Allogeneic Hemopoietic Cell Transplantation Research Articles

Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion

A nine-year boy with adrenoleukodystrophy due to an ABCD1 whole gene deletion was diagnosed with the active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hemopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel, elivaldogene autotemcel) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient’s MRI showed gadolinium resolution; whole blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the ABCD1 gene product were detectable 9 months after transplant showing reactivity to peroxisomes, suggesting an immune response, however, no antibody binding to human CD34+ cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient’s whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

Clinical Outcomes and Treatment Patterns in Adults With FLT3-ITDmut+ Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the United States and Canada

Allogeneic hematopoietic cell transplantation (alloHCT) is used to treat patients with acute myeloid leukemia (AML) with internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITDmut+). However, the effect of different characteristics on outcomes after transplant is not fully understood. The aim of this study was to determine the impact of patient, disease, and transplant characteristics on clinical outcomes and trends in maintenance therapy for patients with FLT3-ITDmut+ AML who underwent their first alloHCT. This was an observational cohort study of adults ≥18 years who were recipients of human leukocyte antigen identical sibling, haploidentical, 8/8 or 7/8 unrelated, or cord blood donor alloHCT in the United States and Canada between 2014 and 2019. Patient, disease, and transplant characteristics were collected from Center for International Blood & Marrow Transplant Research between 2014 and 2022. Patients enrolled in the MORPHO clinical trial (NCT02997202) were excluded. Clinical outcomes were measured from the time of alloHCT by disease status: first complete remission (CR1), second or greater complete remission (≥CR2), or relapsed/refractory (R/R). The primary endpoints of this study were overall survival (OS) and leukemia-free survival (LFS). Key secondary endpoints included relapse after alloHCT, nonrelapse mortality (NRM), time from diagnosis to complete remission, time from complete remission to alloHCT, and maintenance therapy before and after alloHCT. Univariate analyses were conducted with Gray's test and log-rank test, while multivariable analyses were conducted using Cox proportional hazards models. A total of 3147 eligible patients (CR1, n = 2389; ≥CR2, n = 340; R/R, n = 418) were included. Most patient, disease, and transplant characteristics were similar between different disease statuses. In univariate analyses, disease status of CR1 compared with ≥CR2 or R/R was significantly (P < .001) associated with improved OS and LFS, and decreased probability of relapse; NRM likely differed across cohorts after alloHCT (P = .003). In multivariable analyses, patients with a disease status of ≥CR2 and R/R compared with CR1 had significantly shorter OS (hazard ratio [HR] 95% confidence interval [CI], 1.43 [1.19 to 1.72], P = .0001, and 2.14 [1.88 to 2.44], P < .0001, respectively). Patients with a disease status of CR1 at ≤2.6 months had better LFS compared with ≥CR2 and R/R (HR [95% CI], 2.03 [1.56 to 2.63], P < .0001 and 3.98 [3.07 to 5.17], P < .0001, respectively). Patients with a ≥CR2 or R/R disease status at ≤2.6 months had an increased likelihood of relapse compared with CR1 (HR [95% CI], 2.46 [1.82 to 3.33], P < .0001 and 4.68 [3.46 to 6.34], P < .0001, respectively). Disease status was not significantly associated with NRM. We also identified several additional patient, disease, and transplant characteristics that may have been associated with inferior OS and/or LFS and greater relapse and/or NRM. Maintenance therapy usage after alloHCT increased from 2014 to 2019 primarily due to increased FLT3 inhibitor use. In this largest study to date of patients from the United States and Canada with FLT3-ITDmut+ AML, disease status of CR1 at the time of alloHCT was associated with better clinical outcomes. Additional factors were identified that may also impact clinical outcomes, and in total, have the potential to inform clinical decision-making.

