Economic evaluation of azoles as primary prophylaxis for the prevention of invasive fungal infections in Spanish patients undergoing allogeneic haematopoietic stem cell transplant

Patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT) are at risk of developing invasive fungal infections (IFIs). Even with introduction of oral triazole antifungal agents (fluconazole, itraconazole, posaconazole and voriconazole) IFI‐associated morbidity and mortality rates and economic burden remain high. Despite their proven efficacy, it is currently unknown which is the most cost‐effective antifungal prophylaxis (AFP) agent. To determine the costs and outcomes associated with AFP, a decision‐analytic model was used to simulate treatment in a hypothetical cohort of 1000 patients undergoing alloHSCT from the perspective of the Spanish National Health System. Generic itraconazole was the least costly AFP (€162) relative to fluconazole (€500), posaconazole oral suspension (€8628) or voriconazole (€6850). Compared with posaconazole, voriconazole was associated with the lowest number of breakthrough IFIs (36 vs 60); thus, the model predicted fewer deaths from breakthrough IFI for voriconazole (24) than posaconazole (33), and the lowest predicted costs associated with other licensed antifungal treatment and IFI treatment in a cohort of 1000. Voriconazole resulted in cost savings of €4707 per patient compared with posaconazole. Itraconazole demonstrated a high probability of being cost‐effective. As primary AFP in alloHSCT patients 180 days posttransplant, voriconazole was more likely to be cost‐effective than posaconazole regarding cost per additional IFI and additional death avoided.     

Risk factors for early invasive fungal infections in paediatric liver transplant recipients

Invasive fungal infections (IFIs) postliver transplantation are a frequent cause of morbidity and mortality; however, studies reporting on these infections in the paediatric population are scarce. To investigate the incidence and risk factors of IFIs in paediatric liver transplant recipients during the early posttransplantation period (≤3 months). Data were collected for all paediatric liver transplant recipients registered in a national transplantation center from 2004 to 2014. Using a stepwise logistic regression to identify independent risk factors for IFIs, a predictive model was formulated. Ten IFIs were identified in 81 liver transplant recipients (12.3%) all occurring during the first month posttransplantation. Candida species were responsible for nine cases (90%), of which four were non‐albicans Candida (44%). Significant risk factors were identified; recipient of multiple blood product transfusions during transplantation, prolonged use of indwelling intravenous catheter, prolonged IV antibiotic treatment, surgical complications, pulse steroid treatment and living donor liver transplantation. The predictive model used two clinical parameters to define high‐risk patients: a living donor transplantation and duration of IV antibiotic treatment (area under the ROC curve 0.918). IFIs are a significant complication occurring in the first month posttransplantation. Future studies are required to assess efficacy of targeted antifungal prophylaxis in high risk patients.     

Epidemiology and outcome of invasive fungal disease in children after hematopoietic cell transplantation or treated for malignancy: Impact of national programme of antifungal prophylaxis

The objective of the study was the analysis of incidence and outcome of invasive fungal disease (IFD) in children treated for malignancy (PHO, paediatric hematology‐oncology) or undergoing hematopoietic cell transplantation (HCT) over a period of six consecutive years in nationwide study. A total number of 5628 patients with newly diagnosed malignancies and 971 patients after HCT (741 allo‐HCT and 230 auto‐HCT) were screened for infectious complications in biennial reports. IFD incidence was lower among PHO patients: 8.8% vs 21.2% (P < .0001) and survival from IFD was better: 94.2% vs 84.1% (P < .0001). Auto‐HCT patients had lower incidence (10.9% vs 24.4%) and lower mortality than allo‐HCT patients. Introduction of national antifungal prophylaxis programme in HCT and acute leukaemia patients decreased incidence of IFD in HCT (from 23.1% to 13.4%) and AML on conventional chemotherapy (from 36% to 23%) but not in ALL patients during chemotherapy. In multivariate analysis, the incidence of IFD was higher in patients after HCT, diagnosed for ALL, AML or NHL, and in patients > 10 years old. Factors contributing to death with infection were as follows: undergoing HCT, diagnosis of acute leukaemia (ALL or AML) and duration of treatment of infection > 21 days. In conclusion, the incidence of IFD in allo‐HCT and in AML patients on chemotherapy has decreased after introduction of national programme of antifungal prophylaxis, while the incidence of IFD in ALL patients on chemotherapy did not change significantly. The outcome of IFD both in PHO and HCT patients has largely improved in comparison with historical international data.     

