Integrating precision medicine through evaluation of cell of origin in treatment planning for diffuse large B-cell lymphoma

Grzegorz S Nowakowski, Tatyana Feldman, Lisa M Rimsza, Jason R Westin, Thomas E Witzig, Pier Luigi Zinzani, Grzegorz S Nowakowski, Tatyana Feldman, Lisa M Rimsza, Jason R Westin, Thomas E Witzig, Pier Luigi Zinzani

Abstract

Precision medicine is modernizing strategies for clinical study design to help improve diagnoses guiding individualized treatment based on genetic or phenotypic characteristics that discriminate between patients with similar clinical presentations. Methodology to personalize treatment choices is being increasingly employed in clinical trials, yielding favorable correlations with improved response rates and survival. In patients with diffuse large B-cell lymphoma (DLBCL), disease characteristics and outcomes may vary widely, underscoring the importance of patient classification through identification of sensitive prognostic features. The discovery of distinct DLBCL molecular subtypes based on cell of origin (COO) is redefining the prognosis and treatment of this heterogeneous cancer. Owing to significant molecular and clinical differences between activated B-cell-like (ABC)- and germinal center B-cell-like (GCB)-DLBCL subtypes, COO identification offers opportunities to optimize treatment selection. Widespread adoption of COO classification would greatly improve treatment and prognosis; however, limitations in interlaboratory concordance between immunohistochemistry techniques, cost, and availability of gene expression profiling tools undermine universal integration in the clinical setting. With advanced methodology to determine COO in a real-world clinical setting, therapies targeted to specific subtypes are under development. The focus here is to review applications of precision medicine exemplified by COO determination in DLBCL patients.

Conflict of interest statement

G.S.N. has received research funding from Celgene, Bayer, Morphosys, and Roche; T.F. has served on the speakers’ bureau for and consulted with Seattle Genetics, she has served on the speakers’ bureau for Kite Pharma, Abbvie, Janssen, Pharmacyclics, and Celgene, and has consulted for BMS; L.M.R. is the inventor of the Lymph2Cx assay; T.E.W. has consulted for Spectrum without personal compensation, consulted for Sandoz with personal compensation, and received research funding from Celgene and Novartis; P.L.Z. has consulted with and served on the speakers’ bureau for Celgene, Roche, Janssen, Gilead Bristol-Myers Squibb, Merck, and Servier, and has consulted with Verastem; and J.R.W. has nothing to disclose.

Figures

Fig. 1. Outcomes by COO in an…
Fig. 1. Outcomes by COO in an independent validation cohort of 68 patients receiving first-line CHOP or R-CHOP.
a PFS by COO per Lymph2Cx, b OS by COO group per Lymph2Cx, c PFS by COO group per gold standard GEP, and d OS by COO per gold standard GEP. CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; COO cell of origin, GEP gene expression profiling, OS overall survival, PFS progression-free survival, R-CHOP rituximab with CHOP, RR relative risk (with 95% confidence interval). Republished with permission of Blood: a journal of the American Society of Hematology, from Scott et al.; permission conveyed through Copyright Clearance Center, Inc

