Allogeneic Hematopoietic Stem Cell Transplantation Recipients Research Articles

Role of letermovir for prevention of cytomegalovirus infection after allogeneic haematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic haematopoietic stem cell transplantation (HSCT). CMV surveillance-preemptive therapy is the current preferred approach for preventing CMV disease after HSCT. In contrast, antiviral prophylaxis is not commonly used due to myelosuppressive effects of valganciclovir. In this article, the role of the newly approved antiviral compound, letermovir, is reviewed. Letermovir inhibits CMV by interfering viral terminase complex. In a phase 3 randomized placebo-controlled clinical study that enrolled 495 CMV-seropositive HSCT recipients, the primary end point of clinically significant CMV infection was significantly reduced by letermovir prophylaxis. Letermovir was well tolerated without risk of myelotoxicity and nephrotoxicity. Experimental in-vitro data suggest that letermovir may possess low genetic barrier to resistance. In prophylaxis trials, two breakthrough infections were reported due to selection of CMV UL56 V236M mutation. Letermovir is an important addition to the current strategies for CMV prevention after allogeneic HSCT. Its favourable efficacy and safety profile re-opens door for antiviral prophylaxis another first-line option, similar to CMV surveillance-preemptive therapy, for preventing CMV in allogeneic HSCT recipients.

The clinical and economic impact of cytomegalovirus infection in recipients of hematopoietic stem cell transplantation

CMV infection (CMV-I) remains an important complication of hematopoietic stem cell transplantation (HSCT). This was a retrospective, single-center cohort study in HSCT recipients. Primary outcomes were adjusted cost and all-cause mortality. Secondary analyses investigated CMV risk factors and the effect of serostatus. Overall, 690 transplant episodes were included (allogeneic [n=310]; autologous [n=380]). All received preemptive CMV antiviral therapy at first detectable DNAemia. CMV-I occurred in 34.8% of allogeneic and 2.1% of autologous transplants; median time to onset was 45days. In allogeneic HSCT recipients, the primary risk factor for CMV-I was CMV donor/recipient (D/R) serostatus. In a Markov multi-state model for allogeneic HSCT recipients, the hazard ratio for CMV-I and relapse was 1.5 (95% CI 0.8-2.8) and for CMV-I and mortality 2.4 (95% CI 0.9-6.5). In a multivariable model for all patients, CMV-I was associated with increased total cost (coefficient=0.21, estimated incremental daily cost USD $500; P=0.02). Cost was attenuated in allogeneic HSCT recipients (coefficient=0.13, USD $699 vs $613, or $24892 per transplant episode; P=0.23). CMV disease (CMV-D) complicated 29.6% of CMV-I events in allogeneic HSCT recipients, but was not associated with an incrementally increased adjusted risk of mortality compared with CMV-I alone. CMV-I (56.4%) and CMV-D (19.8%) were significantly overrepresented in D-/R+ serostatus HSCT recipients, and mortality was higher in R+ HSCT recipients. Despite early preemptive antiviral treatment, CMV-I impacts clinical outcomes and cost after HSCT, but the impact on cost is less pronounced in allogeneic HSCT recipients compared with autologous HSCT recipients.

Fungal infections in hematopoietic stem cell transplantation in children at a pediatric children's hospital in Argentina.

Our primary objective was to describe the incidence of proven or probable invasive fungal infections (IFIs), a devastating complication of hematopoietic stem cell transplant (HSCT), in HCST in a middle-income country. Secondary objectives were to describe factors associated with IFIs and outcomes. In this single center retrospective study, pediatric patients who underwent a first allogeneic or autologous HSCT from 1998 to 2016 were included. Of the 251 HSCT recipients: 143 transplants were allogeneic and 108 were autologous. Overall, 23 (9%) experienced an IFI, mostly due to yeasts (83%). IFIs were more common in allogeneic HSCT (18/143, 13%) than in autologous HSCT (5/108, 5%; P=.045). Of the 23 patients with IFIs, 14 (61%) died, but only 1 directly from IFI (pulmonary aspergillosis). Overall survival at 3years was 0.42±0.11 in patients with IFIs and 0.60±0.37 in those without IFIs (P=.049). In Argentina, IFIs during HSCT are common. Recipients of allogeneic HSCT are at higher risk, and IFI is associated with reduced overall survival. Future work should focus on interventions to reduce and improve IFI outcomes in children undergoing transplants in low- and middle-income countries.