Engineering the best transplant outcome for high-risk acute myeloid leukemia: the donor, the graft and beyond

Allogeneic hemopoietic cell transplantation remains the goal of therapy for high-risk acute myeloid leukemia (AML). However, treatment failure in the form of leukemia relapse or severe graft-versus-host disease remains a critical area of unmet need. Recently, significant progress has been made in the cell therapy-based interventions both before and after transplant. In this review, the Stem Cell Engineering Committee of the International Society for Cell and Gene Therapy summarizes the literature regarding the identification of high risk in AML, treatment approaches before transplant, optimal transplant platforms and measures that may be taken after transplant to ideally prevent, or, if need be, treat AML relapse. Although some strategies remain in the early phases of clinical investigation, they are built on progress in pre-clinical research and cellular engineering techniques that are already improving outcomes for children and adults with high-risk malignancies.

Clinical Outcomes of Human Rhinovirus/Enterovirus Infection in Pediatric Hemopoietic Cell Transplant Patients.

Respiratory viral infections are common among pediatric transplant patients, with human rhinovirus (HRV) being the most frequent. In pediatric patients undergoing hemopoietic cell transplant (HCT), infection with HRV has been associated with progression to lower respiratory tract infection (LRTI) and adverse outcomes. We describe the clinical presentation and outcomes of HRV infection in children undergoing HCT. Single-center retrospective study. HCT recipients who were positive for HRV/EV (HRV+) or negative for any respiratory virus (VN) by BioFire® FilmArray® panel between October 2014 and December 2017, were included. Primary outcomes were progression to LRTI, ICU admission, all-cause mortality at 3 and 6 months, and respiratory event-related mortality at 6 months. 227 patients (160 allogeneic HCT) were included. Of all patients, 108/227 (47.6%) were HRV+. From all HRV+, 95/108 (88%) were symptomatic and 68/107 (63.6%) of the diagnosis were made pretransplant. The median age of HRV+ was significantly lower than VN patients (5 vs 10 years). Cough and rhinorrhea were more frequently observed in HRV+ (53.7 and 60% vs 19.8 and 22.8%, respectively). No differences were found between both groups pretransplant and overall in rates progression to LRTI, ICU admission, mechanical ventilation, all-cause within 3 and 6 months, and mortality related with respiratory failure. No significant association was found between the severity of respiratory disease and the type of conditioning, type of transplant, or absolute lymphocyte count. HRV infection is frequently detected in HCT recipients but is not associated with severity of respiratory disease, need for intensive care unit or mortality, including those diagnosed before transplant, suggesting that delaying HCT in this scenario may not be needed. Multicenter larger studies are required to confirm these findings.

Secondary Malignancies in Patients after Allogeneic Hematopoietic Cell Transplantation at Triple the Incidence of Malignancies in Their Family Donors

The primary end point of this retrospective study was to determine the incidence, risk factors and clinical outcome of secondary malignancies in 951 patients who were given an allogeneic Hemopoietic Cell Transplantation (HCT) and to compare them with the incidence of malignancy observed in the cohort of 761 stem cell family donors. With a median follow-up of 20 years, 74 HCT recipients (40 males) developed SM at a median of 16.09 years since transplant and at a median age of 47 years. The 35-yr cumulative incidence of SM was 17.0% (95% confidence interval, 12.8-21.6%). In univariate analysis, factors associated with increased incidence of SM were cumulative (limited and extensive) chronic graft-versus-host disease (cGvHD) and duration of cumulative cGvHD &gt;24 months. By multivariate analysis, cumulative cGvHD was the only independent risk factor for SM. Patients with cGvHD had 2.85x higher risk as compared to patients without cGvHD (P&lt;0.001). With a median follow-up of 18 years, 13 family donors (7 males) out of 761 developed malignancy at a median of 15.04 years since stem cell donation and at a median age of 55 years. As compared to the cumulative incidence of SM observed in the cohort of transplant recipients, the cumulative incidence of malignancy in family donors at 35 years since stem cell donation was statistically lower [5.8% vs 17.0% (P=0.001)]. This study demonstrates that HCT recipients have a significantly higher incidence of developing post-transplant malignancy as compared to family donors and that cGvHD is a strong risk factor for SM development.

