Sex as decisive variable in lymphoid neoplasms—an update

The sex of a patient is a strong clinical variable in many malignancies, among which lymphoid neoplasms feature quite prominently. Ignored for a long time, the recognition of the fact that there are sex disparities in incidence, disease course, and outcome has increasingly led to the inclusion of the variable sex in study design, data acquisition and analyses, and reporting. However, there still is a great lack of information as to how and why sex plays a role in lymphoid cancers. The immune system is inherently different between men and women, the genetic basis translating into disparities in, among other aspects, lymphocyte pools, cytokine and chemokine production, and antibody response intensities. In particular, hormones shape development and functioning of the immune system and influence the functional activity of immune cells and responses, which also result in the sex-specific prevalence for infectious and autoimmune diseases, respectively.1Mirandola L. Wade R. Verma R. et al.Sex-driven differences in immunological responses: challenges and opportunities for the immunotherapies of the third millennium.Int Rev Immunol. 2015; 34: 134-142Crossref PubMed Scopus (31) Google Scholar,2Klein S. Flanagan K. Sex differences in immune responses.Nat Rev Immunol. 2016; 16: 626-638Crossref PubMed Scopus (1778) Google Scholar As malignancies originating from immune cells, chronic inflammatory and infectious conditions have been hypothesized and shown to cause the formation and outgrowth of pre-neoplastic cells which may develop into lymphoid neoplasms.3Smedby K. Ponzoni M. The aetiology of B-cell lymphoid malignancies with a focus on chronic inflammation and infections.J Intern Med. 2017; 282: 360-370Crossref PubMed Scopus (27) Google Scholar For chronic lymphocytic leukaemia (CLL), chronic antigenic stimulation has strongly been implicated for leukaemogenesis based on the high frequency of quasi-identical B-cell receptors (BCR) in unrelated patients.4Baliakas P. Hadzidimitriou A. Sutton L. et al.Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study.Lancet Haematol. 2014; 1: e74-e84Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Furthermore, the role of hormones per se has been discussed for development and course of lymphoid malignancies.5Ladikou E. Kassi E. The emerging role of estrogen in B cell malignancies.Leuk Lymphoma. 2017; 58: 528-539Crossref PubMed Scopus (17) Google Scholar Information on hormones and hormone profiles in lymphoid malignancies, however, is scarce. In CLL patients, the hormone profiles of male and female patients were significantly altered compared with sex-matched healthy individuals, for some hormones this was associated with clinical stage and treatment-free survival (TFS).6Everaus H. Hormones and immune responsiveness in chronic lymphocytic leukemia.Leuk Lymphoma. 1992; 8: 483-489Crossref PubMed Scopus (10) Google Scholar,7Allain E. Venzl K. Caron P. et al.Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients.Ann Hematol. 2018; 97: 1649-1661Crossref PubMed Scopus (11) Google Scholar Such a hormonal shift would consequently point towards a potential role for the corresponding receptors for development and/or course of the disease. In this respect, hormone receptors have been detected not only on healthy but also malignant blood cells,8Park H. Bae J. Noh S. et al.Expression of DBC1 and androgen receptor predict poor prognosis in diffuse large B cell lymphoma.Transl Oncol. 2013; 6: 370-381Crossref PubMed Scopus (23) Google Scholar, 9Abdelbaset-Ismail A. Suszynska M. Borkowska S. et al.Human haematopoietic stem/progenitor cells express several functional sex hormone receptors.J Cell Mol Med. 2016; 20: 134-146Crossref PubMed Scopus (34) Google Scholar, 10Mostaghel E. Martin P. Mongovin S. et al.Androgen receptor expression in mantle cell lymphoma: potential novel therapeutic implications.Exp Hematol. 