Cytomegalovirus infection may be oncoprotective against neoplasms of B-lymphocyte lineage: single-institution experience and survey of global evidence

Janković, Marko; Knežević, Aleksandra; Todorović, Milena; Đunić, Irena; Mihaljević, Biljana; Soldatović, Ivan; Protić, Jelena; Miković, Nevenka; Stoiljković, Vera; Jovanović, Tanja

doi:10.1186/s12985-022-01884-1

Virology Journal

Table 6 Country-specific CMV seroprevalence in patient cohorts compared to matched blood/organ donors and healthy general populations

From: Cytomegalovirus infection may be oncoprotective against neoplasms of B-lymphocyte lineage: single-institution experience and survey of global evidence

Continent, country, or region (listed West-to-East)	Hematologic malignancy	Cytomegalovirus seropositivity (CMV⁺)			Transplant type and support medication	References
Continent, country, or region (listed West-to-East)	Hematologic malignancy	Patients N, (CMV⁺ %) (unless otherwise noted)	Country specific blood/organ donors CMV⁺, mean [36]	Country specific general popul. CMV⁺, mean [36]	Transplant type and support medication	References
North & South America
USA, Boston, New York Washington	ALL	1 359 (48%)	0.67	0.64	Allo-HCT, GvHD prophylaxis	Kollman et al. 2001 [46]
USA, Seattle	AL, NHL, HD, MM, CLL	835 (49%)	0.67	0.64	Allo-HCT, GvHD prophylaxis	Nichols et al. 2002 [47]
USA, Arkansas	MM, HD	107 (57%)	0.67	0.64	Auto-HCT, BCNU, BEAM, melphalan alone	Fassas et al. 2001 [82]
USA, Texas	ALL, CLL, NHL	680 (52.4%)	0.67	0.64	Chemo radiation therapy	Nguyen et al. 2001 [83]
USA, The Netherlands, transplant centers	ALL	952 (47.5%)	0.63	0.60	Allo-HCT, GvHD prophylaxis	Lee et al. 2007 [84]
USA, California	AL (children)	144 (55.7%)	0.67	0.64	Allo-HCT, GvHD prophylaxis	Behrendt et al. 2009 [85]
Brazil, Bahia State	Hematology patients (various)	470 (89.4%)	0.91	0.89	N/A	De Matos et al. 2011 [37]
Brazil, Campinas, SP	ALL, MM, HD, NHL,	20 (82.5%)	0.91	0.89	Allo-HCT, GvHD prophylaxis	Dieamant et al. 2011 [86]
Chile, Santiago	Hematolgic malignancies (various)	N/A (86%)	0.91	0.89	HCT, GvHD prophylaxis	Ferrés et al. 2012 [87]
America-Europe
Canada, US, UK, France (33 countries)	ALL (B- & T- cell types)	564 (59.7%)	0.55 (ave.)	0.51		Duval et al. 2010 [88]
Canada, US, UK, Saudi Arabia, The Netherlands (CIBMTR), ~ 200 transpl. centers	ALL (B- & T- cell types)	1 883 (59.7%)	0.62 (ave.)	0.59 (ave.)	Allo-HCT GvHD prophylaxis	Teira et al. 2016 [89]
46 international transpl. centers	Poor risk ALL (B- & T-cell types)	127 (47%)	0.63	0.58	MUD-BMT	Cornelissen et al. 2001 [90]
67 international transpl. centers (20 countries)	ALL, NHL, MM, CLL	165 (60% donors)	0.66 (ave.)	0.68 (ave.)	Allo-HCT	Marty et al. 2017 [91]
Europe
Ireland, Dublin	Hematologic malignancies (various)	72 (48%)	0.43	0.39	Allo-HCT (43 pts.) Chemotherapy (28 pts.)	Fleming et al. 2010 [92]
Sweden & Italy, Gothenburg, Rome	AML	81 (70%)	0.74	0.71	Chemoradio therapy	Bernson et al. [45]
Sweden, Germany, The Netherlands, Italy, France	ALL (B- &T- cell types)	3 539 (55%)	0.62 (ave.)	0.58 (ave.)	Allo-BMT & HCT	Ljungman et al. 2003 [2]
EBMT member centers (whole registry cohort)	ALL, AML, HD, NHL	40 306 (53.9%)	0.62 (ave.)	0.58 (ave.)	Allo- & auto-HCT	Ljungman & Brand 2007 [3]
Sweden, Spain, UK, France, Italy, The Netherlands, Poland, Germany	ALL, LY	31 669 (59.8%)	0.62 (ave.)	0.58 (ave.)	Allo-HCT	Ljungman et al. 2014 [93]
48 transpl. centers (Europe, MENA, South Africa)	ALL, NHL, HD	165 (81.4%)	0.77 (ave.)	0.75 (ave.)	Allo-BMT	Ljungman et al. 2002 [94]
US (CIBMTR), Canada, UK, Spain, Sweden, Saudi Arabia, New Zealand, Japan	Childhood ALL (B- & T-cell)	980 (53%)	0.69	0.65	MRD, URD, UCBT, PB-HCT from URD	Mehta et al. 2019 [95]
France, USA, UK, Germany, Czech Republic, Israel	AML (age > 50)	3 398 (65%)	0.60 (ave.)		MUD HCT	Rubio et al. 2016 [96]
11 European countries with Israel and Turkey	Childhood B-precursor ALL	140 (41%)	0.63 (ave.)	0.65 (ave.)	Allo-HCT	Dalle et al. 2018 [97]
France, Israel, Spain, Germany, Belgium, The Netherlands, UK, Poland (EBMT)	B-ALL (age > 60)	126 (59.3%)	0.61	0.57	RIC allo-HCT	Roth-Guepin et al. 2017 [98]
Belgium, Brussels	n.m (9 children, 7 adults)	16 (35%)	0.56	0.52	Allo-HCT	Debaugnies et al. [99]
