Hematologic Stem Cell Transplantation Research Articles

Effect of Salvage Chemotherapy Before Donor Lymphocyte Infusion in Patients With Relapse After Allogeneic Hematologic Stem Cell Transplantation

ObjectivesAllogeneic hematopoietic stem cell transplantation (AHSCT) is an important treatment option in hematologic malignancies. Relapse after AHSCT is an indicator of poor prognosis. These patients may be treated with donor lymphocyte infusion (DLI). The chemotherapy given before DLI increases the success of the treatment by reducing the burden of disease. The aim of this study is to investigate post-DLI graft vs host disease (GvHD) and survival based on the course of chemotherapy given before DLI. MethodsA total of 23 patients who received DLI because of relapsed disease after AHSCT were enrolled. All of the patients received 1 or more courses of cytoreductive chemotherapy before DLI. ResultsComplete remission (CR) after DLI remained in 78.2% of all patients. There is no difference between 1 or multiple courses of chemotherapy in terms of CR (55.6% vs 44.4%; P = .21). During follow-up after DLI, although it did not reach statistical significance (P = .09), the patients receiving single-course chemotherapy tended to have longer survival (36.1 vs 4.3 months, respectively). Four patients who received multiple courses of chemotherapy were lost because of infection-related disease (pneumonia, sepsis) while they were in CR. GvHD development was more frequent in patients receiving multiple courses of chemotherapies (60% of all GvHD patients). ConclusionIt has been demonstrated that reducing the tumor burden by multiple-cycle chemotherapy does not have any advantage in terms of CR and does not improve the overall survival.

A prospective study on the long-term outcome of prepubertal and pubertal boys undergoing testicular biopsy for fertility preservation prior to hematologic stem cell transplantation.

Few studies have reported the long-term outcomes of prepubertal and pubertal boys undergoing testicular biopsy for fertility preservation (FP). This prospective longitudinal study examined 21 boys (aged 1.5-14.5 years) who underwent testicular biopsy for FP prior to allogeneic (n=20) or autologous (n=1) hematological stem cell transplantation (HSCT) between 2003 and 2010. During counseling, pubertal boys were encouraged to produce a sperm sample by masturbation , while prepubertal boys were presented with surgical testicular tissue retrieval as an option for experimental FP. Clinical outcomes included postoperative complications, pubertal development, and sex-hormone levels. Survivors approaching adulthood were encouraged to provide semen samples. Twenty boys, including 14 in prepuberty and six in early puberty (Tanner stage 2-3), underwent open testicular biopsies. Two pubertal biopsies contained mature sperms, which were cryopreserved. Testicular tissue was vitrified in the remaining 18 cases. One pubertal boy (Tanner stage 4) underwent percutaneous testicular sperm aspiration and sperms obtained were cryopreserved. Postoperative complications (hematoma or infection) were rare. Overall, 14 boys survived>5 years (mean follow-up after HSCT, 7.2 years) and 11 showed advanced puberty. Semen samples were provided by five boys and obtained sperm were cryopreserved from two. Individuals at adulthood had normal testosterone levels but subnormal testicular size, high follicle stimulating hormone, and low inhibin B and anti-Müllerian hormone levels. No long-term risks were detected during continuous clinical follow-up. Experimental testicular biopsies for FP were well accepted by the patients and families, despite the absence of methods to use prepubertal tissue for fertility treatment.

Exercise before, during, and after Hospitalization for Allogeneic Hematological Stem Cell Transplant: A Feasibility Randomized Controlled Trial.

