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Introduction The immune reconstitution (IR) after the allogenic hematopoietic stem cell transplantation (allo-HSCT) is a progressive process intrinsically correlated to the therapeutic success. It is essential to understand the interfering factors in IR to prevent the HSCT-related mortality. Methods We retrospectively evaluated the clinical outcomes, absolute lymphocyte counts (ALCs) and lymphocyte subtypes at different time-points of 111 pediatric patients with allogeneic HSCT for malignant and non-malignant diseases from 2013 to 2018. Results The ALCs gradually increased on D+30, D+100, and D+180 (medians 634/μL, 1022/μL and 1541/μL, respectively). On D+100, the CD3+CD8+ achieved the highest recovery rate (68%), followed by the CD16+CD56+ (47%), CD3+CD4+ (39%) and CD19+ (8%). The adequate ALC recovery was associated with age < 8 years, bone marrow grafts, myeloablative conditioning, non-use of serotherapy and non-haploidentical donors. The ALC and CD3+CD8+ on D+100 counts were higher in patients with the cytomegalovirus infection. The CD3+CD4+ recovery was associated with an age < 8 years, a non-malignant disease and a lower incidence of acute graft-versus-host disease ≥ grade 2. Furthermore, the ALC recovery on D+100 resulted in a higher overall survival, regardless of the disease type (HR 3.65, 1.05 - 12.71, p= 0.04). Conclusion Several factors influenced the IR after the allo-HSCT. The ALC ≥ 500/μL on D+100 was a simple IR predictor of survival, easily available to resource-limited centers.

Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.

Refractory cytomegalovirus reactivation (RCR) after allo-hematopoietic stem cell transplantation (HSCT) is associated with poor outcomes. Current studies for the risk factors and survival of patients with post-transplantation RCR remain limited.163 patients with Cytomegalovirus (CMV) reactivation undergoing allo-HSCT in Jiangsu Province hospital from Jan 2013 to Dec 2020 were analyzed retrospectively.Multivariate analysis revealed that highest CMV viremia1 × 10Factors such as higher viral load, thrombocytopenia, and ATG used in conditioning therapy increased the incidence of RCR. Patients with RCR had worse NRM, OS, and RFS within 100 days after transplantation.

Although sickle cell disease can be cured using allogeneic hematopoietic stem cell transplantation and possibly gene therapy and gene editing, these treatments remain unavailable to most patients. As understanding of the disease pathophysiology increases, progress is being made in developing drug therapies. Hydroxyurea, l-glutamine, crizanlizumab, and voxelotor are currently approved by the US Food and Drug Administration, with multiple others at various stages of testing. With the limited efficacy of individual agents, combinations of agents will likely be required for optimal outcomes. Clinical and surrogate endpoints, other than vaso-occlusive crisis, are increasingly being considered in the evaluation of novel drugs.

Significant advances in maternal-fetal medicine and gene sequencing technology have fostered a new frontier of in utero molecular and cellular therapeutics, including gene editing, enzyme replacement therapy, and stem cell transplantation to treat single-gene disorders with limited postnatal treatment strategies. In utero therapies take advantage of unique developmental properties of the fetus to allow for the correction of monogenic disorders before irreversible disease pathology develops. While early preclinical studies in animal models are encouraging, more studies are needed to further evaluate their safety and efficacy prior to widespread clinical use.

Induction chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard first-line treatment for fit patients with mantle cell lymphoma (MCL). We conducted a single-center phase I trial investigating post-transplant maintenance with ixazomib, an oral proteasome inhibitor.Patients enrolled between days +70 and +180 post ASCT. Patients received ixazomib per dose cohort on days 1, 8, and 15 of each 28-day cycle for up to 10 cycles. During recruitment, published phase III data reported a survival benefit with rituximab maintenance, so all subsequent patients received ixazomib 4 mg at the same schedule along with rituximab 375 mg/mSeven patients received ixazomib monotherapy; 1 dose limiting toxicity (grade 3 neutropenia) occurred at dose level 2 (4 mg). Five patients received combination Ixazomib plus rituximab, with 2 experiencing DLTs (both Grade 4 neutropenia). Grade 3-4 neutropenia, lymphopenia, and thrombocytopenia occurred in 57%, 8%, and 8% of patients, respectively. Non-hematologic adverse events (AE) included nausea (42%), peripheral neuropathy (42%), and abdominal discomfort (33%), all of which were grade 1 or 2 in severity. There were no infectious AEs. With a median follow up of 46 months, all patients are alive and in complete remission.The trial was closed to further accrual due to high rates of treatment-related myelosuppression. The current dose and schedule of ixazomib, especially when combined with rituximab, results in unacceptable hematologic toxicity when administered as post-transplant maintenance in MCL. Ixazomib maintenance micro abstract: The authors conducted a phase I study investigating the use of ixazomib, an oral proteasome inhibitor, with or without rituximab in patients with mantle cell lymphoma in first remission following chemoimmunotherapy and autologous stem cell transplantation. All patients treated on study remain in complete remission with a median follow-up of 46 months, but the study was closed early due to a high rate of hematologic adverse events.

IL-26 is a Th17 cytokine, with its gene being absent in rodents. To characterize the in vivo immunological effects of IL-26 in chronic systemic inflammation, we used human IL26 transgenic (hIL-26Tg) mice and human umbilical cord blood mononuclear cells (hCBMC) in mouse allogeneic-graft-versus-host disease (GVHD) and chronic xenogeneic-GVHD model, respectively. Transfer of bone marrow and spleen T cells from hIL-26Tg mice into B10.BR mice resulted in GVHD progression, with clinical signs of tissue damage in multiple organs. IL-26 markedly increased neutrophil levels both in the GVHD-target tissues and peripheral blood. Expression levels of Th17 cytokines in hIL-26Tg mice-derived donor CD4 T cells were significantly increased, whereas IL-26 did not affect cytotoxic function of donor CD8 T cells. In addition, granulocyte-colony stimulating factor, IL-1β, and IL-6 levels were particularly enhanced in hIL-26Tg mice. We also developed a humanized neutralizing anti-IL-26 monoclonal antibody (mAb) for therapeutic use, and its administration after onset of chronic xenogeneic-GVHD mitigated weight loss and prolonged survival, with preservation of graft-versus-leukemia effect. Taken together, our data elucidate the in vivo immunological effects of IL-26 in chronic GVHD models and suggest that a humanized anti-IL-26 mAb may be a potential therapeutic agent for the treatment of chronic GVHD.

