Outcomes for patients with EBV-positive PTLD post-allogeneic HCT after failure of rituximab-containing therapy.

Epstein-Barr virus-positive (EBV+) post-transplant lymphoproliferative disease (PTLD) is an ultra-rare and aggressive condition that may occur following allogeneic hematopoietic cell transplant (HCT) due to immunosuppression. Approximately half of EBV+ PTLD cases are relapsed or refractory (R/R) to initial rituximab-containing therapy. There are limited treatment options and no standard of care for patients with R/R EBV+ PTLD, and little is known about their treatment history and outcomes. We performed a multinational, multicenter, retrospective chart review of patients with R/R EBV+ PTLD following HCT to describe patients' demographic and disease characteristics, treatment history, and overall survival (OS) from rituximab failure. Among 81 patients who received initial treatment with rituximab as monotherapy (84.0%) or in combination with chemotherapy (16.0%), median time from HCT to PTLD diagnosis was 3.0 months and median OS was 0.7 months. Thirty-six patients received a subsequent line of treatment. The most frequent causes of death were PTLD (56.8%), graft-versus-host disease (13.5%) and treatment-related mortality (10.8%). In multivariate analysis, early PTLD onset and lack of response to initial treatment were associated with mortality. This real-world study demonstrates that the prognosis of patients with R/R EBV+ PTLD following HCT remains poor, highlighting the urgent unmet medical need in this population.

Feasibility of allogeneic hematopoietic stem cell transplantation in advanced age.

Although it is known that increasing age is associated with increased morbidity and mortality in allogeneic transplantation (allo-HSCT), individualization of the process may allow to perform it in progressively older patients.This study analyzed the outcome of 97 patients older than 60 years with a first allo-HSCT performed at our institution between 2011 and 2019.Median age was 66 years (range 60-79) and 15.4% were older than 70 years. The most frequent diagnosis was acute leukemia (50.5%), and 58.8% received a myeloablative conditioning. With a median follow-up of 33.9 months (range 7.9-111.5), at 3-years overall survival (OS) was 50%; progression-free survival (PFS), 46%; cumulative incidence of relapse, 22%; and non-relapse mortality (NRM), 32%. There were no significant differences in OS (p = 0.415), PFS (p = 0.691), cumulative incidence of relapse (p = 0.357) or NRM (p = 0.658) between patients of 60-64 years (n = 37), 65-69 (n = 45) and ≥ 70 years (n = 15). No differences were observed either depending on the intensity of the conditioning regimen in terms of OS (p = 0.858), PFS (p = 0.729), cumulative incidence of relapse (p = 0.416) or NRM (p = 0.270).In conclusion, older adults can safely and effectively undergo allo-HSCT with proper patient selection and individualized transplantation procedures.

Adherencia y calidad de vida en los pacientes con leucemia linfocítica crónica tratados con antineoplásicos orales / Adherence and quality of life in patients with chronic lymphocytic leukemia treated with oral antineoplastic drugs

Objetivos: evaluar la adherencia y la calidad de vida de los pacientes con leucemia linfocítica crónica tratados con antineoplásicos orales. Comparar la adherencia y la calidad de vida según el fármaco recibido y según la línea de tratamiento.Métodoestudio descriptivo prospectivo realizado de junio a noviembre de 2021 en un hospital terciario. Se incluyeron pacientes con leucemia linfocítica crónica, atendidos en la consulta de Farmacia Oncológica y tratados con antineoplásicos orales desde al menos 6 meses antes de la inclusión en el estudio. Se estimó la adherencia mediante el cuestionario Morisky’s 8 item Medication Adherence Scale y el recuento de medicación sobrante, considerándose adherentes si su tasa de adherencia era ≥ 90%. Para evaluar la calidad de vida, se utilizó el cuestionario EQ-5D-3L del grupo EuroQol, la escala Functional Assessment of Chronic Illness Therapy – Fatigue y el QLQ-C30 de la European Organization for Research and Treatment of Cancer. Se programaron 2 entrevistas: en el momento de la inclusión y a los 3 meses. Se revisó la historia clínica, recogiéndose variables demográficas y clínicas. El análisis estadístico se realizó con el programa SPSS® 25.0.Resultadosse incluyeron 23 pacientes, todos fueron adherentes según el recuento de medicación, 20 presentaron adherencia alta, y 3 media, según Morisky’s 8 item Medication Adherence Scale. Los resultados del cuestionario EQ-5D-3L mostraron que los pacientes eran autónomos para su cuidado personal y sus actividades cotidianas, el 69,6% no tenían problemas de movilidad, el 78,3% no tenía ansiedad/depresión y el 56,5% presentaba algún tipo de dolor. (AU)