People with cancer who undergo allogeneic hematological stem cell transplant (allo-HSCT) experience significant deconditioning that can compromise quality of life. Exercise has shown to be beneficial before or after allo-HSCT; however, little is known about exercise therapy delivered across the continuum of care. We conducted a feasibility randomized controlled trial of exercise delivered prior to admission, during the inpatient stay, and after discharge versus control in people with planned allo-HSCT. Feasibility was assessed via recruitment and retention rates, the incidence of adverse events, and adherence to the exercise prescription. Estimates of efficacy were measured at baseline, one week prior to hospital admission, and 100 days and one year after transplant. The recruitment and retention rates were 20% and 33%, respectively. One serious adverse event occurred during the baseline six-minute walk test that precluded participation in the study and no adverse events were associated with the intervention. From baseline to pre-transplant, the intervention group improved six-minute walk test distances by 45 m (95% CI: −18.0 to 108.7)—a finding that warrants further investigation with an adequately powered trial. Our study contributes important feasibility considerations and pilot data for future exercise intervention research in allo-HSCT recipients.

COVID-19 in New York City Pediatric Hematology and Oncology Patients

Background: Little is known about the effect of COVID-19 disease on pediatric hematology, oncology and hematopoietic stem cell transplant (HCT) patients brbr

Clinical Usefulness of Bronchoalveolar Lavage in the Management of Pulmonary Infiltrates in Adults with Hematological Malignancies and Stem Cell Transplantation.

IntroductionPulmonary complications are frequent in patients with hematologic malignancies and stem cell transplantation. Regardless of the microbiological usefulness of bronchoalveolar lavage (BAL), little information exists on both its benefits as a guide for therapeutic decisions and its impact on patients’ clinical outcome.MethodsA prospective observational single-center study was performed between July 2011 and July 2016. Consecutive episodes of pulmonary infiltrates were analyzed in subjects over 18 years of age who presented hematologic malignancies and underwent chemotherapy or stem cell transplantation.ResultsNinety-six episodes of pulmonary infiltrates were analyzed. Acute leukemia was the most frequent underlying condition. Thirty-seven patients (38.5%) received a stem cell transplant. Sixty-one (62.9%) were neutropenic at the moment of inclusion in the study. A definitive etiologic diagnosis was obtained in 41 cases (42.7%), where infection accounted for the vast majority of cases (33 cases, 80.5%). Definitive diagnosis was reached by non-invasive methods in 13 cases (13.5%). BAL was performed in 47 cases and led to a diagnosis in 40.4% of the cases. BAL results led to therapeutic changes in 27 cases (57.4%), including the addition of new antimicrobials to empiric treatments in 10. Regarding BAL’s safety, two patients experienced minor adverse events and one a severe adverse event; no procedure-related deaths were observed.ConclusionsInfection was the leading cause of pulmonary infiltrates in patients with hematologic malignancies and stem cell transplantation. BAL was a useful decision-making diagnostic tool, with minor adverse events.

Central Line Care: Reducing Central Line-Associated Bloodstream Infections on a Hematologic Malignancy and Stem Cell Transplant Unit.

Patients with hematologic malignancies and stem cell transplant recipients are at increased risk for infections because of their prolonged periods of profound neutropenia. Central line-associated bloodstream infections (CLABSIs) can result in lengthy hospitalizations, increased healthcare costs, and increased morbidity and mortality. The aim of this comprehensive educational training program was to reduce CLABSI rates by focusing on the standardized practices associated with use, care, and maintenance of all types of central lines. A pretest was administered to nursing staff. Based on the responses, an education program was then created. The program consisted of a comprehensive two-hour class using different modalities of teaching, including standardized practices associated with central line care. The comprehensive education program was effective in standardizing education and improving knowledge gaps, resulting in the reduction of CLABSI rates. Overall, staff knowledge surrounding central line care and maintenance increased by 16%. In addition, no CLABSI events have been reported on the unit from the time of program initiation.

Analysis of the Whole CDR3 T Cell Receptor Repertoire after Hematopoietic Stem Cell Transplantation in 2 Clinical Cohorts.

