Improved Outcome of Allogeneic Transplantation in Older Patients Treated for Myeloid Malignancies Using Post-Transplantation Cyclophosphamide and Reduced Duration of Immune Suppression.

Allogeneic stem cell transplantation (alloSCT) offers curative potential for older patients with myeloid malignancies. We evaluated the efficacy and safety of alloSCT using post-transplantation cyclophosphamide (PTCy) in combination with a very short duration of immune suppression (IS) in this population. We retrospectively analyzed 92 consecutive patients aged 65 years and older who underwent an alloSCT for myeloid malignancies between February 2018 and December 2022 at our institution. Data on patient characteristics, treatment modalities, and outcomes were collected. Ninety-two patients received an alloSCT with PTCy-based graft versus host disease (GVHD) prophylaxis. The majority had minimal comorbidities and were diagnosed with acute myeloid leukemia. Patients mostly received conditioning regimens with low to intermediate transplant conditioning intensity scores. In 43% of patients, IS could be permanently stopped at day +90, resulting in a median time of IS of 2.93 months in high-risk patients. At a median follow-up of 21.3 months, the 1- and 2-year overall survival rates were 89% and 87%, respectively. Relapse-free survival rates were 88% and 84% at 1 and 2 years, respectively. The 1- and 2-year cumulative incidences of relapse were 8% and 13%, while treatment-related mortality (TRM) estimates were 9% at both time points. Acute GVHD grade 3 to 4 occurred in 7% within the first 180 days and severe chronic GVHD in 6% of patients. This all resulted in a 1- and 2-year graft versus host and relapse-free survival of 74% and 70%, respectively. AlloSCT using PTCy in combination with a short duration of IS in older patients with myeloid malignancies demonstrates favorable survival outcomes due to low relapse rates and a low TRM. The low incidence of relapse and acceptable rates of graft-versus-host disease suggest the efficacy and safety of this approach. Further studies are warranted to validate these findings and optimize transplant strategies for older patients with myeloid malignancies.

Convenience and satisfaction in direct oral anticoagulant-treated patients with atrial fibrillation.

BACKGROUND: Direct oral anticoagulants (DOACs) are the preferred anticoagulants for thromboprophylaxis in atrial fibrillation. We aimed to identify determinants of quality of life related to DOAC treatment to optimize DOAC treatment convenience and satisfaction. METHODS: We conducted a cross-sectional study in DOAC users. DOAC treatment-related convenience and satisfaction were measured by Perception of Anticoagulant Treatment Questionnaire. Higher scores are more favorable (range, 0-100). Patient-reported outcome measures and drug- and organization-related factors were collected. Multiple regression analyses were used to evaluate the association between these factors (ie, exposure variables) and DOAC treatment-related convenience and treatment satisfaction (ie, outcome variables). RESULTS: Of 1598 patients invited, 1035 responded, and 962 were included. The median convenience score was 98.1 (94.2-100.0), mean satisfaction score 66.5± 14.9. Twenty-four percent felt not well informed at the start of DOAC; 6.9% did not know who to turn to with questions. Multiple regression analyses showed that lacking sense of security, the predefined composite of receiving insufficient information at start of DOAC and/or not knowing who to turn to with questions was associated with lower convenience (regression coefficient, -1.29; 95% confidence interval [CI], -2.16 to -0.41). Bleeding, gastrointestinal complaints, and lower medication adherence were also associated with lower convenience. Missing sense of security (regression coefficient -6.59; 95% CI, -8.94 to -4.24) and bleeding without consultation were associated with lower treatment satisfaction. CONCLUSIONS: Accessible interventions to improve DOAC care could be providing more instruction at treatment initiation and ensuring that patients know who to contact in case of problems.

Quality of life after switching from well-controlled vitamin K antagonist to direct oral anticoagulant: Little to GAInN.