Objective: To evaluate adherence and quality of life to oral antineoplastic treatment in patients with chronic lymphocytic leukemia. To compare adherence and QoL according to treatment subgroups and treatment-line subgroups.MethodsWe conducted a descriptive prospective study from June to November 2021 in a tertiary care hospital. Patients treated at the Oncology Pharmacy with a diagnosis of chronic lymphocytic leukemia and treatment with oral antineoplastics for at least 6 months before inclusion in the study were included. Adherence was assessed using Morisky’s 8 item Medication Adherence Scale and leftover pills counts, considering adherents if their adherence rate was ≥ 90%. Quality of life was assessed with Euro-Qol EQ-5D-3L questionnaire, Functional Assessment of Chronic Illness Therapy – Fatigue scale and QLQ-C30 questionnaire from European Organization for Research and Treatment of Cancer. Two interviews were scheduled: at the time of inclusion and at 3 months. Variable collected: demographic data, clinical data (disease and treatment); and response (scores obtained from questionnaires and adherence rate). The data statistical analysis was carried out with SPSS® 25.0 software.ResultsTwenty three patients were included, all of them showed an adherence rate higher than 90%; 20 patients were considered high adherent, and 3 patients medium adherent to treatment according to Morisky’s 8 item Medication Adherence Scale. (AU)

Adherence and quality of life in patients with chronic lymphocytic leukemia treated with oral antineoplastic drugs. / Adherencia y calidad de vida en los pacientes con leucemia linfocítica crónica tratados con antineoplásicos orales.

OBJECTIVE: To evaluate adherence and quality of life to oral antineoplastic treatment in patients with chronic lymphocytic leukemia. To compare adherence and QoL according to treatment subgroups and treatment-line subgroups. METHODS: We conducted a descriptive prospective study from June to November 2021 in a tertiary care hospital. Patients treated at the Oncology Pharmacy with a diagnosis of chronic lymphocytic leukemia and treatment with oral antineoplastics for at least 6 months before inclusion in the study were included. Adherence was assessed using Morisky's 8 item Medication Adherence Scale and leftover pills counts, considering adherents if their adherence rate was ≥ 90%. Quality of life was assessed with Euro-Qol EQ-5D-3L questionnaire, Functional Assessment of Chronic Illness Therapy - Fatigue scale and QLQ-C30 questionnaire from European Organization for Research and Treatment of Cancer. Two interviews were scheduled: at the time of inclusion and at 3 months. Variable collected: demographic data, clinical data (disease and treatment); and response (scores obtained from questionnaires and adherence rate). The data statistical analysis was carried out with SPSS® 25.0 software. RESULTS: Twenty three patients were included, all of them showed an adherence rate higher than 90%; 20 patients were considered high adherent, and 3 patients medium adherent to treatment according to Morisky's 8 item Medication Adherence Scale. The results of the EQ-5D-3L questionnaire showed that the patients were all of them autonomous in their personal care and daily activities, 69.6% did not have any mobility problems and 78.3% did not have anxiety/depression; 56.5% had some type of pain. Eighteen patients had no fatigue, and 5 had mild/moderate fatigue according to Functional Assessment of Chronic Illness Therapy - Fatigue scale. The results of the EORTC QLQ-C30 questionnaire showed that patients had a high /healthy functional level, a good quality of life and a low level of symptoms. Analysis by treatment subgroups and by treatment-line subgroups did not show statistically significant differences in adherence or quality of life. CONCLUSIONS: Patients diagnosed with chronic lymphocytic leukemia and treated with oral antineoplastic therapies showed a high adherence rate and referred a good quality of life.

[Translated article] Adherence and quality of life in patients with chronic lymphocytic leukemia treated with oral antineoplastic drugs.