POSTER: AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

POSTER: AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

AML-197 Clinical Outcomes and Treatment Patterns in Adult Patients With FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication Positive Acute Myeloid Leukemia Undergoing Allogeneic Hemopoietic Cell Transplantation in the US and Canada: CIBMTR® (Center for International Blood and Marrow Transplant Research Analysis)

Acrobat: A Multicenter Prospective Study to Monitor Chimerism in Post Allogeneic Hemopoietic Cell Transplant Patients with AML, ALL, or MDS for Prediction of Engraftment and Relapse

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) remains the treatment of choice for leukemia patients, yet its success is limited at least in part by disease relapse, which can be as high as 50% or more at two years post-HCT. While engraftment post-HCT is routinely measured by semi-quantitative fluorescent PCR of short tandem repeats (STRs), its low sensitivity (1-5%) limits its usefulness as a routine relapse monitoring tool. We have developed an ultra-sensitive, accurate, and precise microchimerism monitoring solution, AlloHeme that can potentially improve allogeneic HCT patient surveillance for engraftment and relapse. NGS-based AlloHeme can accurately measure microchimerism (mC, defined as <1% recipient DNA) with a limit of detection down to 0.035%. We hypothesized that detection of microchimerism and precise measurement of increasing mixed chimerism (iMC) using a highly sensitive test can predict disease relapse in patients post allo-HCT. OBJECTIVES: To study the role of mC and iMC measured by AlloHeme on relapse detection in patients with acute leukemias and myelodysplastic syndrome, we designed a prospective multicenter clinical trial - ACROBAT (Assessment of Chimerism in Recipients of Allogeneic Bone Marrow / Hematopoietic Cell Transplantation using AlloHeme Test). METHODS: The ACROBAT study will enroll approximately 260 allo-HCT recipients with AML, ALL and MDS across about 10 centers in the US. All patients will undergo serial chimerism monitoring in the first two years post-HCT. All AlloHeme testing will be conducted at CareDx's CLIA-certified/CAP-accredited laboratory. Chimerism will be monitored in the whole blood as well as for its constituent CD3+, CD15+ and CD33+ cellular subtypes. Bone marrow (whole bone marrow and CD34+ sub-type) chimerism will also be evaluated at specific timepoints. The study will determine the predictive value of mC and iMC for relapse detection and the lead time to relapse. Univariable and multivariable sub-distributional hazard regression models and joint models of longitudinal and time-to-event data will be used to determine the impact of mC and iMC measured at different time points on relapse post-HCT. A time-dependent ROC curve will be used to investigate the predictive ability of AlloHeme, MRD, and chimerism by STR for relapse detection. CONCLUSIONS: The ACROBAT study is a multicenter prospective clinical study designed to evaluate the role of increasing mixed chimerism and microchimerism for early relapse detection in patients who have undergone allo-HCT for AML, ALL or MDS.

Allogeneic haemopoietic cell transplant services in Australia and New Zealand in the first year of the COVID-19 pandemic: a report from Australia and New Zealand transplant and cellular therapies.

BackgroundThe COVID‐19 pandemic has caused major disruption to health systems, with allogeneic haematopoietic cell transplant (alloHCT) services a particularly vulnerable area. Ongoing provision of alloHCT has required dynamic responses at national and local levels. In Australia and New Zealand (ANZ), a high reliance on unrelated donors from overseas registries has posed an additional challenge.AimsTo describe the impact of COVID‐19 on alloHCT services in ANZ in the first year of the pandemic.MethodsData from the national alloHCT recipient and unrelated donor registries was extracted for a 2‐year time frame. Comparisons were made between a pre‐pandemic period of 1st March 2019 to 29th February 2020 and the corresponding dates during the pandemic, 1st March 2020 to 28th February 2021.ResultsThere was a 13% decrease in the number of allogeneic transplants, a reversal of steady increases in previous years, with the largest decrease in unrelated donor transplants. Local donors supplied a greater proportion of unrelated stem cell products. With a switch to universal cryopreservation, the time from request of a product to infusion increased by a median of 25.5 days for overseas products and 14 days for local products. There was a significant increase in the number of products collected but not used.ConclusionsA strong public health response and coordinated transplant community activities allowed for safe provision of alloHCT in ANZ, however our data suggests that the timely delivery of allogeneic transplants was affected by the COVID‐19 pandemic. Continued dedicated efforts are required to minimise further impacts.This article is protected by copyright. All rights reserved.