The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP) have formed the ACCESS Initiative to address and reduce barriers to hematopoietic cell transplantation (HCT) and cellular therapy (CT) in an effort to ensure equal access and outcomes for all patients in need. In addition to cellular therapy physicians, the initiative includes program administrators, health policy and health equity experts, health service researchers, participants from commercial payer organizations, and federal stakeholders. The inaugural ASTCT-NMDP ACCESS Workshop was held in Washington, DC on July 28 and 29, 2022, wherein committee members met to discuss and to define goals for 3 focus areas: awareness, poverty, and racial and ethnic inequity. This position paper reviews the mission, vision, and structure of the ACCESS Initiative and the proceedings from the inaugural workshop and provides an initial roadmap for the group's efforts at reducing access barriers and outcome disparities in HCT/CT.

Sickle cell disease (SCD) is a common genetic blood disorder associated with acute and chronic pain, progressive multiorgan damage, and early mortality. Recent advances in technologies to manipulate the human genome, a century of research and the development of techniques enabling the isolation, efficient genetic modification, and reimplantation of autologous patient hematopoietic stem cells (HSCs), mean that curing most patients with SCD could soon be a reality in wealthy countries. In parallel, ongoing research is pursuing more facile treatments, such as in-vivo-delivered genetic therapies and new drugs that can eventually be administered in low- and middle-income countries where most SCD patients reside.

Mycobacterial infections, both tuberculosis and nontuberculous, are more common in patients with haematological malignancies and haematopoietic stem cell transplant recipients than in the general population-although these infections remain rare. Mycobacterial infections pose both diagnostic and therapeutic challenges. The management of mycobacterial infections is particularly complicated for patients in haematology because of the many drug-drug interactions between antimycobacterial drugs and haematological and immunosuppressive treatments. The management of mycobacterial infections must also consider the effect of delaying haematological management. We surveyed the management practices for latent tuberculosis infection (LTBI) in haematology centres in Europe. We then conducted a meticulous review of the literature on the epidemiology, diagnosis, and management of LTBI, tuberculosis, and nontuberculous mycobacterial infections among patients in haematology, and we formulated clinical guidelines according to standardised European Conference on Infections in Leukaemia (ECIL) methods. In this Review, we summarise the available literature and the recommendations of ECIL 8 for managing mycobacterial infections in patients with haematological malignancies.

Treatment options for neuromyelitis optica spectrum disorder (NMOSD) are corticosteroids, immunosuppressive drugs, emerging monoclonal antibodies, rituximab, eculizumab, satralizumab, and inebilizumab. Due to disabling and deadly nature of NMOSD, there is a great motivation among physicians for finding new treatment options. Recently, several studies have been conducted on the therapeutic effects of autologous hematopoietic stem cell transplantation (AHSCT) on NMOSD patients.Several databases including PubMed, Scopus, Web of Science, and Google scholar were searched for studies on AHSCT in NMOSD patients.After screening titles and abstracts, and reviewing full texts, nine studies with 39 severe cases of NMOSD met the criteria of our study. The pooled standardized mean difference (SMD) for EDSS score before and after treatment was -0.81 (95 %CI:-1.07, -0.15; Q = 1.99, P = 0.58, IAccording to the present study, AHSCT could be an alternative therapy for NMOSD in severe cases instead of conventional immunotherapies. However, physicians should pay attention to its serious complications. The diversity of results from the published trials on the efficacy and safety of AHSCT calls for further investigations on determining the ideal AHSCT conditioning and the characteristics of patients.

INTRODUCTION: The onset of symptoms and the diagnosis of acute myeloid leukemia (AML) often occur suddenly and may lead to a range of emotional responses. Understanding patients’ experiences and emotional states allows clinicians to tailor care to patients’ needs. Previous studies have largely focused on patients’ experiences at diagnosis and after remission has achieved among those who received intensive chemotherapy. In this study, we evaluated experiences of older patients with AML who had received or were receiving treatments of varying intensity, in both outpatient and inpatient settings, and who were at different stages in their treatment course at the time of our interviews. MATERIALS AND METHODS: We conducted a single center qualitative study which aimed to understand factors influencing older patients’ treatment decision-making and the findings were previously reported. This analysis specifically explored older patients’ experiences at various stages after AML diagnosis. We purposively sampled patients based on treatment intensity and stage of treatment (undergoing induction treatment, post-remission treatment, or post-allogeneic hematopoietic stem cell transplant). We recruited 15 patients aged ≥60 years with AML. The sample size was determined based on reaching data saturation for the primary study aim. For this analysis, data saturation was reached by the 14(th) manuscript. In-depth semi-structured interviews that had been recorded and transcribed were re-analyzed using inductive thematic analysis to explore patients’ experiences. Coding was performed using Atlas.ti. We identified themes with the aim of capturing the most commonly shared experiences. RESULTS: Mean age of the 15 patients was 72.1 years; all had received one or more treatments including intensive induction therapy (10/15), lower-intensity treatment (7/15), and/or hematopoietic stem cell transplant (3/15). Patients experienced strong negative emotional responses including shock that were barriers to processing information and meaningful communication. Patients also shared their perspectives on communication with healthcare professionals (including thoughts on adequacy of information provided) and coping strategies. CONCLUSION: Understanding older patients’ experiences including emotional responses and barriers to communication and decision making at AML diagnosis and throughout the illness trajectory allows clinicians to address patients’ supportive care needs during this difficult period.

The main advantages of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) are the immediate availability of donors, the possibility of developing cell therapy approaches with different novel transplant platforms, and the procedure's cost savings.We retrospectively analyzed the pediatric haplo-HSCT activity of the Spanish hematopoietic stem-cell transplantation group (GETH) between 1999 and 2016, aiming to study clinical characteristics and outcomes by describing patient groups with non-malignant disease (NMD) or malignant disease (MD) and the impact of 2 different periods (1999-2009 and 2010-2016) on long-term outcomes.Twelve centers performed 232 haplo-HSCTs in 227 children, representing 10% of all pediatric allogeneic HSCT activity in Spain from 1999 to 2016, with a notable increase since 2013. Most haplo-HSCTs (86.7%) were performed in patients with MD; 95% received peripheral blood stem cells from donors, and 78.9% received ex vivo T-cell depleted grafts. Non-manipulated grafts using post-transplantation cyclophosphamide have been incorporated since 2012. We observed a higher percentage of graft failure in NMD versus MD (32% vs. 15.6%; p=0.029). Relapse and transplant-related mortality were the procedure's main limitations in MD and NMD, respectively. Five-year overall survival was 48.5% (SE 3.9), with no statistically significant difference when comparing the MD and NMD cohorts. Patients who received previously a HSCT the overall survival was significantly decreased. We observed no survival improvement over time.Although haplo-HSCT is an increasingly employed treatment option, our patients' results need improvement. We need to develop reference centers, especially for NMD whose rarity makes it difficult to gain experience.