Epidemiology of invasive fungal diseases in children with solid tumours undergoing autologous haematopoietic stem cell transplantation: a 10‐year experience in a tertiary Italian centre

The objective of the study was to determine the incidence of invasive fungal disease (IFD) in children undergoing autologous haematopoietic stem cell transplantation (auHSCT) for solid tumours (ST). Retrospective study on auHSCT was performed in children with ST (January 2006‐December 2015). Data on the number of patient‐days at risk (pdr) during the first 30 and 90 days after auHSCT and cases of proven/probable IFDs were collected. Infection rate (IR, episodes/1000 pdr) and proportions and cumulative risk (CR) of IFD were evaluated. In 186 patients, 270 auHSCT were performed, for a total of 8327 pdr during the first 30 days and 24 366 up to day 90. Median age was 5 years (interquartile range 2;8), 63% were male. At day 30, seven procedures were complicated by IFD, with an IR of 0.84 (95% CI 0.66‐1.02) and aCR of 2.6% (95% CI 1.4‐5.4) at 18 days after HSCT. Within day 90, two further IFDs were detected with an IR of 0.37 (95% CI ?0.49 to 1.23) and a CR of 3.3% (95% CI 1.7‐6.3) at day 69. Children undergoing auHSCT for ST have a low incidence of IFDs in the first 90 days after the procedure.     

Assessment of Aspergillus‐specific PCR as a screening method for invasive aspergillosis in paediatric cancer patients and allogeneic haematopoietic stem cell recipients with suspected infections

Invasive aspergillosis (IA) remains difficult to diagnose in immunocompromised patients, because diagnostic EORTC/MSG criteria are often not met. As biomarkers might elucidate the pathogen, we analysed the performance of an Aspergillus PCR assay in blood for diagnosis of IA in immunocompromised paediatric patients with suspected infections. Ninety‐five haemato‐oncological paediatric patients were included over a period of 3 years, the underlying diseases consisting of acute leukaemia, solid tumours, non‐malignant immunocompromising disorders and haematopoietic stem cell transplantation recipients. We retrospectively analysed 253 consecutive episodes of suspected infections. Thirty‐eight patients had possible IA, none of the patients fulfilled EORTC/MSG criteria of probable/proven IA. PCR positivity was observed in 97/967 analyses. Sensitivity, specificity, positive and negative predictive value of the PCR per episode were 34%, 78%, 31% and 81% using possible IA as endpoint. Taken together, an undirected blood screening by Aspergillus‐specific PCR is of little diagnostic value in a heterogenous paediatric patient cohort. Harnessing PCR for diagnosis of IA should thus be focused on blood analyses of more homogenous high‐risk patients and/or analyses of bronchoalveolar lavage, tissue or cerebrospinal fluid specimens.     

Efficacy of caspofungin in prophylaxis and treatment of an adult leukemic patient with invasive pulmonary aspergillosis in allogeneic stem cell transplantation

Summary Invasive aspergillosis is a major problem in the management of immunocompromised patients, its prevalence is rising and it is still a major cause of death in this group. The clinical success rate with classical drugs is far away from expectations. New drugs are needed in the treatment of this complication. Belonging to the new class of echinocandins, caspofungin is a newly introduced and promising drug in this fatal situation. We report a patient with acute myeloid leukemia who had invasive pulmonary aspergillosis during induction therapy being treated with amphotericin B in first step and afterwards with caspofungin. The patient received consolidation therapy and allogeneic stem cell transplantation while using caspofungin, and did not experience any adverse effect related to drug. Many side effects, e.g. derangements in liver and kidney functions, hypokalemia, infusion-related side effects and especially thrombocytopenia, which are common with amphotericin B treatment are no longer problem with caspofungin. The efficacy of caspofungin in terms of regression of pulmonary lesions and control of fever is quite successful. The optimal therapies for opportunistic fungal infections are still debated, and further evaluation is needed.     