Predictors and outcomes of dose reduction of methotrexate and cyclosporin graft-versus-host disease prophylaxis following allogeneic haemopoietic cell transplantation.

Concern regarding dose-related toxicities of methotrexate (MTX) and cyclosporin (CYA) graft-versus-host disease (GVHD) prophylaxis occasionally leads to dose alterations post allogeneic haemopoietic cell transplant (alloHCT). To clarify causes of MTX and CYA dose alteration and assess impact on patient outcomes, including GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS). Analysis of retrospective data was performed in a single tertiary centre of patients who underwent alloHCT for any indication and who received GVHD prophylaxis with CYA and MTX between the years 2011 and 2015. Univariate analysis was conducted using the log-rank test for OS and using competing risk regression for NRM, relapse and GVHD. Fisher exact tests were used to determine if an association existed between each of the pre-transplant variables and MTX alteration. Multivariate models for OS and NRM were constructed using Cox proportional hazards modelling and competing risk regression respectively. Fifty-four (28%) of 196 had MTX alterations and 61/187 (33%) had CYA alterations. Reasons for MTX alteration included mucositis, renal or liver impairment, fluid overload and sepsis. Causes of CYA alteration were numerous, but most commonly due to acute kidney impairment. MTX alteration was associated with inferior OS (hazard ratio 2.4; P = <0.001) and higher NRM (odds ratio (OR) 4.6; P < 0.001) at 6 years post-landmark. CYA alteration was associated with greater NRM (OR 2.7; P = 0.0137) at 6 years. GVHD rates were unaffected by dose alteration. Our findings suggest dose alteration in MTX and CYA GVHD prophylaxis is associated with adverse survival outcomes in alloHCT, without a significant impact on GVHD rates.

Potential benefits of a virtual, home-based combined exercise and mindfulness training program for HSC transplant survivors: a single-arm pilot study

PurposeImpaired quality of life (QOL) including reduced physical fitness is a recognized late effect of hemopoietic cell transplantation (HCT). Guided exercise and mindfulness-based stress management (MBSM) programs have shown promise, mainly in the inpatient setting. We aimed to examine the feasibility of a virtual, home-based, combined exercise and MBSM program.MethodsPatients attending post-HCT clinic were invited to participate in this single-arm pre-post study. Eligibility criteria included age 18–75 years, > 6 months post allogeneic HCT. Consented participants attended an in-person session, followed by weekly exercise and MBSM training for 6 weeks via videoconferencing. Assessments were performed pre-training, and at 3-, 6- and 12-months and compared using a linear mixed effects model.Results21 of 24 patients consenting to the study completed the program (median age 56 years [IQR 46–62], median time post-HCT 37 months [IQR 26–46]). Six-minute walk test scores were significantly higher at 3 (mean difference 79.6, 95%CI 28–131, ES 0.55) and 12 months (mean difference 48.4, 95%CI 13–84, ES 0.33) compared to baseline. Sit-to-stand test was significantly higher at 3 (mean difference 4.4, 95%CI 1.4–7.4, ES 0.68) and 12 months (mean difference 3.9, 95%CI 0.24–7.6, ES 0.61). Dominant hand grip was significantly stronger at 3 (mean difference 0.16, 95%CI 0.04–0.28, ES 0.45), and 12 months (mean difference 0.21, 95%CI 0.08–0.24, ES 0.62). Significantly higher FACT-BMT total (mean difference 6.9, 95%CI 1.5–12.4, ES 0.49) and FACT-G scores (mean difference 5.2, 95%CI 1.4–9.1, ES 0.48) were found at 3 months. Over 80% of participants rated the virtual combined modal program highly and no adverse events were reported.ConclusionA 6-week virtual, home-based exercise and MBSM program was an acceptable, and potentially effective intervention for sustained improvement of some physical capacity and QOL outcomes in HCT survivors. Virtual-based healthcare service is highly relevant particularly during pandemics. To our knowledge, this study has the longest follow-up observation period for Internet based combined modality training program reported to date and warrants additional investigation.Trial Registration Research protocol approved by St Vincent’s Hospital Ethics Committee (HREC 12/SVH/175), approved 27/09/2012, trial commenced 24/05/13 and the first participant 07/06/13. Retrospectively registered with ANZCTR (ACTRN12613001054707) 23/09/2013.