A major cause of morbidity and mortality for patients who undergo hematologic stem cell transplantation (HSCT) is acute graft-versus-host disease (aGVHD), a mostly T cell-mediated disease. Examination of the T cell receptor (TCR) repertoire of HSCT recipients and the use of next-generation nucleotide sequencing have raised the question of whether features of TCR repertoire reconstitution might reproducibly associate with aGVHD. We hypothesized that the peripheral blood TCR repertoire of patients with steroid-nonresponsive aGVHD would be less diverse. We also hypothesized that patients with GVHD who shared HLA might also share common clones at the time of GVHD diagnosis, thereby potentially providing potential clinical indicators for treatment stratification. We further hypothesized that HSCT recipients with the same HLA mismatch might share a more similar TCR repertoire based on a potentially shared focus of alloreactive responses. We studied 2 separate patient cohorts and 2 separate platforms for measuring TCR repertoire. The first cohort of patients was from a multicenter Phase III randomized double-blinded clinical trial of patients who developed aGVHD (NCT01002742). The second cohort comprised samples from biobanks from 2 transplantation centers and the Center for International Blood and Marrow Transplant Research of patients who underwent mismatched HSCT. There were no statistically significant differences in the TCR diversity of steroid responders and nonresponders among patients with aGVHD on the day of diagnosis. Most clones in the repertoire were unique to each patient, but a small number of clones were found to be both exclusive to and shared among aGVHD nonresponders. We were also able to show a strong correlation between the presence of Vβ20 and Vβ29 and steroid responsiveness. Using the Bhattacharya coefficient, those patients who shared the same HLA mismatch were shown to be no more similar to one another than to those who had a completely different mismatch. Using 2 separate clinical cohorts and 2 separate platforms for analyzing the TCR repertoire, we have shown that the sampled human TCR repertoire is largely unique to each patient but contains glimmers of common clones of subsets of clones based on responsiveness to steroids in aGVHD on the day of diagnosis. These studies are informative for future strategies to assess for reproducible TCR responses in human alloreactivity and possible markers of GVHD responsiveness to therapy.

Oral disorders in patients with newly diagnosed haematological diseases

This study aimed to examine saliva flow rates and prevalence of dental and periodontal diseases of patients with newly diagnosed severe haematological diseases and compare these findings with age-matched controls of normal population. A total of 149 patients diagnosed with haematological diseases aimed to be treated with haematological stem cell transplantation between 2008 and 2018 and 154 controls were included in the study. A dental examination was performed for patients within a maximum of 6months after diagnosis. Differences were compared in terms of the stimulated salivary flow rate (SSFR); decayed, missing and filled teeth (DMFT) index; number of teeth; caries prevalence; presence of periodontitis and acute infections. The mean SSFR of the patient group was significantly lower (1.1ml/min ± 0.7ml/min) than the mean SSFR of the controls (1.3ml/min ± 0.5ml/min; p = 0.004). The number of caries lesions was significantly higher in the patient group (mean ± SD, 1.1 ± 1.9) than in the control group (mean ± SD, 0.4 ± 1.2; p < 0.001). There were fewer teeth and a higher DMFT index in the patient group compared to the control group, but the differences were not significant. Acute symptomatic infections were observed in eight (5.4%) patients and in none of the controls (p < 0.01). Oral examinations in patients with newly diagnosed severe haematological disease demonstrated a higher prevalence of caries, acute infections and lower mean SSFR compared with the controls. These findings support the recommendations for early dental examination at the time of diagnosis.

Evaluation of clinical outcomes of allogeneic hematopoietic stem cell transplantation for relapsed/refractory peripheral T-cell lymphoma with chemoresistance