Epidemiology of invasive fungal infections and rationale for antifungal therapy in patients with haematological malignancies

Invasive fungal infections (IFIs) in patients with haematological malignancies are difficult to diagnose and outcome is often fatal. Over the 7‐month study period, 117 cases with haematological malignancies receiving systemic antifungal treatment were included. Data regarding antifungal agents, dosage and reason for administration were recorded. Fungal infections in study patients were classified as possible, probable or proven according to recent European Organization for Research and Treatment of Cancer criteria. During the study period, 690 cases with haematological malignancies were admitted. A total of 117 cases received systemic antifungal therapy. Twenty‐four of 117 patients (21%) had possible, six (5.1%) had probable and four (3.4%) had proven IFI. Seven of 10 probable and proven infections were caused by Candida spp., 2 by Aspergillus spp. and 1 by a fungus belonging to Zygomycetes. Fifty‐two of 117 patients (44%) received antifungal prophylaxis, 81 of 117 (69%) received empirical (31/117; 26%) or pre‐emptive (50/117; 43%) antifungal therapy and four of 117 patients (3.4%) directed antifungal therapy. Mostly, systemic antifungal therapy was administered empirically or pre‐emptively. Twenty‐nine per cent of cases receiving systemic antifungal treatment met the international consensus criteria of mostly possible IFI, whereas 71% did not. Proven invasive fungal infections were rare.     

Safety and feasibility of physical therapy in cytopenic patients during allogeneic haematopoietic stem cell transplantation

This study aimed to investigate the safety and feasibility of physical therapy in cytopenic patients undergoing allogeneic haematopoietic stem cell transplantation (allo‐HSCT), and to investigate the effect of physical therapy on physiological functions and quality of life (QOL) in allo‐HSCT patients. The study cohort included 321 patients who underwent allo‐HSCT. To investigate the safety and feasibility of physical therapy during cytopenia, patients were assigned to the physical therapy group (n = 227) or the control group (n = 94). To determine the effects of physical therapy, patients were divided according to the frequency with which they underwent physical therapy (n = 51 per group). Handgrip strength, knee extensor strength and a 6‐min walk test were used as measures of physiological function. Short‐Form 36 was used to assess QOL. The physical therapy group had higher rate of achieving engraftment and lower death rate than the control group (P < 0.05). After HSCT, the high‐frequency physical therapy group showed significantly less decline than the low‐frequency physical therapy group with respect to physical functioning of QOL (P < 0.01). Physical therapy is quite beneficial and can be performed safely and feasibly in cytopenic patients during allo‐HSCT.     

Dendritic cells in allogeneic hematopoietic stem cell transplantation

In allogeneic hematopoietic stem cell transplantation (SCT), dendritic cells (DCs) as the most potent antigen-presenting cells play a central role in the development of acute and chronic graft-vs-host disease (GVHD), in graft-vs-leukemia or -malignancy reactions and in fighting infectious complications. Functional maturity and distribution of DC sub-types (DC1 and DC2) differ between the different stem cell sources used (bone marrow, granulocyte colony-stimulating factor-mobilised peripheral blood and cord blood) resulting in various rates of graft-vs-host disease and graft-vs-leukemia activity. Although DC recovery following stem cell transplantation is prompt, graft-vs-host disease and the use of immunosuppressive drugs result in qualitative and quantitative disturbances in DC  homeostasis and have been observed for up to 1 year after transplantation. Complete donor DC chimerism seems to be a pre-requisite for the development of chronic GVHD and for graft-vs-leukemia activity, at least following reduced-intensity transplants, although in the early phase of acute graft-vs-host disease the presence of host antigen-presenting cells is essential. Preliminary data show promising results with DC-based immunotherapy for treatment of viral and fungal infections and of leukemic relapse following allogeneic stem cell transplantation. More information on the mechanisms and interactions between dendritic cells and regulatory T cells is needed for DC vaccination concepts for modulation of graft-vs-host disease.     

Fludarabine and melphalan conditioning with tacrolimus as GVHD prophylaxis for allogeneic stem cell transplant recipients is an effective reduced-intensity combination regimen compared to the conventional regimen

