Predictors of fluid overload in allogeneic hematopoietic cell transplant patients receiving post-transplant cyclophosphamide.

BACKGROUND: Fluid overload (FO) commonly occurs during hospitalization for allogeneic hematopoietic cell transplantation (HCT). Grade 2-4 FO is associated with day +100 non-relapse mortality.1 Post-transplant cyclophosphamide (PTCY) for graft-versus-host disease prevention requires aggressive IV hydration to prevent hemorrhagic cystitis. MATERIALS AND METHODS: This is a single-center, retrospective, observational study conducted at an academic medical center via electronic chart review. Included patients received allogeneic HCT followed by PTCY on days +3 and +4. Patients were excluded for age < 18 years or incarceration. Primary endpoints are incidence of Grade 2-4 FO and associated risk factors. Descriptive and inferential statistics (i.e., Fisher's exact test, multivariable regression analysis) were used. RESULTS: Of 97 patients screened, 95 were included and 2 were excluded due to absence of weight measurements needed to grade FO. Median age was 60 years, 66.3% were male, 91.6% received reduced-intensity conditioning, 72.6% received haploidentical HCT, 44.2% were ECOG 0, and 11.6% had diastolic dysfunction. Incidence of grade 2-4 FO was 33.7% (n = 32). Univariate analyses found age (continuous; p = 0.04) and BSA < 1.7 m2 (p = 0.006) as independent factors associated with grade 2-4 FO. Multivariable regression analysis found 3.3% higher risk with every 1-year increase in age ranging from f 20 to 78 years (OR 1.033, 95% CI 1.001, 1.006; p = 0.0453) and 82.8% lower risk with BSA ≥ 1.7 m2 (OR 0.172, 95% CI 0.051, 0.588; p = 0.005) after adjusting for co-variates. CONCLUSION(S): Increasing age and BSA < 1.7 m2 are risk factors associated with grade 2-4 FO during hospitalization for allogeneic HCT with PTCY.

Age and dose dependent changes to the bone and bone marrow microenvironment after cytotoxic conditioning with busulfan.

Preparative regimens before Hematopoietic Cell Transplantation (HCT) damage the bone marrow (BM) microenvironment, potentially leading to secondary morbidity and even mortality. The precise effects of cytotoxic preconditioning on bone and BM remodeling, regeneration, and subsequent hematopoietic recovery over time remain unclear. Moreover, the influence of recipient age and cytotoxic dose have not been fully described. In this study, we longitudinally investigated bone and BM remodeling after busulfan treatment with low intensity (LI) and high intensity (HI) regimens as a function of animal age. As expected, higher donor chimerism was observed in young mice in both LI and HI regimens compared to adult mice. Noticeably in adult mice, significant engraftment was only observed in the HI group. The integrity of the blood-bone marrow barrier in calvarial BM blood vessels was lost after busulfan treatment in the young mice and remained altered even 6 weeks after HCT. In adult mice, the severity of vascular leakage appeared to be dose-dependent, being more pronounced in HI compared to LI recipients. Interestingly, no noticeable change in blood flow velocity was observed following busulfan treatment. Ex vivo imaging of the long bones revealed a reduction in the frequency and an increase in the diameter and density of the blood vessels shortly after treatment, a phenomenon that largely recovered in young mice but persisted in older mice after 6 weeks. Furthermore, analysis of bone remodeling indicated a significant alteration in bone turnover at 6 weeks compared to earlier timepoints in both young and adult mice. Overall, our results reveal new aspects of bone and BM remodeling, as well as hematopoietic recovery, which is dependent on the cytotoxic dose and recipient age.

Outcomes of older adults undergoing allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide based prophylaxis.

