Post-allogeneic Hematopoietic Stem Cell Research Articles

System dynamics analysis of mortality post allogeneic hematopoietic stem cell transplant

Allogeneic hematopoietic stem cell transplantation is a well-proven treatment for hematologic malignancies and non-malignancies, but it has a high risk of disease recurrence and severe transplant-related morbidity and death. The mortality and long-term survival of post-allogeneic hematopoietic stem cell transplant patients are improving due to improvements in condition procedures, methods, novel medicines, and supportive care practices. Allogeneic hematopoietic stem cell transplant (allo-HCT) findings, nonetheless, still present a chance for recovery. The results of this investigation updated previous research on risk factors for death following allogeneic HCT. We performed a systematic review and meta-analysis to assess mortality post allo-HCT through a comprehensive literature search using PUBMED/MEDLINE, CINAHL, Web of Science, and EMBASE up to April 30, 2023 and extracted clinical outcome data relating to benefits followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search identified 551 studies. Only 12 studies (n = 450 patients) met our inclusion criteria. OS rates were the subject of the meta-analysis. The following were the outcomes of heterogeneity tests: According to Chi2=9.14, df=6, P=0.17, and I2=34 percent, the study's data did not appear to be heterogeneous. The OS rate did not differ significantly (P>0.05) using the fixed-effect model analysis. In conclusion, the HSCT must offer the best overall survival, quality of life, and cost outcomes compared to any other treatment strategy. More studies will need a lot of data, and careful data analysis will help get clear data on HSCT outcomes.

Psychological states and needs among post-allogeneic hematopoietic stem cell transplantation survivors.

To analyze psychological states and needs of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Questionnaires were sent to 101 allo-HSCT survivors and 96 questionnaires were returned. The questionnaire covered several categories: (1) demographics and general information, (2) physical conditions, (3) psychologic status and sleep quality, (4) survivor's comments on transplantation, (5) demands and needs, (6) preferred forms and channels of information. Depression and poor sleep quality were major concerns troubling allo-HSCT survivors. A notable discrepancy exists between clinically diagnosed depression (4.2%) and self- reported depression based on BDI-13 (55.2%). Young adults (18-49 years old), chronic graft-versus-host disease, the ECOG performance score of 2-4, surviving within 5 years since HSCT, no or low dose of ATG used and being single were significantly associated with self-reported depression. Based on the PSQI score, 75% of survivors experienced varying degrees of sleep quality impairment. Young adults, chronic GVHD and the ECOG score of 2-4 were significantly associated with worse sleep quality. The majority of patients reported unmet needs on physical and psychosocial aspects. Nutrition information was the most important topic, followed by disease treatments and fatigue. Differences in informational needs were found in the survivors according to age, time since HSCT and gender. WeChat public account and WeChat applet, mobile interactive platform and one-to-one conversation were the favorite channel for information. Clinicians should establish more appropriate survivorship care plans focusing on survivors' psychologic states, demands and needs.

Mesenchymal stem cells reversibly de-differentiate myofibroblasts to fibroblast-like cells by inhibiting the TGF-β-SMAD2/3 pathway

BackgroundMyofibroblasts (MFB), one of the major effectors of pathologic fibrosis, mainly derived from the activation of fibroblast to myofibroblast transition (FMT). Although MFBs were historically considered terminally differentiated cells, their potential for de-differentiation was recently recognized and implied with therapeutic value in treating fibrotic diseases, for instance, idiopathic pulmonary fibrosis (IPF) and post allogeneic hematopoietic stem cell transplantation bronchiolitis obliterans (BO). During the past decade, several methods were reported to block or reverse MFB differentiation, among which mesenchymal stem cells (MSC) have demonstrated potential but undetermined therapeutic values. However, the MSC-mediated regulation of FMT and underlying mechanisms remained largely undefined.MethodBy identifying TGF-β1 hypertension as the pivotal landmark during the pro-fibrotic FMT, TGF-β1-induced MFB and MSC co-culture models were established and utilized to investigate regulations by MSC on FMT in vitro. Methods including RNA sequencing (RNA-seq), Western blot, qPCR and flow cytometry were used.ResultOur data revealed that TGF-β1 readily induced invasive signatures identified in fibrotic tissues and initiated MFB differentiation in normal FB. MSC reversibly de-differentiated MFB into a group of FB-like cells by selectively inhibiting the TGF-β-SMAD2/3 signaling. Importantly, these proliferation-boosted FB-like cells remained sensitive to TGF-β1 and could be re-induced into MFB.ConclusionOur findings highlighted the reversibility of MSC-mediated de-differentiation of MFB through TGF-β-SMAD2/3 signaling, which may explain MSC's inconsistent clinical efficacies in treating BO and other fibrotic diseases. These de-differentiated FB-like cells are still sensitive to TGF-β1 and may further deteriorate MFB phenotypes unless the pro-fibrotic microenvironment is corrected.