BACKGROUND: Direct oral anticoagulants (DOAC) and vitamin K antagonists (VKA) prevent thromboembolism in atrial fibrillation (AF). DOAC have a fixed dosing regimen and obviate INR monitoring. Therefore, DOAC presumably affect quality of life (QoL) less than VKA. However, some VKA users appreciate the monitoring. A high time in the therapeutic range (TTR) leads to a lower impact on QoL. We assessed the influence of switching from well-controlled VKA to a DOAC on QoL. METHODS: In the GAInN study, 241 patients with AF, a TTR ≥ 70%, and neither bleeding nor thrombosis while on VKA were randomised to switching to DOAC (n = 121) or continuing VKA (n = 120). Health-related (SF-36) and anticoagulation-related QoL (PACT-Q) was assessed at baseline and after six and twelve months of follow-up. RESULTS AND CONCLUSION: SF-36 development did not differ between groups. After one year, average PACT-Q Convenience improvement was 2.5 (0.3-4.7) higher on DOAC. DOAC users were 6percentage points (95%CI -4-16) more likely to improve >5 points on Convenience; 22 pp. (95%CI 1-43) in patients who scored <95/100 at baseline. The probability to meaningfully improve on PACT-Q Satisfaction was 12 pp. (95%CI 0-25) higher on DOAC. However, 5 (4.1%) and 4 (3.3%) DOAC users resumed VKA because of side-effects and patient preference. Switching from well-controlled VKA to DOAC for AF leads to a higher probability of improved PACT-Q convenience and satisfaction, but also to a higher risk of side-effects. Arguably only patients who are not satisfied with VKA should switch, because they have more to gain by switching.

CD47 Expression Defines Efficacy of Rituximab with CHOP in Non-Germinal Center B-cell (Non-GCB) Diffuse Large B-cell Lymphoma Patients (DLBCL), but Not in GCB DLBCL.

Addition of rituximab (R) to "CHOP" (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy improved outcome for diffuse large B-cell lymphoma (DLBCL) patients. Approximately 40% of patients who receive R-CHOP still succumb to disease due to intrinsic resistance or relapse. A potential negative regulator of DLBCL treatment outcome is the CD47 "don't eat me" immune checkpoint. To delineate the impact of CD47, we used a clinically and molecularly well-annotated cohort of 939 DLBCL patients, comprising both germinal center B-cell (GCB) and non-GCB DLBCL subtypes, treated with either CHOP or R-CHOP. High (above median) CD47 mRNA expression correlated with a detrimental effect on overall survival (OS) when DLBCL patients received R-CHOP therapy (P = 0.001), but not CHOP therapy (P = 0.645). Accordingly, patients with low CD47 expression benefited most from the addition of rituximab to CHOP [HR, 0.32; confidence interval (CI), 0.21-0.50; P < 0.001]. This negative impact of high CD47 expression on OS after R-CHOP treatment was only evident in cancers of non-GCB origin (HR, 2.09; CI, 1.26-3.47; P = 0.004) and not in the GCB subtype (HR, 1.16; CI, 0.68-1.99; P = 0.58). This differential impact of CD47 in non-GCB and GCB was confirmed in vitro, as macrophage-mediated phagocytosis stimulated by rituximab was augmented by CD47-blocking antibody only in non-GCB cell lines. Thus, high expression of CD47 mRNA limited the benefit of addition of rituximab to CHOP in non-GCB patients, and CD47-blockade only augmented rituximab-mediated phagocytosis in non-GCB cell lines. Patients with non-GCB DLBCL may benefit from CD47-targeted therapy in addition to rituximab.

Risk factors for venous thromboembolism in patients treated for differentiated thyroid carcinoma.

Although cancer in general is a strong risk factor for developing venous thromboembolism (VTE), the risk factors for venous thromboembolic events in patients with differentiated thyroid carcinoma (DTC) have never been assessed. This is remarkable, as several parts of the treatment comprise a hypercoagulable state that could in subgroups of DTC patients lead to an increased risk of VTE. The aim of this study was to assess which risk factors could cause DTC patients to develop VTE. We performed a nested case-control study, involving cases of DTC patients treated between 1980 and 2014 with confirmed VTE after diagnosis of DTC. Controls were defined as DTC patients without VTE. In all subjects, we collected information about thyroid cancer characteristics, treatment characteristics, traditional risk factors for VTE and additional clinical data, and we performed univariable and multivariable regression analyses. We included 28 cases and 56 controls matched for age at DTC diagnosis, sex and date of DTC diagnosis. In the univariable regression analysis, histology, distant metastases, DTC risk classification, recent surgery and other active malignancy were associated with VTE. In the multivariable analysis, distant metastases (odds ratio 7.9) and recent surgery (odds ratio 6.1) were independently associated with VTE. In conclusion, surgery and presence of distant metastases are independent risk factors for developing VTE in DTC patients. The risk factors identified in this study could be considered when making decisions regarding thromboprophylaxis for patients with thyroid cancer.

Risk of Bleeding and Thrombosis in Patients 70 Years or Older Using Vitamin K Antagonists.

