Incidence of cardiovascular disease in healthy Swedish peripheral blood stem cell donors - a nationwide study.

Granulocyte colony-stimulating factor (G-CSF) is used in a majority of healthy donors to obtain peripheral blood stem cells for allogeneic stem cell transplantation. Since high levels of G-CSF activates endothelial cells and can induce a pro-coagulatory state, and fuelled by case reports of cardiovascular events in donors, some concerns have been raised about a potential for an increased risk of cardiovascular events for the donors after donation. We studied the incidence of cardiovascular disease following stem cell donation in a Swedish national register based cohort of 1098 peripheral blood stem cell donors between 1998 and 2016. The primary objective was to evaluate if the incidence of cardiovascular disease was increased for donors treated with G-CSF. The incidence of any new cardiovascular disease was 6.0 cases per 1000 person years, with a median follow up of 9.8 years. The incidence did not exceed that of age- sex- and residency-matched population controls (hazard ratio 0.90, 95% confidence interval (CI) 0.76-1.07, p-value 0.23), bone marrow donors, or non-donating siblings. Long-term cardiovascular disease incidence was not increased in this national register based study of peripheral blood stem cell donors treated with G-CSF.

MDS-Comorbidity Index using register data has prognostic impact in Swedish MDS patients.

Comorbidities influence the mortality in patients with myelodysplastic syndromes, and a growing body of evidence suggest that comorbidity history should be used in addition to established prognostic indices. A comorbidity index specific for MDS, the MDS-CI, was introduced a decade ago. In this study we aim to construct an MDS-CI version based on diagnoses from register data only, to expand its use beyond the clinical setting to retrospective and register based studies. We further test this version on a Swedish population-based MDS cohort of 2947 patients, and compare its prognostic accuracy to that of Charlson Comorbidity Index. Our register based MDS-CI divided patients into three risk groups of similar proportions as have been published for the original MDS-CI. Compared to low risk patients, intermediate and high risk patients had 50 % and 70 % higher mortality, respectively. The prognostic value of MDS-CI was equal to that of Charlson comorbidity index. Adding MDS-CI to the established prognostic factors IPSS-R and age increased the prognostic accuracy. In summary, we demonstrate that MDS-CI can be adequately estimated from diagnoses recorded in registers only, and that it is a useful tool in any future study on myelodysplastic syndromes with a need to adjust for comorbidities.

Despite warnings, co-medication with proton pump inhibitors and dasatinib is common in chronic myeloid leukemia, but XS004, a novel oral dasatinib formulation, provides reduced pH-dependence, minimizing undesirable drug-drug interactions.

BACKGROUND: Dasatinib and other tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML). However, as a lipophilic weak base, crystalline monohydrate, dasatinib (Sprycel®) is poorly soluble, rendering a pH-dependent absorption and a highly variable bioavailability. Thus, co-medication with proton pump inhibitors (PPI) profoundly impairs dasatinib uptake and is clearly recommended against. XS004 is a novel oral immediate release and amorphous solid dispersion (ASD) formulation of dasatinib and is bioequivalent to the original crystalline dasatinib at 30% lower dosages. XS004 is designed to mitigate gastric pH dependency, thus optimizing absorption and bioavailability. METHODS: We investigated the prevalence of dasatinib and PPI co-medication among chronic-phase CML patients in a real-world setting and assessed the plasma pharmacokinetics (PK) of XS004 with and without PPI co-medication (omeprazole) in healthy volunteers. RESULTS: Using the Swedish CML and Prescribed Drug Registers, we identified 676 TKI-treated CML patients; 320 (47%) had been prescribed PPI at some point after CML diagnosis. Among dasatinib-treated patients, the 2-year cumulative PPI co-medication was 24%. Interestingly, the 5-year overall survival was significantly lower for TKI-treated CML patients with versus without PPI co-medication (79% vs. 94%; hazard ratio 3.5; 95% confidence interval, 2.1-5.3; p < .0001). When assessing PK of XS004, neither Cmax nor area under the plasma concentration curve levels in plasma were significantly altered by the PPI co-medication. CONCLUSION: In conclusion, despite warnings, PPI co-medication is common among dasatinib-treated CML patients in a real-world setting. The new XS004 ASD formulation of dasatinib provided, in contrast to original crystalline dasatinib, superior pH independence with stable bioavailability, thereby minimizing drug-drug interactions. This may improve the long-term efficacy and tolerability of dasatinib in CML.

Worries and Psychological Well-Being in Potential Hematopoietic Stem Cell Donors Before Donation-A Swedish National Study.