Thrombotic and hemorrhagic complications in children and young adult recipients of Hematopoietic Stem Cell Transplant (HSCT)

BackgroundOverall incidence of hemostatic complications in pediatric recipients of Hematopoietic Stem Cell Transplant (HSCT) is scarcely studied. This retrospective review explored the incidence and underlying risk factors of bleeding and thrombotic complications in children. ProcedureClinical characteristics, hemorrhagic events (HE), thrombotic events (TE) and follow up data were abstracted from medical records on patients aged <21 years undergoing HSCT during January 2000–June 2015. ResultsFrom start of conditioning until last follow up, 238 pediatric patients were reviewed during this study. There were 16 symptomatic thrombotic complications in 15 patients, along with 13 major bleeding events. Incidence of HE or TE was higher in allogeneic HSCT compared to autologous HSCT (p = 0.02). Severe thrombocytopenia could not be identified as a major contributor to bleeding. All patients with HE had platelets between 20,000–50,000 × 109/L, except one patient, who had platelets <20,000 × 109/L. All patients with hemorrhagic cystitis (n = 7) had received cyclophosphamide (Cy). For patients with sinusoidal obstruction syndrome, conditioning included either busulfan (Bu)/Cy (n = 5), Cy with total body irradiation (n = 4), or thiotepa (n = 2). Among allogeneic HSCT recipients, 60% of HE and 92% with TE had underlying myeloid neoplasms. Graft versus Host disease contributed to both types of complications (p = 0.07), although not reaching statistical significance. ConclusionsAllogeneic pediatric HSCT patients had higher overall risk of hemorrhagic or thrombotic complications compared to autologous recipients in this study. HSCT for myeloid malignancies was a risk factor for higher complications.

Does matching for SNPs in the MHC gamma block in 10/10 HLA-matched unrelated donor-recipient pairs undergoing allogeneic stem cell transplant improve outcomes?

BackgroundMatching at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci is important in donor selection for patients undergoing unrelated allogeneic hematopoietic stem cell transplantation (ASCT). Additional matching across the MHC gamma region may further improve outcomes. MethodsThe MHC gamma region was retrospectively genotyped in 66 adult recipients of ASCT and their 10/10 matched unrelated donors. A chart review was performed to determine whether MHC gamma matching impacted survival, relapse, or graft-versus-host disease. ResultsOf 66 donor-recipient pairs, 26(39.4%) were gamma-type matches, 34(51.5%) were mismatches, and 6(9.1%) were “indeterminate.” Matching status was not associated with overall survival (p = 0.43), relapse (p = 0.21), acute GVHD (p = 0.43), severe aGVHD (p = 0.31), or chronic GVHD (p = 0.23) in univariate analyses, nor in multivariate analyses (p = 0.28, 0.13, 0.29, 0.16, and 0.67, respectively), with or without adjusting for HLA-DPB1 matching status. ConclusionsIn our single institution study, gamma-type matching status was not associated with outcomes of adult ASCT recipients.

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-versus-Host Disease

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤−2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤−2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF.