Denmark, Copenhagen	Childhood ALL & adults	118 (54%)	0.60	N/A	Allo-HCT	Kielsen et al. 2018 [100]
The Netherlands, Utrecht	ALL, NHL, HD	101 (50.6%)	0.57	0.53	Allo-BMT	Meijer et al. 2002 [101]
The Netherlands, Rotterdam	ALL, NHL, MM	47 (66%)	0.57	0.53	Allo-HCT (sibling)	Broers et al. 2000 [102]
Poland, Wroclaw	ALL, LY	26 (78%)	0.7	0.66	HCT	Jaskula et al. 2015 [103]
Czech Republic, Brno	Childhood & adolescent ALL, NHL, HD	104 (37.6%)	n.m	0.42 (healthy age-matched control)	Conventional chemotherapy	Michálek & Horvath 2002 [104]
Germany, Russian Federation, Hamburg, St. Petersburg	ALL, NHL	54 (39%)	0.62	0.57	Allo-HCT	Kröger et al. 2001 [105]
Russian Federation, Moscow	AML, Mantle cell lymphoma	183 (45.9%)	0.74	0.7	Allo-HCT	Vdovin et al. 2016 [106]
Croatia, Zagreb	ALL, NHL, MM, HD, CLL	47 (77%)	0.83	0.8	Allo-HCT	Peric et al. 2018 [107]
Hungary, Szeged	LY	224 (75%)	0.87	0.84	Auto-HCT Chemotherapy	Piukovics et al. 2017 [1]
Italy, Rome	AML	52 (93%)	0.76	0.73	Chemoradio therapy	Capria et al. 2010 [40]
Italy, Rome	LY	327 (93%)	0.76	0.73	Auto-BMT & Auto-HCT	Marchesi et al. 2015 [39]
Italy, Milan, Udine, Bergamo, Ancona, Alessandria	B-cell lymphoma	265 (70%)	0.76	0.73	Allo-HCT	Mariotti et al. 2014 [108]
Germany, France, Finland	ALL (B- & T-cell)	5 158 (60%)	0.58	0.54	Allo-HCT	Schmidt-Hieber et al. 2013 [109]
Serbia, Belgrade-Srem-Šumadija	ALL, HD, WD, CLL, MM,	83 (88%)	N/A	0.9	Allo-HCT, Chemoradio therapy	this work
Spain, Barcelona	AL, NHL, CLL, MM, HD/ST	150 (66%)	0.72	0.69	Allo-HCT-RIC GvHD prophylaxis	Piñana et al. 2010 [110]
Middle East North Africa Region
Kingdom of Saudi Arabia, Jeddah	ALL, NHL, HD, MM, CLL	1 252 (95.76%)	0.89	0.88	Chemothrapy HCT	Zaidi et al. 2019 [41]
Kingdom of Saudi Arabia, Jordan, Riyadh, Irbid	ALL (children)	82 (1.22%)	0.85	0.87	Allo-HCT UCBT GvHD prophylaxis	Al-Sweedan et al. 2017 [111]
Kingdom of Saudi Arabia, Riyadh	AL (children)	73 (68%)	0.89	0.88	Allo-cord blood HCT	Al-Hajjar et al. 2011 [112]
Jordan, Amman	AL (children)	72 (31%)	0.83	0.85	Auto-HCT	Hussein et al. 2015 [113] & Al Mana et al. 2019 [114]
Israel, Tel Aviv, Petah Tikva	AL, LY	121 (61%)	0.75	0.72	Allo-HCT GvHD prophylaxis	Cohen et al. 2015 [115]
Iran, Tehran, Rasht	ALL, AML, NHL, MM & various disease	126 (97.6%)	0.96	0.95	Allo-HCT GvHD prophylaxis	Valadkhani et al. 2016 [116]
Iran, Mashhad	Voluntary blood donors	1 000 (99.2%)	0.96	0.95	N/A	Safabakhsh et al. 2013 [117]
Iran, Urmia	End-stage renal disease (immunodeficiency)	65 (77.4%)	0.96	0.95	Pre-transplant hemodialysis	Sepehrvand et al. 2010 [118]
Iran, Shiraz, Tehran,	Leukemia (unspecified)	6 (100%)	0.96	0.95	Allo-BMT	Behzad-Behbahani et al. 2004 [119]
Iran, Tehran, Shiraz	AML, Thalassemia, CML, AA, ALL	26 (100%)	0.96	0.95	BMT	Ziyaeyan et. al. 2006 [120]
Tunisia, Sousse, Sfax	ALL	39 (90%)	0.94	0.93	Chemotherapy (different phases)	Handous et al. 2020 [121]
Egypt, Alexandria	Voluntary blood donors	88 (96.6%)	0.94	0.93	N/A	Gawad et al. 2016 [122]
Egypt, Cairo	AML & ALL	28 (39%, active CMV)	0.94	0.93	BMT	Zekri et al. 2004 [123]
Egypt, Cairo	B-ALL (40) T-ALL (10) (children & adolesc.)	40 (36% CMV DNA/serum)	30 (46.7% CMV DNA control)	0.93	Consolidation Tx Salvage Tx	Loutfy et al. 2017 [124]
Australia, India
Australia, Victoria	AL, B-NHL, HD, CLL, MM	28 (88%)	0.69	0.65	Conventional-dose chemotherapy Auto-HCT	Ng et al. 2005 [38]
Australia, Sydney	ALL, NHL, MM	103 (63%)	0.69	0.65	Allo-HCT, MUD-HCT	George et al. 2010 [125]
India, Vellore	Malignant & non-malignant diseases Patients: Donors:	463 (97.4) 403 (84.8%)	0.88	0.86	Allo-HCT	Devasia et al. 2018 [126]
East Asia
Malaysia, Australia. Kuala Lumpur, Melbourne	ALL N = 71, AML N = 6, med. age: 28 yr	77 (73%)	0.78 (ave.)	0.75 (ave.)	Chemoradiotherapy	Azanan et al. 2016 [127]
China, Guangzhou province	B-ALL, B-NHL	156 (86%)	0.92	0.9	Allo-HCT (intensified condit.)	Xuan et al. 2012 [42]
China, Beijing	ALL, CML, MDS, AA, NHL	60 (87%)	0.92	0.9	Allo-HCT	Du et al. 2007 [128]
Taiwan, Kaohsiung, Taipei	AL, NHL	117 (91.8%)	0.95	0.93	Allo-HCT	Liu et al. 2012 [43]
Japan, Tokyo	Childhood AL	184 (81%)	0.76	0.72	UCBT	Tomonari et al. 2008 [44]
Japan, Fukuoka	Childhood ALL	101 (72%)	0.76	0.72	Allo-HCT	Inagaki et al. 2015 [26]

