Clinical trial NCT03907553: Aging of Hematopoietic Stem Cells - Molecular Architecture of Marrow Dysplasia and Clinical Contribution of Ineffective Hematopoiesis to Frailty in the Elderly
Official title: Aging of Hematopoietic Stem Cells - Molecular Architecture of Marrow Dysplasia and Clinical Contribution of Ineffective Hematopoiesis to Frailty in the Elderly
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Anemia
Clonal Hematopoiesis
Lead sponsor: Istituto Clinico Humanitas
Sponsor class: OTHER
Collaborators: name: Istituto Di Ricerche Farmacologiche Mario Negri
First posted: 2019-04-09
Enrollment: 5000
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: 4280 subjects with a biobanked blood sample available for genetic analysys out of the 8740 subjects enrolled in the Health \& Anemia Trial.

Brief summary: The prevalence and incidence of anemia tend to increase with advancing age. Relatively low hemoglobin concentrations are a common laboratory finding in the elderly, for the most part judged by physicians as a sign without clinical relevance or as a marker of an underlying chronic disease having no independent influence on health.

In recent years several studies have started to challenge the widespread and self-perpetuating perception of anemia as an innocent bystander, reporting worse cognitive and quality of life outcomes and increased risk of hospitalization and mortality in the general population. Focusing on elderly people, anemia has a clear association with the phenotypic features of frailty syndrome affecting 3-5% of individuals of 65-70 years of age and, more importantly 30% of those aged 85 years or older.

Among frail older adults, anemia is a powerful prognostic factor for the development of frailty-related problems such as muscle weakness, reduced performance, falls, and mortality. Nutrient deficiency, chronic inflammation and renal insufficiency account for the large majority of cases of anemia in the elderly, while underlying cause remained unexplained in 25% of the cases. Preliminary evidence indicates that a significant proportion of ''unexplained anemia'' may account for myelodysplasia(MDS). MDS is a condition typically occurring in elderly people, characterized by clonal proliferation of hematopoietic stem cells (HSC), which partly retain their capacity to differentiate and maturate, but do so in an inefficient manner (ineffective hematopoiesis). Anemia represents the most important prognostic factor in MDS. With time a portion of patients evolve into overt myeloid malignancy (i.e., acute leukemia).

Somatic mutations occur in the genomes of healthy HSC at a low, but detectable frequency during normal DNA replication. Although most mutations are rapidly corrected by DNA repair mechanisms, those that persist are propagated during HSC self-renewal. Some evidence suggest that these early driver mutations dictate future trajectories of evolution with distinct clinical phenotypes. There has been much excitement in the research community about the translational opportunities offered by genome sequencing, possibly leading to the identification of specific types of mutational processes of how genome interact with environmental factors in determining clinical conditions associated with aging and to the implementation of a personalized molecular diagnosis and treatment for every patient. In this translational research project, using an integrated genomic analysis based on next generation sequencing (NGS) technologies,the investigators plan to dissect the genomic architecture of MDS, significantly contributing to many features of frailty and to individual vulnerability. The investigators will perform mutation analysis of candidate genes in a large and well characterized cohort of individuals belonging to the "Health and Anemia'' study. "Health and Anemia" is a prospective population-based observational study (2003-2013) of all elderly residents in the municipality of Biella, Piedmont, a town in the north-west of Italy. Hematological parameters together with data on cognition and functional status, mood and quality of life, fatigue, hospitalization and mortality were collected for all patients. Moreover, complete information on the development of hematological malignancies was provided by local tumor registry up to 2018. The investigators aim to identify genes associated with the induction of clonal hematopoiesis in elderly people, and then to correlate somatic mutations with clinical/hematological features and progression into MDS and/or overt leukemia. Moreover, The investigators will genotype single-cell-derived hematopoietic colonies from CD34+ compartments (hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, and granulocyte progenitors) in order to clarify the clonal architecture of marrow dysplasia in HSC, the dynamics of clonal establishment and expansion during hematopoietic differentiation, and their relationship with the disease phenotype and evolution. Finally, by analysing clinical data from "Health and Anemia study" the investigators will investigate the clinical contribution of myelodysplasia-related anemia to the development of frailty syndrome and its clinical sequela. The definition of molecular architecture of marrow dysplasia would allow us to improve the current diagnosis and classification of anemia in the elderly and the assessment of individual patient's risk of disease associated morbidity/mortality. Finally, in patients with marrow dysplasia, gene sequencing is expected to predict the vulnerability of a particular genotype to specific treatment, thus providing a basis for optimizing at individual level timing and modality of therapeutic intervention. The study population of the MOnzino 80-plus study will be used as validation cohort.


