Cyclophosphamide and treosulfan in the conditioning regimen prior to allogeneic stem cell transplantation

Allogeneic stem cell transplantation (SCT) is a curative treatment for malignant and non-malignant diseases. However, transplantation related morbidity and mortality are major drawbacks affecting the survival and life quality of the patients. The major complications of SCT are infections, hemorrhagic cystitis, liver toxicity, interstitial pneumonia and GVHD. Busulphan (Bu), treosulfan (Tr) and cyclophosphamide (Cy) are alkylating agents. They are currently used in high doses as preparative regimen before SCT. Pharmacokinetics and pharmacodynamics of these drugs have been intensively studied with the aim of defining a therapeutic window to achieve a satisfactory myeloablation and immunosuppression with less treatment related toxicity. Study I: We administered N-acetyl-L-cysteine (NAC) during conditioning to patients at risk of Sinusoidal obstructive Syndrome (SOS) due to pretransplant liver disorders or elevated liver enzymes. No side effects related to the NAC administration were observed and Bu-kinetics was not affected. All patients became pancytopenic and engrafted with100% donor cells. None of the patients developed SOS or liver failure. Increased liver enzymes during conditioning decreased or normalized in all patients. We suggested that NAC therapy is safe and does not impair the myeloablative effect of Bu during conditioning prior to SCT and hence NAC may be an effective prophylactic treatment against SOS and hepatic toxicity during conditioning. Study II In a preclinical study, myeloablative as well as immunosuppressive properties of Tr were compared with those of Bu and Cy in a mouse model. The animals were treated with Tr, Cy, or Bu at sublethal doses that maintained survival without bone marrow support. The myeloablative effect was evaluated using colony-forming unit granulocyte macrophages (CFU-GM), while the immunological effect was studied using spleen cells. We found that Tr and Bu induced a high and persistent myeloablation compared to Cy. Moreover, Tr was more effective in depletion splenic B and T cells compared to Bu and Cy. T-cells isolated from the spleens of Tr- or Bu-treated mice were not responsive to allogeneic cells compared with those observed in Cy treated mice. Our findings suggested that Tr possesses both myeloablative and immunosuppressive properties and may be used as a single agent for conditioning prior to SCT. Study III. Therapeutic drug monitoring (TDM) of Bu-iv was performed in 34 pediatric SCT patients. Bu-iv was administered twice daily according to recommended weight-based doses. Bu levels were measured and pharmacokinetic analysis was performed. The targeted Bu exposure was aimed to range between areas under the curve (AUC) of 9000–12000 ng/mLxh. In 23/34 patients (68%) Bu dose had to be adjusted at least once. In 16/23 patients the dose had to be increased in a range of 7-33%, while in 7/23 patients (30%) the dose had to be decreased by 7-20%. The need of dose adjustment was not related to weight, age or underlying disease. SOS was observed in 21% of the patients in spite of total AUC’s within the target AUC. We concluded that TDM of iv Bu is essential to increase the efficacy and safety of Bu-based conditioning protocols in pediatric HSCT recipients. Study IV. Limited sampling models for use in TDM of Bu in patients treated for hematologic malignancies. 23 patients were sampled according to standard protocol (8 samples). AUC calculated from three limited sampling models were compared with WinNonLin compartment modeling. Combining a curve fitting model and a compartment model, using the average AUC estimate, gave a intraclass correlation coefficient of 0.86 with the described standard sampling protocol. Using Bland-Altman plots it was evident that most patients would have been treated the same regarding dose adjustment using the combined method as well as standard rich sampling. The results support the use of limited sampling in clinical therapeutic drug monitoring, provided adequate algorithms are used for evaluation. Both models included in the combined method utilized four concentrations points. The model is reliable, solid and user friendly providing the clinician with a graph and a numeric AUC estimate. These four studies taken together may provide a step forward in treatment optimization and dose individualization to the benefit of SCT patients

Economic burden of sickle cell disease in Sweden : a population-based national register study with 13 years follow up