BACKGROUND: The physical risks involved in donating hematopoietic stem cells have been thoroughly studied, but little is known about the psychological risks potential donors might face before donation. The aim of this study was to describe potential the pre-donation worries and psychological well-being of hematopoietic stem cell donors and investigate possible associations between donor characteristics and psychological well-being. METHODS: In a cross-sectional, national cohort study, we describe pre-donation worries and psychological well-being and investigate possible associations between donor characteristics and psychological well-being. A questionnaire was sent to prospective adult hematopoietic stem cells donors. RESULTS: The study included 210 participants, 47% of whom were related and 53% unrelated to the recipient. Of the participants, 39% reported great worry about the recipient and 12% great worry about themselves as potential donors. Symptoms of anxiety were expressed by 21%, whereas symptoms of depression were uncommon and perceived general mental health was slightly lower than in the Swedish population. Great worry about oneself, lower age, and female sex were related to increased anxiety and lower mental health. CONCLUSION: This study highlighted that some potential donors report high levels of pre-donation worry and that greater worry about oneself, lower age, and female sex are associated with lower psychological well-being. Although further studies are needed to investigate this psychological risk over time, it is clear that some potential donors are particularly vulnerable.

Cancer incidence in healthy Swedish peripheral blood stem cell donors.

Granulocyte colony-stimulating factor (G-CSF) has been used for over 20 years to obtain peripheral blood stem cells from healthy donors for allogeneic stem cell transplantation. Concerns have been raised about a potentially increased cancer incidence in donors after donation, especially regarding haematological malignancies. In a prospective Swedish national cohort study, we studied the cancer incidence after donation in 1082 Swedish peripheral blood stem cell donors, donating between 1998 and 2014. The primary objective was to evaluate if the cancer incidence increased for donors treated with G-CSF. With a median follow-up time of 9.8 years, the incidence of haematological malignancies was 0.85 cases per 1000 person-years, and did not significantly differ from the incidence in age-, sex- and residence-matched population controls (hazard ratio 1.70, 95% confidence interval (CI) 0.79-3.64, p value 0.17), bone marrow donors or non-donating siblings. The total cancer incidence for peripheral blood stem cell donors was 6.0 cases per 1000 person-years, equal to the incidence in matched population controls (hazard ratio 1.03, 95% CI 0.78-1.36, p value 0.85), bone marrow donors or non-donating siblings. In this study of healthy peripheral blood stem cell donors, the cancer incidence was not increased after treatment with G-CSF.

Efficacy of a novel device for cryoprevention of oral mucositis: a randomized, blinded, multicenter, parallel group, phase 3 trial.

Cryoprevention (CP) using ice (IC) is an effective strategy to prevent chemotherapy-induced oral mucositis (OM). However, the use of IC may cause adverse reactions and requires water of safe quality to minimize risk of serious infections. This randomized, blinded, parallel group, phase 3 trial was conducted in five Scandinavian centers. Eligible patients were diagnosed with multiple myeloma or lymphoma, scheduled to receive conditioning with high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (ASCT). Patients were assigned to cooling with IC or a novel intraoral cooling device (ICD). The primary outcome was the highest OM score during the study period, expressed as peak value on the Oral Mucositis Assessment Scale (OMAS-total). When the entire study population (n = 172) was analyzed for peak OMAS-total, the two cooling methods were equally effective. However, when the lymphoma group was analyzed separately, the ICD significantly reduced the peak OMAS-total score to a greater extent compared to IC (x̄ ± SD; 1.77 ± 1.59 vs. 3.08 ± 1.50; p = 0.047). Combined with existing evidence, the results of the present trial confirm that CP is an effective method to prevent OM. ClinicalTrials.gov. NCT03203733.

Income, education and their impact on treatments and survival in patients with myelodysplastic syndromes.

OBJECTIVES: To assess whether socioeconomic indices such as income and educational level can explain part of the variation in survival among patients with myelodysplastic syndromes, and further to assess whether these factors influence care and treatment decisions. METHODS: Population-based cohort study on 2945 Swedish patients diagnosed between 2009 and 2018 and included in the Swedish MDS Register. Relative mortality was assessed by Cox regression, whereas treatment differences were assessed by Poisson regression. Regarding mortality, patients were also compared to a matched comparison group from the general population. RESULTS: Mortality was 50% higher among patients in the lowest income category compared to the highest and 40% higher in patients with mandatory school education only compared to those with college or university education. Treatment with hypomethylating agents and allogeneic stem cell transplantation, as well as investigation with cytogenetic diagnostics were also linked to income and education. The findings were not explained by differences in risk class or comorbidity at the time of diagnosis. CONCLUSIONS: Income and education are linked to survival among patients with myelodysplastic syndromes. Socioeconomic status also seems to influence treatment intensity as patients with less income and education to a lesser degree receive hypomethylating agents and transplants.

Birthweight and all-cause mortality after childhood and adolescent leukemia: a cohort of children with leukemia from Denmark, Norway, Sweden, and Washington State.