Severe graft‐versus‐host disease post allogeneic hematopoietic stem cell transplantation due to loss of HLA heterozygosity in recipient lymphocytes after full graft rejection

AbstractGerm cell tumors complicated by hematological malignancy (HM) are a rare clinical phenomenon. Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a potentially effective therapy, but graft‐versus‐host disease (GVHD) is a life‐threatening complication. We report a case of a 13‐year‐old female patient diagnosed with germ cell tumors followed by acute lymphoblastic leukemia. After chemotherapy, she received allo‐HSCT and her chimerism rate decreased rapidly to near zero by 6 months without evidence of HM recurrence. However, she developed severe, multiorgan GVHD‐like manifestations. DNA analysis revealed the pathogenesis of GVHD to be loss of HLA heterozygosity in recipient hematopoietic cells.

Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) in second complete remission (CR2) transplanted from unrelated donors with post-transplant cyclophosphamide (PTCy). A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Post-transplant cyclophosphamide (PTCy) is being increasingly used as graft-versus-host disease (GVHD) prophylaxis post allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) transplanted in first complete remission (CR1). However, results may differ in patients transplanted in CR2. We retrospectively evaluated transplant outcomes of adult AML patients transplanted between 2010-2019 from 9-10/10 human leukocyte antigen (HLA)-matched unrelated donor (UD) in CR2. In total, 127 patients were included (median age 45.5 years, 54% male). Median follow-up was 19.2 months. Conditioning was myeloablative (MAC) in 50.4% and the graft source was peripheral blood in 93.7% of the transplants. Incidence of acute (a)GVHD II-IV and III-IV was 26.2% and 9.2%. Two-year total and extensive chronic (c)GVHD were 34.3% and 13.8 %, respectively. Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were 17.2%, 21.1%, 61.7, %, 65.2%, and 49.3%, respectively. Time from diagnosis to transplant (>18 months) was a favorable prognostic factor for RI, LFS, OS, and GRFS while favorable risk cytogenetics was a positive prognostic factor for OS. The patient's age was a poor prognostic factor for NRM and cGVHD. Finally, the female-to-male combination and reduced intensity conditioning (RIC) were poor and favorable prognostic factors for cGVHD, respectively. We conclude that PTCy is an effective method for GVHD prophylaxis in AML patients undergoing allo-HCT in CR2 from UD.

Screening Chest CT Prior to Allogenic Hematopoietic Stem Cell Transplantation

Pulmonary complications constitute a major cause of morbidity and mortality in the post-allogenic hematopoietic stem cell transplant (alloHSCT) period. While Chest X-ray (CXR) is customarily used for screening, we have utilized chest computed tomography (CT). To characterize the prevalence of abnormalities and explore their impact on alloHSCT eligibility and outcomes post-transplant, we conducted a retrospective analysis utilizing real-world data collected at our center for adult patients who were evaluated for alloHSCT from January 2013 through December 2020 and identified 511 eligible patients. The most common primary disease was acute myeloid leukemia in 49% of patients, followed by myelodysplastic syndrome in 23%, lymphoma in 11%, and acute lymphocytic leukemia in 10%. Abnormal screening chest CT was found in 199 patients (39%). The most frequent detected abnormality was pulmonary nodule in 78 patients (35%), followed by consolidation in 42 (19%), ground-glass opacification in 33 (15%), bronchitis and bronchiolitis in 25 (11%), pleural effusions in 14 (6%), and new primary cancer in 7 (2%). CXR detected abnormalities in only about half of the patients (48%) with an abnormal chest CT. Among 199 patients with abnormal chest CT, 98 patients (49%) underwent further assessment and/or intervention before transplant. The most common work up was pulmonary consultation in 32%, infectious diseases consultation in 24%. Lung biopsy was obtained in 20% and antimicrobial therapy was initiated after confirming an infection diagnosis in 20% of patients. Patients with abnormal chest CT demonstrated worse overall survival (P= 0.032), non-relapse mortality (P=0.015), and pulmonary related death (P < 0.001) compared to those who had normal chest CT. Our study suggests that pre-transplant screening chest CT is beneficial in uncovering invasive infections and underlying malignancies and allows appropriate interventions before alloHSCT to prevent potentially serious post-transplant complications without causing a delay in alloHSCT. Nevertheless, abnormal CT findings prior to transplant may be associated with overall worse prognosis.

