Thrombotic microangiopathy associated with bortezomib treatment in a patient with relapsed multiple myeloma

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) describe microvascular occlusive disorders characterized by thrombocytopenia due to increased platelet aggregation and fragmentation hemolysis. We report here what to our knowledge is the second case of TTP/HUS associated with bortezomib treatment

Early CD8+-recovery independently predicts low probability of disease relapse but also associates with severe GVHD after allogeneic HSCT

In this single-center study we retrospectively evaluated the impact of early reconstitution of different lymphocyte subsets on patient outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that CD8+ T-cell counts exceeding 50x106/l as early as on day 28 post-transplantation correlated significantly with decreased relapse risk, with three-year relapse rates of 17.0% and 55.6% (P = 0.002), but were also associated with severe acute and chronic GVHD. Incidence of grade III-IV acute GVHD was 30.5% for those with early CD8+T-cell recovery compared to 2.1% for those with lower CD8+ T-cell counts on day 28 post-transplant (HR = 20.24, P = 0.004). Early CD8+ T-cell reconstitution did not, however, affect the overall survival. Multivariate analysis showed that slow CD8+ T-cell reconstitution was strongly associated with increased risk of relapse (HR = 3.44, P = 0.026). A weaker correlation was found between CD4+ reconstitution and relapse-risk, but there was no such association with CD19+ B-cells or NK-cells. In conclusion, the early CD8+ T-cell recovery on day 28 post-transplant is associated with the lower risk of relapse but also predicts the impending severe GVHD, and thus could be useful in guiding timely treatment decisions.</p

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

Immunomonitoring of MSC-Treated GvHD Patients Reveals Only Moderate Potential for Response Prediction but Indicates Treatment Safety

Mesenchymal stromal cells (MSCs) are used as salvage therapy to treat steroid-refractory acute graft-versus-host disease (aGvHD). We studied the immunological response to MSC treatment in 16 aGvHD patients by assessing lymphocyte profiles and three proposed aGvHD serum markers during the MSC treatment. Surprisingly, there were no obvious differences in the lymphocyte profiles between the responders and non-responders. The numbers of T, B, and NK cells were below the normal reference interval in all patients. CD4+ T helper (Th) cell levels remained particularly low throughout the follow-up period. The relative proportion of Th1 cells decreased, while regulatory T cells remained unaltered, and only very few Th2 and Th17 cells could be detected. Serum concentrations of regenerating islet-derived protein 3-alpha, cytokeratin-18 fragments (CK18F), and elafin were significantly elevated in patient samples compared with healthy controls, but only CK18F showed any potential in the prediction of patients’ response to MSCs. No obvious markers for MSC therapy response were revealed in this study, but the results suggest that allogeneic MSCs do not provoke overt T cell-mediated immune responses at least in immunosuppressed aGvHD patients. The results advocate for the safety of MSC therapy and bring new insights in MSC immunomodulation mechanisms.</p

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

Kantasolusiirrot - soluterapia murroksessa

Vertaisarvioitu.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.Peer 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

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

Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1-mutated acute myeloid leukemia:A study from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party

In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1)-mutated acute myeloid leukemia (AML) were classified in the adverse-risk category in the presence of high-risk cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1-mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse-risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3-ITD. On univariate analysis, only FLT3-ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72, p =.009). In the subgroup of 493 patients with aberrant CG, the 2-year leukemia-free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p =.025; and 1.99, p =.003 respectively) and worse LFS (HR 1.62, p =.018; and 1.64, p =.011 respectively) while FLT3-ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p =.002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1-mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long-term posttransplant survival.</p