Eligibility criteria: Health \& Anemia Trial population

Inclusion Criteria:

* 65 years or older
* residence in the town of Biella, Italy
* consence fo biobanking

Exclusion Criteria:

No exclusion criteria other than age, residence and lack of a biobanked sample

Primary outcomes:
measure: genotype-phenotype correlation
timeFrame: 2016-2019
Secondary outcomes:
Other outcomes:
Locations:
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
state: Milano
Study officials:
References:
citation: Guralnik JM, Eisenstaedt RS, Ferrucci L, Klein HG, Woodman RC. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004 Oct 15;104(8):2263-8. doi: 10.1182/blood-2004-05-1812. Epub 2004 Jul 6.
citation: Riva E, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M, Tempia P, Guala A, Fasolo G, Lucca U. Association of mild anemia with hospitalization and mortality in the elderly: the Health and Anemia population-based study. Haematologica. 2009 Jan;94(1):22-8. doi: 10.3324/haematol.13449. Epub 2008 Nov 10.
citation: Rohrig G. Anemia in the frail, elderly patient. Clin Interv Aging. 2016 Mar 17;11:319-26. doi: 10.2147/CIA.S90727. eCollection 2016.
citation: Juarez-Cedillo T, Basurto-Acevedo L, Vega-Garcia S, Manuel-Apolinar L, Cruz-Tesoro E, Rodriguez-Perez JM, Garcia-Hernandez N, Perez-Hernandez N, Fragoso JM. Prevalence of anemia and its impact on the state of frailty in elderly people living in the community: SADEM study. Ann Hematol. 2014 Dec;93(12):2057-62. doi: 10.1007/s00277-014-2155-4. Epub 2014 Jul 10.
citation: Cazzola M, Malcovati L. Myelodysplastic syndromes--coping with ineffective hematopoiesis. N Engl J Med. 2005 Feb 10;352(6):536-8. doi: 10.1056/NEJMp048266. No abstract available.
citation: Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Chambert K, Mick E, Neale BM, Fromer M, Purcell SM, Svantesson O, Landen M, Hoglund M, Lehmann S, Gabriel SB, Moran JL, Lander ES, Sullivan PF, Sklar P, Gronberg H, Hultman CM, McCarroll SA. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014 Dec 25;371(26):2477-87. doi: 10.1056/NEJMoa1409405. Epub 2014 Nov 26.
citation: Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, Lindsley RC, Mermel CH, Burtt N, Chavez A, Higgins JM, Moltchanov V, Kuo FC, Kluk MJ, Henderson B, Kinnunen L, Koistinen HA, Ladenvall C, Getz G, Correa A, Banahan BF, Gabriel S, Kathiresan S, Stringham HM, McCarthy MI, Boehnke M, Tuomilehto J, Haiman C, Groop L, Atzmon G, Wilson JG, Neuberg D, Altshuler D, Ebert BL. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014 Dec 25;371(26):2488-98. doi: 10.1056/NEJMoa1408617. Epub 2014 Nov 26.
citation: Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A, Shlien A, Groves MJ, Forbes SA, Raine K, Hinton J, Mudie LJ, McLaren S, Hardy C, Latimer C, Della Porta MG, O'Meara S, Ambaglio I, Galli A, Butler AP, Walldin G, Teague JW, Quek L, Sternberg A, Gambacorti-Passerini C, Cross NC, Green AR, Boultwood J, Vyas P, Hellstrom-Lindberg E, Bowen D, Cazzola M, Stratton MR, Campbell PJ; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013 Nov 21;122(22):3616-27; quiz 3699. doi: 10.1182/blood-2013-08-518886. Epub 2013 Sep 12.
citation: Cazzola M, Della Porta MG, Malcovati L. The genetic basis of myelodysplasia and its clinical relevance. Blood. 2013 Dec 12;122(25):4021-34. doi: 10.1182/blood-2013-09-381665. Epub 2013 Oct 17.
