Low lymphocyte-to-monocyte ratio predicts poor outcome in high-risk aggressive large B-cell lymphoma

Heli Vajavaara, Suvi-Katri Leivonen, Judit Jørgensen, Harald Holte, Sirpa Leppä, Heli Vajavaara, Suvi-Katri Leivonen, Judit Jørgensen, Harald Holte, Sirpa Leppä

Abstract

Low lymphocyte-to-monocyte-ratio (LMR) has been associated with unfavorable survival in patients with diffuse large B-cell lymphoma (DLBCL). To date, however, the impact of LMR on survival has not been examined in a uniformly treated cohort of patients with high-risk aggressive large B-cell lymphoma. We collected peripheral blood absolute lymphocyte counts (ALCs) and absolute monocyte counts (AMC) prior to treatment and calculated LMR from 112 adult patients, who were less than 65 years of age, had age-adjusted International Prognostic Index 2-3, or site-specific risk factors for central nervous system (CNS) recurrence, and were treated in a Nordic Lymphoma Group LBC-05 trial with dose-dense immunochemotherapy and early systemic CNS prophylaxis (www.ClinicalTrials.gov, number NCT01325194). Median pretreatment ALC was 1.40 × 109/l (range, 0.20-4.95), AMC 0.68 × 109/l (range, 0.10-2.62), and LMR 2.08 (range, 0.10-12.00). ALC did not correlate with tumor-infiltrating lymphocytes, AMC did not correlate with tumor-associated macrophages, and neither ALC nor AMC correlated with survival. However, low LMR (<1.72) translated to unfavourable progression-free survival (PFS) (5-year PFS 70% vs. 92%, p = 0.002) and overall survival (OS) (5-year OS, 77% vs. 92%, p = 0.020). In the patients with low LMR, relative risk of progression was 4.4-fold (95% confidence interval [CI] 1.60-12.14, p = 0.004), and relative risk of death was 3.3-fold (95% CI 1.18-9.50, p = 0.024) in comparison to the patients with high LMR. We conclude that low LMR is an adverse prognostic factor in uniformly treated young patients with high-risk aggressive large B-cell lymphoma.

Keywords: diffuse large B‐cell lymphoma; lymphocyte count; monocytes; prognosis; prospective studies.

Conflict of interest statement

Sirpa Leppä: Incyte*: consultancy and honoraria; Roche*: consultancy, honoraria, and research funding; Genmab*: research funding; Orion*: consultancy; Novartis*: consultancy, research funding, and honoraria; Bayer*: research funding; Celgene*: consultancy and research funding; Gilead*: consultancy. Harald Holte: Gilead*: consultancy and honoraria; Takeda*: consultancy and honoraria; Novartis*: consultancy; Genmab*: consultancy; Incyte*: consultancy and honoraria; Roche*: consultancy and honoraria. Other authors declare no conflict of interest. *Not related to this study.Heli Vajavaara designed and conceived the study, analyzed data, and wrote the manuscript. Suvi‐Katri Leivonen analyzed the data. Judit Jørgensen and Harald Holte provided samples. Sirpa Leppä designed and supervised the study and wrote the manuscript. All authors have read and approved the manuscript.

© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Association of absolute monocyte count (AMC) and lymphocyte‐to‐monocyte‐ratio (LMR) level with clinical factors. (A) Association of AMC with gender. Association of LMR with (B) gender and (C) B‐symptoms. FDR, false discovery rate
FIGURE 2
FIGURE 2
Survival association of lymphocyte‐to‐monocyte‐ratio (LMR). (A) Overall survival (OS) and (B) progression free survival (PFS) according to LMR level