Transplant associated thrombotic micro angiopathy (TMA) post allogeneic hematopoietic stem cell transplantation (HSCT) : A single center experience in India

Transplant associated thrombotic micro angiopathy (TMA) post allogeneic hematopoietic stem cell transplantation (HSCT) : A single center experience in India

FLT3 inhibitors as maintenance therapy post allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia patients with FLT3 mutations: A meta-analysis.

Acute myeloid leukemia (AML) patients with a Fms-like tyrosine kinase 3 (FLT3) mutation have a high incidence of relapse despite allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a subsequent poor prognosis. FLT3 inhibitors (FLT3i) have been suggested to reduce the post-transplant relapse risk in recent studies. As more evidence is accumulated, we perform the present meta-analysis to assess the efficacy and safety of FLT3i as post-transplant maintenance therapy in AML patients. Literature search was performed in public databases from inception to December 31, 2021. Overall survival (OS), relapse-free survival (RFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), graft-versus-host disease (GVHD) and adverse events were compared between FLT3i and control groups. Pooled hazard ratio (HR) or relative risk (RR) with corresponding 95% confidence interval (CI) were calculated. We identified 12 eligible studies with 2282 FLT3-mutated AML patients who had received HSCT. There was no between-study heterogeneity and a fix-effect model was used. Post-transplant FLT3i maintenance significantly prolonged OS (HR=0.41, 95%CI: 0.32-0.52, p < 0.001) and RFS (HR=0.39, 95%CI 0.31-0.50, p < 0.001), and reduced CIR (HR=0.31, 95%CI 0.20-0.46, p < 0.001) as compared with control. There were no significant risk differences in NRM (RR=0.69, 95%CI 0.41-1.17, p=0.169), acute GVHD (RR=1.17, 95%CI 0.93-1.47, p=0.175), chronic GVHD (RR=1.31, 95%CI 0.91-1.39, p=0.276) and grade ≥3 adverse events between both groups, except for skin toxicity (RR=5.86, 95%CI 1.34-25.57, p=0.019). Post-transplant FLT3i maintenance can improve survival and reduce relapse in FLT3-mutated AML patients and is tolerable.

Outcomes of Acute Myeloid Leukemia Relapsed Post-Allogeneic Hematopoietic Stem Cell Transplant Treated with Hypomethylating Agents and Venetoclax Combination: A Single Center Experience