IMPORTANCE: Previous studies have shown that, despite the higher risk of bleeding, the elderly still benefit from taking anticoagulants if they have a stringent indication. However, owing to the relatively low number of patients older than 90 years in these studies, it is unknown whether this benefit is also seen with the eldest patients. OBJECTIVE: To determine how the risk of bleeding and thrombosis is associated with age in patients older than 70 years who were treated with a vitamin K antagonist (VKA). DESIGN, SETTING, AND PARTICIPANTS: A matched cohort study was conducted of patients at a thrombosis service who were treated with a VKA between January 21, 2009, and June 30, 2012. All 1109 patients 90 years or older who were treated with a VKA were randomly matched 1:1:1 with 1100 patients aged 80 to 89 years and 1104 patients aged 70 to 79 years based on duration of VKA treatment. Data analysis was conducted from April 2015 to April 2016. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of clinically relevant nonmajor and major bleeding. Secondary outcomes included thromboses and quality of VKA control. RESULTS: During 6419 observation-years, 713 of the 3313 patients (1394 men and 1919 women) had 1050 bleeding events. The risk of bleeding was not significantly increased in patients aged 80 to 89 years (event rate per 100 patient-years [ER], 16.7; hazard ratio [HR], 1.07; 95% CI, 0.89-1.27) and mildly increased in patients 90 years or older (ER, 18.1; HR, 1.26; 95% CI, 1.05-1.50) compared with patients aged 70 to 79 years (ER, 14.8). The point estimates for major bleeding (including fatal) were comparable for patients aged 80 to 89 years (ER, 1.0; HR, 1.09; 95% CI, 0.60-1.98) and those 90 years or older (ER, 1.1; HR, 1.20; 95% CI, 0.65-2.22) compared with those aged 70 to 79 years (ER, 0.9). The increase in bleeding risk was sharper in men than in women. Eighty-five patients (2.6%) developed a thrombotic event. Risk of thrombosis was higher for patients in their 90s (HR, 2.14; 95% CI, 1.22-3.75) and 80s (HR, 1.75; 95% CI, 1.002-3.05) than for patients in their 70s. Vitamin K antagonist control became significantly poorer with rising age, which partly explained the increased bleeding risk in patients 90 years or older, but most of the increased risk of thrombosis was not mediated by VKA control. CONCLUSIONS AND RELEVANCE: These clinical practice data of patients considered eligible for anticoagulation show that the bleeding risk with a VKA only mildly increases after the age of 80 years, while there is a sharp increase in the risk of thrombosis in the same age group.

Impact of Vitamin K Antagonists on Quality of Life in a Prospective Cohort of 807 Atrial Fibrillation Patients.

BACKGROUND: Vitamin K antagonists (VKA) use is challenging because of frequent blood monitoring and complex dosing. Therefore, many patients and physicians are reluctant to start VKA. However, it is unclear whether VKA use actually lowers quality of life. We aimed to determine the impact of VKA initiation on quality of life and to analyze the correlation between patient and treatment characteristics and VKA perception in atrial fibrillation patients. METHODS AND RESULTS: In a prospective cohort of 240 new and 567 long-term VKA users, general quality of life and VKA perception (satisfaction and convenience) were measured at inclusion and at 3 months by the validated Study Short-Form 36 and Perception of Anticoagulant Treatment Questionnaire. Scores were converted to a 0 to 100 scale. Higher scores are more favorable. In the new patients, Medical Outcomes Study Short-Form 36 scores improved during the initial 3 months to a level comparable with the general population. At 3 months, the median convenience score was 95 (Q1-Q3, 88-98) and was higher in older patients (regression coefficient, 0.47 per year; 95% confidence interval, 0.25-0.69) and lower after bleeding (regression coefficient, -12; 95% confidence interval, -20 to -4.7). The median satisfaction score was 64. For the long-term patients, VKA perception scores were highly comparable with the new patients. The convenience score mildly improved in patients with increased individual time in therapeutic range (regression coefficient, 0.03; 95% confidence interval, 0.01-0.05; r(2)=0.01), and satisfaction scores decreased in patients with new comedication (regression coefficient, -7.0; 95% confidence interval, -12 to -1.9; r(2)=0.02). CONCLUSIONS: VKA were well tolerated in real-life, and the influences of patient and treatment related factors on VKA perception were very limited.

Independent predictors of poor vitamin K antagonist control in venous thromboembolism patients. Data from the EINSTEIN-DVT and PE studies.