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia.Material and methods: In a cohort of childhood and adolescent leukemia (0-19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967-2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down's syndrome or other malformations, and type of leukemia.Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >1-2 years old; 1.0 (95% CI: 0.6, 1.5) for 3-8 years old; 1.0 (95% CI: 0.6, 1.8) for 9-13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14-19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37-41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8).Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

Increased Risk of Chronic Myeloid Leukemia Following Gastric Conditions Indicating Helicobacter pylori Infection: A Case-Control Study.

BACKGROUND: On the basis of a previous report of increased chronic myeloid leukemia (CML) risk following peptic ulcer, we hypothesized that chronic Helicobacter pylori infection could serve as a risk factor for CML. METHODS: In a population-based, retrospective case-control study, we used Swedish registry data on 980 patients with CML and 4,960 age- and sex-matched controls to investigate associations between markers of previous infection with Helicobacter pylori and CML incidence. RESULTS: Previous diagnoses of dyspepsia, gastritis or peptic ulcers, as well as previous proton pump inhibitor (PPI) medication, were all associated with a significantly increased risk of CML (RRs, 1.5-2.0; P = 0.0005-0.05). Meanwhile, neither inflammatory bowel disease nor intake of NSAIDs were associated with CML, indicating that it is not gastrointestinal ulcer or inflammation per se that influences risk. CONCLUSIONS: The consistent associations suggest a shared background between gastric conditions and CML, and strengthen the case that Helicobacter pylori could constitute this common risk factor. IMPACT: As the etiology of CML is practically unknown, and Helicobacter pylori could potentially be a therapeutic target, even this indirect evidence encourages further studies on the potential involvement of Helicobacter pylori in CML etiology.

Characterization of neural crest-derived stem cells isolated from human bone marrow for improvement of transplanted islet function.

Background: Murine boundary cap-derived neural crest stem cells (NCSCs) are capable of enhancing islet function by stimulating beta cell proliferation as well as increasing the neural and vascular density in the islets both in vitro and in vivo. This study aimed to isolate NCSC-like cells from human bone marrow.Methods: CD271 magnetic cell separation and culture techniques were used to purify a NCSC-enriched population of human bone marrow. Analyses of the CD271+ and CD271- fractions in terms of protein expression were performed, and the capacity of the CD271+ bone marrow cells to form 3-dimensional spheres when grown under non-adherent conditions was also investigated. Moreover, the NCSC characteristics of the CD271+ cells were evaluated by their ability to migrate toward human islets as well as human islet-like cell clusters (ICC) derived from pluripotent stem cells.Results: The CD271+ bone marrow population fulfilled the criterion of being multipotent stem cells, having the potential to differentiate into glial cells, neurons as well as myofibroblasts in vitro. They had the capacity to form 3-dimensional spheres as well as an ability to migrate toward human islets, further supporting their NCSC identity. Additionally, we demonstrated similar migration features toward stem cell-derived ICC.Conclusion: The results support the NCSC identity of the CD271-enriched human bone marrow population. It remains to investigate whether the human bone marrow-derived NCSCs have the ability to improve transplantation efficacy of not only human islets but stem cell-derived ICC as well.

Short-term side effects and attitudes towards second donation: A comparison of related and unrelated haematopoietic stem cell donors.

The Nordic Register of Haematopoietic Stem Cell Donors (NRHSD) has registered related and unrelated donors from 10 transplant centres in Sweden, Norway, Finland and Denmark since 1998. We present a prospective, observational study of 1,957 donors, focusing mainly on the differences between related and unrelated donors. Related donors are reported to have more comorbidities, but similar side effects compared with unrelated donors. Side effects after BM or PBSC donation are generally of short duration and in this study no deaths, myocardial infarctions, splenic ruptures, or thromboembolic events are reported. Interestingly, related donors express more hesitancy towards donating again when asked 1 month after donation.

Parental Age and Risk of Lymphoid Neoplasms.

High parental age at childbirth has repeatedly been linked to childhood malignancies, while few studies have focused on the offspring's risk of adult cancer. In this population-based case-control study, we identified 32,000 patients with lymphoid neoplasms, diagnosed at ages 0-79 years during the period 1987-2011, and 160,000 matched controls in Sweden. Using prospectively registered data on their first-degree relatives, we evaluated the impact of parental age on the risk of lymphoid neoplasms by subtype. Overall, each 5-year increment in maternal age was associated with a 3% increase in incidence of offspring lymphoid neoplasms (hazard ratio = 1.03, 95% confidence interval: 1.02, 1.04). The association was similar for paternal age and present even among individuals older than 70 years of age at diagnosis. Stratified analyses further revealed that the association was limited to certain subtypes, mostly of indolent nature. Risks of chronic lymphocytic leukemia, follicular lymphoma, and mantle cell lymphoma were 5%-10% higher per 5-year increment in maternal age, but no associations were observed for acute lymphoblastic leukemia, plasma cell neoplasms, or diffuse large B-cell lymphoma. These findings indicated that prenatal genetic or epigenetic changes influence risk of adult lymphoid neoplasms and suggest a difference in this association between aggressive and indolent lymphoma subtypes.