Objective: To evaluate the clinical outcomes in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) who had undergone allogeneic hematological stem cell transplantation (allo-HSCT). Methods: From June 2007 to June 2017, the clinical data of PTCL patients who underwent HSCT from eight hospitals were assessed retrospectively. Results: There were 23 patients diagnosed as relapsed or refractory PTCL with chemoresistance who underwent allo-HSCT. Among these patients, 18 were identified as progressive disease (PD) status and 5 patients as stable disease (SD) status before allo-HSCT. Seventeen patients received allo-HSCT from matched sibling donor (MSD),2 patients from matched unrelated donor and 4 patients from related haplo-identical donor (HD). After a median follow-up of 29 months, 21 patients survived longer than 28 days after allo-HSCT. Hematopoietic reconstitution was achieved in 20 of the 21 patients. The median time of myeloid and platelet engraftment were+13 (9-22) d and+16(10-38) d, respectively. The 100-d treatment-related mortality rate was 13.1%. Acute GVHD occurred in 11(47.8%) patients at a median time of 22(6-82) d after transplantation. Grade Ⅱ~Ⅳ aGVHD occurred in 6 patients. Chronic GVHD occurred in 10 patients at a median of 7.9 (3.5-27) months. After a median follow-up of 29 months, 13 patients died after HSCT. Four of them died of complications associated with allo-HSCT, and other 9 patients died of the primary lymphoma. The 3-years cumulative overall survival (OS) and progress-free survival (PFS) were 43.03% (95%CI: 29.79-69.16) and 39.13% (95%CI: 23.50-65.14), respectively. No significant difference was found in the 3-year PFS between patients with PD status and SD status before allo-HSCT (P=0.133). Conclusion: Allo-HSCT can be a promising treatment for relapsed or refractory PTCL with chemoresistance.

Subgroup Analysis Can Optimize the Relapse-Prediction Cutoff Value for WT1 Expression After Allogeneic Hematologic Stem Cell Transplantation in Acute Myeloid Leukemia

High WT1 expression after allogeneic hematologic stem cell transplantation (allo-HSCT) can strongly predict relapse in acute myeloid leukemia (AML). However, the cutoff values obtained have been inconsistent. Precise cutoff values may be optimized through subtype analysis; the RUNX1-RUNX1T1 fusion transcript provides an ideal reference. RUNX1-RUNX1T1 and WT1 transcript levels were simultaneously measured in 1299 bone marrow samples serially collected from 176 t(8;21) AML patients after allo-HSCT. The upper limit of the normal bone marrow WT1 level was 0.6%, which we previously reported to be the cutoff value for significant relapse prediction in AML as a whole. WT1 cutoff values of 0.6%, 1.2%, and 1.8% significantly differentiated patients in relapse after allo-HSCT. Nonetheless, patients with WT1 levels of 0.6% to 1.2% and those with levels of >1.2% and 1.8% after HSCT had rates of cumulative incidence of relapse similar to those with a continuous WT1 level of ≤0.6%, and both were significantly lower than that in patients with a WT1 level of >1.8%. WT1 expression was significantly related to RUNX1-RUNX1T1 transcript levels at WT1 levels of >1.8% but not at levels of 0.6% to 1.2% or >1.2% to 1.8%. Therefore, subgroup analysis can optimize the relapse-prediction cutoff value of WT1 expression. A cutoff level of 1.8% more accurately differentiates t(8;21) AML patients in relapse after allo-HSCT than does a cutoff level of 0.6%.

Classical Monocyte Deficiency Calculated By the Mono-Index Can Predict Mortality in Allogeneic Hematopoietic Stem Cell Transplantation Patients