OBJECTIVE: To evaluate adherence and quality of life to oral antineoplastic treatment in patients with chronic lymphocytic leukemia. To compare adherence and quality of life according to treatment subgroups and treatment-line subgroups. METHODS: We conducted a descriptive prospective study from June to November 2021 in a tertiary care hospital.  Patients with chronic lymphocytic leukaemia, seen at the Oncology Pharmacy and treated with oral antineoplastic drugs for at least 6 months prior to inclusion in the study were included. Adherence was assessed using Morisky's 8 item Medication Adherence Scale and leftover pills counts, considering adherents if their adherence rate was ≥90%. Quality of life was assessed with Euro-Qol EQ-5D-3L questionnaire, Functional Assessment of Chronic Illness Therapy - Fatigue scale and QLQ-C30 questionnaire from European Organization for Research and Treatment of Cancer. Two interviews were scheduled: at the time of inclusion and at 3 months. The clinical history was reviewed and demographic and clinical variables were collected. The data statistical analysis was carried out with SPSS® 25.0 software. RESULTS: Twenty three patients were included, all of them showed an adherence rate higher than 90%; 20 patients were considered high adherent, and 3 patients médium adherent to treatment according to Morisky's 8 item Medication Adherence Scale. The results of the EQ-5D-3L questionnaire showed that the patients were all of them autonomous in their personal care and daily activities, 69.6% did not have any mobility problems and 78.3% did not have anxiety/depression; 56.5% had some type of pain. Eighteen patients had no fatigue, and 5 had mild/moderate fatigue according to Functional Assessment of Chronic Illness Therapy - Fatigue scale. The results of the EORTC QLQ-C30 questionnaire showed that patients had a high /healthy functional level, a good quality of life and a low level of symptoms. Analysis by treatment subgroups and by treatment-line subgroups did not show statistically significant differences in adherence or quality of life. CONCLUSIONS: Patients diagnosed with chronic lymphocytic leukemia and treated with oral antineoplastic therapies showed a high adherence rate and referred a good quality of life.

Adjuvanted recombinant zoster vaccine in adult autologous stem cell transplant recipients: polyfunctional immune responses and lessons for clinical practice.

Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18-49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.

PLAIN LANGUAGE SUMMARYWhat is the context?After haematopoietic stem cell transplantation, patients have impaired immunity from conditioning chemotherapy regimens, often exacerbated by underlying diseases, putting them at high risk of developing herpes zoster. In this population, antiviral prophylaxis is the current standard of care to reduce herpes zoster risk. Vaccination provides an additional means to prevent herpes zoster. Live-attenuated vaccines are generally contraindicated in immunocompromised patients. A non-live, adjuvanted recombinant zoster vaccine (RZV, Shingrix, GSK), has been approved for use in adults ≥50 years of age in the European Union, United States, Canada, Australia, Japan, and China. This vaccine is highly efficacious at preventing herpes zoster in adults over 50 years of age, as demonstrated in large, placebo-controlled randomised trials. Importantly, Shingrix use is not contraindicated in immunocompromised conditions, and was found to be highly efficacious in adults who had recently undergone autologous haematopoietic stem cell transplant.What is new?In autologous haematopoietic stem cell transplant recipients in whom Shingrix has demonstrated efficacy, two doses elicited high and persistent immune responses. Date presented here further support our understanding of the impact of specific factors such as age or underlying diseases on the vaccine's effect in the population studied, as well as the characteristics of the elicited cell-mediated immune responses.What is the impact?These results indicate that Shingrix, given shortly after haematopoietic stem cell transplant, can induce robust immune responses and reduce the risk of herpes zoster, even in individuals with immunosuppression due to underlying disease and/or use of immunosuppressive therapies, regardless of age or underlying disease.

Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells.

Patients who develop chimeric antigen receptor (CAR) T-cell-related severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL]/platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX], which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day -1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell-related toxicities.

Intercontinental study on pre-engraftment and post-engraftment Gram-negative rods bacteremia in hematopoietic stem cell transplantation patients: Risk factors and association with mortality.

