Allogeneic Stem Cell Transplantation in Refractory Acute Myeloid Leukaemia.

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25-57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.

Neuromuscular electrical stimulation for physical function maintenance during hematopoietic stem cell transplantation: Study protocol.

Hematopoietic stem cell transplantation is a common life-saving treatment for hematologic malignancies, though can lead to long-term functional impairment, fatigue, muscle atrophy, with decreased quality of life. Although traditional exercise has helped reduce these effects, it is inconsistently recommended and infrequently maintained, and most patients remain sedentary during and after treatment. There is need for alternative rehabilitation strategies, like neuromuscular electrical stimulation, that may be more amenable to the capabilities of hematopoietic stem cell transplant recipients. Patients receiving autologous HCT are being enroled in a randomized controlled trial with 1:1 (neuromuscular electrical stimulation:sham) design stratified by diagnosis and sex. Physical function, body composition, quality of life, and fatigue are assessed prior to hematopoietic stem cell transplant (prior to initiating preparatory treatment) and 24±5 days post hematopoietic stem cell transplant (Follow-up 1); physical function and quality of life are also assessed 6-months post hematopoietic stem cell transplant (Follow-up 2). The primary outcome is between-group difference in the 6-minute walk test change scores (Follow-up 1-Pre-transplant; final enrolment goal N = 23/group). We hypothesize that 1) neuromuscular electrical stimulation will attenuate hematopoietic stem cell transplant-induced adverse effects on physical function, muscle mass, quality of life, and fatigue compared to sham at Follow-up 1, and 2) Pre-transplant physical function will significantly predict fatigue and quality of life at Follow-up 2. We will also describe feasibility and acceptability of neuromuscular electrical stimulation during hematopoietic stem cell transplant. This proposal will improve rehabilitative patient care and quality of life by determining efficacy and feasibility of a currently underutilized therapeutic strategy aimed at maintaining daily function and reducing the impact of a potent and widely used cancer treatment. This trial is registered with clinicaltrials.gov (NCT04364256).

Philadelphia chromosome-positive acute myeloid leukemia successfully treated by allogeneic hematopoietic stem cell transplantation: A case report and review of the literature.

RATIONAL: The Philadelphia chromosome (Ph) is seen in most patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia. However, Ph-positive acute myeloid leukemia (Ph + AML) is a rare entity with a poor prognosis and a short median survival period. To date, there have been few clinical reports on this disease. And the treatment regimen of this disease has not been uniformly determined. PATIENT CONCERNS: We report a case of a Ph + AML. A 32-year-old male who was admitted to our hospital with weakness for 2 months. DIAGNOSIS: Philadelphia chromosome-positive acute myeloid leukemia. INTERVENTIONS: The patient achieved complete remission by the administration of a tyrosine kinase inhibitor, combined with low-intensity chemotherapy and a B-cell lymphoma 2 inhibitor. Then, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his sister was successfully performed. OUTCOMES: The patient has been in a continuous remission state for 6 months after transplantation. LESSONS: We reported a rare Ph + AML case, successfully treated with allo-HSCT. This case provided strong support for treating Ph + AML with allo-HSCT.

Combining serum microRNAs and machine learning algorithms for diagnosing infectious fever after HSCT.

Infection post-hematopoietic stem cell transplantation (HSCT) is one of the main causes of patient mortality. Fever is the most crucial clinical symptom indicating infection. However, current microbial detection methods are limited. Therefore, timely diagnosis of infectious fever and administration of antimicrobial drugs can effectively reduce patient mortality. In this study, serum samples were collected from 181 patients with HSCT with or without infection, as well as the clinical information. And more than 80 infectious-related microRNAs in the serum were selected according to the bulk RNA-seq result and detected in the 345 time-pointed serum samples by Q-PCR. Unsupervised clustering result indicates a close association between these microRNAs expression and infection occurrence. Compared to the uninfected cohort, more than 10 serum microRNAs were identified as the combined diagnostic markers in one formula constructed by the Random Forest (RF) algorithms, with a diagnostic accuracy more than 0.90. Furthermore, correlations of serum microRNAs to immune cells, inflammatory factors, pathgens, infection tissue, and prognosis were analyzed in the infection cohort. Overall, this study demonstrates that the combination of serum microRNAs detection and machine learning algorithms holds promising potential in diagnosing infectious fever after HSCT.

