How important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by conditioning regimen in... Show moreHow important is choice of conditioning regimen in allogeneic haematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD)? We compared HSCT outcomes by conditioning regimen in paediatric patients with SCD from the EBMT registry. In 2010–2020, 251 patients aged <18 years underwent a first matched sibling donor (MSD) HSCT with conditioning based on busulfan–fludarabine (bu–flu; n = 89) or treosulfan–fludarabine (treo–flu; n = 162). In the bu–flu and treo–flu groups, 51.7% and 99.4% of patients, respectively, received thiotepa. Median follow-up was 2.7 years. Two-year overall survival (OS) was 98.7% (95% confidence interval [CI]: 90.9–99.8) with bu–flu and 99.3% (95% CI: 95.2–99.9) with treo–flu (p = 0.63). Grade III–IV acute graft-versus-host disease (GVHD) at 100 days was 2.4% (95% CI: 0.4–7.5) and 0.6% (0.1%–3.2%) for bu–flu and treo–flu respectively (p = 0.25). The 2-year incidence of extensive chronic GVHD was 1.5% (95% CI: 0.1–7.3) with bu–flu and 8.0% (95% CI: 4.1–13.3) with treo–flu (p = 0.057). These multinational data confirm the excellent curative capacity of MSD HSCT with myeloablative conditioning. Both conditioning regimens yielded excellent OS, low rates of acute and chronic GVHD, and low rates of graft failure. Show less
We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving... Show moreWe investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML. Show less
The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic... Show moreThe risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I-2 = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I-2 = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I-2 = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE. Show less
Haemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve... Show moreHaemolytic disease of the newborn (HDN) can be associated with significant morbidity. Prompt treatment with intensive phototherapy (PT) and exchange transfusions (ETs) can dramatically improve outcomes. ET is invasive and associated with risks. Intravenous immunoglobulin (IVIG) may be an alternative therapy to prevent use of ET. An international panel of experts was convened to develop evidence-based recommendations regarding the effectiveness and safety of IVIG to reduce the need for ETs, improve neurocognitive outcomes, reduce bilirubin level, reduce the frequency of red blood cell (RBC) transfusions and severity of anaemia, and/or reduce duration of hospitalization for neonates with Rh or ABO-mediated HDN. We used a systematic approach to search and review the literature and then develop recommendations from published data. These recommendations conclude that IVIG should not be routinely used to treat Rh or ABO antibody-mediated HDN. In situations where hyperbilirubinaemia is severe (and ET is imminent), or when ET is not readily available, the role of IVIG is unclear. High-quality studies are urgently needed to assess the optimal use of IVIG in patients with HDN. Show less
Swinkels, M.; Atiq, F.; Burgisser, P.E.; Moort, I. van; Meijer, K.; Eikenboom, J.; ... ; WiN Study Grp 2022
Von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 or 3) or qualitative (type 2A/2B/2M/2N) defects of circulating von Willebrand factor (VWF). Circulating VWF levels... Show moreVon Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 or 3) or qualitative (type 2A/2B/2M/2N) defects of circulating von Willebrand factor (VWF). Circulating VWF levels not always fully explain bleeding phenotypes, suggesting a role for alternative factors, like platelets. Here, we investigated platelet factor 4 (PF4) in a large cohort of patients with VWD. PF4 levels were lower in type 2B and current bleeding phenotype was significantly associated with higher PF4 levels, particularly in type 1 VWD. Based on our findings we speculate that platelet degranulation and cargo release may play a role across VWD subtypes. Show less
Vos, T.W.; Porcelijn, L.; Hofstede-van Egmond, S.; Pajkrt, E.; Oepkes, D.; Lopriore, E.; ... ; Haas, M. de 2022
The standardized EuroFlow protocol, including CD19 as primary B-cell marker, enables highly sensitive and reliable minimal residual disease (MRD) assessment in B-cell precursor acute lymphoblastic... Show moreThe standardized EuroFlow protocol, including CD19 as primary B-cell marker, enables highly sensitive and reliable minimal residual disease (MRD) assessment in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients treated with chemotherapy. We developed and validated an alternative gating strategy allowing reliable MRD analysis in BCP-ALL patients treated with CD19-targeting therapies. Concordant data were obtained in 92% of targeted therapy patients who remained CD19-positive, whereas this was 81% in patients that became (partially) CD19-negative. Nevertheless, in both groups median MRD values showed excellent correlation with the original MRD data, indicating that, despite higher interlaboratory variation, the overall MRD analysis was correct. Show less
Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare, commonly fatal complication of transfusion preventable by irradiation of blood units. The revision of the Dutch transfusion... Show moreTransfusion-associated graft-versus-host disease (TA-GVHD) is a rare, commonly fatal complication of transfusion preventable by irradiation of blood units. The revision of the Dutch transfusion guideline addressed the question whether irradiation is still necessary if blood components are prestorage leukodepleted. We searched for published cases of TA-GVHD following transfusion of prestorage leukodepleted blood and through contacting haemovigilance systems. Six presumed cases were found, dating from 1998 to 2013. Four out of six patients had received one or more non-irradiated units despite recognised indications for irradiated blood components. In the countries providing information, over 50 million prestorage leukodepleted, non-irradiated, non-pathogen-reduced cellular components were transfused in a 10-year period. Potential benefits of lifting indications for irradiation were considered. These include reduced irradiation costs (euro 1.5 million annually in the Netherlands) and less donor exposure for neonates. Findings were presented in an invitational expert meeting. Recommendations linked to human leukocyte antigen similarity between donor and recipient or intra-uterine transfusion were left unchanged. Indications linked to long-lasting deep T-cell suppression were defined with durations of 6 or 12 months after end of treatment (e.g. autologous or allogeneic stem cell transplantation). Need for continued alertness to TA-GVHD and haemovigilance reporting of erroneous non-irradiated transfusions was emphasised. Show less
Vos, T.W. de; Porcelijn, L.; Hofstede-van Egmond, S.; Pajkrt, E.; Oepkes, D.; Lopriore, E.; ... ; Haas, M. de 2021
Fetal neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal alloantibodies directed against the human platelet antigens (mostly HPA-1a or HPA-5b) of the (unborn) child and can lead to... Show moreFetal neonatal alloimmune thrombocytopenia (FNAIT) is caused by maternal alloantibodies directed against the human platelet antigens (mostly HPA-1a or HPA-5b) of the (unborn) child and can lead to severe bleeding. Anti-HPA-1a-mediated FNAIT shows a severe clinical outcome more often than anti-HPA-5b-mediated FNAIT. Given the relatively high prevalence of anti-HPA-5b in pregnant women, the detection of anti-HPA-5b in FNAIT-suspected cases may in some cases be an incidental finding. Therefore we investigated the frequency of anti-HPA-5b-associated severe bleeding in FNAIT. We performed a retrospective nationwide cohort study in cases with clinical suspicion of FNAIT. HPA antibody screening was performed using monoclonal antibody-specific immobilisation of platelet antigens. Parents and neonates were typed for the cognate antigen. Clinical data were collected by a structured questionnaire. In 1 864 suspected FNAIT cases, 161 cases (8 center dot 6%) had anti-HPA-1a and 60 (3 center dot 2%) had anti-HPA-5b. The proportion of cases with severe bleeding did not differ between the cases with anti-HPA-1a (14/129; 11%) and anti-HPA-5b (4/40; 10%). In multigravida pregnant women with a FNAIT-suspected child, 100% (81/81) of anti-HPA-1a cases and 79% (38/48) of anti-HPA-5b cases were HPA-incompatible, whereas 86% and 52% respectively were expected, based on the HPA allele distribution. We conclude that anti-HPA-5b can be associated with severe neonatal bleeding symptoms. A prospective study is needed for true assessment of the natural history of anti-HPA-5b mediated FNAIT. Show less
Oud, J.A.; Evers, D.; Haas, M. de; Vooght, K.M.K. de; Kerkhof, D. van de; Som, N.; ... ; Zwaginga, J.J. 2021
Maternal alloantibodies directed against fetal red blood cell (RBC) antigens may cause potentially life-threatening haemolytic disease of the fetus and newborn (HDFN). Dutch transfusion guidelines... Show moreMaternal alloantibodies directed against fetal red blood cell (RBC) antigens may cause potentially life-threatening haemolytic disease of the fetus and newborn (HDFN). Dutch transfusion guidelines therefore prescribe preventive cEK matching for all (pre-)fertile females. To quantify the impact of cEK matching, we compared overall and antigen-specific cumulative RBC alloimmunisation incidences in females and males aged <45 years. Among a multicentre cohort comprised of patients who received their first and subsequent RBC unit between 2005 and 