Reconstitution of MAIT cells after allogeneic haematopoietic stem cell transplantation

The factors leading to reconstitution of distinct T cell subsets after allogeneic haematopoietic stem cell transplantation (HCT) have not been fully elucidated. Mucosal-associated invariant T (MAIT) cells express a semi-invariant Vα7.2+ T cell receptor (TCR) that recognises ligands from distinct bacterial and fungal species. We conducted an observational study of MAIT cell reconstitution in allogeneic HCT recipients, and found that cord blood transplant recipients and those who received post-HCT cyclophosphamide for graft versus host disease (GVHD) prophylaxis had profoundly impaired MAIT cell reconstitution.1 Sharing of TCRB gene sequences between MAIT cells isolated from HCT grafts and blood of recipients after HCT showed early MAIT cell reconstitution was due at least in part to proliferation of MAIT cells transferred in the HCT graft. Inflammatory cytokines and signalling through the MAIT cell TCR were required for in vivo MAIT cell proliferation after HCT, suggesting that distinct bacterial Vα7.2+ TCR ligands might promote MAIT cell reconstitution after HCT.1,2 MAIT cell reconstitution was associated with increased gastrointestinal abundance of Blautia spp. MAIT cells suppressed proliferation of conventional T cells consistent with a possible regulatory role. The data suggest modifiable factors may impact MAIT cell reconstitution and could influence the risk of GVHD after HCT.

Prognostic factors and outcome of pediatric allogeneic hematopoietic stem cell transplant patients admitted in intensive care unit

Background : Multiple studies have shown outcome and prognostic factors of mortality for childhood allogeneic hematopoietic stem cell transplantation (HSCT) patients requiring pediatric intensive care unit (PICU) care but there is no such study from India. In our study we analyzed the data in our centre. Methods : Retrospective analysis of data from bone marrow unit and PICU of our hospital was done. We reviewed all charts to find out the indication of admission, outcome and probable prognostic factors. Results : A total of 152 patients underwent allogeneic HSCT in last 2 years. 22 patients were admitted in PICU out of which 17 (77.2%) patients were of non malignant disorders and 5 cases (22.7%) of acute leukemia. Admissions were for various transplant related complications including multiorgan dysfunction syndrome/MODS (40.9%), respiratory distress or failure (40.9%) and neurological complication (18.2%). Total 16 patients (72.7%) expired and 6 were discharged. 1 patient died within 1 month of PICU discharge. Bacterial sepsis and septic shock (43.7%) was the commonest etiology of death followed by disseminated adenovirus infection (18.7%). All of the MODS patients expired and those with only neurological problem were discharged. On statistical analysis delayed neutrophil recovery (p=0.01), MODS (p=0.00), use of vasoactive support (p=0.00), high plasma creatinine (p=0.00), low platelet count (p=0.00) and bacterial septic shock (p=0.02) were important predictor of mortality. Conclusion : In our study, pediatric allogeneic HSCT recipients who were admitted in PICU had high mortality. Sepsis was the one of the commonest etiology for MODS leading to poor outcome. Prevention of sepsis and early transfer in PICU can reduce overall mortality in HSCT patients.

Low T-Cell Responses to Mitogen Stimulation Predicts Poor Survival in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

Successful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). A clinically meaningful and simple biomarker of immunosuppression could potentially assist clinicians in their decision-making. We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients. A prospective observational multicenter study of 73 adult allogeneic HSCT recipients was conducted in Melbourne, Australia. Eligible participants were >18 years and at risk of cytomegalovirus disease. T-cell responses to PHA were assessed at 3, 6, 9, and 12 months post-HSCT using the commercial quantiferon-cytomegalovirus assay, which quantifies IFN-γ production by ELISA following stimulation with PHA. A low response was defined as IFN-γ <0.5 IU/ml following stimulation with PHA. At 3 months post-HSCT, high responses to PHA (median IFN-γ 7.68 IU/ml) were seen in 63% of participants and low responses to PHA (median IFN-γ 0.06 IU/ml) in 37%. IFN-γ responses to PHA were significantly associated with the severity of acute graft versus host disease (AGVHD) (spearman r = -0.53, p < 0.001) and correlated with blood lymphocyte count (spearman r = 0.52, p < 0.001). Twelve month overall survival was greater in individuals with high compared to low IFN-γ response to PHA at 3 months [92 vs. 62%, respectively, Cox proportional hazard ratio (HR): 4.12 95% CI: 1.2-13.7, p = 0.02]. Non-relapse mortality (NRM) was higher in individuals with low IFN-γ response to PHA (competing risk regression HR 11.6 p = 0.02). In individuals with no AGVHD compared to AGVHD and high IFN-γ response to PHA compared to AGVHD and low IFN-γ response to PHA, 12-month survival was 100 vs. 80 vs. 52%, respectively (log rank test p < 0.0001). Low IFN-γ response to PHA at the 3-month time-point following allogeneic HSCT was predictive of reduced 12-month overall survival, increased NRM, and reduced survival in recipients with AGVHD. Assessing IFN-γ response to PHA post-HSCT may be a clinically useful immune biomarker.