OBJECTIVES: We present here data on Gram-negative rods bacteremia (GNRB) rates, risk factors and associated mortality. METHODS: Data on GNRB episodes were prospectively collected in 65 allo-/67 auto-HSCT centers in 24 countries (Europe, Asia, Australia). In patients with and without GNRB, we compared: demography, underlying disease, HSCT-related data, center` fluoroquinolone prophylaxis (FQP) policy and accreditation status, and involvement of infection control team (ICT). RESULTS: The GNRB cumulative incidence among 2818 allo-HSCT was: pre-engraftment (pre-eng-allo-HSCT), 8.4 (95% CI 7-9%), post-engraftment (post-eng-allo-HSCT), 5.8% (95%CI: 5-7%); among 3152 auto-HSCT, pre-eng-auto-HSCT, 6.6% (95%CI: 6-7%), post-eng-auto-HSCT, 0.7% (95%CI: 0.4-1.1%). GNRB, especially MDR, was associated with increased mortality. Multivariate analysis revealed the following GNRB risk factors: (a) pre-eng-allo-HSCT: south-eastern Europe center location, underlying diseases not at complete remission, and cord blood source; (b) post-eng-allo-HSCT: center location not in northwestern Europe; underlying non-malignant disease, not providing FQP and never accredited. (c) pre-eng-auto-HSCT: older age, autoimmune and malignant (vs. plasma cell) disease, and ICT absence. CONCLUSIONS: Benefit of FQP should be explored in prospective studies. Increased GNRB risk in auto-HSCT patients transplanted for autoimmune diseases is worrying. Infection control and being accredited are possibly protective against bacteremia. GNRB are associated with increased mortality.

Microbiota as Predictor of Mortality in Allogeneic Hematopoietic-Cell Transplantation.

BACKGROUND: Relationships between microbiota composition and clinical outcomes after allogeneic hematopoietic-cell transplantation have been described in single-center studies. Geographic variations in the composition of human microbial communities and differences in clinical practices across institutions raise the question of whether these associations are generalizable. METHODS: The microbiota composition of fecal samples obtained from patients who were undergoing allogeneic hematopoietic-cell transplantation at four centers was profiled by means of 16S ribosomal RNA gene sequencing. In an observational study, we examined associations between microbiota diversity and mortality using Cox proportional-hazards analysis. For stratification of the cohorts into higher- and lower-diversity groups, the median diversity value that was observed at the study center in New York was used. In the analysis of independent cohorts, the New York center was cohort 1, and three centers in Germany, Japan, and North Carolina composed cohort 2. Cohort 1 and subgroups within it were analyzed for additional outcomes, including transplantation-related death. RESULTS: We profiled 8767 fecal samples obtained from 1362 patients undergoing allogeneic hematopoietic-cell transplantation at the four centers. We observed patterns of microbiota disruption characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota was associated with a lower risk of death in independent cohorts (cohort 1: 104 deaths among 354 patients in the higher-diversity group vs. 136 deaths among 350 patients in the lower-diversity group; adjusted hazard ratio, 0.71; 95% confidence interval [CI], 0.55 to 0.92; cohort 2: 18 deaths among 87 patients in the higher-diversity group vs. 35 deaths among 92 patients in the lower-diversity group; adjusted hazard ratio, 0.49; 95% CI, 0.27 to 0.90). Subgroup analyses identified an association between lower intestinal diversity and higher risks of transplantation-related death and death attributable to graft-versus-host disease. Baseline samples obtained before transplantation already showed evidence of microbiome disruption, and lower diversity before transplantation was associated with poor survival. CONCLUSIONS: Patterns of microbiota disruption during allogeneic hematopoietic-cell transplantation were similar across transplantation centers and geographic locations; patterns were characterized by loss of diversity and domination by single taxa. Higher diversity of intestinal microbiota at the time of neutrophil engraftment was associated with lower mortality. (Funded by the National Cancer Institute and others.).

Células CAR T: el futuro ya es presente / CAR T cells: The future is already present

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Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study of the Infectious Diseases Working Party of the European Bone Marrow Transplantation Group.

BACKGROUND: This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). METHODS: GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas ß-lactams (noncarbapenems), carbapenems, and multidrug resistance. RESULTS: Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and ß-lactam/ß-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on ß-lactam/ß-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. CONCLUSIONS: Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. CLINICAL TRIALS REGISTRATION: NCT02257931.

Bloodstream infection caused by Acinetobacter junii in a patient with acute lymphoblastic leukaemia after allogenic haematopoietic cell transplantation.

Acinetobacter junii is a rare human pathogen associated with bacteraemia in neonates and paediatric oncology patients. We present a case of A. junii causing bacteraemia in an adult transplant patient with leukaemia. The correct identification of Acinetobacter species can highlight the clinical significance of the different species of this genus.