The impact of regulatory T cells on the graft-versus-leukemia effect.

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies, whereby the Graft-versus-Leukemia (GVL) effect plays a pivotal role in controlling relapse. However, the success of GVL is hindered by Graft-versus-Host Disease (GVHD), where donor T cells attack healthy tissues in the recipient. The ability of natural regulatory T cells (Treg) to suppress immune responses has been exploited as a therapeutical option against GVHD. Still, it is crucial to evaluate if the ability of Treg to suppress GVHD does not compromise the benefits of GVL. Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type. Human trials using Treg as GVHD prophylaxis or treatment show promising results, emphasizing the importance of infusion timing and Treg/Tcon ratios. In this review, we discuss strategies that can be used aiming to enhance GVL post-Treg infusion and the proposed mechanisms for the maintenance of the GVL effect upon the adoptive Treg transfer. In order to optimize the therapeutic outcomes of Treg administration in allo-HSCT, future efforts should focus on refining Treg sources for infusion and evaluating their specificity for antigens mediating GVHD while preserving GVL responses.

Clinical manifestations, prognostic factors, and outcomes of adenovirus pneumonia after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Severe pneumonia is one of the most important causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Adenovirus (ADV) is a significant cause of severe viral pneumonia after allo-HSCT, and we aimed to identify the clinical manifestations, prognostic factors, and outcomes of ADV pneumonia after allo-HSCT. METHODS: Twenty-nine patients who underwent allo-HSCT at the Peking University Institute of Hematology and who experienced ADV pneumonia after allo-HSCT were enrolled in this study. The Kaplan-Meier method was used to estimate the probability of overall survival (OS). Potential prognostic factors for 100-day OS after ADV pneumonia were evaluated through univariate and multivariate Cox regression analyses. RESULTS: The incidence rate of ADV pneumonia after allo-HSCT was approximately 0.71%. The median time from allo-HSCT to the occurrence of ADV pneumonia was 99 days (range 17-609 days). The most common clinical manifestations were fever (86.2%), cough (34.5%) and dyspnea (31.0%). The 100-day probabilities of ADV-related mortality and OS were 40.4% (95% CI 21.1%-59.7%) and 40.5% (95% CI 25.2%-64.9%), respectively. Patients with low-level ADV DNAemia had lower ADV-related mortality and better OS than did those with high-level (≥ 106 copies/ml in plasma) ADV DNAemia. According to the multivariate analysis, high-level ADV DNAemia was the only risk factor for intensive care unit admission, invasive mechanical ventilation, ADV-related mortality, and OS after ADV pneumonia. CONCLUSIONS: We first reported the prognostic factors and confirmed the poor outcomes of patients with ADV pneumonia after allo-HSCT. Patients with high-level ADV DNAemia should receive immediate and intensive therapy.

The Efficacy of Three Different Oral Hygiene Regimens in Preventing Chemotherapy-Induced Oral Mucositis in Pediatric Patients Receiving Hematopoietic Stem Cell Transplantation.

BACKGROUND: Oral mucositis is one of the side effects developed post-hematopoietic stem cell transplant. This retrospective study aimed to assess the efficacy of a mouthwash mixture (lidocaine, sodium alginate, sucralfate, pheniramine) versus hyaluronic acid and a solution of sodium bicarbonate in terms of healing time and weight gain in the treatment of oral mucositis in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation with hemato-oncological malignancies. METHODS: A total of 171 patients that received chemotherapy for the hematopoietic stem cell transplant were divided into three groups; group 1, treated with a mixed mouthwash of lidocaine, sodium alginate, sucralfate, and pheniramine; group 2, treated with hyaluronic acid; and group 3, treated with an aqueous solution of 5% sodium bicarbonate. Weight and mucositis scale scores derived from medical records of patients. RESULTS: There was a statistically significant difference in the mucositis scale scores between the groups on the transplant day and days 5, 10, 15 and 20 after the transplantation. At these measurement points, Group 2 (receiving hyaluronic acid) had a lower score, and Group 3 (who received sodium bicarbonate) had a higher score, especially on days 5 and 10 after the transplantation. CONCLUSION: The results suggest that hyaluronic acid is a more effective treatment option than the other oral care solutions that are frequently used for prophylaxis and treatment of oral mucositis.

Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement.

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.

Factors influencing overall survival and GvHD development after allogeneic hematopoietic stem cell transplantation - single centre experience.

BACKGROUNDS: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a substantial therapeutic procedure for the treatment of a wide spectrum of severe diseases. Despite advancements in treatment and supportive care, alloHSCT still carries a considerable mortality risk, primarily caused by graft-versus-host disease (GvHD). Our retrospective analysis aimed to identify the factors influencing overall survival and GvHD development in HLA-identical sibling alloHSCT. We have analyzed patients' and donors' age, AB0 compatibility, recipient-donor gender match, stem cell source, time from the diagnosis to alloHSCT, conditioning regimen type, GvHD prophylaxis, and relapse. PATIENTS AND METHODS: Our study included 96 patients (54 male, 42 female) who underwent HLA-identical sibling alloHSCT. The median follow-up was 64.5 months (range 1-218 months), and the median age of both recipients and donors was 34 years. Malignant hematological diseases were the most common indications for alloHSCT. RESULTS: GvHD and its complications accounted for the highest number of deaths (N = 24; 46.2%), followed by relapse (N = 18; 34.6%). Acute GvHD developed in 30 patients (31.3%), while chronic GvHD occurred in 25 patients (26.0%), resulting in a total of 45 patients (46.9%) experiencing GvHD. Male recipients with female donors had significantly worse overall survival compared to other patients (P = 0.01; HR = 2.33). Overall survival was better in patients transplanted within 1 year from the diagnosis compared to those transplanted after 1 year (P = 0.03; HR = 1.93). No factor reached statistical significance regarding the impact on acute GvHD, chronic GvHD, or overall GvHD. CONCLUSION: We confirmed that sex mismatch, specifically in the case of a female donor and a male recipient, significantly negatively affects overall survival after alloHSCT. Additionally, overall survival is significantly shorter when the interval between the diagnosis and alloHSCT exceeds one year.

Nirmatrelvir/ritonavir treatment of patients with COVID-19 taking tacrolimus: case series describing the results of drug-drug interactions.

Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.

Case report: Preventive infusion of donor-derived CD7 chimeric antigen receptor T cells after allogeneic hematopoietic stem cell transplantation.

Chimeric antigen receptor T cells (CAR T) targeting CD7 for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) showed promising efficacy and safety in some clinical trials. However, most of them were bridged with allogeneic hematopoietic stem cell transplantation (allo-HSCT). We described successful treatment with preventive donor-derived anti-CD7 CAR-T therapy in a case of refractory T lymphoblastic lymphoma following allo-HSCT, who could not receive autologous anti-CD7 CAR-T products due to the low-quality of T lymphocytes. To date, the patient's complete remission has persisted for 20 months after HSCT.

SARS-CoV-2 shedding, infectivity, and evolution in an immunocompromised adult patient.

This study aimed to provide further insight into the evolutionary dynamics of SARS-CoV-2 by analyzing the case of a 40-year-old man who had previously undergone autologous hematopoietic stem cell transplantation due to a diffuse large B-cell lymphoma. He developed a persistent SARS-CoV-2 infection lasting at least 218 days and did not manifest a humoral immune response to the virus during this follow-up period. Whole-genome sequencing and viral cultures confirmed a persistent infection with a replication-positive virus that had undergone genetic variation for at least 196 days after symptom onset.

Risk factors for hemorrhagic cystitis in children undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis.