2017; 49: 34-38.e2Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar, 11Hasni M. Yakimchuk K. Expression and effects of ligand-activated estrogen receptors in chronic lymphocytic leukemia.Anticancer Res. 2019; 39: 167-172Crossref PubMed Scopus (3) Google Scholar some of which were found to be overexpressed and of prognostic value, thus suggesting some degree of functional relevance.8Park H. Bae J. Noh S. et al.Expression of DBC1 and androgen receptor predict poor prognosis in diffuse large B cell lymphoma.Transl Oncol. 2013; 6: 370-381Crossref PubMed Scopus (23) Google Scholar,10Mostaghel E. Martin P. Mongovin S. et al.Androgen receptor expression in mantle cell lymphoma: potential novel therapeutic implications.Exp Hematol. 2017; 49: 34-38.e2Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar,11Hasni M. Yakimchuk K. Expression and effects of ligand-activated estrogen receptors in chronic lymphocytic leukemia.Anticancer Res. 2019; 39: 167-172Crossref PubMed Scopus (3) Google Scholar The male to female ratio seen in many lymphoid neoplasms, including CLL, at diagnosis is 2 : 1, and is preceded by a similar incidence in monoclonal B-cell lymphocytosis, the CLL precursor condition, where men also have a higher risk to develop the malignancy.12Goldin L. Lanasa M. Slager S. et al.Common occurrence of monoclonal B-cell lymphocytosis among members of high-risk CLL families.Br J Haematol. 2010; 151: 152-158Crossref PubMed Scopus (55) Google Scholar This ratio has been observed in other ethnic and for most age groups,13Shenoy P. Malik N. Sinha R. et al.Racial differences in the presentation and outcomes of chronic lymphocytic leukemia and variants in the United States.Clin Lymphoma Myeloma Leuk. 2011; 11: 498-506Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,14Nabhan C. Aschebrook-Kilfoy B. Chiu B. et al.The impact of race, ethnicity, age and sex on clinical outcome in chronic lymphocytic leukemia: a comprehensive surveillance, epidemiology, and end results analysis in the modern era.Leuk Lymphoma. 2014; 55: 2778-2784Crossref PubMed Scopus (25) Google Scholar the ratio may become more equal in patients over 70 years of age.15Baumann T. Delgado J. Santacruz R. et al.Chronic lymphocytic leukemia in the elderly: clinico-biological features, outcomes, and proposal of a prognostic model.Haematologica. 2014; 99: 1599-1604Crossref PubMed Scopus (46) Google Scholar As one of the causes for the sex disparities observed in cancer incidence and survival, the sex chromosomes have been implicated. A study by Dunford and colleagues (2017), carried out in mostly solid but also lymphoid tumours, found sex-specific loss-of-function mutations in and, consequently, differential expression of several genes on the sex chromosomes.16Dunford A. Weinstock D. Savova V. et al.Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias.Nat Genet. 2017; 49: 10-16Crossref PubMed Scopus (154) Google Scholar However, the genes reported in this study only occur at very low frequencies in CLL and appear to be of limited importance for development and disease course.17Ojha J. Ayres J. Secreto C. et al.Deep sequencing identifies genetic heterogeneity and recurrent convergent evolution in chronic lymphocytic leukemia.Blood. 2015; 125: 492-498Crossref PubMed Scopus (44) Google Scholar Also loss of the sex chromosomes can be found at regular albeit low frequencies in CLL, however, they do not show differences between women and men.18Chapiro E. Antony-Debre I. Marchay N. et al.Sex chromosome loss may represent a disease-associated clonal population in chronic lymphocytic leukemia.Genes Chromosomes Cancer. 2014; 53: 240-247Crossref PubMed Scopus (20) Google Scholar In addition, sex-specific differential DNA methylation has been reported, some autosomal but the majority on the sex chromosomes. These differences translated into different expression levels for the affected genes in male and female CLL patients, with as yet unknown consequences.19Lin S. Liu Y. Goldin L. et al.Sex-related DNA methylation differences in B cell chronic lymphocytic leukemia.Biol Sex Differ. 