Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenström macroglobulinemia
The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. We compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients’ MYD88L265P mutation status. Of 160 consecutive patients, 60 received BR (43 with relapsed/refractory WM) and 100 received DRC (50 had relapsed/refractory WM). In the treatment-naïve setting, overall response rate (ORR) was 93% with BR versus 96% with DRC (p = 0.55). Two-year progression-free survival (PFS) with BR and DRC was 88 and 61%, respectively (p = 0.07). In salvage setting, ORR was 95% with BR versus 87% with DRC, p = 0.45; median PFS with BR was 58 versus 32 months with DRC (2-year PFS was 66 versus 53%; p = 0.08). Median disease-specific survival was not reached with BR versus 166 months with DRC (p = 0.51). The time-to-event endpoints and depth of response were independent of the MYD88 mutation status. Grade ≥ 3 adverse events of both regimens were comparable. A trend for longer PFS was observed with BR although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients’ MYD88 mutation status.
KeywordsMYD88 Drug therapy Lymphoma Immunoglobulin M Lymphoplasmacytic lymphoma
J.P., P.K., and S.M.A. designed the research. J.P., J.P.A., A.S., S.A., R.K., A.B.H., and P.K. collect and assembled the data. J.P, J.P.A, and P.K. analyzed the data. All authors interpreted the data. J.P., J.P.A., S.K., and P.K. wrote the draft of the paper and all authors contributed in writing and approved the final version of the manuscript.
Compliance with ethical standards
The study was approved by the institutional review board and conducted in accordance with the Declaration of Helsinki.
Informed consent prior to the data collection and analysis for research purposes was obtained from the subjects in the study.
Conflict of interest
Dr. Ansell has received research funding from Bristol-Myers Squibb, Celldex, Merck, Affimed, and Seattle Genetics. Dr. Kumar has received honoraria from Skyline Diagnostics. Research support from Abbvie, Celgene, Novartis, Amgen, Takeda, Sanofi, and Janssen has been provided to Institution for conduct of clinical trials on which Dr. Kumar serves as a principal investigator. Dr. Ailawadhi has served as a consultant for Novartis Pharmaceuticals, Amgen Pharmaceuticals, Pharmacyclics, Inc., and Takeda and has received research funding from Pharmacyclics, Inc. Dr. Reeder has received research support from Celgene, Novartis, and Millennium. No other disclosures are reported. Dr. Dispenzieri has received research support from Celgene, Takeda, Pfizer, Alnylam, Prothena, and Jannsen. Dr. Lacy receives research funding from Celgene. Dr. Dingli has received research funding from Takeda, Karyopharm, and Amgen. Dr. Witzig reports receiving research funding from Celgene (Institution), Novartis (Institution), Spectrum Pharmaceuticals (Institution), and Acerta Pharma (Institution). Dr. Lin receives research funding from Janssen. Dr. Gertz has received research support from Ionis Pharmaceuticals and Prothena and honoraria from Celgene, Millennium Pharmaceuticals, and Novartis. Dr. Kapoor has received research funding from Takeda (Institution), Onyx (Institution), and Celgene (Institution) and consulting fees from Celgene and Sanofi (Institution). The rest of the authors declare that they have no conflict of interest.
