Essential Thrombocythaemia : Diagnosis, Prognostic Aspects, and the Outcome of Finnish patients

Essential thrombocythaemia (ET) is a myeloproliferative disease (MPD) characterized by thrombocytosis, i.e. a constant elevation of platelet count. Thrombocytosis may appear in MPDs (ET, polycythaemia vera, chronic myeloid leukaemia, myelofibrosis) and as a reactive phenomenon. The differential diagnosis of thrombocytosis is important, because the clinical course, need of therapy, and prognosis are different in patients with MPDs and in those with reactive thrombocytosis. ET patients may remain asymptomatic for years, but serious thrombohaemorrhagic and pregnancy-related complications may occur. The complications are difficult to predict. The aims of the present study were to evaluate the diagnostic findings, clinical course, and prognostic factors of ET. The present retrospective study consists of 170 ET patients. Two thirds had a platelet count < 1000 x 109/l. The diagnosis was supported by an increased number of megakaryocytes with an abnormal morphology in a bone marrow aspirate, aggregation defects in platelet function studies, and the presence of spontaneous erythroid and/or megakaryocytic colony formation in in vitro cultures of haematopoietic progenitors. About 70 % of the patients had spontaneous colony formation, while about 30 % had a normal growth pattern. Only a fifth of the patients remained asymptomatic. Half had a major thrombohaemorrhagic complication. The proportion of the patients suffering from thrombosis was as high as 45 %. About a fifth had major bleedings. Half of the patients had microvascular symptoms. Age over 60 years increased the risk of major bleedings, but the occurrence of thrombotic complications was similar in all age groups. Male gender, smoking in female patients, the presence of any spontaneous colony formation, and the presence of spontaneous megakaryocytic colony formation in younger patients were identified as risk factors for thrombosis. Pregnant ET patients had an increased risk of complications. Forty-five per cent of the pregnancies were complicated and 38 % of them ended in stillbirth. Treatment with acetylsalicylic acid alone or in combination with platelet lowering drugs improved the outcome of the pregnancy. The present findings about risk factors in ET as well as treatment outcome in the pregnancies of ET patients should be taken into account when planning treatment strategies for Finnish patients.Essentiaalinen trombosytemia (ET) on myeloproliferatiivisten sairauksien (ET, polysytemia vera, krooninen myelooinen leukemia, myelofibroosi) ryhmään kuuluva pahanlaatuinen veritauti, jolle on ominaista trombosytoosi eli pysyvästi koholla oleva veren verihiutale- eli trombosyyttitaso. Myeloproliferatiivisten tautien lisäksi trombosytoosia todetaan reaktiivisena monissa tiloissa. Trombosytoosin erotusdiagnostiikka on tärkeää, sillä myeloproliferatiivisten tilojen yhteydessä trombosytoosiin liittyy komplikaatioita, joita ei todeta reaktiivisessa trombosytoosissa. ET-potilaat voivat olla oireettomia vuosia, jopa vuosikymmeniä, mutta tautiin voi liittyä vaikeita tukos- tai vuoto-oireita, ja ET-potilaiden raskaudet voivat olla ongelmallisia. Komplikaatioita on vaikea ennustaa. Väitöskirjatyön tarkoituksena oli selkiyttää taudin diagnostiikkaa, arvioida komplikaatioiden ilmaantuvuutta, ja löytää komplikaatioita ennustavia tekijöitä. Potilasaineisto koostui 170 ET-potilaasta, joiden tauti oli diagnosoitu vuosina 1980 1996. Lisääntynyt trombosyyttien esiasteiden määrä luuytimessä ja niiden rakenteelliset poikkeavuudet, trombosyyttien toimintahäiriöt, ja poikkeava kantasolukasvu verta muodostavien kantasolujen viljelyissä tukivat ET:n diagnoosia. Noin 70 %:lla potilaista todettiin poikkeava kantasolukasvu. Vain viidesosa potilaista pysyi seurannassa oireettomina. Puolella potilaista esiintyi merkittäviä tukos- tai vuoto-oireita. Tukosoireita oli 45 %:lla potilaista, ja merkittäviä vuotoja viidesosalla. Puolet potilaista kärsi pienten suonten verenkiertohäiriöistä. Yli 60-vuoden ikä lisäsi vuotoriskiä, mutta tukosoireita esiintyi likimain yhtä paljon eri ikäryhmissä. Miessukupuoli, naisten tupakointi, ja poikkeava kantasolukasvu ennustivat tukoskomplikaatioiden ilmaantuvuutta. Naisilla tukosongelmia esiintyi miehiä vähemmän. Raskauskomplikaatioiden riski oli merkittävä ja 38 % raskauksista päätyi keskenmenoon. Hoito joko asetyylisalisyylihapolla yksinään tai yhdistettynä trombosyyttitasoa alentavaan lääkitykseen vähensi raskauteen liittyviä ongelmia merkittävästi. Aiemmat essentiaalista trombosytemiaa käsittelevät tutkimukset on tehty maissa, joissa valtimoiden kovettumistautia esiintyy vähemmän kuin suomalaisessa väestössä. Tämän väitöskirjatyön löydöksiä voi hyödyntää suomalaisten ET-potilaiden usein ongelmallisissa hoitoratkaisuissa.Essentiell trombocytos (ET) är en elakartad blodsjukdom, som hör till de myeloproliferativa sjukdomarna (ET, polycythaemia vera, kronisk myeloisk leukemi, myelofibros). Karakteristiskt för ET är trombocytos, ett konstant högt antal blodplättar eller trombocyter i blodet. Utom vid myeloproliferativa sjukdomar konstateras trombocytos som en reaktiv företeelse vid många tillstånd. Differentialdiagnostiken av trombocytos är viktig, för trombocytos vid de myeloproliferativa sjukdomarna innebär en komplikationsrisk som inte finns vid reaktiv trombocytos. ET-patienter kan vara symptomfria i många år, till och med årtionden, men sjukdomen kan orsaka svåra blodpropps- eller blödningssymptom. ET-patienternas graviditeter kan även vara problematiska. Det är svårt att förutsäga komplikationerna. Ändamålet av avhandlingsarbetet var att klargöra denna sjukdoms diagnostik, bedöma komplikationernas incidens samt finna faktorer associerade med komplikationsrisken. Materialet bestod av 170 ET-patienter, vilkas sjukdom hade diagnostiserats år 1980-1996. ET-diagnosen stöddes av ett ökat antal trombocyternas moderceller i benmärgen samt deras strukturella avvikelser, trombocyternas funktionsrubbningar samt en onormal växt i odlingen av blodcellsbildande stamceller. Hos ungefär 70 % konstaterades en avvikande stamcellsväxt. Bara en femtedel av patienterna förblev symptomfria under studieperioden. Hälften hade signifikanta blodpropps- eller blödningssymptom. 45 % av patienterna hade blodproppssymptom och en femtedel signifikanta blödningar. Hälften av patienterna led av cirkulationsstörningar i småkärl. Över 60 års ålder ökade risken av blödning, men blodproppssymptom förekom ungefär lika ofta i olika åldersgrupper. Det manliga könet, rökning hos kvinnor samt avvikande stamcellsväxt förutsade tromboskomplikationernas incidens. Kvinnorna hade mindre blodproppsproblem än männen. Risken av graviditetskomplikationer var betydande, och 38 % av graviditeterna slutade i missfall. Behandling med antingen salicylsyra ensam eller kombinerad med trombocytreducerande medel minskade betydligt de graviditetsassocierade problemen. De tidigare undersökningarna gällande essentiell trombocytemi har gjorts i länder, var det förekommer mindre ateroskleros än i den finska befolkningen. Fynden i detta avhandlingsarbete kan utnyttjas vid de ofta problematiska vårdsbesluten hos finska ET-patienter

Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease

Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III-IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1 beta, IFN gamma, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.Peer reviewe

Hidden genomic MHC disparity between HLA-matched sibling pairs in hematopoietic stem cell transplantation

Matching classical HLA alleles between donor and recipient is an important factor in avoiding adverse immunological effects in HSCT. Siblings with no differences in HLA alleles, either due to identical-by-state or identical-by-descent status, are considered to be optimal donors. We carried out a retrospective genomic sequence and SNP analysis of 336 fully HLA-A, -B, -DRB1 matched and 14 partially HLA-matched sibling HSCT pairs to determine the level of undetected mismatching within the MHC segment as well as to map their recombination sites. The genomic sequence of 34 genes locating in the MHC region revealed allelic mismatching at 1 to 8 additional genes in partially HLA-matched pairs. Also, fully matched pairs were found to have mismatching either at HLA-DPB1 or at non-HLA region within the MHC segment. Altogether, 3.9% of fully HLA-matched HSCT pairs had large genomic mismatching in the MHC segment. Recombination sites mapped to certain restricted locations. The number of mismatched nucleotides correlated with the risk of GvHD supporting the central role of full HLA matching in HSCT. High-density genome analysis revealed that fully HLA-matched siblings may not have identical MHC segments and even single allelic mismatching at any classical HLA gene often implies larger genomic differences along MHC.Peer reviewe

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR]Peer reviewe

Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients

Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients' pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.Peer reviewe

Extracorporeal photopheresis in the treatment of acute graft-versus-host disease : a single-center experience