Cytomegalovirus DNAemia and disease: current-era epidemiology, clinical characteristics and outcomes in cancer patients other than allogeneic haemopoietic transplantation.

High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.

Effect of donor age on adult unrelated donor haemopoietic cell transplant outcome: the Australian experience.

Results have been varied regarding the effect of donor age on the outcome of unrelated donor haemopoietic cell transplantation (HCT). To determine the influence of donor age on adult unrelated donor HCT outcome in Australia. Patients were included in the study if they were aged 16 years or above and underwent first allogeneic unrelated donor HCT in Australia for the indications of acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), chronic myelogenous leukaemia (CML) or myelodysplastic syndromes (MDS) between the years of 2001 and 2014 inclusive. The main outcome measure was overall survival (OS), which was tested against independent variables using univariate Kaplan-Meier methods and multivariate Cox regression. A total of 1158 unrelated donor HCT were represented in the data. Cumulative incidences of engraftment, transplant related mortality (TRM), acute graft-versus-host disease (GvHD), chronic GvHD and relapse were not significantly affected by donor age. OS probability at 5 years post-transplant was 48.3%. In multivariate analysis of OS, year of transplant 2001-2007, recipient age 40 years or greater, poor risk disease, human leukocyte antigen (HLA) match less than 6/6 and poor performance status at transplant (Karnofsky scale) were independently significant adverse OS risk factors. Donor age was not a significant risk factor for OS in univariate or multivariate analysis. The conclusion from this study was that donor age (up to 59 years) did not influence post-transplant outcome among adult unrelated donor HCT performed in Australia for haematologic malignancies.

Long-Term Efficacy of Reduced-Intensity Conditioning Compared to Standard Myeloablative Conditioning before Allogeneic Hemopoietic Cell Transplantation in Patients with Acute Myeloid Leukemia in First Complete Remission: 10-Year Follow-up of a Prospective, Open-Label Randomized Phase III Trial