citation: Ades L, Itzykson R, Fenaux P. Myelodysplastic syndromes. Lancet. 2014 Jun 28;383(9936):2239-52. doi: 10.1016/S0140-6736(13)61901-7. Epub 2014 Mar 21.
citation: Malcovati L, Porta MG, Pascutto C, Invernizzi R, Boni M, Travaglino E, Passamonti F, Arcaini L, Maffioli M, Bernasconi P, Lazzarino M, Cazzola M. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005 Oct 20;23(30):7594-603. doi: 10.1200/JCO.2005.01.7038. Epub 2005 Sep 26.
citation: Malcovati L, Della Porta MG, Cazzola M. Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica. 2006 Dec;91(12):1588-90. No abstract available.
citation: Della Porta MG, Travaglino E, Boveri E, Ponzoni M, Malcovati L, Papaemmanuil E, Rigolin GM, Pascutto C, Croci G, Gianelli U, Milani R, Ambaglio I, Elena C, Ubezio M, Da Via' MC, Bono E, Pietra D, Quaglia F, Bastia R, Ferretti V, Cuneo A, Morra E, Campbell PJ, Orazi A, Invernizzi R, Cazzola M; Rete Ematologica Lombarda (REL) Clinical Network. Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes. Leukemia. 2015 Jan;29(1):66-75. doi: 10.1038/leu.2014.161. Epub 2014 May 20.
citation: Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009 Jul 30;114(5):937-51. doi: 10.1182/blood-2009-03-209262. Epub 2009 Apr 8.
citation: Snoeck HW. Aging of the hematopoietic system. Curr Opin Hematol. 2013 Jul;20(4):355-61. doi: 10.1097/MOH.0b013e3283623c77.
citation: Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D, Sato-Otsubo A, Sato Y, Liu D, Suzuki H, Wu CO, Shiraishi Y, Clemente MJ, Kataoka K, Shiozawa Y, Okuno Y, Chiba K, Tanaka H, Nagata Y, Katagiri T, Kon A, Sanada M, Scheinberg P, Miyano S, Maciejewski JP, Nakao S, Young NS, Ogawa S. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med. 2015 Jul 2;373(1):35-47. doi: 10.1056/NEJMoa1414799.
citation: Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC, McMichael JF, Schmidt HK, Yellapantula V, Miller CA, Ozenberger BA, Welch JS, Link DC, Walter MJ, Mardis ER, Dipersio JF, Chen F, Wilson RK, Ley TJ, Ding L. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014 Dec;20(12):1472-8. doi: 10.1038/nm.3733. Epub 2014 Oct 19.
citation: Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, Ebert BL. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015 Jul 2;126(1):9-16. doi: 10.1182/blood-2015-03-631747. Epub 2015 Apr 30.
citation: Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z, Mollica L, Li J, Viale A, Heguy A, Hassimi M, Socci N, Bhatt PK, Gonen M, Mason CE, Melnick A, Godley LA, Brennan CW, Abdel-Wahab O, Levine RL. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet. 2012 Nov;44(11):1179-81. doi: 10.1038/ng.2413. Epub 2012 Sep 23.
citation: Woll PS, Kjallquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S, Erlandsson R, Ngara M, Anderson K, Deng Q, Mead AJ, Stenson L, Giustacchini A, Duarte S, Giannoulatou E, Taylor S, Karimi M, Scharenberg C, Mortera-Blanco T, Macaulay IC, Clark SA, Dybedal I, Josefsen D, Fenaux P, Hokland P, Holm MS, Cazzola M, Malcovati L, Tauro S, Bowen D, Boultwood J, Pellagatti A, Pimanda JE, Unnikrishnan A, Vyas P, Gohring G, Schlegelberger B, Tobiasson M, Kvalheim G, Constantinescu SN, Nerlov C, Nilsson L, Campbell PJ, Sandberg R, Papaemmanuil E, Hellstrom-Lindberg E, Linnarsson S, Jacobsen SE. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 2014 Jun 16;25(6):794-808. doi: 10.1016/j.ccr.2014.03.036. Epub 2014 May 15.
citation: Ebert BL, Pretz J, Bosco J, Chang CY, Tamayo P, Galili N, Raza A, Root DE, Attar E, Ellis SR, Golub TR. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature. 2008 Jan 17;451(7176):335-9. doi: 10.1038/nature06494.