Background  As a reduced-intensity stem-cell transplantation (RIST) regimen, the combination of fludarabine and melphalan (FM) with an appropriate immunosuppressant reduces nonrelapse mortality (NRM). Methods  We retrospectively compared the efficacy of a RIST regimen with FM with that of a conventional stem cell transplantation (CST) regimen. Eighty-two consecutive hematological patients who underwent allogeneic stem-cell transplantation (SCT) at our hospital were enrolled. Preparation for RIST consisted of 25 mg/m² fludarabine and melphalan 70 mg/m². The conventional regimen employed high-dose cyclophosphamide and total-body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis for RIST consisted of tacrolimus alone or in conjunction with short-term methotrexate for unrelated donors. Results  Of the 82 patients, 42 received the conventional CST regimen (median age, 35 years) and 40 received the RIST regimen (median age, 51 years). The probability of NRM was 17% (7/42) in the CST group and 8% (3/40) in the RIST group. Grade II to IV GVHD occurred in significantly more CST patients (38%) than RIST patients (28%). However, the overall survival was the same in the two groups (43%). Conclusion  The RIST regimen with FM incorporating tacrolimus and methotrexate demonstrated low TRM incidence and moderate control of GVHD and had efficacy comparable to that of the CST regimen, despite the advanced age of the RIST patient group.     

Patients' quality of life after allogeneic haematopoietic stem cell transplantation: mixed-methods study

Allogeneic haematopoietic stem cell transplantation (HSCT) is an increasingly widespread therapy method. It is associated with many socio-psychological and physical risks. Forty-four subjects, who were clinically monitored at the Bolzano BMT Centre including a follow-up period of at least 3 months, completed the questionnaire Functional Assessment of Chronic Illness Therapy-Bone Marrow Transplantation (version 4). Semi-structured, problem-oriented interviews were conducted with seven randomly selected subjects, the results of which were subjected to a summarising content analysis according to Mayring. The results from the quantitative and qualitative parts were compared based on triangulation. In the random sample, 22.7% stated that they were highly satisfied with their current quality of life (QOL). Throughout all dimensions of the questionnaire, women showed lower scores than men. The results revealed a positive correlation between the post-HSCT period and QOL (r(s)=0.338, P=0.025), especially regarding the social/family (r(s)=0.411, P=0.006) and emotional well-being (r(s)=0.306, P=0.043). The interviews primarily revealed dependence and inability to work. The support received from family, friends and hospital staff and the shift in priorities because of the transplantation were perceived as positive. The comparison mainly leads to corresponding results of the quantitative and qualitative parts of the study. Patient self-rating using questionnaires and interviews plays a direct and relevant role in the assessment of the QOL after allogeneic HSCT.     

Frequent and long‐term follow‐up of health‐related quality of life following allogeneic haematopoietic stem cell transplantation

Health‐related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n = 18) or reduced intensity conditioning (RIC, n = 76). HRQL was assessed with the EORTC QLQ C‐30 during the inpatient period as well as during the following 3 years, i.e. at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3 weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1 year for HRQL to return to the baseline level. The only function that improved significantly 3 years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft‐versus‐host disease experienced reduced HRQL. These results provide a clinically useful overview of patients’ HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow‐ups during the first year after HSCT to improve preventive or supportive interventions.     

Attenuated humoral response against SARS-CoV-2 mRNA vaccination in allogeneic stem cell transplantation recipients

Antibody persistence several months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination in allogeneic stem cell transplantation recipients remains largely unknown. We sequentially evaluated the humoral response to two doses of mRNA vaccines in 128 adult recipients and identified the risk factors involved in a poor response. The median interval between stem cell transplantation and vaccination was 2.7 years. The SARS-CoV-2 S1 Ab became positive after the second vaccination dose in 87.6% of the recipients, and the median titer was 1235.4 arbitrary units (AU)/ml. In patients on corticosteroid treatment, the corticosteroid dose inversely correlated with Ab titer. Multivariate analysis identified risk factors for poor peak response such as an interval from stem cell transplantation ≤1 year, history of clinically significant CMV infection, and use of >5 mg/day prednisolone at vaccination. Six months after vaccination, the median titer decreased to 185.15 AU/ml, and use of >5 mg/day prednisolone at vaccination was significantly associated with a poor response. These results indicate that early vaccination after stem cell transplantation (<12 months) and CMV infection are risk factors for poor peak response, while steroid use is important for a peak as well as a persistent response. In conclusion, although humoral response is observed in many stem cell transplantation recipients after two doses of vaccination, Ab titers diminish with time, and factors associated with persistence and a peak immunity should be considered separately.     