BACKGROUND: Steroid-refractory acute graft-versushost disease (aGVHD) is a serious complication after hematopoietic stem cell transplantation. The long-term outcome of the patients is poor. Various immunosuppressive agents have been proposed as the second-line therapy but none of them has turned out more effective than the others. Extracorporeal photopheresis (ECP) is a treatment option that does not predispose the patients to severe side effects of the immunosuppressive drugs. STUDY DESIGN AND METHODS: We analyzed the treatment results of ECP in 52 patients with steroidrefractory or steroid-dependent aGVHD. Eighty-one percent of the patients suffered from a severe, Grade III or IV, aGVHD. ECP was started alone as the second-line treatment in 23 patients and in combination with an immunosuppressive drug in 18 patients. Eleven patients received ECP as the third-line or later treatment. RESULTS: A total of 62% of the patients responded, with 48% achieving complete response. In the patients with complete or partial response, the probabilities of survival at 4 years were 54 and 17%, respectively. The outcome of nonresponders was poor. The 1-year overall survivals of the patients with ECP as the second-line treatment either alone or in combination with an immunosuppressive drug or as the third-line treatment were 51, 28, and 18%, respectively. In multivariate analysis, starting ECP no later than 10 days after the start of the first-line treatment correlated with a good response and a consequent survival benefit. CONCLUSION: Extracorporeal photopheresis is an effective and well-tolerated treatment that should be considered as a second-line treatment for aGVHD.Peer reviewe

Donor haplotype B of NK KIR receptor reduces the relapse risk in HLA-icentical sibling hematopoetic stem cell transplantation of AML patients

Creative Commons Attribution License (CC BY 4.0)Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GyL) effect. Natural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obviously due to enhanced GyL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diagnoses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients.Peer reviewe

Increased MHC matching by C4 gene compatibility in URD HSCT

HLA matching is a prerequisite for successful allogeneic hematopoietic stem cell transplantation (HSCT) because it lowers the occurrence and severity of graft-versus-host disease (GVHD). However, matching a few alleles of the classic HLA genes only may not ensure matching of the entire MHC region. HLA haplotype matching has been reported to be beneficial in HSCT because of the variation relevant to GVHD risk in the non-HLA region. Because polymorphism in the MHC is highly population specific, we hypothesized that donors from the Finnish registry are more likely to be matched at a higher level for the Finnish patients than donors from other registries. In the present study we determined 25 single nucleotide polymorphisms (SNPs) of the complement component 4 (C4) gene in the γ-block segment of MHC from 115 Finnish HSCT patients and their Finnish (n = 201) and non-Finnish (n = 280) donor candidates. Full matching of HLA alleles and C4 SNPs, independently or additively, occurred more likely in the Finnish–Finnish group as compared with the Finnish–non-Finnish group (P C4 matched donor, regardless of donor origin, as compared with patients without AH (P C4 matching and clinical outcome. The results suggest that screening C4 SNPs can be advantageous when an extended MHC matching or HLA haplotype matching in HSCT is required. This study also supports the need for small population-specific stem cell registries.</p

Allogeneic stem cell transplant in patients with acute myeloid leukemia and karnofsky performance status score less than or equal to 80% : A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation (EBMT)

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo-SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two-year leukemia-free survival (LFS), overall survival (OS) and graft-versus-host disease (GVHD)-free, and relapse-free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non-relapse mortality (NRM) and superior OS in comparison to patients with a KPS scorePeer reviewe

Kantasolusiirrot - soluterapia murroksessa

Kantasolusiirrot ovat vakiinnuttaneet asemansa hematologisten syöpätautien sekä synnynnäisten luuytimen ja immuunijärjestelmän toiminnanvajavuustilojen hoidossa. Kehitys on viiden vuosikymmenen aikana mahdollistanut luovuttajakirjon laajentamisen, ikääntyneempien potilaiden hoidon sekä hoitotulosten paranemisen. Aikuispotilaiden allogeenisen siirron aiheena on edelleen pääasiassa leukemia, mutta lapsipotilaiden osalta yhä enemmän myös immuunijärjestelmän ja verenmuodostuksen häiriöt. Autologisen kantasolutuen käyttö puolestaan painottuu aikuispotilaiden lymfoomien sekä myelooman hoitoon, ja sen käyttö lapsipotilaiden hoidossa on verraten vähäistä. Käänteishyljintä muodostaa edelleen keskeisen ongelman. Kantasolusiirto edeltävine hoitoineen aiheuttaa pitkäaikaishaittavaikutuksia ja elinikäisen seurantatarpeen. Uudet immunologisen täsmähoidon muodot ovat tulleet vastikään kliiniseen käyttöön, mutta kantasolusiirrot säilyttänevät asemansa erityisesti leukemian hoidossa vielä nähtävillä olevassa tulevaisuudessa