References

    1. Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, 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(4):235–42.
    1. Pfreundschuh M, Trümper L, Österborg A, Pettengell R, Trneny M, Imrie K, 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(5):379–91.
    1. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo‐Lopez A, Gilman P, et al. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non‐Hodgkin's lymphoma. J Clin Oncol. 2001;19(2):389–97.
    1. International Non‐Hodgkin's Lymphoma Prognostic Factors Project . A predictive model for aggressive non‐Hodgkin's lymphoma. N Engl J Med. 1993;329(14):987–94.
    1. Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R‐IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B‐cell lymphoma treated with R‐CHOP. Blood 2007;109(5):1857–61.
    1. Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby‐Thompson A, et al. An enhanced International Prognostic Index (NCCN‐IPI) for patients with diffuse large B‐cell lymphoma treated in the rituximab era. Blood 2014;123(6):837–42.
    1. Wight JC, Chong G, Grigg AP, Hawkes EA. Prognostication of diffuse large B‐cell lymphoma in the molecular era: moving beyond the IPI. Blood Rev. 2018;32(5):400–15.
    1. Johnson NA, Slack GW, Savage KJ, Connors JM, Ben‐Neriah S, Rogic S, et al. Concurrent expression of MYC and BCL2 in diffuse large B‐cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30(28):3452–9.
    1. Meriranta L, Alkodsi A, Pasanen A, Lepistö M, Blaker YN, Autio M, et al. Genomic profiling of circulating tumor DNA reveals patterns of response and refractoriness in aggressive B‐cell lymphoma ‐ a nordic lymphoma group correlative study. Blood 2019;134(1):1481.
    1. Fiskvik I, Beiske K, Delabie J, Yri O, Spetalen S, Karjalainen‐Lindsberg M‐L, et al. Combining MYC, BCL2 and TP53 gene and protein expression alterations improves risk stratification in diffuse large B‐cell lymphoma. Leuk Lymphoma. 2015;56(6):1742–9.
    1. Young KH, Weisenburger DD, Dave BJ, Smith L, Sanger W, Iqbal J, et al. Mutations in the DNA‐binding codons of TP53, which are associated with decreased expression of TRAILreceptor‐2, predict for poor survival in diffuse large B‐cell lymphoma. Blood 2007;110(13):4396–405.
    1. Young KH, Leroy K, Møller MB, Colleoni GWB, Sánchez‐Beato M, Kerbauy FR, et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B‐cell lymphoma: an international collaborative study. Blood. 2008;112(8):3088–98.
    1. Ansell SM, Stenson M, Habermann TM, Jelinek DF, Witzig TE. Cd4+ T‐cell immune response to large B‐cell non‐Hodgkin's lymphoma predicts patient outcome. J Clin Oncol. 2001;19(3):720–6.
    1. Keane C, Gill D, Vari F, Cross D, Griffiths L, Gandhi M. CD4+ Tumor infiltrating lymphocytes are prognostic and independent of R‐IPI in patients with DLBCL receiving R‐CHOP chemo‐immunotherapy. Am J Hematol. 2013;88(4):273–6.
    1. Autio M, Leivonen S‐K, Brück O, Mustjoki S, Jørgensen JM, Karjalainen‐Lindsberg M‐L, et al. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B‐cell lymphoma. Haematologica 2021;106(3):718–29.
    1. Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, et al. Stromal gene signatures in large‐B‐cell lymphomas. N Engl J Med. 2008;359(22):2313–23.
    1. Kotlov N, Bagaev A, Revuelta MV, Phillip JM, Cacciapuoti MT, Antysheva Z, et al. Clinical and biological subtypes of B‐cell lymphoma revealed by microenvironmental signatures. Cancer Discov. 2021;11(6):1468–89.