References

    1. Jameson JL, Longo DL. Precision medicine--personalized, problematic, and promising. N. Engl. J. Med. 2015;372:2229–2234. doi: 10.1056/NEJMsb1503104.
    1. Carneiro BA, et al. Is personalized medicine here? Oncology. 2016;30:293–303.
    1. Slamon DJ, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 2001;344:783–792. doi: 10.1056/NEJM200103153441101.
    1. Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011;364:2507–2516. doi: 10.1056/NEJMoa1103782.
    1. Ravnan MC, Matalka MS. Vemurafenib in patients with BRAF V600E mutation-positive advanced melanoma. Clin. Ther. 2012;34:1474–1486. doi: 10.1016/j.clinthera.2012.06.009.
    1. Schwaederle M, et al. Impact of precision medicine in diverse cancers: a meta-analysis of phase II clinical trials. J. Clin. Oncol. 2015;33:3817–3825. doi: 10.1200/JCO.2015.61.5997.
    1. Jardim DL, et al. Impact of a biomarker-based strategy on oncology drug development: a meta-analysis of clinical trials leading to FDA approval. J. Natl Cancer. Inst. 2015;107:djv253. doi: 10.1093/jnci/djv253.
    1. Sujobert P, Salles G, Bachy E. Molecular classification of diffuse large B-cell lymphoma: what Is clinically relevant? Hematol. Oncol. Clin. N. Am. 2016;30:1163–1177. doi: 10.1016/j.hoc.2016.07.001.
    1. Alizadeh AA, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–511. doi: 10.1038/35000501.
    1. Coiffier B, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 2002;346:235–242. doi: 10.1056/NEJMoa011795.
    1. Pfreundschuh M, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379–391. doi: 10.1016/S1470-2045(06)70664-7.
    1. Friedberg JW. Relapsed/refractory diffuse large B-cell lymphoma. Hematol. Am. Soc. Hematol. Educ. Prog. 2011;2011:498–505. doi: 10.1182/asheducation-2011.1.498.
    1. Rosenwald A, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 2002;346:1937–1947. doi: 10.1056/NEJMoa012914.
    1. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125:22–32. doi: 10.1182/blood-2014-05-577189.
    1. Pasqualucci L, Dalla-Favera R. The genetic landscape of diffuse large B-cell lymphoma. Semin. Hematol. 2015;52:67–76. doi: 10.1053/j.seminhematol.2015.01.005.
    1. Lenz G, et al. Stromal gene signatures in large-B-cell lymphomas. N. Engl. J. Med. 2008;359:2313–2323. doi: 10.1056/NEJMoa0802885.
    1. Roschewski M, Staudt LM, Wilson WH. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat. Rev. Clin. Oncol. 2014;11:12–23. doi: 10.1038/nrclinonc.2013.197.
    1. Nowakowski G. S. & Czuczman, M. S. ABC, GCB, and double-hit diffuse large B-cell lymphoma: does subtype make a difference in therapy selection? In American Society of Clinical Oncology Educational Book / ASCO. e449–e457 (American Society of Clinical Oncology). Meeting 2015.
    1. Swerdlow SH, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–2390. doi: 10.1182/blood-2016-01-643569.
    1. Ennishi D, et al. Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin-specific clinical impact. Blood. 2017;129:2760–2770. doi: 10.1182/blood-2016-11-747022.
    1. Scott DW, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J. Clin. Oncol. 2015;33:2848–2856. doi: 10.1200/JCO.2014.60.2383.
    1. McPhail E. D., et al. Prognostic impact of morphology, MYC gene partner and BCL2/BCL6 translocation status in “high grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements”. Blood, 128, abstract 1750 (2016).
    1. Schmidt-Hansen M, Berendse S, Marafioti T, McNamara C. Does cell-of-origin or MYC, BCL2 or BCL6 translocation status provide prognostic information beyond the International Prognostic Index score in patients with diffuse large B-cell lymphoma treated with rituximab and chemotherapy? A systematic review. Leuk. Lymphoma. 2017;58:2403–2418. doi: 10.1080/10428194.2017.1287364.