citation: Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, Pellagatti A, Wainscoat JS, Hellstrom-Lindberg E, Gambacorti-Passerini C, Godfrey AL, Rapado I, Cvejic A, Rance R, McGee C, Ellis P, Mudie LJ, Stephens PJ, McLaren S, Massie CE, Tarpey PS, Varela I, Nik-Zainal S, Davies HR, Shlien A, Jones D, Raine K, Hinton J, Butler AP, Teague JW, Baxter EJ, Score J, Galli A, Della Porta MG, Travaglino E, Groves M, Tauro S, Munshi NC, Anderson KC, El-Naggar A, Fischer A, Mustonen V, Warren AJ, Cross NC, Green AR, Futreal PA, Stratton MR, Campbell PJ; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011 Oct 13;365(15):1384-95. doi: 10.1056/NEJMoa1103283. Epub 2011 Sep 26.
citation: Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, Sato Y, Sato-Otsubo A, Kon A, Nagasaki M, Chalkidis G, Suzuki Y, Shiosaka M, Kawahata R, Yamaguchi T, Otsu M, Obara N, Sakata-Yanagimoto M, Ishiyama K, Mori H, Nolte F, Hofmann WK, Miyawaki S, Sugano S, Haferlach C, Koeffler HP, Shih LY, Haferlach T, Chiba S, Nakauchi H, Miyano S, Ogawa S. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature. 2011 Sep 11;478(7367):64-9. doi: 10.1038/nature10496.
citation: Malcovati L, Papaemmanuil E, Bowen DT, Boultwood J, Della Porta MG, Pascutto C, Travaglino E, Groves MJ, Godfrey AL, Ambaglio I, Galli A, Da Via MC, Conte S, Tauro S, Keenan N, Hyslop A, Hinton J, Mudie LJ, Wainscoat JS, Futreal PA, Stratton MR, Campbell PJ, Hellstrom-Lindberg E, Cazzola M; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative. Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Blood. 2011 Dec 8;118(24):6239-46. doi: 10.1182/blood-2011-09-377275. Epub 2011 Oct 12.
citation: Dolatshad H, Pellagatti A, Fernandez-Mercado M, Yip BH, Malcovati L, Attwood M, Przychodzen B, Sahgal N, Kanapin AA, Lockstone H, Scifo L, Vandenberghe P, Papaemmanuil E, Smith CW, Campbell PJ, Ogawa S, Maciejewski JP, Cazzola M, Savage KI, Boultwood J. Disruption of SF3B1 results in deregulated expression and splicing of key genes and pathways in myelodysplastic syndrome hematopoietic stem and progenitor cells. Leukemia. 2015 May;29(5):1092-103. doi: 10.1038/leu.2014.331. Epub 2014 Nov 27.
citation: Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G, Kantarjian H, Raza A, Levine RL, Neuberg D, Ebert BL. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011 Jun 30;364(26):2496-506. doi: 10.1056/NEJMoa1013343.
citation: Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C, Della Porta MG, Fenaux P, Gattermann N, Germing U, Jansen JH, Mittelman M, Mufti G, Platzbecker U, Sanz GF, Selleslag D, Skov-Holm M, Stauder R, Symeonidis A, van de Loosdrecht AA, de Witte T, Cazzola M; European Leukemia Net. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013 Oct 24;122(17):2943-64. doi: 10.1182/blood-2013-03-492884. Epub 2013 Aug 26.
citation: Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres M, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012 Sep 20;120(12):2454-65. doi: 10.1182/blood-2012-03-420489. Epub 2012 Jun 27.
citation: Della Porta MG, Tuechler H, Malcovati L, Schanz J, Sanz G, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Levis A, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Krieger O, Luebbert M, Maciejewski J, Magalhaes SM, Miyazaki Y, Pfeilstocker M, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL, Cazzola M. Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM). Leukemia. 2015 Jul;29(7):1502-13. doi: 10.1038/leu.2015.55. Epub 2015 Feb 27.
citation: Schneider RK, Schenone M, Ferreira MV, Kramann R, Joyce CE, Hartigan C, Beier F, Brummendorf TH, Germing U, Platzbecker U, Busche G, Knuchel R, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016 Mar;22(3):288-97. doi: 10.1038/nm.4047. Epub 2016 Feb 15.