Factors Affecting Survival in Children With Pericardial Effusion After Hematopoietic Stem Cell Transplantation

The objective of this study was to determine the incidence, risk factors, outcome, and clinical significance of pericardial effusion (PE). We retrospectively analyzed outcomes of 272 pediatric patients undergoing their first hematopoietic stem cell transplantation (HSCT) from 1998 to 2016. In total, 15% (3/20) and 5.9% (15/252) of autologous and allogeneic HSCT recipients, respectively, were identified with PE. However, there was no statistically significant difference in the incidence of PE between the 2 groups. The mean age at transplantation was 11.12 ± 5.41 y. Eighteen patients developed PE at 4.13 ± 4.44 mo after HSCT. PE was confirmed by echocardiogram in all patients. Three patients presented with severe PE with cardiac tamponade and required urgent pericardiocentesis. Overall survival (OS) rates for patients who developed PE were 83.3% and 38.9% at 100 d and 3 y, respectively, after HSCT. Death was not directly attributable to PE in patients who died in the first year after HSCT. Multivariable analysis identified the following variables to be associated with OS: PE (relative risk[RR]: 3.70; 95% confidence interval [95% CI]: 1.89-7.23; P < 0.001), active disease at HSCT (RR: 1.59; 95% CI: 1.02-2.49; P < 0.001), and thalassemia (RR: 0.62; 95% CI: 0.45-0.84; P < 0.001). PE is, thus, a debilitating and significant complication of pediatric HSCT. Therefore, prospective studies are required for better determination of the etiology and optimal method of PE treatment after HSCT.

Antifungal prophylaxis with fluconazole in allogeneic stem cell transplantation recipients who had prior invasive aspergillosis with subsequent complete resolution by computed tomography

Background: Consensus has yet to be reached regarding secondary prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT) with a complete resolution of invasive aspergillosis (IA) confirmed by chest computed tomography (CT).Methods: We retrospectively evaluated the feasibility of antifungal prophylaxis with fluconazole in allogeneic HSCT recipients who had previously developed IA which showed complete resolution as confirmed by chest CT before HSCT. Consecutive adult patients who underwent allogeneic HSCT at our institution and who had received fluconazole as systemic antifungal prophylaxis from June 2007 to January 2015 were included. We compared the clinical outcomes between patients with a past history of IA who showed a complete resolution of chest CT abnormalities (n = 13) and those without a previous history of IA (n = 137).Results: The cumulative incidence of proven or probable IA was 8.8% in the group without a past history of IA and 0.0% in the group with a past history of IA (p = .268). The cumulative incidence of proven or probable invasive fungal disease (IFD) within 100 days after allogeneic HSCT was 10.9% in the group without a past history of IA and 15.4% in the group with a past history of IA (p = .647). Fluconazole was switched to anti-mould agents in two-thirds of the patients in each group by day 100 after HSCT.Conclusions: Fluconazole was confirmed to be an acceptable prophylactic agent early after allogeneic HSCT in appropriately selected patients.