- 1.Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, Morra E, Pangalis GA, San Miguel JF, Branagan AR, Dimopoulos MA (2003) Clinicopathological definition of Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol 30(2):110–115. https://doi.org/10.1053/sonc.2003.50082 CrossRefPubMedGoogle Scholar
- 2.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 (2012) MYD88 L265P somatic mutation in Waldenstrom’s macroglobulinemia. N Engl J Med 367(9):826–833. https://doi.org/10.1056/NEJMoa1200710 CrossRefPubMedGoogle Scholar
- 3.Xu L, Hunter Z, Tsakmaklis N, Cao Y, Yang G, Chen J, Liu X, Kanan S, Castillo J, Tai YT, Zehnder JL, Brown JR, Carrasco R, Advani R, Argyropoulos KV, Palomba ML, Morra E, Trojani A, Greco A, Tedeschi A, Varettoni M, Arcaini L, Munshi M, Anderson KC, Treon S (2015) The clonal architecture of CXCR4 mutations in Waldenstrom’s macroglobulinemia shows highly variable subclonal distribution, and multiple mutations within individual patients indicative of targeted genomic instability. Paper presented at the ASH Annual Meeting December 5, 2015Google Scholar
- 4.Dimopoulos MA, Kantarjian H, Weber D, O'Brien S, Estey E, Delasalle K, Rose E, Cabanillas F, Keating M, Alexanian R (1994) Primary therapy of Waldenstrom’s macroglobulinemia with 2-chlorodeoxyadenosine. J Clin Oncol 12(12):2694–2698. https://doi.org/10.1200/JCO.19220.127.116.1194 CrossRefPubMedGoogle Scholar
- 9.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 (2015) Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med 372(15):1430–1440. https://doi.org/10.1056/NEJMoa1501548 CrossRefPubMedGoogle Scholar
- 11.Shanafelt TD, Borah BJ, Finnes HD, Chaffee KG, Ding W, Leis JF, Chanan-Khan AA, Parikh SA, Slager SL, Kay NE, Call TG (2015) Impact of ibrutinib and idelalisib on the pharmaceutical cost of treating chronic lymphocytic leukemia at the individual and societal levels. J Oncol Pract 11(3):252–258. https://doi.org/10.1200/JOP.2014.002469 CrossRefPubMedGoogle Scholar
- 12.Lexicomp® (2016) Drug information handbook. In: Lexicomp (ed) Drug facts and comparisons, 25th edn. Ohio Lexi-Comp, Inc., HudsonGoogle Scholar
- 13.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 (2007) Primary treatment of Waldenstrom macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol 25(22):3344–3349. https://doi.org/10.1200/JCO.2007.10.9926 CrossRefPubMedGoogle Scholar
- 14.Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Durk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W (2013) 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 381(9873):1203–1210. https://doi.org/10.1016/S0140-6736(12)61763-2 CrossRefPubMedGoogle Scholar
- 15.Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhodapkar M, Lister TA, Merlini G, Morel P, Stone M, Branagan AR, Leblond V (2003) Prognostic markers and criteria to initiate therapy in Waldenstrom’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom’s macroglobulinemia. Semin Oncol 30(2):116–120. https://doi.org/10.1053/sonc.2003.50038 CrossRefPubMedGoogle Scholar
- 16.Owen RG, Kyle RA, Stone MJ, Rawstron AC, Leblond V, Merlini G, Garcia-Sanz R, Ocio EM, Morra E, Morel P, Anderson KC, Patterson CJ, Munshi NC, Tedeschi A, Joshua DE, Kastritis E, Terpos E, Ghobrial IM, Leleu X, Gertz MA, Ansell SM, Morice WG, Kimby E, Treon SP, macroglobulinaemia VIIWoW (2013) Response assessment in Waldenstrom macroglobulinaemia: update from the VIth International Workshop. Br J Haematol 160(2):171–176. https://doi.org/10.1111/bjh.12102 CrossRefPubMedGoogle Scholar
- 17.Institute NC (2009) Common terminology criteria for adverse events v4.0 NIH publication # 09-7473Google Scholar
- 19.Leblond V, Kastritis E, Advani R, Ansell SM, Buske C, Castillo JJ, Garcia-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 (2016) Treatment recommendations from the Eighth International Workshop on Waldenstrom’s macroglobulinemia. Blood 128(10):1321–1328. https://doi.org/10.1182/blood-2016-04-711234 CrossRefPubMedGoogle Scholar
- 20.Rummel MJ, Maschmeyer G, Ganser A, Heider A, Gruenhagen U, Losem C, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk HA, Ballo H, Stauch M, Blau W, Burchardt A, Barth J, Kauff F, Brugger W (2017) Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study. J Clin Oncol 35(15_suppl):7501. https://doi.org/10.1200/JCO.2017.35.15_suppl.7501 Google Scholar