citation: Itzykson R, Kosmider O, Cluzeau T, Mansat-De Mas V, Dreyfus F, Beyne-Rauzy O, Quesnel B, Vey N, Gelsi-Boyer V, Raynaud S, Preudhomme C, Ades L, Fenaux P, Fontenay M; Groupe Francophone des Myelodysplasies (GFM). Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011 Jul;25(7):1147-52. doi: 10.1038/leu.2011.71. Epub 2011 Apr 15.
citation: Itzykson R, Thepot S, Quesnel B, Dreyfus F, Beyne-Rauzy O, Turlure P, Vey N, Recher C, Dartigeas C, Legros L, Delaunay J, Salanoubat C, Visanica S, Stamatoullas A, Isnard F, Marfaing-Koka A, de Botton S, Chelghoum Y, Taksin AL, Plantier I, Ame S, Boehrer S, Gardin C, Beach CL, Ades L, Fenaux P; Groupe Francophone des Myelodysplasies(GFM). Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood. 2011 Jan 13;117(2):403-11. doi: 10.1182/blood-2010-06-289280. Epub 2010 Oct 12.
citation: Blank U, Karlsson S. TGF-beta signaling in the control of hematopoietic stem cells. Blood. 2015 Jun 4;125(23):3542-50. doi: 10.1182/blood-2014-12-618090. Epub 2015 Apr 1.
citation: Penninx BW, Pahor M, Cesari M, Corsi AM, Woodman RC, Bandinelli S, Guralnik JM, Ferrucci L. Anemia is associated with disability and decreased physical performance and muscle strength in the elderly. J Am Geriatr Soc. 2004 May;52(5):719-24. doi: 10.1111/j.1532-5415.2004.52208.x.
citation: Penninx BW, Guralnik JM, Onder G, Ferrucci L, Wallace RB, Pahor M. Anemia and decline in physical performance among older persons. Am J Med. 2003 Aug 1;115(2):104-10. doi: 10.1016/s0002-9343(03)00263-8.
citation: Cesari M, Penninx BW, Lauretani F, Russo CR, Carter C, Bandinelli S, Atkinson H, Onder G, Pahor M, Ferrucci L. Hemoglobin levels and skeletal muscle: results from the InCHIANTI study. J Gerontol A Biol Sci Med Sci. 2004 Mar;59(3):249-54. doi: 10.1093/gerona/59.3.m249.
citation: Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation. 2003 Jan 21;107(2):223-5. doi: 10.1161/01.cir.0000052622.51963.fc.
citation: Hayashi T, Suzuki A, Shoji T, Togawa M, Okada N, Tsubakihara Y, Imai E, Hori M. Cardiovascular effect of normalizing the hematocrit level during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney Dis. 2000 Feb;35(2):250-6. doi: 10.1016/s0272-6386(00)70334-9.
citation: Kim DH, Schneeweiss S. Measuring frailty using claims data for pharmacoepidemiologic studies of mortality in older adults: evidence and recommendations. Pharmacoepidemiol Drug Saf. 2014 Sep;23(9):891-901. doi: 10.1002/pds.3674. Epub 2014 Jun 24.
citation: Artz AS. Anemia and the frail elderly. Semin Hematol. 2008 Oct;45(4):261-6. doi: 10.1053/j.seminhematol.2008.06.002.
citation: Triscott JA, Dobbs BM, McKay RM, Babenko O, Triscott E. Prevalence and Types of Anemia and Associations with Functional Decline in Geriatric Inpatients. J Frailty Aging. 2015;4(1):7-12. doi: 10.14283/jfa.2015.35.
citation: Ng TP, Feng L, Nyunt MS, Larbi A, Yap KB. Frailty in older persons: multisystem risk factors and the Frailty Risk Index (FRI). J Am Med Dir Assoc. 2014 Sep;15(9):635-42. doi: 10.1016/j.jamda.2014.03.008. Epub 2014 Apr 17.
citation: Lucca U, Tettamanti M, Mosconi P, Apolone G, Gandini F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M, Tempia P, Guala A, Fasolo G, Riva E. Association of mild anemia with cognitive, functional, mood and quality of life outcomes in the elderly: the "Health and Anemia" study. PLoS One. 2008 Apr 2;3(4):e1920. doi: 10.1371/journal.pone.0001920.