Introduction: Sickle cell disease (SCD) describes a group of inherited disorders of hemoglobin. Globally, SCD occurs in approximately 300,000-400,000 births annually and is most prevalent in malaria-endemic countries. However, migration has impacted the epidemiology of SCD but data on the matter are scarce. The objective of this study was to describe the epidemiology, treatment uptake, and economic burden of SCD in Sweden, a country with substantial immigration over the last decades. Methods: This nationwide retrospective observational registry cohort study identified patients with SCD from 2001 to 2018 and followed them from 2006 to 2018. Using data from high-quality population-based Swedish registers, we estimated prevalence, treatment uptake, and SCD-related health care resource use, sick leave and disability pension. Results: Between 2006 and 2018 the number of patients with SCD increased from 504 to 670; inpatient hospital stays and outpatient visits increased by 200% and 300%, respectively. Patients with pain crises had approximately twice the number of inpatient episodes and outpatient visit per year, and had higher productivity losses compared to patients without crises. Conclusion: In an era of emerging treatments for SCD, we have, to the best of our knowledge, for the first time comprehensively described epidemiological and economic aspects of SCD in a country where the disease is still rare and not well recognized by the healthcare system

Uncontrolled asthma predicts severe COVID-19: a report from the Swedish National Airway Register

Background: Severe asthma increases the risk of severe COVID-19 outcomes such as hospitalization and death. However, more studies are needed to understand the association between asthma and severe COVID-19. Methods: A cohort of 150,430 adult asthma patients were identified in the Swedish National Airway Register (SNAR) from 2013 to December 2020. Data on body mass index, smoking habits, lung function, and asthma control test (ACT) were obtained from SNAR, and uncontrolled asthma was defined as ACT ⩽19. Patients with severe COVID-19 were identified following hospitalization or in death certificates based on ICD-10 codes U07.1 and U07.2. The Swedish Prescribed Drug register was used to identify comorbidities and data from Statistics Sweden for educational level. Multivariate logistic regression analyses were used to estimate associations with severe COVID-19. Results: Severe COVID-19 was identified in 1067 patients (0.7%). Older age (OR = 1.04, 95% CI = 1.03–1.04), male sex (1.42, 1.25–1.61), overweight (1.56, 1.27–1.91), obesity (2.12, 1.73–2.60), high-dose inhaled corticosteroids in combination with long-acting β-agonists (1.40, 1.22–1.60), dispensed oral corticosteroids ⩾2 (1.48, 1.25–1.75), uncontrolled asthma (1.64, 1.35–2.00), cardiovascular disease (1.20, 1.03–1.40), depression (1.47, 1.28–1.68), and diabetes (1.52, 1.29–1.78) were associated with severe COVID-19, while current smoking was inversely associated (0.63, 0.47–0.85). When comparing patients who died from COVID-19 with those discharged alive from hospital until 31 December 2020, older age, male sex, and current smoking were associated with COVID-19 death. Conclusion: Patients with uncontrolled asthma and high disease burden, including increased asthma medication intensity, should be identified as risk patients for severe COVID-19. Furthermore, current smoking is strongly associated with COVID-19 death in asthma

Uncontrolled asthma predicts severe COVID-19 : a report from the Swedish National Airway Register

Background: Severe asthma increases the risk of severe COVID-19 outcomes such as hospitalization and death. However, more studies are needed to understand the association between asthma and severe COVID-19. Methods: A cohort of 150,430 adult asthma patients were identified in the Swedish National Airway Register (SNAR) from 2013 to December 2020. Data on body mass index, smoking habits, lung function, and asthma control test (ACT) were obtained from SNAR, and uncontrolled asthma was defined as ACT ⩽19. Patients with severe COVID-19 were identified following hospitalization or in death certificates based on ICD-10 codes U07.1 and U07.2. The Swedish Prescribed Drug register was used to identify comorbidities and data from Statistics Sweden for educational level. Multivariate logistic regression analyses were used to estimate associations with severe COVID-19. Results: Severe COVID-19 was identified in 1067 patients (0.7%). Older age (OR = 1.04, 95% CI = 1.03–1.04), male sex (1.42, 1.25–1.61), overweight (1.56, 1.27–1.91), obesity (2.12, 1.73–2.60), high-dose inhaled corticosteroids in combination with long-acting β-agonists (1.40, 1.22–1.60), dispensed oral corticosteroids ⩾2 (1.48, 1.25–1.75), uncontrolled asthma (1.64, 1.35–2.00), cardiovascular disease (1.20, 1.03–1.40), depression (1.47, 1.28–1.68), and diabetes (1.52, 1.29–1.78) were associated with severe COVID-19, while current smoking was inversely associated (0.63, 0.47–0.85). When comparing patients who died from COVID-19 with those discharged alive from hospital until 31 December 2020, older age, male sex, and current smoking were associated with COVID-19 death. Conclusion: Patients with uncontrolled asthma and high disease burden, including increased asthma medication intensity, should be identified as risk patients for severe COVID-19. Furthermore, current smoking is strongly associated with COVID-19 death in asthma