ID: 1046 Antifungal prophylaxis in hematopoietic stem cell transplantation recipients: drug use evaluation at Vietnam National Institute of Hemotology and Blood transfusion

&#x0D; &#x0D; &#x0D; &#x0D; *For correspondence:&#x0D; tungson94@gmail.com&#x0D; &#x0D; Competing interests: The authors declare that no competing interests exist.&#x0D; Received: 2017-07-13 &#x0D; Accepted: 2017-08-04&#x0D; Published: 2017-09-05&#x0D; &#x0D; Copyright The Author(s) 2017. This article is published with open access by BioMedPress (BMP).&#x0D; This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0) which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. &#x0D; &#x0D; &#x0D; &#x0D; &#x0D; Background: Hematopoietic stem cell transplantation (HSCT) recipients were known to be in high risk of fungal infection. However, not all HSCT patients need antifungal prophylaxis. The aim of this study was to describe the characteristics of the use of antifungal prophylaxis in hematopoietic stem cell transplantation recipients and to evaluate the appropriateness of use.&#x0D; Methods: In this observational prospective study, adult hematopoietic stem cell transplantation recipients without using antifungal treatment were recruited from start of stem cell transfusion in Vietnam National Institute of Hematology and Blood Transfusion (from April to December 2016) to end of antifungal prophylaxis or start of antifungal treatment. Appropriateness was defined based on National Comprehensive Cancer Network (NCCN) guidelines. Clinically significant Drug-drug interactions related to antifungals were defined based on Hansten and Horn’s Drug interaction and management 2013.&#x0D; Results: 38 patients (mean age: 35.7 ± 12.0; 57.9% male) were admitted, included 21 autologous and 17 allogeneic HSCT recipients. After HSCT, 3 deaths, 1 to ICU, 1 IFI. Azoles prophylaxis was given to 100% of patients with median 17.5 days (13 - 47.5). Fluconazole was the most used antifungal agents, in 94.7% of patients and 74.5% of episodes. 10 patients had been changed antifungal agents. Indication was appropriate in 44.7%, 0% in autologous and 100% in allogeneic group. In patients with appropriate indication, choice of antifungal agents was 100% appropriate. 100% of patients used inappropriate dosage, mostly lower than recommeded dosage with azoles. 12.7% had appropriate prophylactic time. Potential drug-drug interactions were identified in 92.1% of patients. Most frequent interactions involved azoles-diazepam (80.4% of episodes) and azoles-immunosuppressive drugs (49% of episodes).&#x0D; Conclusion: Our evaluation revealed a high proportion of inappropriate of antifungal prophylaxis. An antifungal stewardship programme is needed to strengthen rational use of antifungal in this specific circumstance.

Concurrent Hepatic Tuberculosis and Hepatic Graft-versus-host Disease in an Allogeneic Hematopoietic Stem Cell Transplant Recipient: A Case Report

BackgroundInfection and graft-versus-host disease (GVHD) are among the most common complications after hematopoietic stem cell transplantation (HSCT). With well-known risk factors including allogeneic HSCT and GVHD, tuberculosis (TB) has a higher incidence and shorter survival rate in HSCT recipients than in the general population. Case ReportA 55-year-old Indonesian female with a history of latent TB was found to have acute myeloid leukemia 3 months after allogeneic HSCT. She presented with fever, abdominal pain, and predominant cholestatic-type liver function tests derangement. Computed tomography scans showed a relatively unremarkable liver. Liver biopsy specimens revealed multiple necrotizing granulomas with numerous acid-fast bacilli shown using Ziehl-Neelsen histochemical stain. No fungal organisms are detected by Grocott's methenamine silver and periodic acid–Schiff stains. There was also mild portal hepatitis with prominent bile duct injury and scattered apoptotic bodies, compatible with GVHD. In addition, the patient was also discovered to have cutaneous and intestinal TB as well as cutaneous and colonic GVHD during investigation. She was started on anti-TB treatment and adjusted immunosuppression scheme accordingly. Unfortunately, our patient died of spontaneous intracranial haemorrhage approximately 2 months after the diagnosis of post-transplantation TB and GVHD. ConclusionWe report a case of concurrent hepatic TB and GVHD in an allogeneic HSCT recipient. Recognition of the dual pathology in the biopsy results aids proper treatment.