This study evaluates the feasibility of using post-transplant cyclophosphamide (PTCY) prophylaxis in allo-hematopoietic cell transplantation (HCT) for adults aged 65 and older. PTCY is increasingly used to prevent graft-versus-host disease (GVHD) across all donor types, but concerns remain about potential risks, especially in older patients. Fifty-seven adults aged 65 or older with hematological malignancies, undergoing their first allo-HCT with PTCY prophylaxis between January 2011 and January 2023 were included. Overall, 94.8% of patients achieved primary engraftment. The median durations for neutrophil and platelet engraftments were 19 and 21 days. The day +30 cumulative incidence of bacterial bloodstream infection was 43.9%. No CMV reactivations occurred within the first 100 days after letermovir implementation. The day +180 cumulative incidences of grade II-IV and III-IV acute GVHD, and the 2-year cumulative incidence of moderate/severe chronic GVHD were 26.3%, 10.5%, and 4.8%. Eighteen patients (31.6%) relapsed, and 30 (52.6%) died, with relapse (16.4%) and infection (11.5%) being the main causes of death. The estimated 2-year overall survival, non-relapse mortality, cumulative incidence of relapse, and GVHD-free relapse-free survival rates were 45.5%, 27.1%, 33.9%, and 37.0%. Adults aged 70 or older had similar outcomes to those aged 65-69. This study confirms the safety and feasibility of PTCY-based allo-HCT in older adults.

Allogeneic hematopoietic cell transplantation from alternative donors in acute myeloid leukemia.

Allogeneic hematopoietic cell transplantation (HCT) potentially provides a cure for patients with acute myeloid leukemia (AML) who are unlikely to be cured with chemotherapy alone. Previously, human leukocyte antigen (HLA)-matched related donors were used exclusively, which made the procedure available for a limited proportion of patients. The introduction of high-resolution HLA-typing technology, innovations in immunosuppressive therapy, and improved supportive care measures have significantly changed the situation. Now, patients without a matched related donor have an ample opportunity to receive allogeneic HCT with the use of matched or mismatched unrelated donors, umbilical cord blood grafts, or haploidentical related donors. The outcomes of alternative donor transplantations have improved over the past decades, and the growth of unrelated donor registries as well as the donor diversification have enhanced the chance of finding a suitable donor. With multiple alternative donor choices available for most patients, the donor selection is becoming increasingly important. To discuss the optimal donor choice in case of unavailability of an HLA-matched related donor, this article reviews the existing literature of retrospective and prospective comparisons of different alternative donor transplantations in AML and discusses the current state-of-art modalities in allogeneic HCT using alternative donors.

Celebrating the registration of 9.000 patients treated with CAR T cells in the EBMT registry: Collection of real-world data in the context of hematopoietic cellular therapies.

The European society for Blood and Marrow Transplantation (EBMT) has a long-standing interest in the evaluation of hematopoietic cell transplantation. More than three decades ago, its members established a continental registry. Today, more than 700,000 patients have been registered, and information has been gathered on more than 800,000 transplants. This huge amount of information has allowed conducting multiple retrospective studies, evaluating changes in practices over time and for different categories of diseases, benchmarking outcome across EBMT affiliated centers, and increasingly serves to build synthetic comparators to evaluate the introduction of therapeutic innovations in the field of hematology. CAR-T cells therapies draw on human and technical resources that are also used to deliver HCT; they elicit side effects that require the implementation of risk mitigation plans; they are living drugs that persist in the body of the recipient and thus deserve prolonged follow-up; the introduction of CAR-T cells in the pharmacopeia is likely to significantly impact on the practice of BMT; for all these reasons and even before the first approvals of CAR-T Cells in Europe, EBMT engaged in a project aiming at complementing the EBMT Registry with a Cellular Therapy Form, with the objective to register CAR-T cells treated patients and collect information on their short-, middle- and long-term outcome. The goal is to provide EBMT investigators with a tool for primary analyses of the collected information and to support secondary use of data transferred at the individual level to Marketing Authorization Holders and other interested parties, to fulfill their obligations to health authorities and further evaluate the actual medical values of CAR-T Cells in different contexts and indications. The EBMT Registry received a positive opinion from the European Medicines agency in 2019, and five years later contains information on more than 9.000 treated patients. This article describes the journey to start this new activity, lessons to be drawn in view of improving the collection of real-world data, and what existing information tells us in terms of patient access.

The role of registries in hematological disorders.

Hematopoietic cell transplantation (HCT) was developed more than 65 years ago to treat malignant blood disorders and irreversible bone marrow failures, with the aim of replacing a diseased hematopoietic system with a healthy one (allogeneic HCT). Decades later, the procedure was adapted to apply maximal chemotherapy or radiotherapy, which would result in bone marrow failure, but could be remedied by an infusion of a patient's own cryopreserved bone marrow (autologous HCT). Both treatments are high-risk and complex, especially during the initial phases. However, concerted efforts, vision, and collaboration between physicians and centers worldwide have resulted in HCT becoming a standard of care for many hematological disorders with progressive improvements in outcomes. Registries and the collaboration of societies worldwide have enabled the delivery of this curative therapy to many patients with fatal hematological diseases. More than 1.5 million HCT were performed between 1957 and 2019, and activity is continuously increasing worldwide.