2019; 10: 2Crossref PubMed Scopus (16) Google Scholar Clinically, sex-specific differences are subtle, and sex-specific bias with regard to genetic aberrations is rarely reported, and often information is conflicting. On the one hand, for diffuse large B-cell lymphoma (DLBCL) and CLL no differences have been observed for the clinically relevant chromosomal changes between men and women.7Allain E. Venzl K. Caron P. et al.Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients.Ann Hematol. 2018; 97: 1649-1661Crossref PubMed Scopus (11) Google Scholar,20Schiefer A. Kornauth C. Simonitsch-Klupp I. et al.Impact of single or combined genomic alterations of TP53, MYC, and BCL2 on survival of patients with diffuse large B-cell lymphomas: a retrospective cohort study.Medicine. 2015; 94: e2388Crossref PubMed Scopus (20) Google Scholar On the other hand, Cantú (2013) found skewed male-to-female ratios for standard CLL FISH probes (M : F 1.5), and the loss of ATM gene was higher in men compared with women [odds ratio (OR) 1.7045, P = 0.0049].21Cantú E. McGill J. Stephenson C. et al.Male-to-female sex ratios of abnormalities detected by fluorescence in situ hybridization in a population of chronic lymphocytic leukemia patients.Hematol Rep. 2013; 5: 13-17Crossref PubMed Scopus (8) Google Scholar Studies on gene variants or single nucleotide polymorphisms (SNPs) for various genes showed variable associations of gene mutations with the sex of patients and did not find sex-specific functional consequences on response or survival.22Allan J. Sunter N. Bailey J. et al.Variant IRF4/MUM1 associates with CD38 status and treatment-free survival in chronic lymphocytic leukaemia.Leukemia. 2010; 24: 877-881Crossref PubMed Scopus (17) Google Scholar, 23Oscier D. Rose-Zerilli M. Winkelmann N. et al.The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial.Blood. 2013; 121: 468-475Crossref PubMed Scopus (164) Google Scholar, 24Benner A. Mansouri L. Rossi D. et al.MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis.Haematologica. 2014; 99: 1285-1291Crossref PubMed Scopus (2) Google Scholar, 25Jeromin S. Weissmann S. Haferlach C. et al.SF3B1 mutations correlated to cytogenetics and mutations in NOTCH1, FBXW7, MYD88, XPO1 and TP53 in 1160 untreated CLL patients.Leukemia. 2014; 28: 108-117Crossref PubMed Scopus (168) Google Scholar, 26Larrayoz M. Rose-Zerilli M. Kadalayil L. et al.Non-coding NOTCH1 mutations in chronic lymphocytic leukemia; their clinical impact in the UK CLL4 trial.Leukemia. 2017; 31: 510-514Crossref PubMed Scopus (24) Google Scholar Most often, sex-specific disparities are found and reported for the mutational status of the immunoglobulin heavy chain variable region (IgHV) gene. Sex was differently distributed between the mutated (M) and unmutated (UM) subgroups, with men more likely showing UM IgHV (P = 0.009), in addition to having a higher prevalence in the UM stereotyped BCR subsets (M : F between 1 and 4.4, P = 0.001, compared with 0.8 to 2.0 for the M stereotyped BCR subsets, P = 0.03).4Baliakas P. Hadzidimitriou A. Sutton L. et al.Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study.Lancet Haematol. 2014; 1: e74-e84Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar,27Raponi S. Ilari C. Della Starza I. et al.Redefining the prognostic likelihood of chronic lymphocytic leukaemia patients with borderline percentage of immunoglobulin variable heavy chain region mutations.Br J Haematol. 2020; 189: 853-859Crossref PubMed Scopus (6) Google Scholar,28Shi K. Sun Q. Qiao C. et al.98% IGHV gene identity is the optimal cutoff to dichotomize the prognosis of Chinese patients with chronic lymphocytic leukemia.Cancer Med. 2020; 9: 999-1007Crossref PubMed Scopus (2) Google Scholar Furthermore, epigenetic silencing of the NfκB gene RELB through heterochromatinization has been found in aggressive subsets of male and female CLL patients, but was most pronounced in males and led to reduced response to drugs in vitro.29Marteau J. Rigaud O. Brugat T. et al.Concomitant heterochromatinisation and down-regulation of gene expression unveils epigenetic silencing of RELB in an aggressive subset of chronic lymphocytic leukemia in males.BMC Med Genomics. 