International audience; Autologous stem cell transplantation (ASCT) and chimeric antigen receptor (CAR) T-cells are two therapeutic options for relapsed/refractory diffuse large B-cell lymphoma. Both are intensive and potentially curative therapies but differ in their efficacy and toxicity. ASCT may be offered to 'fit' patients (i.e. usually young with limited comorbidities) with chemosensitive disease. On the other hand, real world studies have shown that CAR T-cells may be safely administered to less fit and older patients. Thus, there is a potentially significant population of patients who may be offered CAR T-cell therapy despite not being eligible for ASCT. As the relative role of ASCT and CAR T-cells evolves, recognising and defining this population may be increasingly relevant. Here, we review criteria which may help identify this 'ASCT-ineligible but CAR T-cells eligible' population of patients.

Cellular therapy modalities, including autologous (auto-) hematopoietic cell transplantation (HCT), allogeneic (allo-) HCT, and now chimeric antigen receptor (CAR) T cell therapy, have demonstrated long-term remission in advanced hematologic malignancies. Auto-HCT and allo-HCT, through hematopoietic rescue, have permitted the use of higher doses of chemotherapy. Allo-HCT also introduced a nonspecific immune-mediated targeting of malignancy resulting in protection from relapse, although at the expense of similar targeting of normal host cells. In contrast, CAR T therapy, through genetically engineered immunotherapeutic precision, allows for redirection of autologous immune effector cells against malignancy in an antigen-specific and MHC-independent fashion, with demonstrated efficacy in patients who are refractory to cytotoxic chemotherapy. It too has unique toxicities and challenges, however. Non-Hodgkin lymphoma (including large B cell lymphoma, mantle cell lymphoma, and follicular lymphoma), B cell acute lymphoblastic leukemia, and multiple myeloma are the 3 main diseases associated with the use of fully developed CAR T products with widespread deployment. Recent and ongoing clinical trials have been examining the interface among the 3 cellular therapy modalities (auto-HCT, allo-HCT, and CAR T) to determine whether they should be "complementary" or "competitive" therapies. In this review, we examine the current state of this interface with respect to the most recent data and delve into the controversies and conclusions that may inform clinical decision making.

Host immune depletion has been recognized as a necessary step for successful adoptive immune cell transfer in both the autologous and allogeneic settings. The chemotherapy agent fludarabine as an immune suppressive agent has a central role in multiple conditioning regimens for both transplantation and immune effector cell therapies. With the recent and sudden recognition of an imminent worldwide fludarabine shortage, novel approaches to overcome supply chain disruption are needed, including exploration of alternative therapies. The fludarabine shortage has highlighted the need to prioritize the development of institutional algorithms for maintaining ongoing clinical trials and standard of care procedures in the setting of critical drug shortages.

To investigate the characteristics of the ocular surface microbiome in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the associations between the microbial dysbiosis and chronic ocular graft-versus-host disease (oGVHD).Prospective cohort study.Ocular surface samples from 48 healthy subjects and 76 patients after allo-HSCT, including 50 patients with chronic oGVHD and 26 patients without oGVHD, were collected. Species-level composition of the ocular surface microbiome was surveyed via metagenomic shotgun sequencing. OGVHD was diagnosed and graded according to the International Chronic Ocular GVHD Consensus Group criteria.The α-diversity of the microbiota was significantly decreased in patients after allo-HSCT. Nevertheless, we detected more types of viral species in the allo-HSCT group than the healthy group, especially anelloviruses. The mismatch of donor-recipient sex was only negatively associated with the α-diversity in male but not female recipients. Moreover, the microbiome of patients with oGVHD was distinct from patients without oGVHD. Gordonia bronchialis and Pseudomonas parafulva were enriched in patients with oGVHD and positively associated with International Chronic Ocular GVHD score.This study suggests that the ocular surface microbiome after allo-HSCT is characterized by a loss of diversity. Furthermore, the microbial dysbiosis at the ocular surface is associated with the status and severity of chronic oGVHD. These results lay the groundwork for future investigations of the potential microbial mechanism for oGVHD.

To explore the clinical effect of allogeneic sclera transplantation combined with tarso-conjunctival flap in total excision of divided eyelid nevus.Eleven patients (three male and eight female patients) who experienced divided nevus of the eyelids between January 2014 and April 2020 were recruited to this retrospective study. All lesions were thick, darkly pigmented, presented with a wart-like appearance, and invaded the eyelid margin and tarsal conjunctiva. The surgical method involved a full-thickness lesion excision; then, the posterior defect was reconstructed by sliding the residual tarso-conjunctival flap forward and allogeneic sclera transplantation, and the anterior defect was reconstructed with sliding flaps, rotating flaps, and free skin grafts.Neither malignant transformations nor recurrences were observed after a follow-up of more than one year. The eyelid shape was normal, the rim of the eyelid was smooth, there was no dissolution or rejection of the allogeneic sclera, and the eyelid had good mobility. All the flaps used were viable, soft, and thin. The most frequent complication was the loss of eyelashes in the reconstructed area.For divided nevus of the eyelids invaded the eyelid margin and tarsal conjunctiva, total excision is a better decision, regardless of tumor recurrence or aesthetic considerations. The posterior defect reconstruction through sliding residual tarso-conjunctival flaps combined with allogeneic sclera transplantation is simple and effective.

An estimated 30-40% of patients with diffuse large B cell lymphoma (DLBCL) will either relapse or have refractory disease with first-line chemoimmunotherapy. The standard approach for relapsed/refractory disease is salvage chemotherapy followed by autologous stem cell transplantation, but this approach cures fewer than 20% of patients in the modern era. This low cure rate is a result of refractory disease despite salvage therapy, medical ineligibility for transplantation, or relapse following transplantation. CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with relapsed or refractory disease, leading to response rates that range between 52% to 93%, and overall survival rates at one year between 48% and 83%. However, the time from apheresis to infusion of CAR T-cell therapy currently takes several weeks, leaving many patients in need of bridging therapy to control disease progression. Radiation therapy (RT) has been utilized as a bridging therapy prior to CAR T infusion in select patients, with some remarkable responses in chemorefractory disease. Furthermore, the potential synergy between RT and CAR T-cells due to immunomodulatory mechanisms has generated considerable excitement, as it has been hypothesized that RT could also be considered as a salvage therapy following CAR T failure, based on limited case series published to date. Prospective trials are warranted to validate the significance of this modality following CAR T-cell therapy.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for many hematologic and nonhematologic disorders. Graft-versus-host-disease (GVHD) in its acute or chronic form remains the most important nonrelapse post-HCT complication. Biomarkers offer objective, unbiased information on systemic disorders, and significant attention has focused on identifying biomarkers for GVHD. Ideally, a GVHD biomarker is actionable, with the results of biomarker testing used to guide clinical management of disease and clinical trial design. Although many GVHD biomarkers have been identified, none have been properly qualified for clinical use. The National Institutes of Health (NIH) and Food and Drug Administration (FDA) have provided biomarker subtype definitions; however, confusion remains about the proper definition and application of these subtypes in the HCT field. The 2014 NIH consensus development project provided a framework for the development of biomarkers for clinical practice. This review aims to clarify the biomarker subtype definitions and reemphasize the developmental framework. Armed with this knowledge, clinicians can properly translate GVHD biomarkers for clinical use.