Introduction: The combination of hypomethylating agents (HMA) and the Bcl-2 inhibitor venetoclax (HMA+Ven) has changed the treatment landscape for acute myeloid leukemia (AML). For relapsed AML post-allogeneic hematopoietic stem cell transplant (alloHCT), there is no established standard treatment and outcomes remain poor. In this largest report to date, we systemically investigated the outcomes of post-alloHCT relapsed AML treated with HMA+Ven to identify key factors associated with clinical responses. Methods: This was a retrospective analysis of AML patients with relapse following alloHCT between May 2016 and April 2022. The study population was obtained via the BMT Research Analysis Information Network (BRAIN) database. Co-primary endpoints were the rates of complete responses with or without hematologic recovery (CR/CRi), the duration of CR (DoCR) and overall survival (OS) measured from the date of HMA and/or Ven initiation. Secondary endpoints explored the toxicity of HMA+Ven, as well as rates of conversion to 100% donor chimerism and minimal residual disease (MRD) negativity assessed by multiparametric flow cytometry (sensitivity 0.1%) or qPCR. Exploratory analyses focused on molecular aberrations associated with CR/CRi rate and DoCR. Cytogenetic and molecular risks were considered according to ELN 2017 criteria. Results: A total of 51 patients with relapsed AML post-alloHCT were included. Baseline characteristics are presented in Table 1. Information on response was available in 48/51 subjects: 22 had CR/CRi (46%) and 4 had partial response (PR, 8%). Non-responders included 2 with stable disease (4%) and 20 with progressive disease (PD, 42%). The median number of HMA +Ven cycles/patient was 2 (IQR 1-4, range 1-20) and CR/CRi was achieved after a median of 2 cycles (IQR 1-3 cycles). HMA+Ven led to two deaths (4%) in responders due to neutropenic fever. One patient discontinued Ven due to toxicity. The rate of CR/CRi was similar if HMA+Ven was given as the first or subsequent regimen at relapse (46.2% vs 44%; p = 1.0), if AML was secondary vs de novo (52.6% vs 41.4%; p = 0.56) and if HMA had been used prior to alloHCT (35.7% vs 51.5%; p = 0.35). Adverse-risk cytogenetics at relapse were associated with lower CR/CRi rate (33.3% vs 60.9%; p = 0.08). The median DoCR was 16.6 months (mos) (95% confidence interval [CI] 5.5 months to not reached [NR]). The DoCR was not impacted by the time from alloHCT to relapse, prior history of MDS/MPN and adverse-risk cytogenetics at relapse. IDH 1/2 mutation was associated with a numerically longer DoCR (16.6 [95% CI 6.7 to NR] vs 5.5 [95% CI 2.5 to NR] mos, p=0.5). Among CR/CRis, MRD negativity was documented in 3/4 tested subjects while disappearance of pathogenic mutations on next generation sequencing occurred in 12/18 and conversion to 100% donor genotype on chimerism studies in 16/17. Four went on to receive DLI and two a second alloHCT. Overall, 38 patients died (75%) and the median OS was 5.4 mos (95% CI 3.1 to 8.7 months). Median OS was superior for patients who achieved CR/CRi (19.7 [95% CI 5.6 to NR] vs 3.4 [95% CI 1.9 to 5.8] mos, Figure). Compared to wild-type alleles, certain recurrent mutations were associated with higher CR/CRi rates [FLT3-ITD or FLT3-TKD (75.0% vs 41.0%; p = 0.12), NPM1 (77.8% vs 39.5%; p = 0.06), IDH1/2 (87.5% vs 38.5%; p = 0.02)], whereas TP53 mutations were not (40.0% vs 48.6%; p = 0.73). In a multivariate logistic regression model, female sex (adjusted odds ratio [aOR] 5.8, p = 0.03), time from alloHCT to relapse (aOR 1.08 per 1-mo increase, p = 0.02) and mutated IDH 1/2 (aOR 14.0, p = 0.03) significantly increased odds of CR/CRi. In a separate multivariate model not including mutations, favorable/intermediate-risk cytogenetics at relapse were associated with higher odds of CR/CRi (aOR 3.62, p = 0.04). Notably, a new high-risk cytogenetic or molecular abnormality at relapse compared to original diagnosis was recorded in 6/50 (12%) and 10/41 (24%) patients with evaluable data, respectively. Conclusions: The prognosis of relapsed AML post-alloHCT remains poor. In this largest retrospective cohort study to date, HMA+Ven appeared to be effective and well-tolerated in this setting, with the potential for durable remissions and MRD negativity, especially in the presence of certain molecular aberrations such as NPM1 and IDH 1/2 mutations. Prospective trials evaluating the efficacy, safety and immunogenicity of this approach are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Older patients' experiences following initial diagnosis of acute myeloid leukemia: A qualitative study

IntroductionThe 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 been 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 methodsWe 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 fifteen 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 fourteenth 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. ResultsMean age of the fifteen 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. DiscussionUnderstanding 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.

Relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia: an overview of prevention and treatment.

Despite therapeutic progress in acute myeloid leukemia (AML), relapse post-allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a major challenge. Here, we aim to provide an overview of prevention and treatment of relapse in this population, including cell-based and pharmacologic options. Post-transplant maintenance therapy is used in patients who have undetectable measurable residual disease (MRD), while pre-emptive treatment is administered upon detection of MRD. Prompt transfusion of prophylactic donor lymphocyte infusion (DLI) was found to be effective in preventing relapse and overcoming the negative impact of detectable MRD. In addition, patients with persistent targetable mutations can benefit from targeted post-transplant pharmacological interventions. IDH inhibitors have shown promising results in relapsed/refractory AML. Hypomethylating agents, such as decitabine and azacitidine, have been studied in the post-allo-HSCT setting, both as pre-emptive and prophylactic. Venetoclax has been shown effective in combination with hypomethylating agents or low-dose cytarabine in patients with newly diagnosed AML, especially those unfit for intensive chemotherapy. FLT3 inhibitors, the topic of another section in this review series, have significantly improved survival in FLT-3-ITD mutant AML. The role of other cell-based therapies, including CAR-T cells, in AML is currently being investigated.