The impact of socio-economic factors on treatment choice and mortality in chronic myeloid leukaemia.

PURPOSE: To evaluate the influence of socio-economic variables on treatment selection and survival of patients with chronic myeloid leukaemia (CML). METHODS: Using information available in population-based Swedish registries, we evaluated indices of health, education and economy from the 980 patients in the Swedish CML register diagnosed between 2002 and 2012. Apart from internal comparisons, five age-, gender- and region-matched control subjects per patient served as control cohort. Median follow-up time from CML diagnosis was 4.8 years. RESULTS: Among patients with CML, low personal or household income, short education, living alone, poor performance status and high age (>60 years) were significantly associated with an inferior survival (in univariate analyses). However, similar findings were noted also in the matched control group, and in comparisons adjusted for calendar year, age and performance status, socio-economic variables were not significantly associated with CML survival. Meanwhile, both education and income were independently linked to TKI treatment overall and to upfront treatment with second-generation TKIs. CONCLUSIONS: In conclusion, socio-economic conditions were associated with survival in the studied CML cohort but these associations could be explained by differences at baseline. Meanwhile, socio-economic conditions appeared to influence treatment choice.

Parental age, family size, and offspring's risk of childhood and adult acute leukemia.

BACKGROUND: An association between childhood acute leukemia and advanced parental age was observed more than 50 years ago, and the association has been repeated in several, but not all, subsequent studies. In contrast to the many studies addressing childhood leukemia, few have included adult patients. METHODS: In this register-based case-control study, we examined the association between parental age and incidence of acute leukemia in 2,660 childhood cases and 4,412 adult cases of acute leukemia, compared with 28,288 age-matched controls selected from a population-based register. Relative risks were estimated with conditional logistic regression. RESULTS: We found a small increased risk of childhood acute lymphoblastic leukemia with increasing paternal age (adjusted OR, 1.05 per 5-year increase in age). Risk estimates were similar for childhood acute myeloid leukemia (AML), whereas no association was found with adult leukemia. Meanwhile, we observed a decreased risk of adult AML with increasing number of siblings, both older and younger. CONCLUSIONS: The results support the idea of a prenatal etiology of leukemia but indicate that parental age effects are limited to childhood cases. IMPACT: This is the first large study on parental age and leukemia risk, which includes adult cases. The finding on family size and risk of adult AML needs to be validated in future studies.

Pregnancy and risk of acute myeloid leukaemia--a case-control study.

Although maternal haematopoiesis is characterised by rapid proliferation and immunological adjustment, leukaemia seldom occurs in pregnant women. In this case-control study, we investigated pregnancy and risk of acute myeloid leukaemia (AML). A total of 785 women with AML diagnosed in ages 15-50 were compared with 1576 age- and sex-matched controls. At the time of diagnosis, 13 cases and 53 controls were pregnant (1.3% and 3.4%, respectively), resulting in a significantly reduced odds ratio of 0.44 (95% confidence interval 0.22-0.85). Odds ratios of AML during the years following childbirth were close to unity. The results suggest that pregnancy conveys a strong short-term protection against AML.

Placental weight and breast cancer survival in young women.

A growing body of evidence indicates that reproductive history influences survival in breast cancer, especially among women diagnosed during or shortly after a pregnancy. However, little is known about the underlying mechanisms. We hypothesized that increasing placental weight, as an indirect marker of exposure to elevated hormone levels during pregnancy, would be associated with reduced survival in breast cancer. A cohort of 1873 women with at least one pregnancy after January 1st, 1973, and a subsequent breast cancer diagnosis before the end of 1991 were followed up for death or emigration through 2006. Information on placental weight and potential confounding factors were collected from medical records and from nationwide registers, which resulted in data on placental weight in the most recent pregnancy before diagnosis for 1,057 cases. For each 100-gram increase in placental weight, the adjusted hazard ratio of death was 1.09 [95% confidence interval (CI), 0.99-1.19]. The association was stronger among primiparous women (adjusted hazard ratio, 1.26; 95% CI, 1.09-1.47), and among women diagnosed during pregnancy or within 2 years from last birth (adjusted hazard ratio, 1.30; 95% CI, 1.06-1.59). Increasing placental weight is associated with reduced breast cancer survival. These findings are consistent with the hypothesis that the reduced survival in breast cancer among women with a recent childbirth is linked to pregnancy hormone exposure.