Background: Most studies in immune reconstitution after allogeneic hematologic stem cell transplantation (alloHSCT) focus on adaptive immunity, particularly in lymphocyte recovery. Classical monocytes (cMo) are part of the innate immunity, playing an important role in the defense against fungal and bacterial infections. The innate and adaptive immunity are closely related, and non-classical monocytes (ncMo) participate in this connection, regulating T cell response. However, the role of these cells in the graft versus tumor effect and graft versus host disease (GVHD) is still unclear. Objectives: The aim of the study was to investigate cMo and ncMo reconstitution after alloHSCT and a possible impact of these cells subsets on acute and chronic GVHD, relapse, non-relapse related mortality (NRM) and overall survival (OS). Patients and Methods: This is a retrospective analysis of 77 patients who underwent alloHSCT in 4 different transplant centers in Brazil. Peripheral blood samples were collected from patients at neutrophil engraftment (NE) and 3, 7, 14, 21, and 42 days after NE. The cMo (DR+, CD11c+, CD14+, CD16-) and ncMo (DR+, CD11c+, CD14-, CD16+) were classified and analyzed by 8-color multiparametric flow cytometry (FACSCanto II). In order to analyze the possible impact of duration and severity of monocytopenia after transplant, we calculated then the 'mono-index' and the 'ncMo-index', based on the area over the curve (AOC) of absolute cMO counts (AMC) and absolute ncMo counts, respectively, considering a horizontal line of AMC 0.5x10e9/L as cut-off value for both subpopulations. Results: The medium follow up was 82 months. Out of 77 patients, 46 (60%) were male, and the median age was 17 years (range: 1-74). The stem cell source was bone marrow in 36 (47%), cord blood in 23 (30%), and peripheral blood in 18 (23%); and donors were matched unrelated in 61 (79%), and matched related in 16 (21%) cases. Most patients received myeloablative conditioning (n=47, 61%); and acute leukemia was the most common diagnosis (72%). A total of 40 (52%) patients received total body irradiation (TBI), and 27 (35%) patients received antithymocyte globulin (ATG). We calculated the possible impact of cMo at all timepoints and found no differences in the main outcomes between patients with lower or higher counts. We then analyzed the AOC of all cMo counts (the mono-index). A higher index represents a more severe deficiency of cMo. We then used the receiver operating characteristic (ROC) curve to define the cut-off value of 14234.4 cells/days x mm3 to discriminate patients as cMo deficient (n=31, 40%) or non-deficient (n=46, 60%). Non relapse mortality (NRM) at 6 years was higher in cMo deficient patients calculated by the mono-index (40% vs. 16% for non-deficient, p=0.02, Figure 1). Deficient patients also had worse OS at 6 years (58% vs. 37% for non-deficient, p=0.03, Figure 2). In multivariate analyses, cMo deficiency calculated by the mono-index remained significantly associated with NRM (hazard ratio 3.07, 95% confidence interval) and OS (HR 2.05, 95%CI 1.20-7.85). We observed no impact of mono-index on acute or chronic GVHD or relapse. We observed no impact of the ncMo counts at all timepoints or the ncMo-index in any of the analyzed outcomes. Conclusion: cMo deficiency calculated by the mono-index can predict mortality in alloHSCT. Mono-Index is an inexpensive, accessible and easy to perform tool that might help clinicians in predicting unfavorable outcomes. Further studies are needed to confirm these findings and to test how different transplant strategies or therapeutic changes might interfere with monocytes recovery in alloHSCT. Disclosures No relevant conflicts of interest to declare.

A Busulfan Following Cyclophosphamide and Constant Cell Dose Protocol Improved Results in Alternative Donor Hematologic Stem Cell Transplantation in Thalassemia Major: A Result from Long-Term Large-Size Multi-Center Study

Sibling donor transplantation (SDT) is a proven curative therapy for patients with thalassemia major (TM), NF-08-TM protocol improved the outcomes of unrelated donor transplantation (UDT) in single-center. This study aim was to determine whether outcomes of NF-08-TM protocol could be proved in multicenter and long-term follow-up and to compare the outcomes of full-matched (FM) and one-locus mismatch (WM) UDT. 586 patients from 4 pediatric BMT centers in China from Dec. 2008 to Jun. 2016 received NF-08-TM protocol, a newly designed Busulfan following Cyclophosphamide and constant cell dose protocol. With a median follow-up of 57 months (range, 21-116), the 9-year OS, TFS, GR, and TRM were 94.4%, 92.8%, 2.7%, and 5.6%, respectively, in total. The corresponding rates for SDTs (n=224) were 95.9%, 95.5%, 1.4% and 4.1%; for UDTs (n=275) were 92.4%, 89.9%, 4.3% and 7.6%; for parental donor transplantation (PDT, n=40) were 95.0%, 95.0%, 0% and 5.0%; and for cord blood transplantation (CBT, n=47) were 97.9%, 95.4%, 2.6% and 2.1%, respectively.The incidence of grade II-IV aGVHD, III-IV aGVHD, mild cGVHD and moderate/severe cGVHD of the entire cohort was 8.9%, 4.6%, 3.7%, and 1.4%, respectively. There was no statistically significant difference (SSD) in OS, TFS, TRM, and GR when comparing FM-SDTs with those of FM-PDTs, FM-UDTs or FM-CBTs. Among PDTs, no SSD was found in OS, TFS, TRM, GR, and GVHD in comparison of FM-PDTs and WM-PDTs. More moderate/severe cGVHD occurred in WM-UDTs than FM-UDTs. Compared FM-SDTs, WM-UDTs had worse OS, TFS, TRM, and a higher rate of grade II-IV aGVHD and cGVHD. Current study proved that Good outcomes of NF-08-TM protocol in single-center be proved in multicenter and long-term follow-up. Compared to the outcomes of FM-UDT) those of well-UDT was worse and was not recommended to thalassemia patients. Disclosures Wing: Miltenyi Biotec: Employment.