    1. Porrata LF, Ristow KM, Habermann TM, Witzig TE, Colgan JP, Inwards DJ, et al. Peripheral blood absolute lymphocyte/monocyte ratio during rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone treatment cycles predicts clinical outcomes in diffuse large B‐cell lymphoma. Leuk Lymphoma. 2014;55(12):2728–38.
    1. Ho C‐L, Lu C‐S, Chen J‐H, Chen Y‐G, Huang T‐C, Wu Y‐Y. Neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio, and absolute lymphocyte count/absolute monocyte count prognostic score in diffuse large B‐cell lymphoma: useful prognostic tools in the rituximab era. Medicine 2015;94(24):e993.
    1. Li Z‐M, Huang J‐J, Xia Y, Sun J, Huang Y, Wang Y, et al. Blood lymphocyte‐to‐monocyte ratio identifies high‐risk patients in diffuse large B‐cell lymphoma treated with R‐CHOP. PLoS One. 2012;7(7):e41658.
    1. Rambaldi A, Boschini C, Gritti G, Delaini F, Oldani E, Rossi A, et al. The lymphocyte to monocyte ratio improves the IPI‐risk definition of diffuse large B‐cell lymphoma when rituximab is added to chemotherapy. Am J Hematol. 2013;88(12):1062–7.
    1. Markovic O, Popovic L, Marisavljevic D, Jovanovic D, Filipovic B, Stanisavljevic D, et al. Comparison of prognostic impact of absolute lymphocyte count, absolute monocyte count, absolute lymphocyte count/absolute monocyte count prognostic score and ratio in patients with diffuse large B cell lymphoma. Eur J Intern Med. 2014;25(3):296–302.
    1. Watanabe R, Tomita N, Itabashi M, Ishibashi D, Yamamoto E, Koyama S, et al. Peripheral blood absolute lymphocyte/monocyte ratio as a useful prognostic factor in diffuse large B‐cell lymphoma in the rituximab era. Eur J Haematol. 2014;92(3):204–10.
    1. Li Y‐L, Pan Y‐Y, Jiao Y, Ning J, Fan Y‐G, Zhai Z‐M. Peripheral blood lymphocyte/monocyte ratio predicts outcome for patients with diffuse large B cell lymphoma after standard first‐line regimens. Ann Hematol. 2014;93(4):617–26.
    1. Shimono J, Takahashi S, Takemura R, Kakinoki Y. Useful prognostic tools based on complete blood cell counts in diffuse large B‐cell lymphoma. Int J Lab Hematol. 2019;41(6):754–61.
    1. Matsuki E, Bohn OL, El Jamal S, Pichardo JD, Zelenetz AD, Younes A, et al. Lymphocyte‐to‐monocyte ratio may serve as a better prognostic indicator than tumor‐associated macrophages in DLBCL treated with rituximab. Appl Immunohistochem Mol Morphol. 2018;27(8):572–80.
    1. Belotti A, Doni E, Bolis S, Rossini F, Casaroli I, Pezzatti S, et al. Peripheral blood lymphocyte/monocyte ratio predicts outcome in follicular lymphoma and in diffuse large B‐cell lymphoma patients in the rituximab era. Clin Lymphoma Myeloma Leuk. 2015;15(4):208–13.
    1. Wilcox RA, Ristow K, Habermann TM, Inwards DJ, Micallef INM, Johnston PB, et al. The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high‐risk patients in diffuse large‐B‐cell lymphoma. Leukemia 2011;25(9):1502–9.
    1. Wei X, Huang F, Wei Y, Jing H, Xie M, Hao X, et al. Low lymphocyte‐to‐monocyte ratio predicts unfavorable prognosis in non‐germinal center type diffuse large B‐cell lymphoma. Leuk Res. 2014;38(6):694–8.
    1. Kim DH, Baek JH, Chae YS, Kim Y‐K, Kim HJ, Park YH, et al. Absolute lymphocyte counts predicts response to chemotherapy and survival in diffuse large B‐cell lymphoma. Leukemia 2007;21(10):2227–30.
    1. Oki Y, Yamamoto K, Kato H, Kuwatsuka Y, Taji H, Kagami Y, et al. Low absolute lymphocyte count is a poor prognostic marker in patients with diffuse large B‐cell lymphoma and suggests patients’ survival benefit from rituximab. Eur J Haematol. 2008;81(6):448–53.