Serum Vitamin A Levels May Affect the Severity of Ocular Graft-versus-Host Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic option for a range of inherited and acquired hematological disorders. However, graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality in allogeneic HSCT recipients. Ocular involvement occurs in up to 80% of chronic GVHD patients. In our cases, the diagnosis of vitamin A deficiency was suspected for GVHD patients. Serum vitamin A measurements were conducted to confirm clinical suspicions. Our study revealed significant decrease in serum levels of vitamin A in chronic liver GVHD patients. Although there have been many studies evaluating ocular manifestations in patients with GVHD, the present study is, to our knowledge, the first to study the relationship between vitamin A and ocular manifestations of GVHD in humans. Our data suggest that vitamin A deficiency affects the severity of ocular GVHD in adults.

Cost-effectiveness of posaconazole tablets versus fluconazole as prophylaxis for invasive fungal diseases in patients with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

The cost-effectiveness of posaconazole oral suspension versus fluconazole capsules for the prophylaxis of invasive fungal diseases (IFDs) in immunosuppressed allogeneic hematopoietic stem cell transplantation (HSCT) recipients has already been proven. Now, a new solid oral tablet formulation for posaconazole has been developed with improved bioavailability, allowing a reduced daily dosage that can be taken independently of food intake. However, the efficacy of this new formulation should be evaluated since it is associated with a higher cost than the posaconazole oral suspension. To evaluate the cost-effectiveness of solid oral tablets of posaconazole versus fluconazole capsules for the prophylaxis of IFDs in allogeneic HSCT recipients with graft-versus-host disease (GVHD) in Spain. A mathematical model comparing the efficacy and costs of posaconazole versus fluconazole was adapted to the Spanish National Healthcare System. Clinical data were obtained from the pivotal clinical trial of posaconazole oral suspension for allogeneic HSCT recipients, while pharmacological costs and use of resources were obtained from national sources. Deterministic and probabilistic sensitivity analyses (PSA), as well as two alternative scenarios, were run to evaluate the robustness of the results under varying input values. Posaconazole tablets reduced the number of IFD events and enhanced overall survival, while maintaining a controlled budget. When compared to fluconazole, it was found to be a cost-effective alternative, with an incremental cost-effectiveness ratio of €13,193/life years gained. The PSA showed that posaconazole remained cost-effective in 74.6% of the cases, while alternatives scenarios yielded similar results as the base case. Posaconazole tablets are a cost-effective alternative to fluconazole and may show better results than the oral suspension formulation.

Evaluation of COBAS AmpliPrep/COBAS TaqMan CMV Test for use in hematopoietic stem cell transplant recipients

ABSTRACTIntroduction: Cytomegalovirus (CMV) is a common opportunistic infection that contributes to poor outcomes in hematopoietic stem cell transplant (HSCT) recipients. Prevention of CMV end-organ disease in allogeneic HSCT recipients is commonly achieved by preemptive antiviral therapy of asymptomatic CMV reactivation that is detected by serial nucleic acid testing (NAT). However, there was no standardized CMV NAT until the development of the World Health Organization (WHO) International Standard.Areas covered: This article provides a comprehensive review on COBAS AmpliPrep/TaqMan (CAP/CTM) CMV assay (Roche) and emphasizes the limitations in the clinical use of CMV NAT in HSCT recipients.Expert commentary: The CAP/CTM CMV Test is the first US FDA approved commercial quantitative NAT for CMV viral load monitoring of plasma samples in solid organ transplant and HSCT recipients. The CAP/CTM assay has wide linear range of DNA quantification and demonstrates colinearity to the WHO International Standard. Studies of CAP/CTM CMV assay in HSCT recipients are still limited, but are now being reported to define viral thresholds for diagnosis, surveillance and monitoring. Results from these early studies in HSCT recipients suggest that, while the WHO IS has improved the inter-laboratory result variances, there are still important factors that continue to contribute to assay variability. This lack of harmony among NAT highlights the need for further standardization.