Hepatitis B Virus Reactivation: Risk Factors and Current Management Strategies.

Hepatitis B virus (HBV) is a global disease with significant morbidity and mortality. Worldwide, ~257 million people are chronically infected with HBV, defined as having a positive hepatitis B surface antigen, but millions more have prior HBV exposure indicated by positive hepatitis B core antibody. Reactivation of hepatitis B implies a sudden increase in viral replication in a patient with chronic HBV infection or prior HBV exposure. Hepatitis B virus reactivation (HBVr) can occur spontaneously, but it is more commonly triggered by immunosuppressive therapies for cancer, immunologic diseases, or transplantation. Elimination of hepatitis C virus (HCV) in HBV-HCV coinfected individuals treated with direct-acting antivirals (DAAs) has also been identified as an important cause of HBVr. Hepatitis B virus reactivation is an underappreciated but important complication of common medical therapies that can delay treatment or result in clinical episodes of hepatitis, hepatic failure, or death. In this review, factors associated with HBVr, particularly medication-related risks, are explored. We review data involving rituximab and ofatumumab, doxorubicin, corticosteroids, tumor necrosis factor antagonists, tyrosine kinases, bortezomib, hematologic stem cell transplantation, and DAAs for HCV treatment. In addition, we discuss screening strategies, choice of antiviral prophylaxis, and the optimal duration of therapy for HBVr. With additional awareness, screening, and appropriate antiviral therapy, it is expected that most cases of HBVr can be prevented.

Enteropathogenetic nosocomial infections: predisposing clinical characteristics and risk of recurrent infections

Nosocomial infections caused by Clostridium difficile, CP-Kp, ESBL-E or Candida spp. are usually associated with a high mortality rate. In this retrospective study, we evaluated the association between the patient characteristics and the risk of development of nosocomial BSI due to Candida or CP-Kp or ESBL-E. Moreover, we described the cumulative incidence of recurrent infections according to each group of nosocomial BSI. Enteral or parenteral nutrition and indwelling CVC at time of diagnosis were associated with an increased risk of candidemia or CP-Kp over ESBL-E and CDI. ESBL-E BSI was higher in patients undergoing hemodialysis, hematological stem cell transplant and neutropenic patients. The cumulative incidence for recurrent infections was higher for CP-Kp BSI and lower for candidemia. Our data highlight a different role of single patient comorbidities in the development of infections and the higher incidence of recurrent infections in CP-Kp BSI.

Jehovah's Witness Patients: Interventions for Successful Stem Cell Transplantation Without Blood Product Transfusions for Hematologic Malignancies.

Jehovah's Witnesses are members of a religion that prohibits them from accepting blood product transfusions. This refusal makes them a particularly compelling population in the context of hematologic malignancies and stem cell transplantation, because blood product transfusions are a mainstay of supportive treatment. This article presents preventive and supportive measures allowing Jehovah's Witness patients the opportunity to receive a stem cell transplantation without blood product transfusions. A literature review was done that included evidence focusing on optimizing hematopoiesis, blood loss prevention, alterations in chemotherapy regimens, and implications for nursing practice. With proper preventive and supportive care measures, Jehovah's Witness patients can receive stem cell transplantations for hematologic malignancies without blood product transfusions.