Autologous whole cell vaccines use a patient's own tumor cells as a source of antigen to elicit an anti-tumor immune response in vivo. Recently, the authors conducted a systematic review of clinical trials employing these products in hematological cancers that showed a favorable safety profile and trend toward efficacy. However, it was noted that manufacturing challenges limit both the efficacy and clinical implementation of these vaccine products. In the current literature review, the authors sought to define the issues surrounding the manufacture of autologous whole cell products for hematological cancers. The authors describe key factors, including the acquisition, culture, cryopreservation and transduction of malignant cells, that require optimization for further advancement of the field. Furthermore, the authors provide a summary of pre-clinical work that informs how the identified challenges may be overcome. The authors also highlight areas in which future basic research would be of benefit to the field. The goal of this review is to provide a roadmap for investigators seeking to advance the field of autologous cell vaccines as it applies to hematological malignancies.

Hematopoietic Stem Cell Transplantation (HSCT) is a curative treatment for several malignant and non-malignant diseases. Access to this life saving therapy was limited by the requirement of an HLA matched donor. Introduction of platforms allowing transplantation with haploidentical and partially mismatched donors has enlarged the donor pool so that most candidates have a possible donor. HLA circulating antibodies specific for the donor's mismatched antigens may cause delayed engraftment and primary graft failure. The role of the HLA laboratory supporting HSCT has expanded to provide HLA antibody detection and monitoring for selection of compatible donors and for monitoring of desensitization treatments. This review gives an outline of the evolution of HSCT and HLA and the current tools available to the HLA team to support donor selection and desensitization treatments in this new era of transplantation.

To assess genital symptomatology, characterize the findings of genital examination, and describe the incidence and treatment of vulvovaginal graft-versus-host disease (vvGvHD) in girls and adolescents after allogeneic hematopoietic stem cell transplantation (HSCT).Retrospective cohort.Metropolitan-area children's hospital.Female allogeneic HSCT recipients ages 0 to 22 years.Genital symptoms, genital examination, diagnosis, and treatment of vvGvHD.A total of 57 participants were included in the analysis. The median age at the time of HSCT was 10 years (range 4 months-23 years). Most (n = 40, 71%) underwent transplant for a nonmalignant condition, most commonly sickle cell anemia (n = 19, 33%). The median time of onset of GvHD post HSCT was 62 days (IQR = 42 to 151 days). The most common initial site of GvHD was skin (n = 21, 64%), followed by GI tract (n = 10, 30%). Three patients (5%) were diagnosed with vvGvHD. The time of onset of vvGvHD post HSCT ranged from 62 to 1565 days. One patient (33%) was asymptomatic at the time of diagnosis. There was no difference in diagnosis of vvGvHD when race (P = 0.15), age at allogeneic HSCT (P = 0.64), nonmalignant vs malignant indication (P = 0.21), source of stem cells (P = 0.25), partial vs full human leukocyte antigens (HLA) donor match (P = 0.34), and GvHD prophylaxis regimen (P = 0.18) were compared. None had isolated vvGvHD. Vulvovaginal GvHD was preceded by skin GvHD in 1 patient, was preceded by lung GvHD in 1 patient, and occurred concurrently with skin GvHD in the third patient.Pediatric vvGvHD can occur within the first 100 days after transplant and can be asymptomatic. Routine gynecologic evaluation post allogeneic HSCT in children and adolescents should include a thorough review of vulvovaginal symptoms and a gynecologic exam for the detection and treatment of vvGvHD.

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases, have remained largely unexplored. Here, we comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC derivatives in mice. We generated a high-resolution single-cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature that is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson's disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of transgenic protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases.

Cytomegalovirus (CMV) is a major infectious agent causing severe complications in allogeneic hematopoietic cell transplantation (HCT) recipients, thereby warranting the need for aggressive preemptive or targeted antiviral therapy. However, prolonged or repeated use of antiviral agents, such as ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), can result in drug-resistant CMV infection, posing challenges to successful outcomes. Here, we report a case of a patient with acute myeloid leukemia and drug-resistant CMV infection who presented with persistent CMV DNAemia, colitis, pneumonia, and encephalitis. An intra-host diversity of UL97 and UL54 mutations were detected through the genotypic resistance testing conducted on two blood samples (D+199 and D+224) and a cerebrospinal fluid (CSF) specimen (D+260) collected from the patient. UL97 L595W/L595F and L595W mutations were detected in the blood and CSF samples, respectively, that conferred GCV resistance. UL54 F412L mutation detected in all three samples conferred GCV/CDV resistance. However, the V787L mutation of UL54, conferring GCV/FOS resistance, was observed only in the D+224 blood sample. Despite combination therapy with FOS and high dose GCV and adjunctive therapy with leflunomide, the patient died from CMV infection and multiple organ failure on D+279. Further data on resistant mutations and intra-host diversity of CMV should be accumulated to elucidate the antiviral resistance and related outcomes.

Supporting allogeneic hematopoietic cell transplantation (HCT) is an integral function of the clinical HLA laboratory, which provides HLA testing for recipients and donors. However, the timing, scope, and methods of the HLA tests vary significantly in the field. This summary provides a comprehensive and practical HLA testing approach to maximize the efficiency of the donor search process, minimize donor-specific HLA antibody (DSA) associated risks, enable optimal donor selections, and support HCT multidisciplinary teams. This is not a comprehensive donor selection guide, but pertinent donor selection considerations and publicly available online selection tools are highlighted. In the absence of healthy HLA identical siblings, younger 8/8 (HLA-A, -B, -C, -DRB1) HLA-matched unrelated donors remain the most favorable choice for HCT. Emerging practices in preparative regimens and graft versus host disease (GvHD) prophylaxis as well as building evidence of the importance of other HLA (e.g., HLA-DPB1 allele and functional matching) and non-HLA (e.g., age, CMV, and KIR) donor attributes urge the transplant centers and the HLA laboratories to construct a comprehensive approach for the routine histocompatibility testing.