2010; 3: 53Crossref PubMed Scopus (12) Google Scholar The differential distribution of women and men seen in patients with chronic inflammatory or infectious conditions is reflected in lymphoid malignancies. Subgroups of leukaemia and lymphoma patients that also suffer from autoimmune diseases are shifted to females (55% of CLL and 87.05% of non-Hodgkin's lymphoma patients),30Vanura K. Le T. Esterbauer H. et al.Autoimmune conditions and chronic infections in CLL patients at diagnosis are associated with unmutated IgVH genes.Haematologica. 2008; 93: 1912-1916Crossref PubMed Scopus (22) Google Scholar,31Vanura K. Späth F. Gleiss A. et al.Prevalence and clinical impact of autoimmune diseases and chronic infections in malignant lymphomas at diagnosis.Ann Hematol. 2011; 90: 947-954Crossref PubMed Scopus (5) Google Scholar with CLL patients suffering from concomitant chronic inflammatory conditions also being more likely to have bad risk markers.30Vanura K. Le T. Esterbauer H. et al.Autoimmune conditions and chronic infections in CLL patients at diagnosis are associated with unmutated IgVH genes.Haematologica. 2008; 93: 1912-1916Crossref PubMed Scopus (22) Google Scholar Most obvious, male and female CLL patients display differences for TFS and/or overall survival (OS). Hence, sex was included as a variable in several risk scores and prognostic indices for risk stratification, particularly in early stage patients with male sex constituting a risk variable for OS and/or TFS.32Bulian P. Tarnani M. Rossi D. et al.Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia.Hematol Oncol. 2011; 29: 91-99Crossref PubMed Scopus (26) Google Scholar, 33Gentile M. Mauro F. Rossi D. et al.Italian external and multicentric validation of the MD Anderson Cancer Center nomogram and prognostic index for chronic lymphocytic leukaemia patients: analysis of 1502 cases.Br J Haematol. 2014; 167: 224-232Crossref PubMed Scopus (25) Google Scholar, 34Pflug N. Bahlo J. Shanafelt T. et al.Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia.Blood. 2014; 124: 49-62Crossref PubMed Scopus (206) Google Scholar Inclusion of sex was based on statistically significant survival differences between men and women seen both in univariate and multivariate analyses, hazard ratio (HR) for male sex varying from 1.3 to 1.67 in these studies. Independent of risk scores, male sex still conferred shorter OS and/or TFS, the survival difference surpassing 1 year or more in some studies.7Allain E. Venzl K. Caron P. et al.Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients.Ann Hematol. 2018; 97: 1649-1661Crossref PubMed Scopus (11) Google Scholar,35Wu S. Chiang C. Lin C. Tien H. Lai M. Improving but inferior survival in patients with chronic lymphocytic leukemia in Taiwan: a population-based study, 1990-2004.PLoS One. 2013; 8: e62930Crossref PubMed Scopus (18) Google Scholar,36Lenartova A. Johannesen T. Tjønnfjord G. National trends in incidence and survival of chronic lymphocytic leukemia in Norway for 1953-2012: a systematic analysis of population-based data.Cancer Med. 2016; 5: 3588-3595Crossref PubMed Scopus (17) Google Scholar However, such differences were not observed in all investigations, similar survival probabilities between men and women underline the variability of observations.37Shvidel L. Braester A. Bairey O. et al.Survival trends among 1,325 patients with chronic lymphocytic leukemia seen over the past 40 years in Israel.Am J Hematol. 2011; 86: 985-992Crossref PubMed Scopus (10) Google Scholar, 38Gentile M. Shanafelt T. Cutrona G. et al.A progression-risk score to predict treatment-free survival for early stage chronic lymphocytic leukemia patients.Leukemia. 