Cervical Papanicolaou Smears in Hematopoietic Stem Cell Transplant Recipients: High Prevalence of Therapy-Related Atypia during the Acute Phase

Hematopoietic stem cell transplant (HSCT) recipients have a higher risk of cervical cancer. Papanicolaou (Pap) smear is the standard tool for screening cervical cancer, but there is limited research about the cervical cytology in HSCT recipients. Here, we retrospectively included adult female patients who underwent allogeneic or autologous HSCT at National Taiwan University Hospital during 2009 to 2015 and reviewed their Pap smears before and after HSCT. There were 248 allogeneic and 131 autologous HSCT recipients in our study. In allogeneic HSCT recipients, 38.7% (96 of 248) had pre-HSCT Pap smears and 17.1% (44 of 248) had post-HSCT Pap smears. In the autologous HSCT recipients, 35.1% (46 of 131) had pre-HSCT Pap smears and 13.7% (18 of 131) had post-HSCT Pap smears. Compared with allogeneic HSCT recipients without post-HSCT Pap smears, more recipients with post-HSCT Pap smears received bone marrow–derived stem cells (18.2% versus 4.9% respectively; P = .0077) and had longer overall survival (median overall survival, not reached versus 22.1 months; P < .0001). The abnormal rates of post-HSCT Pap smear were 13% (6 of 44) and 11% (2 of 18) in allogeneic and autologous recipients respectively, higher than in the general Taiwanese population (1.22%). Infections were rare in post-HSCT Pap smears. Of note, 11% (5 of 44) of post-HSCT Pap smears from allogeneic recipients showed therapy-related atypia, manifesting as enlarged hyperchromatic nuclei, vacuolated cytoplasm, and occasional tadpole-like cells. These atypical cytological features mimic precancerous lesions, but cervical biopsies and human papilloma virus tests were negative. The atypical cytological features resolved spontaneously in the subsequent follow-up Pap smears. On average, Pap smears with therapy-related atypia were sampled at day +77, significantly earlier than those without therapy-related atypia (P = .016). Therapy-related atypia was more frequent in post-HSCT Pap smears sampled within 100 days after HSCT (before day +100, 4 of 5, 80%, versus after day +100, 1 of 39, 2.56%; P = .0002). The strong temporal relationship suggests these atypical cytological changes resulted from conditioning regimen, most likely busulfan-containing chemotherapy. No therapy-related atypia were observed after total body irradiation or nonbusulfan-containing chemotherapy. In conclusion, therapy-related atypia was common in post-HSCT Pap smears sampled within 100 days after HSCT. Clinical information is critical for correct cytological diagnosis.

Allogeneic hematopoietic stem cell transplant recipients and parasitic diseases: A review of the literature of clinical cases and perspectives to screen and follow-up active and latent chronic infections.

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at substantial risk for a variety of infections depending upon numerous factors, such as degree of immunosuppression, host factors, and period after transplantation. Bacterial, fungal, viral, as well as parasitic infections can occur with high morbidity and mortality. The aim of this study was to evaluate the magnitude of the occurrence of parasitic infections in allogeneic HSCT recipients. Modalities of transmission, methods of diagnosis, treatment, donor and recipient pre-transplant screening and prevention measures of the most serious parasitic infections have also been discussed. We systematically reviewed literature records on post-transplant (allogeneic HSCT) parasitic infections, identified through PubMed database searching, using no language or time restrictions. Search was concluded on December 31, 2015. In the present review, we only discussed post-transplant parasitic infections in allogeneic HSCT. Only exclusion criteria were absence of sufficient information on the transmission of parasitic infection to the recipient. Autologous HSCT recipients have not been included because of the absence of a proper allogeneic transplantation even in presence of blood or blood product transfusions. The methods and findings of the present review have been reported based on the preferred reporting items for systematic reviews and meta-analysis checklist (PRISMA). Regarding allogeneic HSCT recipients, from data published in the literature the real burden of parasitic infections cannot be really estimated. Nevertheless, a positive trend on publication number exists, probably because of more than one reason: (i) the increasing number of patients transplanted and then treated with immunosuppressive agents, (ii) the "population shift" resulting from immigration and travels to endemic areas, and (iii) the increasing of attention for diagnosis/notification/publication of cases. Considering parasitic infections as emerging and potentially serious in their evolution, additional strategies for the prevention, careful screening and follow-up, with a high level of suspicion, identification, and preemptive therapy are necessary in transplant recipients. The Authors' viewpoint in the perspective to screen and follow-up active and latent chronic parasitosis in stem cells donors and recipients: a proposal for a flow chart.