The use of autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is the standard of care in patients who are deemed transplantation eligible. Novel therapies, namely immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies, have revolutionized the treatment algorithm for MM but have not yet resulted in a cure. To achieve long-lasting disease control in MM, a high-dose conditioning regimen followed by ASCT continues to be an essential part of the management of transplantation-eligible patients with MM. High-dose (or conditioning) regimens are preparative chemotherapy-based regimens used before ASCT. High-dose melphalan is the most commonly used regimen in MM treatment. This clinical review provides an evidence-based summary to guide practicing hematologists/oncologists in the various high-dose regimens used before ASCT in MM treatment. We highlight the use of single-agent melphalan along with various combination-based high-dose regimens with their clinical efficacy. Various dosing schedules and modifications, timing of administration, and novel drugs-based combination regimens are discussed.

Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.

BACKGROUND AIMS: An intensified conditioning regimen incorporating medium-dose etoposide (VP16) is an option for patients with acute lymphoblastic leukemia (ALL). However, the prognostic impacts of the addition of VP16 to cyclophosphamide (CY) and total body irradiation (TBI) in patients with Philadelphia chromosome-positive (Ph+) ALL with regard to minimal residual disease (MRD) status have not been elucidated. METHODS: The authors retrospectively compared the outcomes of patients with Ph+ ALL who underwent allogeneic transplantation following VP16/CY/TBI (n=101) and CY/TBI (n=563). RESULTS: At 4 years, the VP16/CY/TBI group exhibited significantly better disease-free survival (DFS) (72.6% versus 61.7%, P=0.027) and relapse rate (11.5% versus 21.1%, P=0.020) and similar non-relapse mortality (16.0% versus 17.2%, P=0.70). In subgroup analyses, the beneficial effects of the addition of VP16 on DFS were more evident in patients with positive MRD status (71.2% versus 48.4% at 4 years, P=0.022) than those with negative MRD status (72.8% versus 66.7% at 4 years, P=0.24). Although MRD positivity was significantly associated with worse DFS in patients who received CY/TBI (48.4% versus 66.7%, P < 0.001), this was not the case in those who received VP16/CY/TBI (71.2% versus 72.8%, P=0.86). CONCLUSIONS: This study demonstrated the benefits of the addition of VP16 in Ph+ ALL patients, especially those with positive MRD status. VP16/CY/TBI could be a potential strategy to overcome the survival risk of MRD positivity.

Since autologous stem cell transplantation is prone to cancer recurrence, in vitro sperm production is regarded a safer approach to fertility preservation. In this study, the spermatogenesis process on testicular tissue extracellular matrix (T-ECM)-derived printing structure was evaluated. Ram testicular tissue was decellularized using a hypertonic solution containing triton and the extracted ECM was used as a bio-ink to print an artificial testis. Following cell adhesion and viability examination, pre-meiotic and post-meiotic cells in the study groups (as testicular suspension and co-culture with Sertoli cells) were confirmed by real-time PCR, flow-cytometry and immunocytochemistry methods. Morphology of differentiated cells was evaluated using transmission electron microscopy (TEM), toluidine blue, Giemsa, and hematoxylin and eosin (HE) staining. The functionality of Leydig and Sertoli cells was determined by their ability for hormone secretion. The decellularization of testicular tissue fragments was successful and had efficiently removed the cellular debris and preserved the ECM compounds. High cell viability, colonization, and increased expression of pre-meiotic markers in cultured testicular cells on T-ECM-enriched scaffolds confirmed their proliferation. Furthermore, the inoculation of neonatal mouse testicular cells onto T-ECM-enriched scaffolds resulted in the generation of sperm. Morphology evaluation showed that the structure of these cells was quite similar to mature sperm with a specialized tail structure. The hormonal analysis also confirmed production and secretion of testosterone and inhibin B by Leydig and Sertoli cells. T-ECM printed artificial testis is a future milestone that promises for enhancing germ cell maintenance and differentiation, toxicology studies, and fertility restoration to pave the way for new human infertility treatments in the future.

The current gold standard for stem cell product potency assessment, the colony-forming unit (CFU) assay, delivers results that are difficult to standardize and requires a substantial amount of time (up to 14 days) for cellular growth. Recently, the authors developed a rapid (24 h) flow cytometry assay based on the measurement of intracellular phosphorylated STAT5 (pSTAT5) in CD34+ cord blood stem and progenitor cells in response to IL-3 stimulation. The present work presents a novel adaptation of the protocol for use with autologous peripheral blood stem cells (PBSCs) and a performance comparison with the CFU assay.The flow cytometry intracellular staining assay was optimized for PBSCs, and patient samples were analyzed using the PBSC-IL-3-pSTAT5 and CFU assays. Warming events were also simulated to emulate impaired potency products.Optimization led to minor protocol adjustments, such as removal of the red blood cell lysis step, the addition of a formaldehyde fixation step and an increase in anticoagulant concentration. The PBSC-IL-3-pSTAT5 assay discriminated between normal and impaired samples and identified 100% (18 of 18) of the impaired samples, thus showing better specificity than the CFU assay.The updated IL-3-pSTAT5 potency assay has several important advantages, such as accelerating the release of autologous stem cell products and enabling the detection of potentially impaired products. The assay could also be used to rapidly assess the potency of any cryopreserved allogeneic stem cell product, such as those processed during the coronavirus disease 2019 pandemic.

Autologous stem cell transplant (ASCT) is a standard therapy for transplant eligible patients of multiple myeloma (MM). To evaluate impact of time to transplant on subsequent outcomes, we analyzed data on consecutive MM patients who received novel agents-based induction prior to transplant.Between 2006 and 2019, 363 MM patients underwent ASCT. Patients' median age was 52 years, ranging from 20 to 72 years, 233 (64.2%) were males. Median interval from diagnosis to transplant was 11.5 months (range, 4-67.5); 201 (55.4%) patients underwent ASCT within 12 months (early) and 162 (44.6%) beyond 12 months since diagnosis (delayed ASCT). Primary objective was progression-free survival. Secondary objectives were-response rate to transplant, overall survival (OS), and transplant-related mortality (TRM).Post-ASCT complete response (CR) (77.1% vs. 64.8%; P.025) and CR+ very good partial response rate (89% vs. 81.5%; P.03) was higher for early ASCT cohort. Engraftment characteristics, regimen-related toxicities, and day +100 TRM (3.5% vs 3.7%; P = .564) were similar in 2 cohorts. Median OS for early versus late cohort from date of diagnosis is 127.0 (95% CI, 98.9-155.1) versus 104.5 months (95% CI, 79.3-129.6; P = .356) and from date of transplant is 119.0 (95% CI, 93.4-144.6) versus 89.5 months (95% CI, 57.4-121.6), P.02. Median PFS is better for early transplant cohort; 69.5 (95% CI, 56.7-82.3) versus 50.0 months (95% CI, 35.6-64.4), P.05, respectively.Early transplant for myeloma is associated with higher response rate and better progression-free survival.

Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who achieve progression-free survival (PFS) at 24 months (PFS24) after immunochemotherapy (IC) have excellent overall survival (OS) comparable to that of the age- and sex-matched general population. However, a similar landmark has not been established for patients with relapsed or refractory (RR) DLBCL following frontline IC who are subsequently treated with salvage therapy followed by autologous stem cell transplantation (ASCT). To evaluate the role of PFS24 as a landmark after ASCT in patients with RR DLBCL, we identified patients with RR DLBCL after frontline R-CHOP or R-CHOP-like IC who underwent salvage therapy and ASCT at Mayo Clinic between July 2000 and December 2017 and University of Iowa between April 2003 and April 2020 from institutional lymphoma and transplantation databases. Clinical characteristics, treatment information, and outcome data were abstracted. PFS, OS, and post-ASCT relapse survival (PRS) were analyzed using Kaplan-Meier method, and cumulative incidences of relapse versus nonrelapse mortality and different causes of death were compared accounting for competing events. A total of 437 patients were identified. Median age at ASCT was 61 years (range 19-78), and 280 (64%) were male. After a median post-ASCT follow-up of 8.0 years (95% confidence interval [CI], 7.2-8.7), 215 patients had a relapse (or disease progression), 180 within 2 years and 35 after 2 years. For the entire cohort, the post-ASCT relapse rate was much higher than the nonrelapse mortality rate (48.1% versus 9.1% at 5 years). Median PFS and OS after ASCT was 2.7 and 5.4 years, respectively. Lymphoma was the primary cause of death after ASCT. In contrast, for patients who had achieved PFS24 (n = 220), rates of post-PFS24 relapse and nonrelapse mortality were similar (14.8% and 12.3% at 5 years). Median PFS and OS after achieving PFS24 was 10.0 and 11.5 years, respectively. Lymphoma-related and -unrelated death rates were similar after achieving PFS24. For all patients who had a post-ASCT relapse, median PRS was 0.7 (95% CI, 0.5-0.9) year, and late relapse (2 versus ≤2 years after ASCT) was associated with better PRS (median 2.3 [1.7-4.8] versus 0.5 [0.3-0.7] years, P.001). The study establishes PFS24 as an important landmark associated with post-ASCT outcomes in patients with RR DLBCL after frontline IC.

Induction therapy for multiple myeloma is traditionally capped at 6 cycles of lenalidomide due to concerns that longer treatment compromises the ability to collect sufficient stem cells for autologous stem cell transplantation (ASCT). However, during the COVID-19 pandemic, many of our patients received prolonged lenalidomide induction due to concerns about proceeding to ASCT. We investigated whether prolonged induction with lenalidomide affects the efficacy of stem cell collection among patients mobilized with cyclophosphamide and/or plerixafor.This single center, retrospective study included patients who were treated with lenalidomide induction regimens, received mobilization with cyclophosphamide or plerixafor, and underwent apheresis in preparation for ASCT. 94 patients were included, 40 of whom received prolonged induction with6 cycles of lenalidomide containing regimen.Patients who received prolonged induction were more likely to require1 day of apheresis (38% vs. 15%; OR 3.45; P = .0154), and there was a significant correlation between the duration of lenalidomide treatment and the apheresis time required to collect sufficient cells for transplant (RAmong patients treated with6 cycles of lenalidomide, mobilization augmented with cyclophosphamide and/or plerixafor will likely facilitate sufficient stem cell harvest to permit ASCT.

The benefit of pre-transplant consolidation in patients with acute lymphoblastic leukemia (ALL) who achieved first complete remission (CR1) has not yet been clearly demonstrated. Here, we aimed to investigate the relationship between the treatments received before transplantation and transplant outcome in Ph-ALL patients who underwent myeloablative allo-HSCT in CR1.A total of 55, 32 (58.2%) men and 23 (41.8%) women, who underwent allo-HSCT with the diagnosis of Ph-ALL were evaluated retrospectively. All patients underwent to allo-HSCT with myeloablative conditioning regimen in the 1st CR from the available donor.In patients who received2 consolidation, the 2-year and 3-year OS was 69% and 65%, respectively, while the 2-year and 3-year OS was 39% and 26%, respectively, in those who received2 consolidation (P =.03). RFS was similar in both groups (P = .8). One year- NRM was found 28% in patients who received ≥ 2 consolidations, and 37% in patients who received2 consolidation (P =.06). L-asparaginase, high dose methotrexate, and cranial treatments given before transplantation had no effect on transplant outcomes (P.05).Contrary to the belief that pre-transplant consolidation is not beneficial in ALL patients who proceed with allo-HCST in CR1, our results showed that consolidation treatments reduce NRM and improve the survival.

Checkpoint inhibitors demonstrated significant efficacy in relapsed/refractory Hodgkin's Lymphoma (R/R cHL) resulting in high responses and prolonged progression free survival in patients, who relapse after or are ineligible for autologous stem cell transplantation (auto-SCT). We aimed to assess the efficacy and toxicity of Pembrolizumab before auto-SCT and in transplant naïve patients and calculate survival outcomes.Fifty-five patients with R/R cHL were included. Patients demographics, including age, sex, risk stratification, therapy received and details pertaining transplantation, were collected.Median age was 28 years (range, 16-62 years). The median follow-up was 15.3 months and the median number of previous treatments was 3 (1-10). The best objective response was 74.5% (CR 32.7%, SD 5.5%) with reasonable safety profile. Twenty-nine of the responding patients received subsequent auto-SCT and 9 allogeneic stem cell transplantation (allo-SCT), 6 are currently alive with ongoing response. At the time of analysis, 6 patients remained on Pembrolizumab and the rest discontinued. The main reason for discontinuation was disease progression (n-49). Twelve-months overall survival and progression free survival (PFS) was 92% (95% CI: 76%-95%) and 51% (95% CI, 39%-67%) respectively. Twelve-month PFS for patients, who achieved CR or PR or PD was 88% (95% CI: 07%-75%); PR 60% (95% CI: 21%-29%) and 5% (95% CI: 5%-0%). Though the number of patients who received auto-SCT after Pembrolizumab was small (n-15), 12 months overall survival and PFS 100% and PFS 92%. 11 patients (20%) deceased during the follow-up and none was regarded to be treatment-related.Checkpoint inhibitors are effective in heavily pretreated cHL patients with reasonable survival outcomes. The results supporting the concept of auto and/or allo-SCT after checkpoint inhibitors use.