BACKGROUND: The risk factors for hemorrhagic cystitis (HC) in children undergoing hematopoietic stem cell transplantation (HSCT) are unclear. Therefore, we conducted this systematic review and meta-analysis to investigate the risk factors for HC in children undergoing HSCT. METHODS: We performed this meta-analysis by retrieving studies from PubMed, EMBASE, and the Cochrane Library up to October 10, 2023, and analyzing those that met the inclusion criteria. I2 statistics were used to evaluate heterogeneity. RESULTS: Twelve studies, including 2,764 patients, were analyzed. Male sex (odds ratio [OR] = 1.52; 95% confidence interval [CI], 1.16-2.00; p = 0.003, I2 = 0%), allogeneic donor (OR = 5.28; 95% CI, 2.60-10.74; p < 0.00001, I2 = 0%), human leukocyte antigen (HLA) mismatched donor (OR = 1.86; 95% CI, 1.00-3.44; p = 0.05, I2 = 31%), unrelated donor (OR = 1.58; 95% CI, 1.10-2.28; p = 0.01, I2 = 1%), myeloablative conditioning (MAC) (OR = 3.17; 95% CI, 1.26-7.97; p = 0.01, I2 = 0%), busulfan (OR = 2.18; 95% CI, 1.33-3.58; p = 0.002, I2 = 0%) or anti-thymoglobulin (OR = 1.65; 95% CI, 1.07-2.54; p = 0.02, I2 = 16%) use, and cytomegalovirus (CMV) reactivation (OR = 2.64; 95% CI, 1.44-4.82; p = 0.002, I2 = 0%) were risk factors for HC in children undergoing HSCT. CONCLUSIONS: Male sex, allogeneic donor, HLA-mismatched, unrelated donor, MAC, use of busulfan or anti-thymoglobulin, and CMV reactivation are risk factors for HC in children undergoing HSCT.

Brave new world: expanding home care in stem cell transplantation and advanced therapies with new technologies.

Hematopoietic stem cell transplantation and cell therapies like CAR-T are costly, complex therapeutic procedures. Outpatient models, including at-home transplantation, have been developed, resulting in similar survival results, reduced costs, and increased patient satisfaction. The complexity and safety of the process can be addressed with various emerging technologies (artificial intelligence, wearable sensors, point-of-care analytical devices, drones, virtual assistants) that allow continuous patient monitoring and improved decision-making processes. Patients, caregivers, and staff can also benefit from improved training with simulation or virtual reality. However, many technical, operational, and above all, ethical concerns need to be addressed. Finally, outpatient or at-home hematopoietic transplantation or CAR-T therapy creates a different, integrated operative system that must be planned, designed, and carefully adapted to the patient's characteristics and distance from the hospital. Patients, clinicians, and their clinical environments can benefit from technically improved at-home transplantation.

Multiple autoimmune disorders refractory to glucocorticoids after allogeneic hematopoietic stem cell transplantation: a case report and review of the literature.

We report here the case of a 50-year-old man who was first diagnosed with myelodysplastic syndrome with excess blasts-2 (MDS-EB-2) and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 2019, resulting in complete remission. However, he was diagnosed in 2021 with several autoimmune disorders, including autoimmune hepatitis (AIH), Hashimoto's thyroiditis (HT), and autoimmune hemolytic anemia (AIHA). This is referred as multiple autoimmune syndrome (MAS), which is a rare occurrence after allo-HSCT, as previously noted in the literature. Despite being treated with glucocorticoids, cyclosporine A, and other medications, the patient did not fully recover. To address the glucocorticoid-refractory MAS, a four-week course of rituximab (RTX) at a weekly dose of 100mg was administered, which significantly improved the patient's condition. Thus, this case report underscores the importance of implementing alternative treatments in patients with post-transplant autoimmune diseases, who are glucocorticoid-refractory or glucocorticoid-dependent, and highlights the effectiveness of RTX as second-line therapy.

The rationale behind grafting haploidentical hematopoietic stem cells.

The ability to perform hematopoietic cell transplant across major histocompatibility complex barriers can dramatically increase the availability of donors and allow more patients across the world to pursue curative transplant procedures for underlying hematologic disorders. Early attempts at haploidentical transplantation using broadly reactive T-cell depletion approaches were compromised by graft rejection, graft-versus-host disease and prolonged immune deficiency. The evolution of haploidentical transplantation focused on expanding transplanted hematopoietic progenitors as well as using less broadly reactive T-cell depletion. Significant outcome improvements were identified with technology advances allowing selective depletion of donor allospecific T cells, initially ex-vivo with evolution to its current in-vivo approach with the infusion of the highly immunosuppressive chemotherapy agent, cyclophosphamide after transplantation procedure. Current approaches are facile and portable, allowing expansion of allogeneic hematopoietic cell transplantation for patients across the world, including previously underserved populations.