Evaluation of A Nutrition Feeding Algorithm for Children and Adolescents Undergoing Haematopoietic Stem Cell Transplantation (HSCT)

Background Nutrition support during the acute phase post allogeneic haematopoietic stem cell transplantation (HSCT) is required to optimise short- and long-term outcomes for children. An algorithm was developed and evaluated to assist clinicians to make objective and consistent enteral feeding decisions. Methods The algorithm was evaluated on all patients who underwent allogeneic HSCT treatment between November 2017 - February 2019. Results Of the 48 patients, 43 had a nasogastric tube (NGT) inserted, of which 36 patients received a hydrolysed peptide-based formula, 5 patients received a whole protein formula only and 2 patients were fed an amino acid-based formula. Parenteral nutrition (PN) was used in 41 of the patients. Eleven did not have an NGT in-situ at the commencement of HSCT. Of the remaining 37 patients, 26 followed the algorithm and 11 patients did not comply. The group of patients who did not follow the algorithm had the longest median length of stay (LOS) of 49 days. Patients receiving only EN had the lowest median LOS of 30 days. The two groups that reported better weight outcomes were those who followed the algorithm and those who were fully EN fed. Conclusions Effective use of the HSCT feeding algorithm indicated improved patient outcomes for children undergoing HSCT, with better weight outcomes and reduced LOS. Recommendations to improve the efficacy and compliance of the algorithm include regular education/input to the oncology medical teams to better understand objective thresholds for EN and PN commencement.

Comparison of the characteristics of NK cells after two different methods of expansion and observation of the clinical efficacy in patients who relapsed post allogeneic hematopoietic stem cell transplantation

目的比较不同扩增体系NK细胞生物学特性的差异以及治疗异基因造血干细胞移植后（allo-HSCT）白血病复发的疗效。方法分别采用CD3/CD52单抗扩增法和饲养层细胞扩增法诱导供者来源NK细胞大量扩增，检测扩增前后NK细胞表型、因子分泌、细胞毒的变化规律；选取16例allo-HSCT后复发白血病患者，8例输注CD3/CD52单抗扩增NK细胞，8例输注饲养层细胞扩增NK细胞，观察患者的治疗反应和长期生存情况。结果①与CD3/CD52单抗扩增体系相比，饲养层细胞扩增体系NK细胞纯度较高、NK细胞表面活化性受体DNAM-1及NKp30表达较高、抑制性受体CTLA-4表达较低，而两种NK细胞NKG2D/CD25/CD69/Trail/PD-1/TIM-3/TIGIT表达差异无统计学意义。②两种扩增体系NK细胞Ki-67指数均明显增加，以饲养层细胞扩增NK细胞尤为明显；饲养层细胞扩增NK细胞穿孔素及颗粒酶B表达水平均明显高于CD3/CD52单抗扩增NK细胞。③16例allo-HSCT后复发白血病患者NK细胞输注过程中均未观察到明显不良反应。NK细胞输注后中位随访时间为2554（917～2583）d，CD3/CD52单抗扩增组中3例患者无白血病存活，5例死亡；饲养层细胞扩增组中6例患者长期存活，2例死亡。5例患者在NK细胞输注前存在移植物抗宿主病，NK细胞输注后移植物抗宿主病未加重甚至缓解。结论CD3/CD52单抗扩增与饲养层细胞扩增体系NK细胞的生物学特性具有明显差异；NK细胞输注对allo-HSCT后复发白血病患者的疗效仍需要进一步验证。

CD26 expression on donor harvest as a risk predictive biomarker for developing graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation: A ten-year follow-up study.

Allogeneic hematopoietic stem cell transplantation (ASCT) is the preferred treatment option for patients with several hematologic disorders and immunodeficiency syndromes. Graft-versus-host disease (GVHD) is an immune mediated post-transplant complication which has a major impact on long-term transplant outcomes. Current efforts are focused on identification of new markers that serve as potential predictors of GVHD and other post-transplant clinical outcomes. This study includes donor harvests collected from twenty-three allogeneic donors during period 2008-2009 and respective transplant recipients followed for clinical outcomes till March 2019. Percent CD26+ and CD34+ cells in donor harvest were analyzed using flow cytometry. Percent expression and infused dose of CD26+ and CD34+ cells were evaluated for association with various clinical outcomes. Total 23 healthy donors with median age of 28 years (13 males), and transplant recipients with median age of 24years (17 males) formed the study cohort. The diagnosis included malignant (n= 13) and non-malignant (n= 10) hematological disorders. Median CD34brCD45lo HSC expression was 0.57% (IQR 0.24-1.03) while median CD26 expression was 19.64% (IQR 8.96-33.56) of all nucleated cells. CD26 expression was associated with donor age (P= 0.037). CD26 percent expression correlated with WBC engraftment (P= 0.015) and with acute GVHD (P= 0.023) whereas infused CD26 cell dose correlated with WBC engraftment (P= 0.004) and risk of CMV reactivation (P= 0.020). There was no statistically significant correlation of either CD26 expression or cell dose with chronic GVHD, EFS or OS. Our findings suggest a role of CD26 expression on human donor harvest as a potential predictor of acute GVHD. This association warrants further exploration.