Evaluation of the Interaction of Intravenous and Oral Voriconazole with Oral Cyclosporine in Iranian HSCT Patients.

Objective:Voriconazole as a triazole antifungal agent is widely used for prophylaxis or treatment of fungal infections in allogeneic hematopoietic stem cell transplantation (HSCT). It can increase blood concentrations of other medications including cyclosporine A (CsA) which are substrates for cytochrome P450 3A4. The aim of this study was to evaluate comparatively the interaction between oral/intravenous (IV) voriconazole and oral CsA.Methods:Twenty-nine recipients of allogeneic HSCT who had been already on a steady dose of CsA and were started on oral or IV voriconazole were evaluated in a prospective cohort study. Blood concentration of CsA was determined before and 5–8 days after voriconazole initiation. Plasma concentration of voriconazole was measured in steady state. The changes in blood concentration of CsA after administration of voriconazole were evaluated.Findings:The concentration/dose (C/D) ratio of CsA increased significantly (P < 0.001) after voriconazole initiation in both routes of administration (8.40%–174.10% increase in C/D ratio). The C/D ratio alteration of CsA did not differ significantly between oral and IV voriconazole group (P = 0.405). There was a significant correlation in all patients between plasma concentration of voriconazole and percentage of CsA C/D ratio increment (P = 0.046).Conclusion:There was a significant intrapatient variability in the magnitude of CsA blood concentration increment after voriconazole initiation. We also demonstrated that magnitude of drug interaction did not differ in IV and oral voriconazole administration. Furthermore, we found that the magnitude of drug interaction was correlated with plasma concentration of voriconazole.

Mycobacterial Infections in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A Cohort Study in a High Endemic Area

BackgroundMycobacterial infection is an important and potentially life-threatening complication of patients receiving organ transplantations. Notably, for the recipients of allogeneic hematopoietic stem cell transplantation (HSCT), there are few supporting results to explore post-transplant mycobacterial infections. Taiwan is a high endemic area of the infection. We therefore aim to investigate the incidence, risk factors, and survival of post-transplant mycobacterial infections, including mycobacterium tuberculosis (MTB) and nontuberculous mycobacterium (NTM).Patients and MethodsWe included in this study 422 adult patients undergoing allogeneic HSCT at an Asian tertiary medical center between January 2003 and December 2013. A total 26 subjects who developed post-transplant mycobacterial infections were identified. Risk factors, clinical features, and survival for post-transplant mycobacterial infections in recipients of HSCT were collected and analyzed.ResultsPost-transplant mycobacterial infections occurred in 26 (6.2%) of 422 HSCT patients. Two-year cumulative incidences in MTB and NTM were 1.4 % and 5.4%. In the multivariate analysis, being age > 45 years (adjusted HR 2.21, 95% CI 1.01-4.83)) and extensive chronic graft-versus-host disease (cGVHD) (adjusted HR 4.95, 95% CI 2.14-11.46) were identified as independent risk factors of post-transplant mycobacterial infections. There was a trend as a risk factors in relapsed patients (P=0.088). For patients with cGVHD, there was a significant difference of post-transplant survival between mycobacterial infections and none (median: 6.82 months versus not reached, P=0.036). Pneumonia with or without other infections contributed most to mortality (n = 11, 42.3%).ConclusionThe 2-year cumulative incidence is higher in NTM (5.4%) than TB (1.4%) in recipients of allogeneic HSCT. Patients with age > 45 years, and extensive cGVHD are at risk of mycobacterial infections. Poor post-transplant survival in cGVHD patients developed mycobacterial infections and 42.3% patients in our study died of pneumonia. Once a high-risk group is identified, much effort is required to target new approaches for prevention, early detection and treatment of infections. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.