HLA-DM and HLA-DO interplay for the peptide editing of HLA class II in healthy tissues and leukemia.

HLA class II antigen presentation is modulated by the activity of the peptide editor HLA-DM and its antagonist HLA-DO, with their interplay controlling the peptide repertoires presented by normal and malignant cells. The role of these molecules in allogeneic hematopoietic cell transplantation (alloHCT) is poorly investigated. Balanced expression of HLA-DM and HLA-DO can influence the presentation of leukemia-associated antigens and peptides targeted by alloreactive T cells, therefore affecting both anti-leukemia immunity and the potential onset of Graft versus Host Disease. We leveraged on a large collection of bulk and single cell RNA sequencing data, available at different repositories, to comprehensively review the level and distribution of HLA-DM and HLA-DO in different cell types and tissues of the human body. The resulting expression atlas will help future investigations aiming to dissect the dual role of HLA class II peptide editing in alloHCT, and their potential impact on its clinical outcome.

Minor histocompatibility antigens to predict, monitor or manipulate GvL and GvHD after allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (alloHCT) provides a potential curative treatment for haematological malignancies. The therapeutic Graft-versus-Leukaemia (GvL) effect is induced by donor T cells attacking patient hematopoietic (malignant) cells. However, if healthy non-hematopoietic tissues are targeted, Graft-versus-Disease (GvHD) may develop. After HLA-matched alloHCT, GvL and GvHD are induced by donor T cells recognizing polymorphic peptides presented by HLA on patient cells, so-called minor histocompatibility antigens (MiHAs). The balance between GvL and GvHD depends on the tissue distribution of MiHAs and T-cell frequencies targeting these MiHAs. T cells against broadly expressed MiHAs induce GvL and GvHD, whereas those targeting MiHAs with hematopoietic-restricted expression induce GvL without GvHD. Recently, the MiHA repertoire identified in natural immune responses after alloHCT was expanded to 159 total HLA-I-restricted MiHAs, including 14 hematopoietic-restricted MiHAs. This review explores their potential relevance to predict, monitor, and manipulate GvL and GvHD for improving clinical outcome after HLA-matched alloHCT.

Shape of the art: TCR-repertoire after allogeneic hematopoietic cell transplantation.

The human adaptive immune repertoire is characterized by specificity and diversity to provide immunity against past and future tasks. Such tasks are mainly infections but also malignant transformations of cells. With its multiple lines of defense, the human immune system contains both, rapid reaction forces and the potential to capture, disassemble and analyze strange structures in order to teach the adaptive immune system and mount a specific immune response. Prevention and mitigation of autoimmunity is of equal importance. In the context of allogeneic hematopoietic cell transplantation (HCT) specific challenges exist with the transfer of cells from the adapted donor immune system to the immunosuppressed recipient. Those challenges are immunogenetic disparity between donor and host, reconstitution of immunity early after HCT by expansion of mature immune effector cells, and impaired thymic function, if the recipient is an adult (as it is the case in most HCTs). The possibility to characterize the adaptive immune repertoire by massively parallel sequencing of T-cell receptor gene rearrangements allows for a much more detailed characterization of the T-cell repertoire. In addition, high-dimensional characterization of immune effector cells based on their immunophenotype and single cell RNA sequencing allow for much deeper insights in adaptive immune responses. We here review, existing - still incomplete - information on immune reconstitution after allogeneic HCT. Building on the technological advances much deeper insights into immune recovery after HCT and adaptive immune responses and can be expected in the coming years.

Is HLA-E with its receptors an immune checkpoint or an antigenic determinant in allo-HCT?