Extended HLA Haplotypes and Their Impact on DPB1 Matching of Unrelated Hematologic Stem Cell Transplant Donors.

Although HLA-DPB1 has long been considered of lesser importance in the selection of an unrelated donor (URD) hematologic stem cell transplantation, currently in many instances the DPB1 type of the donor is relevant or even critical. At present, however, only a minority of registry donors are DPB1 typed. It is also unclear to what extent the DPB1 alleles are linked to the 5-locus HLA-A-, B-, C-, DRB1, -DQB1 haplotypes. We sought to study whether there is such a linkage by using donors in the Finnish Stem Cell Registry as the study population. The 6-locus HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 haplotype frequencies were estimated from a group of 43,365 Finnish registry donors using the German National Bone Marrow Registry algorithm. Five-locus haplotype (HLA-A, -B, -C, -DRB1, -DQB1) and HLA-DPB1 allele frequencies were calculated as marginal frequencies of the estimated 6-locus haplotype frequencies. The Finnish average frequency of individual DPB1 alleles was compared with their respective frequencies in association with individual 5-locus HLA haplotypes (haplotype-specific frequencies). Finally, the probability of DPB1 matching in 10/10 matched URD transplants was assessed. Haplotype-specific DPB1 frequencies differed significantly from the average DPB1 frequencies in 81 of 100 most frequent Finnish 5-locus HLA haplotypes, including some infrequent DPB1 alleles that were associated almost exclusively with certain individual 5-locus haplotypes. Five-locus haplotypes that are enriched in Finland but rare among other Europeans carried stronger DPB1 associations than haplotypes that are frequent European-wide. Finally, 10/10 matched transplants from domestic registry donors were significantly more likely to also be DPB1 matched than those from foreign donors. The results indicate an extension of linkage disequilibrium in the MHC complex in the Finnish population. With continuing upfront DPB1 typing of registry donors, it will be possible to perform similar extended 6-locus haplotype frequency estimations also in other registries. The associations are likely to be population specific but may be weaker in more heterogeneous populations. In the future the results might be used to predict the probability of DPB1 match or permissive/nonpermissive DPB1 mismatch for non-DPB1 typed donors in registry donor searches.

Utility of CT assessment in hematology patients with invasive aspergillosis: a post-hoc analysis of phase 3 data

BackgroundPulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected.MethodsThis post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan.ResultsOf 395 patients included in this post-hoc analysis, 240 patients (60.8%) had ‘confirmed’ proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had ‘non-confirmed’ invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813–21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA.ConclusionsThese findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation.Trial registrationNCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007)

Interim results from a phase Ib/II clinical study of the glutaminase inhibitor telaglenastat (CB-839) in combination with azacitidine in patients with advanced myelodysplastic syndrome (MDS).

7037 Background: Glutaminase (GLS) is an enzyme that catalyzes conversion of glutamine to glutamate, providing key metabolic fuel for tumor cells. GLS is highly expressed in AML and high-risk MDS, particularly in the setting of complex cytogenetics. Preclinical studies of primary AML cells demonstrate dependence on glutamine; glutaminase inhibition led to reduced cell growth and induced apoptosis. This study was designed to evaluate the safety and efficacy of the oral glutaminase inhibitor CB-839 in combination with azacitidine for MDS. Methods: This is a single arm Phase Ib/II trial of CB-839, evaluating the dose of 600 mg BID orally daily in combination with azacitidine (AZA) for intermediate and high-risk MDS in 28-day cycles. The primary outcome for the Phase 1 portion was to confirm the safety and recommended Phase 2 dose of CB-839 in combination with AZA. Secondary endpoints evaluate efficacy and clinical activity using IWG response criteria for MDS including hematological improvement (HI), complete response (CR), marrow CR (mCR), stable disease (SD) and no response (NR). Results: A total of 10 pts with MDS were enrolled; the Phase I portion is now complete, confirming CB-839 600 mg BID with standard AZA. Median age was 71 [47-76], 90% were men. 7 pts were treatment naïve, 3 pts had prior HMA exposure. 6 pts were intermediate-2, and 4 pts intermediate-1 by IPSS with high-risk mutations. 3 pts had complex cytogenetics. The most frequent mutations were ASXL1 (n = 5), TET2 (n = 4) and TP53 (n = 4). Median number of cycles was 3 [1-9]. The most common non-hematological AEs were grade 1-3 nausea (60%) and constipation (50%). No DLTs were identified; one pt experienced grade 3 transaminitis requiring dose reduction of CB-839 (to 400 mg BID) with resolution. Seven pts (70%) achieved mCR/CR with HI, 2 pts had SD, and 1 pt had NR. The median time to mCR was 3 months [1-3]. 4 pts proceed to hematologic stem cell transplant (HSCT) after 2-4 cycles. 1 pt progressed to AML after 3 cycles of therapy, and 3 pts remain on study. Conclusions: 600 mg BID CB-839 is safe and well tolerated in combination with azacitidine in pts with MDS. The Phase II portion is ongoing. Clinical trial information: NCT03047993.