2019, first-formed RBC alloantibodies were detected in 47 of 2998 (1 center dot 6%) females and 49 of 2507 (2 center dot 0%) males. Comparing females and males, overall alloimmunisation incidences were comparable (3 center dot 1% [95% confidence interval (CI) 2 center dot 1-4 center dot 4] versus 3 center dot 5% (95% CI 2 center dot 4-4 center dot 9, P = 0 center dot 853) after 10 units transfused). However, cEK alloimmunisation incidences were significantly lower among females (0 center dot 6% (95% CI 0 center dot 3-1.5) versus 2 center dot 2% (95% CI 1 center dot 5-3 center dot 4, P = 0 center dot 001) after 10 units transfused). Yet, despite cEK-matching guidelines being in effect, 6 center dot 5%, 3 center dot 6% and 0 center dot 2% of all RBC units remained mismatched for c, E or K antigens respectively. Most of these mismatches were almost always due to emergency settings. Even though cEK alloimmunisation was not prevented completely, implementation of cEK matching resulted in an alloantigen-exposure risk reduction of up to 98%. Show less
Glucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to... Show moreGlucocorticoid treatment increases venous thromboembolism (VTE) risk. Whether this is due to the medication or the underlying disease, or affects the risk of VTE recurrence, has been difficult to determine. The aim of our present study was to quantify the risk for first and recurrent VTE associated with oral glucocorticoids use, considering the underlying disease. A total of 2547 patients with VTE from the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study were linked to the Dutch Pharmaceutical Statistics register. The risk of first VTE during periods of exposure with oral glucocorticoids was estimated by the self-controlled case series method and that of recurrent VTE was examined in a cohort design. The incidence rate ratio (IRR) of first VTE in the period of glucocorticoid treatment was 3 center dot 51 [95% confidence interval (CI) 2 center dot 55-4 center dot 80]. This IRR was 2 center dot 53 (95% CI 1 center dot 10-5 center dot 72) in the week before treatment started, 5 center dot 28 (95% CI 2 center dot 89-9 center dot 53) in the first 7 days of treatment, remained elevated afterwards and decreased to 1 center dot 55 (95% CI 0 center dot 85-3 center dot 12) after 6 months, as compared to unexposed periods. The hazard ratio for recurrence was 2 center dot 72 (95% CI 1 center dot 64-4 center dot 78) in treatment periods as compared with no treatment. The increased risk of VTE associated with oral glucocorticoid treatment is due to a combined effect of the treatment and the underlying disease, remaining high during the first months of prescription. Show less
We investigated longitudinally the behaviour of anti-factor VIII (anti-FVIII) IgG subclasses for 6 months from inhibitor development in 43 patients from the Survey of Inhibitors in Plasma-Products... Show moreWe investigated longitudinally the behaviour of anti-factor VIII (anti-FVIII) IgG subclasses for 6 months from inhibitor development in 43 patients from the Survey of Inhibitors in Plasma-Products Exposed Toddlers (SIPPET) trial who developed persistent or transient inhibitors. We first analysed 43 patients within 60 days post inhibitor detection. Then, 14 of these 43 patients were studied at five time points over 6 months. Our study showed that during the first 60 days, the risk of inhibitor persistence increased with the concomitant presence of an increasing number of IgG subclasses. Over the 6-month period post inhibitor detection, only the IgG2 subclass could be considered a hallmark of inhibitor persistence. Show less
Bras, A.E.; Osmani, Z.; Haas, V. de; Jongen-Lavrencic, M.; Marvelde, J.G. te; Zwaan, C.M.; ... ; Velden, V.H.J. van der 2020
Given its myeloid-restricted expression, myeloperoxidase (MPO) is typically used for lineage assignment (myeloid vs. lymphoid) during acute leukaemia (AL) diagnostics. In the present study, a... Show moreGiven its myeloid-restricted expression, myeloperoxidase (MPO) is typically used for lineage assignment (myeloid vs. lymphoid) during acute leukaemia (AL) diagnostics. In the present study, a robust flow cytometric definition for MPO positivity was established based on the standardised EuroFlow protocols, the standardised Acute Leukaemia Orientation Tube and 1734 multicentre AL cases (with confirmed assay stability). The best diagnostic performance was achieved by defining MPO positivity as >= 20% of the AL cells exceeding a lymphocyte-based threshold. The methodology employed should be applicable to any form of standardised flow cytometry. Show less