Hematopoietic cell transplantation (HCT) represents a potentially curative therapeutic approach for various hematologic and non-hematologic malignancies. Human leukocyte antigen (HLA) matching is still the central selection criterion for HCT donors. Nevertheless, post-transplant complications, in particular graft-versus-host disease (GvHD), relapse of disease and infectious complications, represent a major challenge and contribute significantly to morbidity and mortality. Recently, non-classical HLA class I molecules, especially HLA-E, have gained increasing attention in the context of allogeneic HCT. This review aims to summarize the latest findings on the immunomodulatory role of HLA-E, which serves as a ligand for receptors of the innate and adaptive immune system. In particular, we aim to elucidate how (i) polymorphisms within HLA-E, (ii) the NKG2A/C axis and (iii) the repertoire of peptides presented by HLA-E jointly influence the functionality of immune effector cells. Understanding this intricate network of interactions is crucial as it significantly affects NK and T cell responses and thus clinical outcomes after HCT.

Epilepsy after acute central nervous system complications of pediatric hematopoietic cell transplantation: A retrospective, multicenter study.

BACKGROUND: Acute central nervous system (CNS) complications are common and well described among pediatric patients undergoing haematopoietic cell transplantation (HCT). However, their long-term outcomes are not known. The aim of this study is to describe the incidence, characteristics, and risk factors of long-term epilepsy in pediatric patients with acute CNS complications of HCT. METHODS: This retrospective study included pediatric patients who developed acute CNS complications from autologous or allogeneic HCT between 2000 and 2022. Clinical, therapeutic and prognostic data including long-term outcomes were analyzed. A diagnosis of epilepsy was provided if unprovoked seizures occurred during follow-up. RESULTS: Ninety-four patients (63 males, 31 females, median age 10 years, range 1-21 years) were included. The most common acute CNS complications were posterior reversible encephalopathy syndrome (n = 43, 46 %) and infections (n = 15, 16 %). Sixty-five patients (69 %) had acute symptomatic seizures, with 14 (16 %) having one or more episodes of status epilepticus (SE). Nine patients (9.6 %) were diagnosed with long-term focal epilepsy during the follow-up (5-year cumulative incidence from the acute complication, 13.3 %). Acute symptomatic SE during neurological complications of HCT was associated with an increased risk of long-term epilepsy (OR=14, 95 % CI 2.87-68.97). CONCLUSIONS: A higher occurrence of epilepsy has been observed in our cohort compared to the general population. Acute symptomatic SE during HCT was associated with a higher risk of long-term epilepsy. Pediatric patients with CNS complications during HCT could benefit from specific neurological follow-up. Further studies are needed to characterize mechanisms of epileptogenesis in pediatric patients undergoing HCT.

Understanding factors limiting hematopoietic cell transplantation for acute myeloid leukemia patients in Mexico: a comprehensive analysis.

Acute myeloid leukemia (AML) is the most frequent indication for allogeneic hematopoietic cell transplantation (alloHCT) worldwide; social and health system barriers limit its access. We performed an observational retrospective analysis in Mexico to analyze factors limiting alloHCT in fit patients with AML. With a median follow-up of 11.8 months, 301 patients were included, with a median age of 42; 33.5% were classified as adverse risk. Despite 215 patients (92.5%) achieving complete remission, only 103 (34%) had HLA-typing: 44.5% had a matched-sibling donor (MSD), 32% a haploidentical donor, and 23.5% had no donor. Only 23.5% of patients had an HCT consult; merely 36 underwent an HCT: 30 alloHCT, and six an autologous HCT. Age ≥ 60 years, HCT-CI score ≥ three, and the absence of a local transplant program negatively influenced HLA typing likelihood. Patients with an MSD had a higher alloHCT likelihood. The cumulative incidence of transplant (CIT) and relapse (CIR) at 6 and 12 months was 7.3% and 13.8%, 8.2% and 13%, respectively. A lack of HLA-typing was associated with a lower CIT (p < 0.001) and higher CIR (p = 0.033) (HR 11.72, CI 95% 4.39-31.27, p < 0.001), while the presence of an MSD was associated with a higher CIT (p = 0.002) (HR 4.22, CI 95% 1.89-9.44, p < 0.001). The main reasons hindering alloHCT are the lack of access to HLA-typing tests and the absence of an MSD. A national donor registry and improved HLA-typing accessibility are critical for increasing alloHCT access in Mexico.

COVID-19 Outcomes Among Hematopoietic Cell Transplant and Chimeric Antigen Receptor T-cell Recipients in the Era of SARS-CoV-2 Omicron Variants and COVID-19 Therapeutics.