Antimicrobial Stewardship in Patients with Hematological Malignancies: Key Considerations

This review establishes current evidence supporting antimicrobial stewardship programs for malignant hematology and hematopoietic stem cell transplant patients. It describes best practices and identifies opportunities for research. It examines metrics relevant to the patient population, and new approaches to the management of high-risk febrile neutropenia. There is an urgent need for antimicrobial stewardship programs to optimize antimicrobial use in malignant hematology and stem cell transplant patients. Audit and feedback is effective and safe. Febrile neutropenia is a key area to optimize antimicrobial use. Shortening duration of antimicrobial therapy in fever of unknown origin appears to be feasible. Routine antimicrobial prophylaxis has been reexamined. Locally developed guideline for high-risk febrile neutropenia is a major intervention. Antifungal stewardship and rapid diagnostic technologies reduce unnecessary antifungal use. Metrics for antimicrobial stewardship programs in malignant hematology and stem cell transplant are multifaceted. Antimicrobial stewardship in the malignant hematology and stem cell transplant population is feasible, effective, and safe. Current gaps in knowledge include the optimal duration of antimicrobial use in fever of unknown origin, and the safety of targeted therapy despite neutropenia. The ideal human resources requirement is unclear. Cost-effectiveness of antimicrobial stewardship interventions remains to be determined.

Significance of the Reverse Halo Sign in Immunocompromised Patients.

OBJECTIVE. The purpose of this study is to assess the most common causes of the reverse halo sign (RHS) in immunocompromised patients and to identify clinicoradiologic features that help in achieving a specific diagnosis. MATERIALS AND METHODS. This retrospective study included 70 patients with hematologic malignancy, neutropenia, or history of solid organ transplant or stem cell transplant who had the RHS at chest CT. Absolute neutrophil count, imaging features of the RHS, and presence of pleural effusions were noted and correlated with the specific diagnosis. A decision tree was constructed from predictive imaging features and compared with radiologist assessment for infectious versus noninfectious cause. RESULTS. Infection, including fungal and bacterial pneumonia, was the most common cause of the RHS (66%), followed by organizing pneumonia (26%). Noninfectious causes such as organizing pneumonia were more likely in the solid organ transplant group, whereas infections were more likely in patients with hematologic malignancy and stem cell transplant. Among fungal pneumonias, aspergillosis (20%) was as common as mucormycosis (19%). In univariate analysis, neutropenia, rim thickness, central ground-glass attenuation, and lesion diameter correlated with infectious cause. A decision tree using neutropenia, rim thickness, central ground-glass attenuation, and pleural effusion could differentiate infectious from noninfectious cause with accuracy of 78%, compared with radiologist accuracy of 81%. CONCLUSION. Infections are more likely to cause RHS than noninfectious processes in immunocompromised patients, and aspergillosis may be as likely overall as mucormycosis because of its higher frequency in these patients. A decision tree using clinical and imaging features can help differentiate infectious from noninfectious causes of RHS.