Abstract Introduction Early results of a prospective randomized phase III trial comparing 8 Gy total body irradiation (TBI) and fludarabine (reduced-intensity conditioning (RIC)) against 12 Gy TBI and Cyclophosphamide (standard conditioning (SC)) before allogeneic hemopoietic cell transplantation in patients Methods The retrospective data collection was based on medical reports, phone interviews with the attending transplant physician, the outpatient hematologists, the primary care physicians and the patients themselves. In case of lost to follow-up local registration offices were contacted to obtain information about the survival status. Ninety-nine and 96 patients Results Data collection was performed between January 2016 and June 2017. Median follow-up was 9.9 years (interquartile range 8.5-11.4) from the date of transplantation. Completeness of the follow-up was 99% concerning survival status. The incidence of late relapse in the landmark analysis (cumulative incidence at 10 years) was 10% [95% CI 3-18] for the RIC vs 21% [95% CI 11-31] for the SC arm (HR 0.47 [95% CI 0.19-1.17]; p= 0.11). Interestingly, relapses occurred later in the SC arm than in the RIC arm (median time to relapse 5.0 months (interquartile range 3.0-8.8) in the RIC vs 9.5 months the SC arm (interquartile range 4.5-20.5; p=0.12). However, the cumulative incidence at 10 years from transplantation was almost identical. In the analysis of the patient population from baseline (all patients that were initially included in the study) the trend for a reduced NRM in the RIC arm could still be observed and was statistically significant in patients from 41-60 years (13% [95% CI 5-22] vs 32% [95%CI 19-44] HR 0.43 [95% CI 0.19-0.95]; p=0.036). The probability of OS at 10 years was 60% [95% CI 50-70] in the RIC arm and 47% [95% CI 38-59] in the SC arm with a HR of 0.71 (0.47-1.07); p=0.10), respectively. The probability of disease free survival at 10 years was 55% [95% CI 45-66] in the RIC arm vs 43% [95% CI 34-55] in the SC arm (HR 0.76 [0.51-1.14]; p=0.19), respectively. The incidence of chronic GVHD at five years (42% vs 48%), rates of secondary malignancies (4% versus 7%) and rates of late complications did not differ significantly between the RIC and the SC arm. Conclusion RIC with 8 Gy TBI and Fludarabine does not increase the risk of late relapse compared to SC after allogeneic transplantation in patients with AML in 1st CR. Given the significantly lower early morbidity and toxicity, RIC with moderately reduced doses of TBI or alkylating agents can be regarded as optimized conditioning strategy in AML patients Download : Download high-res image (88KB) Download : Download full-size image Figure . Disclosures Schetelig: Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria. Hegenbart: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Prothena: Membership on an entity's Board of Directors or advisory committees. Dreger: Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; Riemser: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; Jansen: Consultancy; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; Gilead: Consultancy, Speakers Bureau; medac: Other: Travel grants; medac: Other: Travel grants; medac: Other: Travel grants; medac: Other; medac: Other; medac: Other; medac: Other; medac: Other: Travel grants; Jansen: Consultancy; Riemser: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Jansen: Consultancy; Jansen: Consultancy; Jansen: Consultancy; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; AbbVie: Consultancy, Other: Travel grants, Speakers Bureau; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding; Riemser: Consultancy, Research Funding. Siepmann: European Academy of Neurology: Research Funding; Michael J. Fox Foundation: Research Funding; Prothena and the German Parkinson's Disease Association (DPG): Research Funding.

Secondary oral cancer following hematopoietic cell transplantation.

The aim of this retrospective study was to determine the incidence and the clinical outcome of secondary oral cancer (SOC) and to assess potential risk factors in a large cohort of patients (n = 908), who received allogeneic hemopoietic cell transplantation (HCT) either for a malignant (n = 733) or nonmalignant hematologic disease (n = 175). The median follow-up of 438 transplant survivors was 17 years. Twelve patients developed SOC at a median of 13.5 years since HCT and at a median age of 47 years. The 35-year cumulative incidence function of SOC development was 3.47%. In univariate analysis, factors associated with increased incidence of SOC were reduced intensity conditioning and chronic graft-versus-host disease (cGvHD). On multivariate analysis, nonmalignant disease and duration of oral cGvHD ≥15 months were independent risk factors for SOC development. Nonmalignant disease recipients had 3.94× higher than expected rate of SOC (95% confidence interval, 1.50-10.39%, p = 0.0055). Recipients whose oral cGvHD persisted for more than ≥15 months had 58.6× higher than expected rate of SOC (95% confidence interval, 13.3-258.1%), p < 0.0001). This study demonstrates that oral cGvHD and a diagnosis of nonmalignant hematologic disease are strong risk factors in the SOC development.

Monocyte Reconstitution and Gut Microbiota Composition after Hematopoietic Stem Cell Transplantation

BackgroundMonocytes are an essential cellular component of the innate immune system that support the host’s effectiveness to combat a range of infectious pathogens. Hemopoietic cell transplantation (HCT) results in transient monocyte depletion, but the factors that regulate recovery of monocyte populations are not fully understood. In this study, we investigated whether the composition of the gastrointestinal microbiota is associated with the recovery of monocyte homeostasis after HCT.MethodsWe performed a single-center, prospective, pilot study of 18 recipients of either autologous or allogeneic HCT. Serial blood and stool samples were collected from each patient during their HCT hospitalization. Analysis of the gut microbiota was done using 16S rRNA gene sequencing, and flow cytometric analysis was used to characterize the phenotypic composition of monocyte populations.ResultsDynamic fluctuations in monocyte reconstitution occurred after HCT, and large differences were observed in monocyte frequency among patients over time. Recovery of absolute monocyte counts and subsets showed significant variability across the heterogeneous transplant types and conditioning intensities; no relationship to the microbiota composition was observed in this small cohort.ConclusionIn this pilot study, a relationship between the microbiota composition and monocyte homeostasis could not be firmly established. However, we identify multivariate associations between clinical factors and monocyte reconstitution post-HCT. Our findings encourage further longitudinal surveillance of the intestinal microbiome and its link to immune reconstitution.