Real world outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation–A single institution experience

Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with a worse prognosis compared to Ph negative ALL. Tyrosine kinase inhibitor (TKI) therapy has led to an improvement in response rates and survival, thus becoming a critical component of therapy. We performed a retrospective cohort study of Ph+ ALL patients treated at the University of Michigan who received TKI therapy pre- and post-allogeneic hematopoietic stem cell transplant (HSCT) from April 2007 to November 2019. The study included 40 patients with Ph+ ALL (47.5% female) with a median age of 54 (24-69) years. Median event-free survival (EFS) was not reached, with a 5-year EFS of 61%. Median overall survival (OS) was not reached, with a 5-year OS of 71%. There was no difference in 2-year EFS or OS for patients on pre-transplant imatinib or dasatinib (p = 0.16, 0.09, respectively), though definitive conclusions are challenging as post-transplant TKI therapy was variable. The incidence of any grade acute graft-versus-host disease (GVHD) was 62.5% (25/40) and any grade chronic GVHD was 77.5% (31/40). Complete molecular remission (CMR) was achieved in 57.5% of patients pre-transplant with no significant difference when stratified by induction TKI (p = 1). Achievement of CMR pre-HSCT showed a trend towards improved 2-year EFS (p=0.0198) but did not significantly change 2-year OS (p = 1). Patients receiving 1st and 2nd generation TKIs pre- and post-HSCT seem to have favorable outcomes, although type of TKI (pre-HSCT) did not significantly impact EFS or OS. In addition, attaining a CMR pre-transplant improved EFS, but did not change OS.

Donor origin precursor B-cell lymphoblastic leukemia post beta-thalassemia haploidentical transplant – A rare case report

Secondary malignancy of donor origin in the form of acute lymphoblastic leukemia (ALL), post-allogeneic hematopoietic stem cell transplant (HSCT) for beta thalassemia (BT) major, is exceedingly rare. A10 year old male child, the first and only product of non-consanguineous conception, was diagnosed with BT major at the age of 9 months when he had diarrhea and his parents (both of whom had thalassemia minor) noticed yellowing of the skin. Until the age of 10 years, he received regular blood transfusion and iron chelation, when the requirements got escalated and he consequently had to undergo myeloablative haploidentical HSCT from his mother. The post-transplant period was uneventful, and follow up with short tandem repeat chimerism analysis revealed complete donor chimerism on all occasions. Five years after the transplant, he developed fever with pancytopenia. Peripheral smear (PS) and bone marrow revealed blasts that were immunophenotypically precursor B-ALL. Cytogenetics revealed twenty diploid female metaphases with modal karyotype 46, XX[20], and again, complete donor chimerism was noted. Thus, a diagnosis of donor cell leukemia (DCL) was considered. Induction chemotherapy was initiated; however, the patient succumbed to systemic sepsis midway through induction therapy. No evidence of leukemia was noted in the patient's mother, who was followed up with PSs for 5 years. DCL has a poor prognosis. Greater understanding of the disease biology could allow for appropriate donor screening, notification and shielding the recipient from DCL and its grave consequences.

Association of early donor chimerism status with survival outcomes in post allogeneic haematopoietic stem cell transplant patients of nonmalignant diseases.

To highlight the association of early donor chimerism status at 2nd month with various survival outcomes. The retrospective study was conducted at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan, and comprised patient data from January 2011 to July 2016. Data related to participants who underwent human leukocyte antigen-matched transplants for bone marrow failure syndrome and beta thalassemia major. Short tandem repeat-based polymerase chain reaction was used to assess donor chimerism status. Overall survival, disease-free survival, relapse-free survival, and graft versus host disease-free survival rates were noted. Data was analysed using SPSS 23. Of the 106, 64(60.4%) had bone marrow failure syndrome and 42(39.6%) had beta thalassemia major. The overall median follow-up was 13.53 months (range: 1.81-62.73 months). Early donor chimerism status was associated with overall survival (p=0.02) and disease-free survival (p=0.01). Mixed donor chimerism was less hazardous in terms of overall survival (p=0.04) and disease-free survival (p=0.02). Early mixed donor chimerism contributed to optimal survival in nonmalignant disease.