- 23.Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD (2008) Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma. J Clin Oncol 26(27):4473–4479. https://doi.org/10.1200/JCO.2008.17.0001 CrossRefPubMedGoogle Scholar
- 24.Rummel MJ, von Gruenhagen U, Niederle N, et al. (2008) Bendamustine plus rituximab versus CHOP plus rituximab in the first-line treatment of patients with Waldenström’s macroglobulinemia—first interim results of a randomized phase III study of the Study Group Indolent Lymphomas (StiL). Paper presented at the 5th International Workshop on Waldenström’s Macroglobulinemia, Stockholm, SwedenGoogle Scholar
- 25.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 (2017) Diagnosis and management of Waldenström macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (msmart) guidelines 2016. JAMA Oncology 3:1257–1265. https://doi.org/10.1001/jamaoncol.2016.5763 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Tedeschi A, Picardi P, Ferrero S, Benevolo G, Margiotta Casaluci G, Varettoni M, Barate 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 (2015) Bendamustine and rituximab combination is safe and effective as salvage regimen in Waldenstrom macroglobulinemia. Leuk Lymphoma 56(9):2637–2642. https://doi.org/10.3109/10428194.2015.1012714 CrossRefPubMedGoogle Scholar
- 28.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 (2015) Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenstrom macroglobulinemia: final analysis of a phase 2 study. Blood 126(11):1392–1394. https://doi.org/10.1182/blood-2015-05-647420 CrossRefPubMedGoogle Scholar
- 29.Auer RL, Owen RG, D'Sa S, Pratt G, Popova B, Clifton Hadley L, Schofield O, Counsell N, Smith P (2016) R2W: subcutaneous bortezomib, cyclophosphamide and rituximab (BCR) versus fludarabine, cyclophosphamide and rituximab (FCR) for initial therapy of Waldenstrőm’s macroglobulinemia: a randomised phase II study. Blood 128(22):618–618Google Scholar
- 31.Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, Lozanski A, Davis M, Gordon A, Smith LL, Mantel R, Jones JA, Flynn JM, Jaglowski SM, Andritsos LA, Awan F, Blum KA, Grever MR, Johnson AJ, Byrd JC, Woyach JA (2015) Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol 1(1):80–87. https://doi.org/10.1001/jamaoncol.2014.218 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Castillo JJ, Gustine J, Meid K, Dubeau T, Ghobrial IM, Treon SP (2016) Lower doses of bendamustine are not associated with lower response rates in previously untreated patients with Waldenström macroglobulinemia. Paper presented at the ASH 58th Annual Meeting and Exposition, San Diego, CAGoogle Scholar
- 33.Jimenez R, Zhang B, Joffe S, Nilsson M, Rivera L, Mutchler J, Lathan C, Paulk ME, Prigerson HG (2013) Clinical trial participation among ethnic/racial minority and majority patients with advanced cancer: what factors most influence enrollment? J Palliat Med 16(3):256–262. https://doi.org/10.1089/jpm.2012.0413 CrossRefPubMedPubMedCentralGoogle Scholar
- 34.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 (2013) 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 121(11):2051–2058. https://doi.org/10.1182/blood-2012-09-454355 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Gachard N, Parrens M, Soubeyran I, Petit B, Marfak A, Rizzo D, Devesa M, Delage-Corre M, Coste V, Laforet MP, de Mascarel A, Merlio JP, Bouabdhalla K, Milpied N, Soubeyran P, Schmitt A, Bordessoule D, Cogne M, Feuillard J (2013) IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenstrom macroglobulinemia/lymphoplasmacytic lymphomas. Leukemia 27(1):183–189. https://doi.org/10.1038/leu.2012.257 CrossRefPubMedGoogle Scholar
- 36.Castillo JJ, Gustine JN, Meid K, Xu L, Hunter ZR, Treon SP (2018) Comparing apples to oranges: a commentary on the Mayo study of MYD88 significance in Waldenstrom’s macroglobulinemia. Am J Hematol. https://doi.org/10.1002/ajh.24997
- 37.Abeykoon JP, King R, Ansell SM, Rajkumar SV, Paludo J, Kyle RA, Kumar S, Gertz MA, Kapoor P (2018) Reply to Castillo et al. Am J Hematol. https://doi.org/10.1002/ajh.25029