2016; 30: 1440-1443Crossref PubMed Scopus (22) Google Scholar, 39Cohen J. Rossi F. Zucchetto A. et al.A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia.Haematologica. 2020; 105: 1613-1620Crossref PubMed Scopus (6) Google Scholar Information on response to treatment by sex is difficult to discern; in many cases, this information is not provided at all. Also, due to the many therapeutic regimens and combinations and small sizes of study cohorts, comparison of response based on a patient's sex often is conflicting. Thus, for treatment of CLL patients with fludarabine + cyclophosphamide (FC), male sex was found to be a risk factor for OS, not for progression-free survival (PFS) (for female patients: HR for OS 0.72, P = 0.04; HR for PFS 0.82, P = 0.15),23Oscier D. Rose-Zerilli M. Winkelmann N. et al.The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial.Blood. 2013; 121: 468-475Crossref PubMed Scopus (164) Google Scholar but also was reported to be associated with PFS, not OS (for female patients: HR for PFS 0.66, P = 0.03; HR for OS not listed).40Lucas D. Ruppert A. Lozanski G. et al.Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997.Leuk Lymphoma. 2015; 56: 3031-3037PubMed Google Scholar In mantle cell lymphoma (MCL), lenalidomide had higher response rates in women with 5/7 women responding compared with 3/19 men (P = 0.02),41Eve H. Carey S. Richardson S. et al.Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences.Br J Haematol. 2012; 159: 154-163Crossref PubMed Scopus (79) Google Scholar such a sex difference was not observed in DLBCL (17/65 females versus 22/65 males, P = 1.0) and CLL patients (HR males, 0.717 and HR females, 0.697).42Badoux X. Keating M. Wen S. et al.Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia.Blood. 2011; 118: 3489-3498Crossref PubMed Scopus (154) Google Scholar,43Thieblemont C. Tilly H. Gomes da Silva M. et al.Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.J Clin Oncol. 2017; 35: 2473-2481Crossref PubMed Scopus (104) Google Scholar The addition of antibodies to chemotherapy and for maintenance in lymphoid malignancies drastically improved the outcome for both sexes. Rituximab (R), a first-generation IgG1 antibody, showed higher response rates and longer survival in male and female patients with CLL, the HRs for female and male patients were between 0.4 and 0.7 in the rituximab-containing arms.44Herishanu Y. Goldschmidt N. Bairey O. et al.Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience.Haematologica. 2015; 100: 662-669Crossref PubMed Scopus (15) Google Scholar, 45Fischer K. Bahlo J. Fink A. et al.Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial.Blood. 2016; 127: 208-215Crossref PubMed Scopus (444) Google Scholar, 46Greil R. Obrtlíková P. Smolej L. et al.Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a mabtenance randomised trial.Lancet Haematol. 2016; 3: e317-e329Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 47Dartigeas C. Van Den Neste E. Léger J. et al.Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study.Lancet Haematol. 2018; 5: e82-e94Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Ofatumumab, a second-generation IgG1 antibody with higher binding affinity than rituximab, when added to chlorambucil (CLB) led to longer PFS in women and men with CLL, both favouring the antibody-containing arm with no differences between the sexes.48Hillmen P. Robak T. Janssens A. et al.Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, phase 3 2015; Full Text Full Text PDF PubMed Scopus Google Scholar added to the PFS in males compared with alone (HR versus for males 0.66, for females when added to + rituximab women had longer PFS than men versus but these differences were not significant between male and female CLL S. Keating M. S. et chemoimmunotherapy with cyclophosphamide, and rituximab for high-risk chronic lymphocytic leukemia.Blood. 