    1. Tadmor T, Bari A, Sacchi S, Marcheselli L, Liardo EV, Avivi I, et al. Monocyte count at diagnosis is a prognostic parameter in diffuse large B‐cell lymphoma: results from a large multicenter study involving 1191 patients in the pre‐ and post‐rituximab era. Haematologica 2014;99(1):125–30.
    1. Cox MC, Nofroni I, Laverde G, Ferrari A, Amodeo R, Tatarelli C, et al. Absolute lymphocyte count is a prognostic factor in diffuse large B‐cell lymphoma. Br J Haematol. 2008;141(2):265–8.
    1. Leppä S, Jørgensen J, Tierens A, Meriranta L, Østlie I, De Nully Brown P, et al. Patients with high‐risk DLBCL benefit from dose‐dense immunochemotherapy combined with early systemic CNS prophylaxis. Blood Adv. 2020;4(9):1906–15.
    1. Vajavaara H, Ekeblad F, Holte H, Jorgensen J, Leivonen S‐K, Berglund M, et al. Prognostic impact of soluble CD163 in patients with diffuse large B‐cell lymphoma. Haematologica 2021;106(9):2502–6.
    1. Autio M, Leivonen S‐K, Brück O, Karjalainen‐Lindsberg M‐L, Pellinen T, Leppä S, et al. Clinical impact of immune cells and their spatial interactions in diffuse large B‐cell lymphoma microenvironment. Clin Cancer Res. 2022;28(4):781–792.
    1. Hothorn T, Lausen B. On the exact distribution of maximally selected rank statistics. Comput Stat Data Anal. 2003;43(2):121–37.
    1. Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24(5):679–90.
    1. Beenakker KGM, Westendorp RGJ, De Craen AJM, Chen S, Raz Y, Ballieux BEPB, et al. Men have a stronger monocyte‐derived cytokine production response upon stimulation with the gram‐negative stimulus lipopolysaccharide than women: a pooled analysis including 15 study populations. J Innate Immun. 2020;12(2):142–53.
    1. Aoki K, Tabata S, Yonetani N, Matsushita A, Ishikawa T. The prognostic impact of absolute lymphocyte and monocyte counts at diagnosis of diffuse large B‐cell lymphoma in the rituximab era. Acta Haematol. 2013;130(4):242–6.
    1. Jelicic J, Balint MT, Jovanovic MP, Boricic N, Micev M, Stojsic J, et al. The role of lymphocyte to monocyte ratio, microvessel density and HiGH CD44 tumor cell expression in non hodgkin lymphomas. Pathol Oncol Res. 2016;22(3):567–77.
    1. Batty N, Ghonimi E, Feng L, Fayad L, Younes A, Rodriguez MA, et al. The absolute monocyte and lymphocyte prognostic index for patients with diffuse large B‐cell lymphoma who receive R‐CHOP. Clin Lymphoma Myeloma Leuk. 2013;13(1):15–8.
    1. Shivakumar L, Ansell S. Targeting B‐Lymphocyte stimulator/B‐cell activating factor and a proliferation‐inducing ligand in hematologic malignancies. Clin Lymphoma Myeloma. 2006;7(2):106–8.
    1. Dirkx AEM, Oude Egbrink MGA, Wagstaff J, Griffioen AW. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol. 2006;80(6):1183–96.
    1. Wilcox RA, Wada DA, Ziesmer SC, Elsawa SF, Comfere NI, Dietz AB, et al. Monocytes promote tumor cell survival in T‐cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. Blood 2009;114(14):2936–44.
    1. Olingy CE, Dinh HQ, Hedrick CC. Monocyte heterogeneity and functions in cancer. J Leukoc Biol. 2019;106(2):309–22.
    1. Nishijima TF, Muss HB, Shachar SS, Tamura K, Takamatsu Y. Prognostic value of lymphocyte‐to‐monocyte ratio in patients with solid tumors: a systematic review and meta‐analysis. Cancer Treat Rev. 2015;41(10):971–8.
    1. Gonzalez‐Mejia ME, Doseff AI. Regulation of monocytes and macrophages cell fate. Front Biosci (Landmark Ed). 2009;14:2413–31.

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