High-Dose Intravenous Acyclovir Is Safe and Effective in the Treatment of EBV Reactivation Post Allogeneic Hematopoietic Stem Cell Transplantation

Backgroud:Reactivation of nasopharyngeal carcinoma virus (EBV) post allogeneic hematopoietic stem cell transplantation(allo-HSCT) is very common, but sustained EBV activation maybe induce EBV-associated lymphoproliferative disease (PTLD), transplant-associated hemophagocytic syndrome and thrombocytopenia after transplantation, which is extremely harmful for long-term survival. Currently, the first-line therapeutic strategy for sustained EBV activation is rituximab, but rituximab leads to increased rates of infections and delayed immune reconstitution. Therefore, for the patients with EBV-DNA copies under 1000000/mL, the pros and cons of rituximab are worth weighing.Objective:To evaluate the efficacy and safety of high-dose intravenous acyclovir in the treatment of EBV reactivation post allo-HSCT.Method:Retrospective analysis of clinical data of patients with EBV reactivation post transplantation treated with high-dose intravenous acyclovir (0.5g Q8H) in Sichuan Provincial People's Hospital from January 2019 to May 2021. A total of 49 patients post allo-HSCT from from January 2019 to May 2021 were enrolled in this study. In this population, 38 patients accepted haplo-SCT and 11 patients accepted sibling-SCT. These patients all don't suffer from PTLD and transplant-associated hemophagocytic syndrome, but are resistant to oral antiviral drugs (Acyclovir, valacyclovir, and famciclovir). Simultaneously with intravenous acyclovir, all patients received human immunoglobulin with one dose of 0.4g/kg. The clinical efficacy was evaluated as follows: Overall response(ORR) was defined as the decrease of EBV copies; Complete remission(CR) was defined as the negative turn of EBV copies; Partial response(PR), Stable disease(SD) and Progression of disease(PD) were respectively defined as the decrease, no significant change and increase of EBV copies.Results:The median transplantation time was +86 (+38 to +1587) days. The median number of EBV-DNA copies/ml was 177000 (6620-8200000). After treatment with high-dose intravenous acyclovir, 29 (59.2%) of 49 patients achieved CR, 10 (20.4%) of 49 patients achieved PR, and 10 (20.4%) of 49 patients had no response, including 2 patients with SD and 8 patients with PD. All 49 patients had responded to this regimen with 79.6% ORR. The median time of response and negative turn was 4 days (2 to 11 days) and 9 days (2 to 23 days) respectively. After 100 days for follow-up, 14 of 39 responding patients suffered from EBV activation again, and the EBV copies were higher than that when high-dose acyclovir was initiated. All 24 patients who did not turn negative were recommended with the treatment of rituximab, and 19 of 20 patients who completed treatment turned negative during the three months post acyclovir treatment. The main adverse events (AEs) of this regimen were neutropenia (CTCAE grade 2-3, 8 in 49 patients), thrombocytopenia (CTCAE grade 2-3, 10 in 49 patients), increased serum creatinine (CTCAE grade 1-2, 4 in 49 patients), phlebitis (6 in 49 patients). These AEs were all reversible, which recovered after withdrawal. There was no significant change in the counts of CD4 + T cells and CD8 + T cells before and after intravenous high-dose acyclovir.Conclusion:High-dose intravenous acyclovir is safe and effective in the treatment of EBV reactivation post allo-HSCT, although nearly half of patients still need rituximab treatment. It is a reasonable strategy for patients with oral antiviral resistance. Most patients can avoid the prescription of rituximab in the first six months post allo-HSCT, without interference of immune reconstitution. DisclosuresNo relevant conflicts of interest to declare.

Impact of Concomitant Genetic Abnormalities on Sorafenib Therapy in FLT3-ITD Positive Acute Myeloid Leukemia Undergoing Allo-HSCT