Comparison of upfront haploidentical hematopoietic stem cell transplantation and salvage haploidentical hematopoietic stem cell transplantation after immunosuppressive therapy in children with acquired severe aplastic anemia - a multicenter study.

Background: For children with severe aplastic anemia, if the first immunosuppressive therapy (IST) fails, it is not recommended to choose a second IST. Therefore, for patients without matched sibling donor (MSD) and matched unrelated donor (MUD), haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) can be chosen as a salvage treatment. This article aims to explore the comparison between upfront Haplo-HSCT and salvage Haplo-HSCT after IST. Methods: 29 patients received salvage Haplo-HSCT, and 50 patients received upfront Haplo-HSCT. The two groups received Bu (Busulfan, 3.2mg/kg/d*2d on days -9 to-8), CY (Cyclophosphamide, 60mg/kg/d*2d on days -4 to-3), Flu (fludarabine, 40mg/m2/d*5d on days -9 to -5) and rabbit ATG (Anti-thymocyte globulin, total dose 10mg/kg divided into days -4 to -2). Results: The OS of the salvage Haplo-HSCT group showed no difference to the upfront Haplo-HSCT group (80.2 ± 8.0% vs. 88.7 ± 4.8%, p=0.37). The FFS of the salvage Haplo-HSCT group also showed no difference to the frontline Haplo-HSCT group (75 ± 8.2% vs. 84.9 ± 5.3%, p=0.27). There was no significant difference in the incidence of other complications after transplantation between the two groups, except for thrombotic microangiopathy (TMA). In the grouping analysis by graft source, the incidence of II-IV aGVHD in patients using PBSC ± BM+UCB was lower than that in the PBSC ± BM group (p=0.010). Conclusion: Upfront Haplo-HSCT and salvage Haplo-HSCT after IST in children with acquired severe aplastic anemia have similar survival outcomes. However, the risk of TMA increases after salvage Haplo-HSCT. This article provides some reference value for the treatment selection of patients. In addition, co-transplantation of umbilical cord blood may reduce the incidence of GVHD.

Personalized Timing for Allogeneic Stem-Cell Transplantation in Hematologic Neoplasms: A Target Trial Emulation Approach Using Multistate Modeling and Microsimulation.

PURPOSE: Decision about the optimal timing of a treatment procedure in patients with hematologic neoplasms is critical, especially for cellular therapies (most including allogeneic hematopoietic stem-cell transplantation [HSCT]). In the absence of evidence from randomized trials, real-world observational data become beneficial to study the effect of the treatment timing. In this study, a framework to estimate the expected outcome after an intervention in a time-to-event scenario is developed, with the aim of optimizing the timing in a personalized manner. METHODS: Retrospective real-world data are leveraged to emulate a target trial for treatment timing using multistate modeling and microsimulation. This case study focuses on myelodysplastic syndromes, serving as a prototype for rare cancers characterized by a heterogeneous clinical course and complex genomic background. A cohort of 7,118 patients treated according to conventional available treatments/evidence across Europe and United States is analyzed. The primary clinical objective is to determine the ideal timing for HSCT, the only curative option for these patients. RESULTS: This analysis enabled us to identify the most appropriate time frames for HSCT on the basis of each patient's unique profile, defined by a combination relevant patients' characteristics. CONCLUSION: The developed methodology offers a structured framework to address a relevant clinical issue in the field of hematology. It makes several valuable contributions: (1) novel insights into how to develop decision models to identify the most favorable HSCT timing, (2) evidence to inform clinical decisions in a real-world context, and (3) the incorporation of complex information into decision making. This framework can be applied to provide medical insights for clinical issues that cannot be adequately addressed through randomized clinical trials.