Vitamin K antagonists (VKA) are used to prevent recurrent disease in patients with venous thromboembolism (VTE). Their efficacy and safety depend on individual time in therapeutic range (iTTR) and variability of International Normalised Ratios (INR). We aimed to identify independent predictors of poor VKA control > 28 days. In a prospective cohort of 3825 VTE patients, separate logistic regression analyses were performed to identify predictors of low iTTR (first quartile) and instability (iTTR median). Subsequently, the association between these predictors and clinical outcomes was investigated. Weight < 50 kg (odds ratio [OR]=1.89; 95 % confidence interval [CI] 1.03-3.49), active cancer at baseline (OR=1.52; CI1.05-2.19), secondary VTE (OR=1.42; CI1.20-1.68), and INR < 2.0 at stop of double therapy (OR=1.35; CI1.09-1.67) were independent predictors of low iTTR. The first two were also predictive for instability (OR=1.96; CI1.06-3.63 and OR=1.95; CI1.36-2.80, respectively). ORs of early (≤ 28 days) low iTTR and instability depended on VKA type. In acenocoumarol users, early low iTTR was an independent predictor of subsequent low iTTR (OR=1.92; CI1.31-2.80) and instability (OR=1.55; CI1.07-2.23). In warfarin users, early low iTTR (OR=1.36; CI1.09-1.69) and instability (OR=1.25; CI1.01-1.55) were additionally predictive for low iTTR, but only the latter was predictive for instability (OR=1.91; CI1.57-2.32). Many predictors of VKA control also predicted premature discontinuation, but only region was prognostic for clinical outcome. In conclusion, we identified several independent predictors of low iTTR and instability > 28 days, which showed some similarities but did not fully overlap. Early VKA control was of additional value for prediction of both, but had to be interpreted in the context of VKA type.

A systematic review of prothrombin complex concentrate dosing strategies to reverse vitamin K antagonist therapy.

Management of patients with a major bleed while on vitamin K antagonist (VKA) is a common clinical challenge. Prothrombin Complex Concentrates (PCC) provide a rapid reversal of VKA induced coagulopathy. However, a well-defined PCC dosing strategy, especially in emergency setting, is still lacking. We performed a systematic review to describe the currently used PCC dosing strategies and to present their efficacy in terms of target INR achievement and clinical outcome. We used outcome definitions as used in the individual studies. MEDLINE and EMBASE databases were searched for studies reporting the use of PCC for emergency VKA reversal. Twenty-eight studies, including 4 randomized trials, were found. In these, fifteen different PCC dosing protocols were identified in which the PCC dose ranged from 8 to 50IU factor IX/kg. These strategies were based on: bodyweight; bodyweight and initial INR; bodyweight and initial INR and target INR; individual doctors decision; or a fixed dose. Study quality was moderate with large variation in outcome definitions. Relatively good clinical and INR outcomes were reported with the use of any treatment protocol while less good results were reported for INR outcome when a predefined protocol was missing (doctor strategy). Lowest PCC dosages were infused in the fixed dose strategy. In emergency VKA reversal, a predefined PCC dosing protocol seems essential. We found no evidence that one dosing strategy is superior. Future studies should be designed to investigate if body weight and INR are relevant for PCC dosing. In these, we need uniform outcome definitions.

Long-term quality of VKA treatment and clinical outcome after extreme overanticoagulation in 14,777 AF and VTE patients.

Vitamin K antagonists (VKA) are widely used in atrial fibrillation and venous thromboembolism (VTE). Their efficacy and safety depend on individual time in the therapeutic range (iTTR). Due to the variable dose-response relationship within patients, also patients with initially stable VKA treatment may develop extreme overanticoagulation (EO). EO is associated with an immediate bleeding risk, but it is unknown whether VKA treatment will subsequently restabilise. We evaluated long-term quality of VKA treatment and clinical outcome after EO. EO was defined as international normalized ratio (INR) ≥ 8.0 and/or unscheduled vitamin K supplementation. We included a consecutive cohort of initially stable atrial fibrillation and venous thromboembolism patients. In EO patients, the 90 days pre- and post-period were compared. In addition, patients with EO were compared with patients without EO using a matched 1:2 cohort. Of 14,777 initially stable patients, 800 patients developed EO. The pre-period was characterised by frequent overanticoagulation, and half of EO patients had an inadequate iTTR (< 65 %). After EO, underanticoagulation became more prevalent. Although the mean time between INR-measurements decreased from 18.6 to 13.2 days, after EO inadequate iTTR became more frequent (62 %), p-value < 0.001. A 2.3 times (95 % confidence interval [CI] 2.0-2.5) higher risk for iTTR< 65 % after EO, was accompanied by increased risk of bleeding (hazard ratio [HR] 2.1;CI 1.4-3.2), VKA-related death 17.0 (HR 17.0;CI 2.1-138) and thrombosis (HR 5.7;CI 1.5-22.2), compared to the 1600 controls. In conclusion, patients continuing VKA after EO have long-lasting inferior quality of VKA treatment despite intensified INR-monitoring, and an increased risk of bleeding, thrombosis and VKA-related death.