    1. Niitsu N, Okamoto M, Miura I, Hirano M. Clinical features and prognosis of de novo diffuse large B-cell lymphoma with t(14;18) and 8q24/c-MYC translocations. Leukemia. 2009;23:777–783. doi: 10.1038/leu.2008.344.
    1. Landsburg DJ, et al. Sole rearrangement but not amplification of MYC is associated with a poor prognosis in patients with diffuse large B cell lymphoma and B cell lymphoma unclassifiable. Br. J. Haematol. 2016;175:631–640. doi: 10.1111/bjh.14282.
    1. National Institute for Health and Care Excellence (2016). Non-Hodgkin’s lymphoma: diagnosis and management. NICE guideline (NG52). . Accessed 6 Mar 2018.
    1. Chapuy B, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat. Med. 2018;24:679–690. doi: 10.1038/s41591-018-0016-8.
    1. Schmitz R, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N. Engl. J. Med. 2018;378:1396–1407. doi: 10.1056/NEJMoa1801445.
    1. Puvvada S, Kendrick S, Rimsza L. Molecular classification, pathway addiction, and therapeutic targeting in diffuse large B cell lymphoma. Cancer Genet. 2013;206:257–265. doi: 10.1016/j.cancergen.2013.07.003.
    1. Wright G, et al. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc. Natl Acad. Sci. USA. 2003;100:9991–9996. doi: 10.1073/pnas.1732008100.
    1. Hans CP, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103:275–282. doi: 10.1182/blood-2003-05-1545.
    1. de Jong D, et al. Immunohistochemical prognostic markers in diffuse large B-cell lymphoma: validation of tissue microarray as a prerequisite for broad clinical applications--a study from the Lunenburg Lymphoma Biomarker Consortium. J. Clin. Oncol. 2007;25:805–812. doi: 10.1200/JCO.2006.09.4490.
    1. Colomo L, et al. Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. Blood. 2003;101:78–84. doi: 10.1182/blood-2002-04-1286.
    1. Schaffer M, et al. Comparison of immunohistochemistry assay results with gene expression profiling methods for diffuse large B-cell lymphoma subtype identification in matched patient samples. J. Mol. Biomark. Diagn. 2018;9:2. doi: 10.4172/21559929.1000386.
    1. Muris JJ, et al. Immunohistochemical profiling based on Bcl-2, CD10 and MUM1 expression improves risk stratification in patients with primary nodal diffuse large B cell lymphoma. J. Pathol. 2006;208:714–723. doi: 10.1002/path.1924.
    1. Natkunam Y, et al. LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. J. Clin. Oncol. 2008;26:447–454. doi: 10.1200/JCO.2007.13.0690.
    1. Nyman H, Jerkeman M, Karjalainen-Lindsberg ML, Banham AH, Leppa S. Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP. Mod. Pathol. 2009;22:1094–1101. doi: 10.1038/modpathol.2009.73.
    1. Choi WW, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin. Cancer Res. 2009;15:5494–5502. doi: 10.1158/1078-0432.CCR-09-0113.
    1. Meyer PN, et al. Immunohistochemical methods for predicting cell of origin and survival in patients with diffuse large B-cell lymphoma treated with rituximab. J. Clin. Oncol. 2011;29:200–207. doi: 10.1200/JCO.2010.30.0368.
    1. Visco C, et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26:2103–2113. doi: 10.1038/leu.2012.83.
    1. Seki R, et al. Prognostic impact of immunohistochemical biomarkers in diffuse large B-cell lymphoma in the rituximab era. Cancer Sci. 2009;100:1842–1847. doi: 10.1111/j.1349-7006.2009.01268.x.
    1. Ott G, et al. Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood. 2010;116:4916–4925. doi: 10.1182/blood-2010-03-276766.
    1. Read JA, et al. Evaluating cell-of-origin subtype methods for predicting diffuse large B-cell lymphoma survival: a meta-analysis of gene expression profiling and immunohistochemistry algorithms. Clinical Lymphoma, Myeloma Leuk. 2014;14:460–467 e462. doi: 10.1016/j.clml.2014.05.002.