It is not known whether the synergistic effect of genetic markers, increasing the risk of venous thrombosis (VT), and combined oral contraceptives (COC) use varies between different types of... Show moreIt is not known whether the synergistic effect of genetic markers, increasing the risk of venous thrombosis (VT), and combined oral contraceptives (COC) use varies between different types of progestogens in these preparations. We investigated the joint effect of genetic risk factor, that is, F5 rs6025, F2 rs1799963, and FGG rs2066865 mutations, and different progestogens on the risk of VT. The constrained maximum likelihood estimation (CMLE) method was used to calculate joint effects, expressed as odds ratio (OR) with 95% confidence intervals [CI]. As the dose of estrogen is known to be a risk factor for VT, analyses were restricted to COC with 30 mu g estrogen and each progestogen. Overall, the joint effect of COC and genetic variants was lowest for COC containing the progestogen levonorgestrel, albeit CIs were wide. The OR (95% CI) of the four different analyses (i.e. joint effect with F5 rs6025, F2 rs1799963, F5 rs6025 or F2 rs1799963 and FGG rs2066865) ranged between 7 center dot 4 (5 center dot 4-10 center dot 2) and 24 center dot 8 (12 center dot 3-50 center dot 0) for levonorgestrel. For gestodene the joint effect ranged between 11 center dot 7 (7 center dot 2-19 center dot 1) and 30 center dot 9 (10 center dot 6-89 center dot 9). Desogestrel and cyproterone acetate had the highest risk estimates: 14 center dot 6 (9 center dot 7-21 center dot 9) and 32 center dot 6 (13 center dot 2-80 center dot 6) and 15 center dot 5 (9 center dot 7-24 center dot 9) and 44 center dot 4 (16 center dot 9-116 center dot 3) respectively. In women with inherited thrombophilia, COC containing levonorgestrel were associated with the lowest risk of VT, albeit the CIs were wide. Show less
We conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce... Show moreWe conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce Thrombophilia (START) study (NCT01613794). Plasma fibrinolytic potential, fibrinogen, plasmin inhibitor, plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) were measured before and after four weeks of rosuvastatin or no treatment in participants with prior confirmed VTE, after ending anticoagulant therapy. In the non-rosuvastatin group (n = 121), plasma fibrinolytic potential and individual fibrinolysis parameters did not change at the end of the study versus the baseline, whereas in the rosuvastatin group (n = 126), plasma fibrinolytic potential increased: the mean clot lysis time decreased by 8 center dot 75 min (95% CI -13 center dot 8 to -3 center dot 72), and plasmin inhibitor levels and TAFI activity were lower at the end of the study (-0 center dot 05 U/ml; 95% CI -0 center dot 07 to -0 center dot 02 and -4 center dot 77%; 95% CI -6 center dot 81 to -2 center dot 73, respectively). PAI-1 levels did not change and fibrinogen levels were 0 center dot 17 g/l (95% CI 0 center dot 04-0 center dot 29) higher. In participants with prior VTE, rosuvastatin use led to an increased fibrinolytic potential compared with non-statin use. Our findings support the need for further studies on the possible role for statins in the secondary prevention of VTE. Show less
Velzen, A.S. van; Eckhardt, C.L.; Peters, M.; Oldenburg, J.; Cnossen, M.; Liesner, R.; ... ; INSIGHT Consortium 2020
Inhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates... Show moreInhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case-control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case-control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2-40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma-derived FVIII concentrates (adjusted odds ratio 0 center dot 96, 95% confidence interval (CI) 0 center dot 36-2 center dot 52) or for specific types of FVIII concentrates. Show less
Outcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was... Show moreOutcome of 333 children with acute myeloid leukaemia relapsing after a first allogeneic haematopoietic stem cell transplantation was analyzed. Four-year probability of overall survival (4y-pOS) was 14%. 4y-pOS for 122 children receiving a second haematopoietic stem cell transplantation was 31% and 3% for those that did not (P = <0 center dot 0001). Achievement of a subsequent remission impacted survival (P = <0 center dot 0001). For patients receiving a second transplant survival with or without achieving a subsequent remission was comparable. Graft source (bone marrow vs. peripheral blood stem cells, P = 0 center dot 046) and donor choice (matched family vs. matched unrelated donor, P = 0 center dot 029) positively impacted survival after relapse. Disease recurrence and non-relapse mortality at four years reached 45% and 22%. Show less
Ypma, P.F.; Geloven, N. van; Kerkhoffs, J.L.H.; Boekhorst, P. te; Zwaginga, J.J.; Beckers, E.A.M.; ... ; Eikenboom, J.C.J. 2019