新药时代造血干细胞移植在多发性骨髓瘤治疗中的地位

 与传统化疗相比,自体造血干细胞移植可提高多发性骨髓瘤（MM）患者的缓解率,延长无进展生存期,是治疗MM的一线方案。但近年来,基于新型药物的联合诱导、巩固和维持治疗提高了MM的治疗效果,对自体造血干细胞移植的地位构成了挑战。异基因造血干细胞移植虽然具有治愈MM的潜能,但移植相关死亡率高,患者的总体生存并未获益。而减低剂量预处理异基因移植虽降低了移植相关死亡率,具有一定的移植物抗骨髓瘤作用,但移植物抗宿主病的发生率高。文章总结了MM干细胞移植相关的临床试验结果,旨在定义新药时代造血干细胞移植在MM治疗中的地位。     

Reduction in incidence of invasive fungal infection in patients receiving allogeneic stem cell transplantation using combined diagnostic‐driven approach and itraconazole oral solution

Invasive fungal infections are an important cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. We evaluated, in our allogeneic stem cell transplant patients, the effect on the incidence of invasive fungal infection during neutropenia of a strategy combining a diagnostic‐driven approach with chemoprophylaxis during higher risk periods of graft vs. host disease and prolonged neutropenia, using itraconazole oral solution with parenteral voriconazole bridging. One hundred and thirty patients admitted for allogeneic stem cell transplantation within two predefined 20 month periods were included in the study. Data for all patients were collected prospectively. Implementation of the protocol resulted in the administration of more prophylactic antifungals to more patients. Following implementation, there was a non‐significant decrease in the overall number of invasive fungal infections (IFI) [11 of 65 patients (17.2%) vs. 4 of 65 patients (6.2%, P = 0.051)], as well as in the occurrence of invasive mould infections [8 of 65 patients (12.5%) vs. 2 of 65 patients (3.1%, P = 0.054)]. Survival rates at three and 6 months were not significantly affected. A combined diagnostic‐driven approach and antifungal prophylaxis with oral itraconazole and an intravenous voriconazole bridging protocol, was associated with a reduced, albeit non‐statistically significant, number of IFI in our medical centre.     

Patients’ experiences of different care settings and a new life situation after allogeneic haematopoietic stem cell transplantation

Over the past 20 years, considerable healthcare resources have shifted from an inpatient to an outpatient setting. To be in an outpatient setting or at home after allogeneic haematopoietic stem cell transplantation (allo‐HSCT) has been shown to be medically safe and beneficial to the patient. In this study we describe patients’ experiences of different care settings (hospital or home) and a new life situation during the acute post‐transplant phase after HSCT. Semi‐structured interviews were conducted with 15 patients (six women and nine men) 29–120 days after HSCT. An inductive qualitative content analysis was performed to analyse the data. The analysis resulted in four categories: To be in a safe place, To have a supportive network, My way of taking control, and My uncertain return to normality. The findings showed that patients undergoing HSCT felt medically safe regardless of the care setting. The importance of a supportive network (i.e. the healthcare team, family and friends) was evident for all patients. Both emotional and problem‐focused strategies were used to cope with an uncertain future. Being at home had some positive advantages, including freedom, having the potential for more physical activity, and being with family members. The study highlights some key areas thought to provide more personalised care after HSCT.     

Factors associated with changes in quality of life in patients undergoing allogeneic haematopoietic stem cell transplantation

KISCH A., LENHOFF S., ZDRAVKOVIC S. & BOLMSJÖ I. (2012) European Journal of Cancer Care Factors associated with changes in quality of life in patients undergoing allogeneic haematopoietic stem cell transplantation It is well known that patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) experience changes in quality of life. We investigated factors associated with quality of life changes in adult HSCT patients. The Functional Assessment of Cancer Therapy – Bone Marrow Transplantation (FACT‐BMT) scale, supplemented with the Functional Assessment of Chronic Illness Therapy – Spiritual Well‐being (FACIT‐Sp) subscale, was administered on three occasions, immediately before transplantation, 100 days and 12 months after transplantation. Analyses of nine selected factors were made where changes in quality of life were found. Seventy‐five patients were included and 40 of these completed the study. Emotional well‐being was found to improve between the baseline and 100 days, while all other dimensions deteriorated, including overall quality of life. Physical and social/family well‐being deteriorated between the baseline and the 12‐month follow‐up, while emotional well‐being improved. The main factors associated with deteriorating quality of life over time were found to be significant infections, female gender and transplantation with stem cells from a sibling donor. In our further studies we aim to focus on the relationships between patients and sibling donors in order to improve the care. Careful attention must be paid to continuous adequate information during the transplantation procedure.