    1. Gutierrez-Garcia G, et al. Gene-expression profiling and not immunophenotypic algorithms predicts prognosis in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Blood. 2011;117:4836–4843. doi: 10.1182/blood-2010-12-322362.
    1. Moskowitz CH, et al. Cell of origin, germinal center versus nongerminal center, determined by immunohistochemistry on tissue microarray, does not correlate with outcome in patients with relapsed and refractory DLBCL. Blood. 2005;106:3383–3385. doi: 10.1182/blood-2005-04-1603.
    1. Thieblemont C, et al. The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study. J. Clin. Oncol. 2011;29:4079–4087. doi: 10.1200/JCO.2011.35.4423.
    1. Coutinho R, et al. Poor concordance among nine immunohistochemistry classifiers of cell-of-origin for diffuse large B-cell lymphoma: implications for therapeutic strategies. Clin. Cancer Res. 2013;19:6686–6695. doi: 10.1158/1078-0432.CCR-13-1482.
    1. Xie Y, Pittaluga S, Jaffe ES. The histological classification of diffuse large B-cell lymphomas. Semin. Hematol. 2015;52:57–66. doi: 10.1053/j.seminhematol.2015.01.006.
    1. Alizadeh A, et al. The lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. Cold Spring Harb. Symp. Quant. Biol. 1999;64:71–78. doi: 10.1101/sqb.1999.64.71.
    1. Rimsza LM. Diffuse large B-cell lymphoma classification tied up nicely with a “string”. Clin. Cancer Res. 2015;21:2204–2206. doi: 10.1158/1078-0432.CCR-15-0253.
    1. Rimsza LM, et al. Accurate classification of diffuse large B-cell lymphoma into germinal center and activated B-cell subtypes using a nuclease protection assay on formalin-fixed, paraffin-embedded tissues. Clin. Cancer Res. 2011;17:3727–3732. doi: 10.1158/1078-0432.CCR-10-2573.
    1. Barrans SL, et al. Whole genome expression profiling based on paraffin embedded tissue can be used to classify diffuse large B-cell lymphoma and predict clinical outcome. Br. J. Haematol. 2012;159:441–453. doi: 10.1111/bjh.12045.
    1. Williams PM, et al. A novel method of amplification of FFPET-derived RNA enables accurate disease classification with microarrays. J. Mol. Diagn. 2010;12:680–686. doi: 10.2353/jmoldx.2010.090164.
    1. Care MA, et al. A microarray platform-independent classification tool for cell of origin class allows comparative analysis of gene expression in diffuse large B-cell lymphoma. PLoS One. 2013;8:e55895. doi: 10.1371/journal.pone.0055895.
    1. Scott DW, et al. Determining cell-of-origin subtypes of diffuse large B-cell lymphoma using gene expression in formalin-fixed paraffin-embedded tissue. Blood. 2014;123:1214–1217. doi: 10.1182/blood-2013-11-536433.
    1. Kendrick S, et al. Diffuse large B-cell lymphoma cell-of-origin classification using the Lymph2Cx assay in the context of BCL2 and MYC expression status. Leuk. Lymphoma. 2016;57:717–720. doi: 10.3109/10428194.2015.1072767.
    1. Bobée V, et al. Determination of molecular subtypes of diffuse large B-cell lymphoma using a reverse transcriptase multiplex ligation-dependent probe amplification classifier: a CALYM Study. J. Mol. Diagn. 2017;19:892–904. doi: 10.1016/j.jmoldx.2017.07.007.
    1. Cascione L, et al. Diffuse large B cell lymphoma cell of origin by digital expression profiling in the REAL07 Phase 1–2 study. Br. J. Haematol. 2017;182:453–456. doi: 10.1111/bjh.14817.
    1. Nowakowski GS, et al. ROBUST: lenalidomide-R-CHOP versus placebo-R-CHOP in previously untreated ABC-type diffuse large B-cell lymphoma. Future Oncol. 2016;12:1553–1563. doi: 10.2217/fon-2016-0130.
    1. Nowakowski G. S., et al. Feasibility of real-time cell-of-origin subtype identification by gene expression profile in the phase 3 trial of lenalidomide plus R-CHOP vs placebo plus R-CHOP in patients with untreated ABC-type diffuse large B-cell lymphoma (ROBUST). J. Clin. Oncol. abstract 7358 (2016).