BACKGROUND: Recipients of cellular therapies, including hematopoietic cell transplant (HCT) and chimeric antigen receptor T-cell (CART) therapy, are at risk for poor outcomes from coronavirus disease 2019 (COVID-19). There are limited data describing outcomes among patients in the pre- and early post-cellular therapy period during the Omicron era when multiple antiviral therapeutics were widely available. OBJECTIVES: Describe COVID-19 treatment and outcomes in patients diagnosed with COVID-19 during the pre- or early post-cellular therapy period. STUDY DESIGN: This is a single-center retrospective cohort study of adult HCT and CART recipients diagnosed with COVID-19 in the pre- and early post-cellular therapy period who tested positive for COVID-19 at our cancer center between January 1, 2022 and March 1, 2023. Primary outcomes were 30-day COVID-19-related hospitalization and death. A secondary outcome was development of persistent COVID-19, defined by a positive SARS-CoV-2 polymerase chain reaction (PCR) 31-90 days after COVID-19 diagnosis. RESULTS: Among 65 patients included, 52 (80%) received at least one COVID-19 therapeutic. The most common treatment after initial COVID-19 diagnosis was nirmatrelvir/ritonavir (29%), followed by monoclonal antibody therapy (26%) and remdesivir (11%). Of the 64 patients with at least 30 days of follow-up, 8 (12%) had at least one COVID-19-related hospitalization and one patient died, though cause of death was not due to COVID-19. Of the 8 patients hospitalized for COVID-19, one had severe disease and 7 had mild or moderate infection. Persistent COVID-19 was observed in 13/65 (20%) patients, with 4 patients requiring additional antiviral therapy. Three pre-cellular therapy patients had delays in receiving cellular therapy due to persistent COVID-19. CONCLUSIONS: During the Omicron era, rates of 30-day COVID-19-related hospitalization and death were relatively low in this cohort of pre- and early post-HCT and CART recipients, the majority of whom received treatment with at least one antiviral agent. Persistent COVID-19 occurred in 1 in 5 patients in the peri-cellular therapy period and led to cellular therapy treatment delays in several patients, highlighting the need for new COVID-19 treatment strategies.

Better clinical outcomes and lower triggering of inflammatory cytokines for allogeneic hematopoietic cell transplant recipients treated in home care versus hospital isolation - the Karolinska experience.

After allogeneic hematopoietic cell transplantation (Allo-HCT) and conditioning, patients are typically placed in isolated hospital rooms to prevent neutropenic infections. Since 1998, we've offered an alternative: home care for patients living within a one to two-hour drive of the hospital. In Sweden this approach includes daily visits by an experienced nurse and daily phone consultations with a unit physician. When necessary, patients receive transfusions, intravenous antibiotics, and total parenteral nutrition at home. Our initial study report compared 36 home care patients with 54 hospital-treated controls. Multivariate analysis found that home care patients were discharged earlier to outpatient clinics, required fewer days of total parenteral nutrition, had less acute graft-versus-host disease (GVHD) grade II-IV, and lower transplantation-related mortality (TRM) and lower costs. Long-term follow-up showed similar chronic GVHD and relapse rates in both groups, with improved survival rates in the home care group. A subsequent comparison of 146 home care patients with hospital-treated controls indicated that home care and longer home stays were associated with lower grades of acute GVHD. Home care was found to be safe and beneficial for children and adolescents. Over two decades, 252 patients received home care post-Allo-HCT without any fatalities at-home. Ten-year outcomes showed a 14% TRM and a 59% survival rate. In 2020, an independent center confirmed the reduced risk of acute GVHD grades II-IV for patients treated in home care. Here, we report for the first time that home care patients also demonstrate a less inflammatory systemic cytokine profile. We found higher levels of IFN-γ, IL-2, IL-5, IL-13, GM-CSF, and G-CSF, but lower VEGF in hospital-treated patients, which may contribute to acute GVHD grades II-IV. In conclusion, home-based treatment following Allo-HCT yields multiple promising clinical outcomes and improved systemic inflammatory markers, which may contribute to less development of life-threatening GVHD.

Hypomethylating agents are Effective in Treatment for Relapsed Myelofibrosis After Allogeneic Hematopoietic Cell Transplantation.