AimIn this study, we investigated the co-occurring mutation landscape in acute myeloid leukemia (AML) patients with FLT3 internal tandem duplication (FLT3-ITD), and explored whether post-allogenic hematopoietic stem cell transplantation (allo-HSCT) sorafenib maintenance therapy could improve the outcomes of FLT3-ITD AML patients combined with other co-occurring genetic abnormalities.MethodsA total of 456 FLT3-ITD AML patients receiving first allo-HSCT were included in this study. Gene mutations were detected using direct sequencing or next generation sequencing. Fusion genes were detected using a 53-gene polymerase chain reaction panel. The frequency of each genetic abnormality was investigated, and the mutation landscape was investigated. The primary outcome of this study was 3-year cumulative incidence of relapse. The secondary outcomes were 3-year overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM). The outcomes were compared between patients who received post-HSCT sorafenib maintenance and those who did not in the whole population and in subgroups referring to co-occurring mutations.ResultsA total of 190 patients received post transplantation sorafenib maintenance therapy (sorafenib group) and 266 patients did not (control group). Of the patients receiving sorafenib pre-transplantation, the median duration of sorafenib therapy was 106 days (IQR 68 - 132) in the sorafenib group, and 99 days (IQR 71 - 142) in the control group (p = 0.883). Of the patients receiving post-transplantation sorafenib maintenance therapy, sorafenib was initiated at a median of 30 days (IQR, 30 - 52 days) after allo-HSCT, and continued for a median of 148 days (IQR, 112 - 150).Median follow-up time was 38.7 months (IQR, 28.1 - 47.9). Thirty-four patients in the sorafenib group and 93 patients in the control group relapsed. The 3-year cumulative incidence of relapse was 18.0% (95% CI 13.1% - 24.3%) in the sorafenib group and 36.1% (95% CI 30.5% - 42.3%) in the control group (HR 0.43, 95% CI 0.29 - 0.64; p < 0.001). A total of 126 patients died, including 39 in the sorafenib group and 87 in the control group. Three-year DFS was 75.8% in the sorafenib group and 57.5% in the control group (HR 0.47, 95% CI 0.34 - 0.66; p < 0.001). Three-year OS was 79.5% for patients in the sorafenib group and 68.4% for patients in the control group (HR 0.57, 95% CI 0.39 - 0.83, p = 0.004).Gene mutations were detected using a 12-mutation panel direct sequencing including FLT3-ITD, FLT3-TKD, NPM1, KIT, DNMT3A, CEBPA, ASXL1, TP53, TET2, IDH1, IDH2 and RUNX1 in all patients, and a 127-gene panel new generation sequencing in 188 patients.Except FLT3, a total of 920 co-occurring gene mutations and 147 cytogenetic abnormalties were detected. The co-occurring mutations that presented in at least 10% the cases were NPM1 (31.6%), DNMT3A (15.4%), TET2 (11.4%), and CEBPA (10.5%). There were 10.5% patients presented with both NPM1 and DNMT3A mutations (Triple-mutated AML patients), and 13.8% patients combined with at least one additional genetic abnormality classified as adverse according to the 2017 ELN risk stratification other than FLT3-ITD. Cytogenetic abnormalities presented in more than 1% the patients were RUNX1-RUNX1T1, which occurred in 23 patients (5.0%), followed by +8 (2.9%), complex karyotype (2.6%), CBFB-MYH11 (2.4%), DEK-NUP214 (1.3%) and -y (1.3%).Patients combined with NPM1(p = 0.009 and 0.009), DNMT3A (p = 0.036 and 0.086), triple-mutated AML patients (p = 0.030 and 0.027), and patients with at least one additional adverse abnormality (p = 0.014 and 0.005) benefit significantly in DFS and OS from post-transplantation sorafenib maintenance, but not those with CEBPA (p = 0.669 and 0.576) or TET2 (p = 0.375 and 0.178) mutations.ConclusionPost transplantation sorafenib maintenance therapy can improve the prognosis of FLT3-ITD AML patients combined with DNMT3A or NPM1, patients with triple-mutated AML, and patients combined with at least one additional adverse abnormalities, but not of those combined with CEBPA or TET2 mutations. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Large-vessel vasculitis in graft-versus-host disease: a case report

BackgroundGraft-versus-host disease is a common complication seen with allogenic stem cell transplant, which is used to treat a variety of hematological malignancies. Graft-versus-host disease is an allogenic syndrome and can present in a variety of ways, including symptoms mimicking various autoimmune diseases; however, it is quite rare to see graft-versus-host disease affecting the vascular system and causing vasculitis.Case presentationWe describe a case of a 59-year-old Caucasian man with follicular lymphoma and diffuse large B-cell transformation who developed graft-versus-host disease post allogenic hematopoietic stem cell transplantation and later progressed to neurological complication foot drop and large-vessel vasculitis.ConclusionThe life-threatening vascular complications associated with large-vessel vasculitis include arterial aneurysms and dissections, and ischemic or hemorrhagic stroke. Thus, this rare immunological association needs to be recognized and treated in a timely manner to prevent the long-term complications.