citation: Malcovati L, Karimi M, Papaemmanuil E, Ambaglio I, Jadersten M, Jansson M, Elena C, Galli A, Walldin G, Della Porta MG, Raaschou-Jensen K, Travaglino E, Kallenbach K, Pietra D, Ljungstrom V, Conte S, Boveri E, Invernizzi R, Rosenquist R, Campbell PJ, Cazzola M, Hellstrom Lindberg E. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015 Jul 9;126(2):233-41. doi: 10.1182/blood-2015-03-633537. Epub 2015 May 8.
citation: Malcovati L, Papaemmanuil E, Ambaglio I, Elena C, Galli A, Della Porta MG, Travaglino E, Pietra D, Pascutto C, Ubezio M, Bono E, Da Via MC, Brisci A, Bruno F, Cremonesi L, Ferrari M, Boveri E, Invernizzi R, Campbell PJ, Cazzola M. Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood. 2014 Aug 28;124(9):1513-21. doi: 10.1182/blood-2014-03-560227. Epub 2014 Jun 26.
citation: Shirai CL, Ley JN, White BS, Kim S, Tibbitts J, Shao J, Ndonwi M, Wadugu B, Duncavage EJ, Okeyo-Owuor T, Liu T, Griffith M, McGrath S, Magrini V, Fulton RS, Fronick C, O'Laughlin M, Graubert TA, Walter MJ. Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell. 2015 May 11;27(5):631-43. doi: 10.1016/j.ccell.2015.04.008.
citation: Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC, Ramakrishnan A, Li Y, Chung YR, Micol JB, Murphy ME, Cho H, Kim MK, Zebari AS, Aumann S, Park CY, Buonamici S, Smith PG, Deeg HJ, Lobry C, Aifantis I, Modis Y, Allain FH, Halene S, Bradley RK, Abdel-Wahab O. SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition. Cancer Cell. 2015 May 11;27(5):617-30. doi: 10.1016/j.ccell.2015.04.006.
citation: Robusto M, Fang M, Asselta R, Castorina P, Previtali SC, Caccia S, Benzoni E, De Cristofaro R, Yu C, Cesarani A, Liu X, Li W, Primignani P, Ambrosetti U, Xu X, Duga S, Solda G. The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy. Eur J Hum Genet. 2015 Jun;23(6):766-73. doi: 10.1038/ejhg.2014.168. Epub 2014 Sep 3.
citation: Lucca U, Tettamanti M, Logroscino G, Tiraboschi P, Landi C, Sacco L, Garri M, Ammesso S, Bertinotti C, Biotti A, Gargantini E, Piedicorcia A, Nobili A, Pasina L, Franchi C, Djade CD, Riva E, Recchia A. Prevalence of dementia in the oldest old: the Monzino 80-plus population based study. Alzheimers Dement. 2015 Mar;11(3):258-70.e3. doi: 10.1016/j.jalz.2014.05.1750. Epub 2014 Aug 20.
citation: Lucca U, Garri M, Recchia A, Logroscino G, Tiraboschi P, Franceschi M, Bertinotti C, Biotti A, Gargantini E, Maragna M, Nobili A, Pasina L, Franchi C, Riva E, Tettamanti M. A Population-based study of dementia in the oldest old: the Monzino 80-plus study. BMC Neurol. 2011 May 25;11:54. doi: 10.1186/1471-2377-11-54.
citation: Tettamanti M, Lucca U, Gandini F, Recchia A, Mosconi P, Apolone G, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M, Tempia P, Savoia L, Fasolo G, Ponchio L, Della Porta MG, Riva E. Prevalence, incidence and types of mild anemia in the elderly: the "Health and Anemia" population-based study. Haematologica. 2010 Nov;95(11):1849-56. doi: 10.3324/haematol.2010.023101. Epub 2010 Jun 9.
citation: Da Via MC, Lionetti M, Marella A, Matera A, Travaglino E, Signaroldi E, Galbussera AA, Lucca U, Mandelli S, Riva E, Tettamanti M, Pettine L, Pompa A, Baldini L, Neri A, Della Porta MG, Bolli N. MGUS and clonal hematopoiesis show unrelated clinical and biological trajectories in an older population cohort. Blood Adv. 2022 Nov 8;6(21):5702-5706. doi: 10.1182/bloodadvances.2021006498.