HIV and lymphoma: from oncological futility to treatment

Cancer and HIV have been inextricably linked since the first report in 1982 of biopsy-confirmed Kaposi's sarcoma among previously healthy homosexual men living in Los Angeles and Orange counties, California, USA. 1 Centers for Disease ControlA cluster of Kaposi's sarcoma and pneumocystis carinii pneumonia among homosexual male residents of Los Angeles and Orange counties, California. MMWR Morb Mortal Wkly Rep. 1982; 31: 305-307 PubMed Google Scholar The cases established concerns for what later would be defined as AIDS. The report speculated: “One hypothesis consistent with the observations reported here is that infectious agents are being sexually transmitted among homosexually active males. Infectious agents not yet identified may cause the acquired cellular immunodeficiency that appears to underlie KS [Kaposi's sarcoma] and/or PCP [Pneumocystis carcinii pneumonia] among homosexual males.” The discovery of HIV proved it to be the aetiological agent. Given the known association between immunodeficiency and cancer and oncogenic virus and cancer, the discovery of human herpesvirus 8 (also known as Kaposi's sarcoma-associated herpesvirus) completed the puzzle on the mysterious outbreak of Kaposi's sarcoma. 2 Chang Y Cesarman E Pessin MS et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994; 266: 1865-1869 Crossref PubMed Scopus (4973) Google Scholar Epidemiology of haematological malignancies in people living with HIVPeople living with HIV or AIDS are at increased risk of Hodgkin and non-Hodgkin lymphoma compared with HIV-negative individuals. Data on the risk of multiple myeloma or leukaemia are inconsistent and of low quality but the risk does not seem to be increased. Specific haematological malignancies occur in different contexts of age, CD4 cell count, HIV control, viral co-infections, or chronic inflammation, and the expansion of combination antiretroviral therapy has led to varied demographic and epidemiological shifts among people with HIV. Full-Text PDF CAR T-cell therapy for cancer and HIV through novel approaches to HIV-associated haematological malignanciesPeople living with HIV are a global population with increased cancer risk but their access to modern immunotherapies for cancer treatment has been limited by socioeconomic factors and inadequate research to support safety and efficacy in this population. These immunotherapies include immune checkpoint inhibitors and advances in cellular immunotherapy, particularly chimeric antigen receptor (CAR) T-cell therapy. Despite the field of cancer immunotherapy rapidly expanding with ongoing clinical trials, people with HIV are often excluded from such trials. Full-Text PDF Haemopoietic cell transplantation in patients living with HIVHaemopoietic cell transplantation is established as a standard treatment approach for people living with HIV who have haematological malignancies with poor prognosis. Studies with autologous and allogeneic haemopoietic cell transplantation suggest that HIV status does not adversely affect outcomes, provided that there is adequate infection prophylaxis. Attention to possible drug–drug interactions is important. Allogeneic haemopoietic cell transplantation substantially reduces the long-term HIV reservoir when complete donor chimerism is established. Full-Text PDF Treatment management of haematological malignancies in people living with HIVAlthough the incidence of HIV-associated lymphomas decreased after the introduction of effective combination antiretroviral therapy, they became the most common AIDS-related cancer in high-income countries. Moreover, as people living with HIV live longer, a wide range of non-AIDS-related cancer has emerged, including other haematological malignancies. Nonetheless, combination antiretroviral therapy has offered people with HIV the opportunity to receive the same therapies as those provided to the general population, and intensive curative therapies have become the standard. Full-Text PDF

Allogeneic haemopoietic transplantation for acute myeloid leukaemia in second complete remission: a registry report by the Acute Leukaemia Working Party of the EBMT.