2011; 118: PubMed Scopus Google C. M. J. et with fludarabine and cyclophosphamide progression-free survival in high-risk 2014; PubMed Scopus Google Scholar However, sex-specific differences still were observed for response and survival in lymphoid In chemoimmunotherapy conferred outcomes for women compared with with PFS for male patients compared with females (HR P = and a survival in women of versus in men (P = S. M. et expression of predicts inferior survival in patients with diffuse large B-cell lymphoma treated with J Haematol. 2010; PubMed Scopus Google S. M. M. S. gender is an prognostic factor in B-cell lymphoma patients treated with J Haematol. 2011; 86: PubMed Scopus Google Scholar In males had inferior PFS + chemotherapy survival for women versus in P = S. M. M. S. gender is an prognostic factor in B-cell lymphoma patients treated with J Haematol. 2011; 86: PubMed Scopus Google C. E. L. et of on clinical outcome of lymphoma treated with first-line J Clin 2019; PubMed Scopus (6) Google Scholar In CLL, the addition of rituximab to chemotherapy improved the outcome of both but being male still was an for OS and TFS with women having outcome HR for OS and for TFS L. C. S. et survival outcomes with the addition of rituximab to initial therapy for chronic lymphocytic leukemia: a analysis in the of Lymphoma. 2018; PubMed Scopus Google Scholar reported sex-specific differences in to response for + rituximab and PFS for females, for P = and + rituximab for women versus for P = not for + difference in O. S. Bahlo J. et al.Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukaemia: a by the CLL Study Group 2017; 31: PubMed Scopus Google Scholar the effects of cyclophosphamide + + + for lymphoma showed male sex still to be an risk factor for survival, PFS, and OS with no difference between the therapeutic HR being and P G. B. M. et plus versus in elderly patients with lymphoma: the trial.Leukemia. 2020; of Scopus Google Scholar In particular, the sex-specific difference in response and survival rituximab-containing chemotherapy and S. M. et expression of predicts inferior survival in patients with diffuse large B-cell lymphoma treated with J Haematol. 2010; PubMed Scopus Google S. M. M. S. gender is an prognostic factor in B-cell lymphoma patients treated with J Haematol. 2011; 86: PubMed Scopus Google Scholar the observation of differences in and M. M. et al.Rituximab of lymphoma with patient and clinical 2012; 97: PubMed Scopus Google Scholar, C. N. M. et al.The role of gender and on rituximab and in elderly patients with 2012; PubMed Scopus Google Scholar, J. G. A. et for the from rituximab and 2013; 5: PubMed Scopus Google Scholar the that the immune system antibodies differently on the variable binding region of an antibody the or the the or receptor region to the which and such as or G. Y. L. et al.Human associations with female sex hormones and 2012; PubMed Scopus Google D. J. both and therapeutic antibody Res. 2015; 3: PubMed Scopus Google Scholar is not only on the ratio of and by an antibody, but also by the binding to which in on the of the mostly by of In addition, of by and the and of and also functional polymorphisms the binding of an antibody to the D. J. both and therapeutic antibody Res. 2015; 3: PubMed Scopus Google Scholar region both with age and G. Y. L. et al.Human associations with female sex hormones and 2012; PubMed Scopus Google X. Y. J. et as potential of and a study in a Chinese 2016; PubMed Scopus Google Scholar changes not only to be more pronounced in women than in the differences associated with age also between the X. Y. J. et as potential of and a study in a Chinese 2016; PubMed Scopus Google Scholar The higher rates observed for rituximab in men in and consequently antibody levels in males compared with the in men was of that found in women, and rates of elderly females to compared with in M. M. et al.Rituximab of lymphoma with patient and clinical 2012; 97: PubMed Scopus Google M.

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