n.m. not mentioned; N/A not applicable; AL denotes acute leukemia (AML and B- and T-cell ALL together); AML, acute myeloblastic leukemia; ALL, acute lymphoblastic leukemia; NHL, non-Hodgkin lymphoma (B- and T-cell); HD, Hodgkin's disease; MM, multiple (plasma cell) myeloma; CLL, chronic lymphocytic leukemia; LY, lymphoid neoplasms (HD, NHL of B- and T-cell types); WD, Waldenström's disease; myeloid neoplasms (AML; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm); AA, aplastic anemia; allo-HCT, allogeneic hematopoietic cell transplant; auto-HCT, autologous HCT; MRD, matched related donor; URD, unrelated donor; UCBT, umbilical cord blood transplantation; PB-HCT, peripheral blood HCT; GvHD, graft vs. host disease; BMT, bone marrow transplantation; MUD, matched unrelated donor; BCNU, BEAM, and melphalan indicate myeloablative protocols; CIBMTR, Center for International Bone Marrow Transplant Research; MENA, Middle East North Africa; RIC, reduced intensity chemotherapy HCT; ST, solid tumors
Studies with significantly lower CMV seropositivities in auto- and allo-HCTed patients, as compared to healthy donors and country-specific CMV prevalences, have seropositivity values indicated in bold. This was to point out the studies evidencing a reduced CMV protection against lymphoproliferation in the patients reported. CMV seroprevalence in patients with hematological diseases across racial and ethnic groups divisions is presented West-to-East. In most studies with mixed disease settings the prevalence of CMV seropositivity in subsets of B-cell diseases was not available. This perturbed the estimates of CMV seropositivity of interest, affecting the veracity of presented data. Notwithstanding partially inadequate representation of patient populations, the prevalence of CMV in hematologic malignancies shown remains mostly lesser than the corresponding country means [36]. This may signal a certain degree of oncoprotection secured to chronic carriers of latent virus. Endemicity of CMV seems to depend on SES defined factors and correlates with the incidence rate of malignant B-cell diseases across distant domains (Tables 4 and 5, Fig. 1 A‒D)

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