The MOSA study (Maastricht Observational study of late effects after Stem cell trAnsplantation) aims to study the prevalence of adverse health effects in hematopoietic stem cell transplantation (HCT) survivors compared to a matched cohort, representing the general population.The MOSA study is a matched cohort study, nested within a large prospective cohort, The Maastricht Study. Participants of The Maastricht Study serve as a reference group matched on age, gender, and education to compare MOSA participants to the general population. In both studies, the same study protocol and extensive phenotyping measurements are used.HCT Survivors: Five hundred and thirty nine survivors were invited of which, so far, 123 (23%) participants completed the study assessments. Data will be analyzed and published separately. Reference Group: For each MOSA participant, four reference cases were matched. After matching, both groups are comparable with respect to age, gender, and education.To our knowledge, this is the first study conducting such detailed phenotyping in HCT survivors. Comparison with a large reference group provides essential information about late effects of HCT and associated risk factors. This may improve screening and prevention strategies, potentially leading to a positive impact on morbidity, mortality, and quality of life.

Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative treatment approach for patients with high-risk acute lymphoblastic leukemia (ALL). Despite development of several novel therapies targeting B-cell ALL, alloHCT continues to play an essential role in management, but the identification of patients who are most likely to benefit from alloHCT in first or subsequent remissions continues to evolve. Broader donor options, including haploidentical donors and umbilical cord blood, have enabled alloHCT for more patients, but improvements in front-line therapy and increasing use of high-sensitivity measurable residual disease (MRD) quantification continue to modify the calculus for selecting which patients require transplantation. MRD quantification has become increasingly important as a prognostic indicator, as well as a trigger for therapeutic intervention, since the achievement of MRD negative complete remission is well-established to be associated with improved transplant outcomes. ALL remains the only malignancy with approved therapy for MRD positivity after achievement of remission, and use of Blinatumomab in this setting currently appears to be most effective when used as a bridge-to-transplant, rather than a destination or purely consolidative therapy. Expanding options for those with relapsed/refractory disease, including chimeric antigen receptor (CAR)-T cells, also render more patient in suitably deep remissions to enable alloHCT with a high likelihood of success. It remains unclear whether CAR-T cell therapies may obviate the need for alloHCT in some patients, and currently available data suggest there remains a role for alloHCT after CAR-T. Together, these therapeutic advances appear to be improving post-transplant outcomes. Nevertheless, more remains to be studied regarding how to optimize use of available and emerging cellular and immune modulating therapies to maximize the likelihood of long-term post-alloHCT remission in high-risk ALL.

Previous studies reporting the response to SARS-CoV-2 mRNA vaccination in alloHSCT recipients used serological and/or cellular assays, but no study has evaluated vaccine-induced neutralizing antibodies. We prospectively studied 28 alloHSCT recipients who received two BNT162b2 doses. Two patients groups were defined according to time from alloHSCT and immunosuppressive treatment, and had different baseline immunologic status. Study end-point was the evaluation of humoral and cellular responses one month after the second vaccine. All patients seroconverted. Anti-S IgG levels and neutralizing antibodies percentages were not significantly different between both groups. Using IFNγ ELISpot assay, five patients showed a strong increase, without correlation with the humoral response. Using flow cytometry lymphocyte proliferation assay, 14 patients exhibited responding T cells, without difference between both groups or correlation with anti-S IgG levels. A few low serological responders had a detectable CD4 + T cell proliferative response. This finding should be confirmed in a larger cohort.

The contribution of related donors to the globally rising number of allogeneic haematopoietic stem cell transplantations (HSCT) remains increasingly important, particularly because of the growing use of haploidentical HSCT. Compared with the strict recommendations on the suitability for unrelated donors, criteria for related donors allow for more discretion and vary between centres. In 2015, the donor outcome committee of the Worldwide Network for Blood and Marrow Transplantation (WBMT) proposed consensus recommendations of suitability criteria for paediatric and adult related donors. This Review provides updates and additions to these recommendations from a panel of experts with global representation, including the WBMT, the European Society for Blood and Marrow Transplantation donor outcome committee, the Center for International Blood and Marrow Transplant Research donor health and safety committee, the US National Marrow Donor Program, and the World Marrow Donor Association, after review of the current literature and guidelines. Sections on the suitability of related donors who would not qualify as unrelated donors have been updated. Sections on communicable diseases, clonal haematopoiesis of indeterminate potential, paediatric aspects including psychological issues, and reporting on serious adverse events have been added. The intention of this Review is to support decision making, with the goal of minimising the medical risk to the donor and protecting the recipient from transmissible diseases.

The earliest conceptual history of gene therapy began with the recognition of DNA as the transforming substance capable of changing the phenotypic character of a bacterium and then as the carrier of the genomic code. Early studies of oncogenic viruses that could insert into the mammalian genome led to the concept that these same viruses might be engineered to carry new genetic material into mammalian cells, including human hematopoietic stem cells (HSC). In addition to properly engineered vectors capable of efficient safe transduction of HSC, successful gene therapy required the development of efficient materials, methods, and equipment to procure, purify, and culture HSC. Increased understanding of the preparative conditioning of patients was needed to optimize the engraftment of genetically modified HSC. Testing concepts in pivotal clinical trials to assess the efficacy and determine the cause of adverse events has advanced the efficiency and safety of gene therapy. This article is a historical overview of the separate threads of discovery that joined together to comprise our current state of gene therapy targeting HSC.

Pediatric lysosomal and peroxisomal storage disorders, leukodystrophies, and motor neuron diseases can have devastating neurologic manifestations. Despite efforts to exploit cross-correction to treat these monogenic disorders for several decades, definitive treatment has yet to be identified. This review explores recent attempts to transduce autologous hematopoietic stem cells with functional gene or provide therapeutic gene in vivo. Specifically, we discuss the rationale behind efforts to treat pediatric neurologic disorders with gene therapy, outline the specific disorders that have been targeted at this time, and review recent and current clinical investigations with attention to the future direction of therapy efforts.

Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/mBetween July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.Juno Therapeutics, a Bristol-Myers Squibb company.

Poor growth in childhood cancer survivors who undergo haematopoietic stem cell transplant (HSCT) without exposure to radiation is reported anecdotally, although literature to support this is limited. The aims of this study were to assess the change in height standard deviation score (SDS) and the final adult height (FAH) in children who underwent chemotherapy-only conditioned HSCT and to identify predictors of poor growth.We conducted a retrospective hospital medical record review (1984-2010) of children (1-10 years) who underwent chemotherapy-only conditioned HSCT, noting anthropology measurements at cancer diagnosis, HSCT, 10 years old and FAH.The median age at HSCT of the 53 patients was 4.5 years, 75% had a haematological malignancy and 25% a solid tumour. Half of the cohort underwent allogenic HSCT and most (89%) conditioned with busulphan. The mean change in height SDS from primary cancer diagnosis to FAH was -1.21 (±1.18 SD), equivalent to 7-8.5 cm loss, with a mean FAH of -0.91 SDS (±1.10 SD). The greatest height loss occurred between diagnosis and HSCT (-0.77 SDS, 95% confidence interval -1.42, -0.12, P = 0.01), with no catch-up growth seen by FAH. Patients with solid tumours had the greatest height loss. Overall body mass index SDS did not change significantly over time, or by cancer type.Chemotherapy-only conditioned HSCT during childhood can impact FAH, with the greatest height loss occurring prior to HSCT and no catch-up growth after treatment finishes. Children transplanted for a solid tumour malignancy seem to be more at risk, possibly due to intensive treatment regimens, both pre-transplant and during conditioning.