    1. Vitolo, U. et al. Real-time cell-of-origin subtype identification by gene expression profile in the phase 3 ROBUST trial of lenalidomide+R-CHOP vs placebo+R-CHOP in previously untreated ABC-type DLBCL. Haematologica101, 392, abstract E954 (2016).
    1. Veldman-Jones MH, et al. Reproducible, quantitative, and flexible molecular subtyping of clinical DLBCL samples using the NanoString nCounter system. Clin. Cancer Res. 2015;21:2367–2378. doi: 10.1158/1078-0432.CCR-14-0357.
    1. Yoon N, et al. Cell-of-origin of diffuse large B-cell lymphomas determined by the Lymph2Cx assay: better prognostic indicator than Hans algorithm. Oncotarget. 2017;8:22014–22022.
    1. de Jong D, Balague Ponz O. The molecular background of aggressive B cell lymphomas as a basis for targeted therapy. J. Pathol. 2011;223:274–282.
    1. Novero A, Ravella PM, Chen Y, Dous G, Liu D. Ibrutinib for B cell malignancies. Exp. Hematol. Oncol. 2014;3:4. doi: 10.1186/2162-3619-3-4.
    1. Zhang LH, et al. Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression. Br. J. Haematol. 2013;160:487–502. doi: 10.1111/bjh.12172.
    1. Ruan J, et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J. Clin. Oncol. 2011;29:690–697. doi: 10.1200/JCO.2010.31.1142.
    1. Younes A, et al. Combination of ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for treatment-naive patients with CD20-positive B-cell non-Hodgkin lymphoma: a non-randomised, phase 1b study. Lancet Oncol. 2014;15:1019–1026. doi: 10.1016/S1470-2045(14)70311-0.
    1. Nowakowski GS, et al. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia. 2011;25:1877–1881. doi: 10.1038/leu.2011.165.
    1. Nowakowski GS, et al. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J. Clin. Oncol. 2015;33:251–257. doi: 10.1200/JCO.2014.55.5714.
    1. Vitolo U, et al. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014;15:730–737. doi: 10.1016/S1470-2045(14)70191-3.
    1. Vose JM. Relapsed diffuse large B-cell lymphoma: clinical utility of cell of origin. J. Clin. Oncol. 2011;29:4065–4066. doi: 10.1200/JCO.2011.37.5733.
    1. Farooq, U. et al. Cell of origin is not associated with survival after DLBCL relapse. Hematol. Oncol.33, 185, abstract 158 (2015).
    1. Gisselbrecht C, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J. Clin. Oncol. 2010;28:4184–4190. doi: 10.1200/JCO.2010.28.1618.
    1. Dunleavy K, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood. 2009;113:6069–6076. doi: 10.1182/blood-2009-01-199679.
    1. Wilson WH, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat. Med. 2015;21:922–926. doi: 10.1038/nm.3884.
    1. Younes Anas, Sehn Laurie H., Johnson Peter, Zinzani Pier Luigi, Hong Xiaonan, Zhu Jun, Patti Caterina, Belada David, Samoilova Olga, Suh Cheolwon, Leppä Sirpa, Rai Shinya, Turgut Mehmet, Jurczak Wojciech, Cheung Matthew C., Gurion Ronit, Yeh Su-Peng, Lopez-Hernandez Andres, Dührsen Ulrich, Thieblemont Catherine, Chiattone Carlos Sergio, Balasubramanian Sriram, Carey Jodi, Liu Grace, Shreeve S. Martin, Sun Steven, Zhuang Sen Hong, Vermeulen Jessica, Staudt Louis M., Wilson Wyndham. Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non–Germinal Center B-Cell Diffuse Large B-Cell Lymphoma. Journal of Clinical Oncology. 2019;37(15):1285–1295. doi: 10.1200/JCO.18.02403.
    1. Hernandez-Ilizaliturri FJ, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117:5058–5066. doi: 10.1002/cncr.26135.
    1. Czuczman MS, et al. A phase 2/3 multicenter, randomized, open-label study of lenalidomide vs investigator’s choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin. Cancer Res. 2017;23:4127–4137. doi: 10.1158/1078-0432.CCR-16-2818.
    1. Feldman T, et al. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br. J. Haematol. 2014;166:77–83. doi: 10.1111/bjh.12846.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe