan E, Maisonneuve H, Benhadji KA, Hossain AM, Nguyen TS, Wooldridge JE, Leblond V. A multicenter phase II study of single-agent enzastaurin in previously treated Waldenstrom macroglobulinemia. Clin Cancer Res. 2012;18:5043-50.
[122] Kahl BS, Byrd J, Flinn IW. Clinical Safety and Activity in a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110?, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma. Blood ASH Annual Meet. 2010;116:abstract 1777.
[123] Castillo JJ, Gustine JN, Meid K, Dubeau T, Yang G, Xu L, Hunter ZR, Treon SP.. Idelalisib in Waldenstrom macroglobulinemia: high incidence of hepatotoxicity. Leuk Lymphoma. 2017;58:1002–4.
[124] Olszewski AJ, Chen C, Gutman R, Treon SP, Castillo JJ. Comparative outcomes of immunochemotherapy regimens in Waldenström macroglobulinaemia. Br J Haematol. 2017;179:106-15.