B cell acute lymphocytic leukemia (B-ALL) patients who have relapsed after hematopoietic stem cell transplantation (HSCT) have a poor prognosis, and there is currently no standard approach available. Chimeric antigen receptor (CAR)-T cells induce high rates of initial response and long-term remission among patients with B-cell malignancies, especially B-ALL. Meanwhile, sequential infusion of CAR19/22 T cells has been proven to be effective at preventing tumor immune escape. In the present study, we retrospectively analyzed 23 B-ALL patients who relapsed after allogeneic (allo)-HSCT and underwent sequential infusion of CAR19/22 T cells, including nine donor-derived and 14 recipient-derived, in our center from July 2016 to July 2020, to evaluate the safety and efficacy of the cocktail of two single-specific CAR-T cells in B-ALL patients relapsed after transplantation. Except for one patient refusing evaluation, the remaining 22 patients achieved minimal residual disease (MRD)-negative complete remission within 30 days after CAR-T infusion. Most toxicities were slight and reversible. The estimated 12-month progression-free survival (PFS) rate was 59.2% (95% confidence interval [CI], 35.9% to 76.5%), and the estimated 12-month overall survival (OS) rate was 67.4% (95% CI, 43.2% to 83.1%). Only two patients had CD19-negative recurrence. In addition, early recurrence after transplantation, graft-versus-host disease (GVHD) and severe infection after CAR-T infusion were poor prognostic factors. Our results indicate that sequential infusion of CAR19/22 T cells is safe and effective for relapsed ALL patients after HSCT. This trial was registered at www.chictr.org.cn as #ChiCTR-OPN-16008526.

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal disease and may also present with central nervous system findings at the beginning without specific diagnostic criteria. Brain magnetic resonance imaging (MRI) findings are diverse and can also be diagnostic. We aimed to emphasize the importance of brain MRI findings in the early diagnosis of this fatal disease. Methods: MRI findings, clinical presentations, treatment response, and prognosis of seven patients with HLH were described. Results: There were seven pediatric patients who were initially diagnosed with HLH with neurological findings without systemic signs of HLH: four as primary, two as secondary, and one as possible primary HLH. All patients had contrast-enhancing diffuse cerebellar and brainstem lesions; patchy periventricular and callosal cerebral lesions were observed. Thalamus involvement was found in three (42.8%), corpus callosum involvement in six (85.7%), and cervical spinal involvement in one (14.2%). Patients were followed up with these MRI findings, with prediagnoses of toxic, metabolic, infectious, vascular, and demyelinating diseases. Not all patients met the HLH diagnostic criteria due to incomplete systemic/laboratory findings; therefore, only two were immediately directed for hematopoietic stem cell therapy. Four died shortly after admission, one patient could not be followed up after HLH treatment, and two patients who fulfilled the HLH diagnostic criteria underwent hematopoietic stem cell transplantation and survived. Conclusions: Brain MRI findings, especially in the presence of neurological findings, allow for early diagnosis, which can be life-saving. These common features in brain MRI findings should be evaluated with this suspicion and included in HLH diagnostic criteria.

Hematopoietic stem cell transplantation (HSCT) represents an example of a highly complex and costly medical procedure with major applications in hematology and oncology. It is associated with life-threatening complications and, consequently, increased demands on healthcare resources. Although improving quality is an integral component of healthcare strategic planning, drivers of quality may be variable, and there is logical debate as to what drives quality in HSCT. Moreover, HSCT programs differ in structure and availability of resources, which drive the type of transplantations provided and determine what is affordable and/or economically feasible. The complexity of HSCT procedures with involvement of different stakeholders necessitates not only regulatory frameworks, but also robust quality systems to ensure consistent standards, demonstrate transparency for regulators, and define what quality means within the HSCT program. In an era of escalating healthcare complexity and heightened fiscal responsibility, transparency and accountability, accreditation contributes to ensuring that care meets the highest standards and can serve as a risk mitigation strategy. Quality management has become an indispensable tool for the management of a complex medical intervention such as HSCT. It allows the transplantation team to monitor its activities and identify areas for continuous improvement. The Worldwide Network for Blood and Marrow Transplantation invited a group of international experts in HSCT and quality management to work on providing a summary document about the key elements in quality and accreditation in HSCT and highlight the foremost challenges of implementing them, with a special focus on low- and middle-income economies.

Hematopoietic stem cell (HSC) transplantation represents an important curative therapy for numerous hematological and immune diseases. Many efforts have been applied to achieve attainable ex vivo HSC expansion. We previously showed that angiopoietin-like proteins 2 (Angptl2) binds and activates the immune inhibitory receptor human leukocyte immunoglobulin (Ig)-like receptor B2 (LILRB2) to support the expansion of HSC. However, soluble Angptl2 is unstable and the downstream signaling would be attenuated by ligand-binding triggered receptor endocytosis, compromising the potential of Angptl2 to expand HSCs. We proposed that membrane anchored Angptl2 will overcome these limitations. In this study, we constructed the C-terminal and N-terminal anchored membrane Angptl2 (Cm-Angptl2 and Nm-Angptl2) by adding a transmembrane domain at the C-terminal or an anchor sequence at the N-terminal respectively. Both forms of Angptl2 showed efficient expression on the surface of feeder cells. Nm-Angptl2, but not Cm-Angptl2, induces a potent activation of LILRB2 reporter, indicating the fibronectin (FBN) domain at the C-terminus of Angptl2 is essential to stimulate LILRB2 signaling. Compared to soluble Angptl2, Nm-Angptl2 displays higher activities to activate LILRB2 reporter, and to promote the expansion of mouse HSCs as determined by transplantation and limiting dilution assay. Our study revealed the importance of FBN domain for Angptl2 to activate LILRB2 and demonstrated that Nm-Angptl2 have enhanced activities than the soluble protein in LILRB2 activation and HSC expansion, providing a strategy to explore the mode of ligand induced receptor signaling, and an optimized approach to expand HSCs ex vivo.