Allogeneic haemopoietic cell transplant (allo-HCT) may be curative in acute myeloid leukaemia (AML) in second complete remission (CR2) but the impact of reduced intensity (RIC) versus myeloablative conditioning (MAC) is uncertain. The Acute Leukaemia Working Party of the European Society for Blood and Bone Marrow Transplantation Registry studied an AML CR2 cohort characterised by age ≥ 18 years, first allo-HCT 2007-2016, available cytogenetic profile at diagnosis, donors who were matched family, volunteer unrelated with HLA antigen match 10/10 or 9/10 or haplo-identical. The 1879 eligible patients included 1010 (54%) MAC allo-HCT recipients. In patients <50 years (y), two year outcomes for MAC vs RIC allo-HCT were equivalent with leukaemia-free survival (LFS) 54% for each, overall survival (OS), 61% vs 62%, non-relapse mortality (NRM) 18% vs 15% and graft versus host disease relapse-free survival (GRFS) 38% vs 42%. In patients ≥50 y, 2 y outcomes for MAC vs RIC allo-HCT were equivalent for LFS 52% vs 49%, OS 58% vs 55% and GRFS 42.4% vs 36%. However, NRM was significantly inferior after MAC allo-HCT, 27% vs 19% (P = 0.01) despite worse cGVHD after RIC-allo (32% vs 39%). These data support the need for ongoing prospective study of conditioning intensity and GVHD mitigation in AML.

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)

Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.

RBC and Platelet Transfusion Requirements in the First 30 Days after Allogeneic Hemopoietic Cell Transplantation and Transfusion Independence: A Single Center Retrospective Study of 1803 Recipients

Background Allogeneic hematopoietic cell transplant (allo-HCT) recipients often require substantial but variable transfusion support. Few studies have quantified their transfusion burden, or identified prognostic factors for increased transfusions to guide patient counseling or inventory management. Data on haploidentical HCT (Haplo-HCT) patients are especially scarce. Objectives To identify factors associated with increased RBC and platelet (PLT) transfusions, and provide for the first time data on a large cohort of Haplo-HCT patients. Methods We retrospectively evaluated 1803 consecutive first time adult allo-HCT patients transplanted at our center in 2011-17. Multivariate linear regression and Fine-Gray subdistribution hazards models were used to examine the associations between baseline characteristics (age, sex, disease stage, graft type, donor type, ABO compatibility and conditioning regimen) and log-transformed transfusion units in the first 30 days after HCT and time to reach transfusion independence respectively. Results The median age of the cohort was 53(18-78); 56.2% were male. Most common diagnoses were AML (38.8%), ALL (19.6%), and lymphoma (14.8%); 50.2% had advanced disease. Patients received nonmyeloablative/reduced intensity (58.9%) or myeloablative conditioning regimens (MAC, 41.1%), followed by peripheral blood stem cell (88.4%), bone marrow (6.9%) or umbilical (UC, 4.7%) HCT. Most grafts were from matched related (MRD, 38.7%) or unrelated (MUD, 49.1%) donors, and 7.6% were haploidentical. ABO incompatibility (Major 15.8%, minor 18.6%, bi-directional 8.5%) was present in 42.9% of the cases (Table 1). Most of the 1764 patients who survived 30+ days received RBC (88.2%) or PLT (97.2%) transfusions during the first 30 days, with a median of 3 (0-37) RBC and 5(0-144) apheresis PLT units. RBC and PLT transfusion independence was reached in 28 (95%CI: 26-31) and 12 (95%CI: 12-13) days respectively. Multivariate analyses showed that Haplo-HCT and UC graft were independently associated with more RBC and PLT transfusions, as were advanced disease, ABO incompatibility, older age, and MAC (P Conclusions We identified patient and transplant factors strongly associated with increased transfusions in the first 30 days after allo-HCT, and quantified the transfusion burden of Haplo-HCT relative to other types of HCT.