BACKGROUND: Myelofibrosis (MF) is a myeloproliferative neoplasm with a relapse rate of 10-30% after allogeneic transplantation (alloHCT). Current recommendations to treat relapse include withdrawal of immunosuppression, donor lymphocyte infusion, and potentially a second alloHCT. Hypomethylating agents (HMA) have shown efficacy as salvage therapy by inducing an immune response and improving donor chimerism for myeloid neoplasm post-HCT. Data is limited on use of HMA for MF post-alloHCT relapse. OBJECTIVE: To determine the benefit of using HMA for MF patients relapsing after alloHCT. STUDY DESIGN: We retrospectively analyzed 12 patients with MF post-alloHCT relapse who received HMA to determine response via restoration of donor chimerism and clearance of molecular mutation. RESULTS: The median age was 61 years (range 41-72) with 92% classified as intermediate-2/high-risk by DIPSS and 83% as high/very high risk by MIPSS70+. The median time to relapse post-alloHCT was 282.5 days (range 96-2388) with median donor chimerism 57.82% (range 2.48-84) prior to starting HMA. After two cycles of HMA, 58% experienced restoration of donor chimerism. Molecular clearance of pre-HCT driver mutations occurred in 50% of patients at the most recent follow-up. New chronic GvHD occurred in 50% of patients with most being mild to moderate that resolved after treatment. CONCLUSION: HMA was safe and effective in a high-risk population after post-alloHCT relapse and is an option for patients in the future.

Successful treatment with mesenchymal stem cells for steroid-refractory late-onset idiopathic pneumonia syndrome following allogeneic hematopoietic cell transplantation.

The reportedly poor outcome of late-onset idiopathic pneumonia syndrome (IPS) necessitates new approaches to its treatment. A 55-year-old man who had undergone allogeneic hematopoietic cell transplantation (allo-HCT) for myelodysplastic syndrome 1 year ago developed dyspnea with acute skin graft-versus-host disease (GVHD) flare-up while tapering immunosuppressive agents. He presented with acute respiratory distress syndrome with ground-glass opacities in the right upper and left lower lobes. All infectious tests, including multiplex polymerase chain reaction of nasal wash, were negative, and broad-spectrum antibiotic therapy was refractory. The patient was diagnosed with late-onset IPS and was refractory to methylprednisolone pulse therapy. He then showed a favorable response to mesenchymal stem cell (MSC) infusion. After eight infusions of MSCs, he had no IPS recurrence for over one year. Recently, preclinical studies have reported the potential therapeutic utility of MSC infusion for treating IPS, and our case supports its potential for treating late-onset IPS.

Salvage Therapy and Allogeneic Hematopoietic Cell Transplantation for the Severe Cytokine Storm Syndrome of Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) can be considered as a severe cytokine storm syndrome disorder. HLH typically manifests as a life-threatening inflammatory syndrome characterized by fevers, cytopenias, hepatosplenomegaly, and various other accompanying manifestations such as coagulopathy, hepatitis or liver failure, seizures or altered mental status, and even multi-organ failure. Standard up-front treatments do not always bring HLH into remission or maintain adequate response, and salvage or alternative therapies are often needed. For patients with genetic diseases that cause HLH, curative allogeneic hematopoietic cell transplantation is usually offered to prevent future episodes of life-threatening HLH. Here, we will discuss the options and approaches for salvage therapy and hematopoietic cell transplantation for patients with HLH.

211At-Labeled Anti-CD45 Antibody as a Nonmyeloablative Conditioning for Canine DLA-Haploidentical Stem Cell Transplantation.

The α-emitter 211At deposits a high amount of energy within a few cell diameters, resulting in irreparable DNA double-strand breaks while minimizing off-target toxicity. We investigated the use of the 211At-labeled anti-CD45 monoclonal antibody (mAb) 211At-CD45-B10 as a nonmyeloablative conditioning regimen for dog-leukocyte-antigen-haploidentical hematopoietic cell transplantation. Methods: Seventeen healthy dogs were injected with either a 0.50 (n = 14) or 0.75 (n = 3) mg/kg dose of anti-CD45 mAb labeled with 211At (8.436-23.199 MBq [0.228-0.627 mCi/kg]) on day -3. Peripheral blood stem cells from dog-leukocyte-antigen-haploidentical donors were given on day 0. Peripheral blood chimerism was calculated by polymerase chain reaction assays, and blood clearance of the radioimmunoconjugate was studied using enzyme-linked immunosorbent assay and radioactivity measurements of serial blood samples. Results: All dogs achieved donor chimerism by day 28 (range, 27%-100%). The hematopoietic engraftment rate was 100%, though engraftment durability was variable. No difference in absorbed dose to blood was seen for the 2 mAb dosing levels studied. Neutropenia (0-29 cells/µL), lymphocytopenia (36-130 cells/µL), and thrombocytopenia (1.5-9 × 103/µL) with prompt recovery were observed. The main adverse nonhematologic event related to 211At-CD45-B10 was mild reversible transaminitis. Graft-versus-host disease was not seen. Twelve of the 17 dogs survived over 30 d, with donor chimerism ranging from 3% to 99%. Conclusion: The results suggest that nonmyeloablative conditioning with 211At-CD45-B10 could be used in haploidentical hematopoietic cell transplantation though with variable engraftment.

Letermovir as secondary prophylaxis of cytomegalovirus infection after allogeneic hematopoietic cell transplantation: A single center experience.

Letermovir, a novel anti-cytomegalovirus (CMV) agent acts by inhibiting the viral terminase complex and is approved for primary prophylaxis in CMV seropositive patients post allogeneic hematopoietic cell transplantation (HCT). The favorable efficacy and safety profile make it an attractive option for use as secondary prophylaxis in patients at high-risk for CMV reactivation. In this study, we report the efficacy and safety of letermovir secondary prophylaxis after at least one treated episode of CMV reactivation in a cohort of 39 high-risk patients. Thirty two (82%) patients received anti-thymocyte globulin (ATG), 27 (69%) received a combination of ATG and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis. Twenty one patients (54%) received CMV seronegative grafts. In addition, 18 (46%) patients had HLA mismatched unrelated or haploidentical donors while 18 (46%) had active GVHD requiring immunosuppression at the time of commencing secondary prophylaxis. Letermovir was initiated at a median of 47 days (range, 41-56) after HCT and was administered for a median duration of 77 days (range, 46-90). A single breakthrough CMV reactivation was noted in this high-risk cohort. Four additional episodes of CMV reactivation occurred at a median of 28 days (range, 23-59 days) after discontinuation of secondary prophylaxis. The drug was well tolerated and 77% of the cohort completed the planned duration of secondary prophylaxis. None of the patients discontinued treatment due to treatment-related adverse effects. In conclusion, letermovir is effective and well tolerated and may be considered for secondary prophylaxis in patients at high risk for CMV reactivation. Prospective studies are required to validate these findings.

Superiority of BM over PBSC for recipients with pre-transplant lung dysfunction in HLA-matched allogeneic HCT.

BACKGROUND AIMS: Pre-transplant lung dysfunction is known to be a risk factor for non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT). It is unclear which cell source gives better outcomes for patients with pulmonary dysfunction. METHODS: We analyzed 3289 adult patients with standard-risk disease who had received HLA-matched allo-HCT, and compared outcomes between those who received peripheral blood stem cell (PBSC) vs. bone marrow (BM) in two cohorts based on the presence of a lung score by the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI): the Lung-scored (LS) and non-LS cohorts. RESULTS: In the LS cohort, the 2-year overall survival (OS) in the BM group tended to be higher than that in the PBSC group (72.4% vs. 61.4%; P = 0.044). In the non-LS cohort, there was no significant difference between the two groups (71.7% vs. 73.2%; P = 0.13). Multivariate analyses confirmed that PBSC was significantly associated with inferior OS in the LS cohort (hazard ratio [HR], 1.66; 95% CI, 1.09-2.54; P = 0.019). On the other hand, the cell source did not affect OS in the non-LS cohort (HR, 0.92; 95% CI, 0.76-1.12; P = 0.41). We found that PBSC was associated with an increased risk of NRM in the LS cohort (HR, 2.17; 95% CI, 1.16-4.05; P = 0.016), while the cell source did not significantly affect NRM in the non-LS cohort. PBSC was not identified as a risk factor for relapse in either cohort. CONCLUSIONS: Our results suggest that BM might be beneficial for recipients with lung dysfunction in HLA-matched allo-HCT.