Post-allogeneic Hematopoietic Stem Cell Research Articles

Association of the pre-transplant CD4/CD8 ratio with the prognosis following allogeneic hematopoietic stem cell transplantation

The tumor microenvironment’s cells can promote or inhibit tumor formation, and there are no reports on the CD4/CD8 ratio’s association with outcomes post allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively evaluated the pre-transplant peripheral blood CD4/CD8 ratio in 168 patients who underwent their first allo-HSCT for hematological malignancies at our institution. When patients were divided into two groups according to the median CD4/CD8 ratio 1.35 (range, 0.09–19.89), the high CD4/CD8 ratio group had a higher incidence of relapse, equivalent non-relapse mortality and worse overall survival (OS) than the low CD4/CD8 ratio group. In a multivariate analysis, the CD4/CD8 ratio was significantly associated with an increased risk of relapse, although there was a marginally significant difference in OS. The pre-transplant peripheral blood CD4/CD8 ratio could be a novel biomarker for predicting the prognosis of allo-HSCT.

Clinical Characteristics and Prognoses of Mucormycosis in Four Children.

Mucormycosis is a fatal invasive fungal infection that commonly affects immunocompromised children. The aim of our study was to investigate the clinical manifestations, treatments, and prognosis of pediatric patients with mucormycosis. We conducted a retrospective search in Shenzhen Children's Hospital from July 2013 to July 2023 for all patients with mucormycosis. The clinical manifestation, pathogen detection, radiology, treatments, and prognosis were analyzed. Four cases were identified. Underlying conditions included acute myeloid leukemia with myeloid sarcoma (n = 1), thalassemia (post-allogeneic hematopoietic stem cell transplantation; n = 1), systemic lupus erythematosus (n = 1), and bilateral nephroblastoma (post-bilateral nephrectomy; n = 1). Two patients were disseminated mucormycosis, one case was pulmonary mucormycosis, and one case was cerebral mucormycosis. Fever, cough, and dyspnea were the main clinical symptoms of pulmonary mucormycosis, headache was the main clinical symptom of cerebral mucormycosis. Lung CT findings included consolidation, multiple nodules, halo sign, air crescent sign, and pleural effusion. The contrast-enhanced CT showed pulmonary artery and pulmonary vein occlusions in two patients and pseudoaneurysm in two patients. Amphotericin B formulations were administered as first-line therapy in all cases; in three cases, Triazole was administered in combination with amphotericin B. Mucormycosis is a life-threatening disease involving multiple systems. Aorta pseudoaneurysm is a rare and fatal complication, enhanced CT can assist in diagnosis. Early diagnosis and appropriate therapeutic strategies are needed.

Reactivation of Multidrug-Resistant HSV-1 in a Post-Allogenic Hematopoietic Stem Cell Transplant Patient: Dynamic Detection of the Rare A605V Mutation by Next-Generation Sequencing.

We present an immunocompromised patient with a multiresistant herpes simplex virus-1 reactivation with a rare mutation (A605V) in the viral DNA polymerase gene. Next-generation sequencing suggests the presence of multiple drug-resistant strains before treatment and altered ratios during treatment, affecting the clinical response to aciclovir and foscarnet.

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

Treatment of post-allogeneic hematopoietic stem cell transplant cytopenias with sequential doses of multipotent mesenchymal stromal/stem cells

Background aimsCytopenias after allogeneic stem cell transplantation (allo-SCT) are a common complication, the underlying pathogenic mechanisms of which remain incompletely understood. Multipotent mesenchymal stromal/stem cell (MSC) therapy has been successfully employed in the treatment of immune-related disorders and can aid in the restoration of the hematopoietic niche. MethodsA phase II clinical trial to assess the efficacy and safety of administering four sequential doses of ex-vivo expanded bone marrow MSCs from a third-party donor to patients with persistent severe cytopenias after allo-SCT was performed. ResultsThe overall response rate on day 90 was 75% among the 27 evaluable patients (comprising 12 complete responses, 8 partial responses, and 7 with no response). The median time to respond was 14.5 days. Responses were observed across different profiles, including single or multiple affected lineages, primary or secondary timing, and potential immune-mediated or post-infectious pathophysiology versus idiopathic origin. With a median follow-up for surviving patients of 85 months after MSC infusion, 53% of patients are alive. Notably, no adverse events related to MSC therapy were reported. ConclusionsIn summary, the sequential infusion of third-party MSCs emerges as a viable and safe therapeutic option, exhibiting potential benefits for patients experiencing cytopenias following allo-SCT.

A phase II study of belumosudil for chronic graft-versus-host disease in patients who failed at least one line of systemic therapy in China

BackgroundChronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit–risk balance.MethodsThis multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient’s response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety.ResultsThirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1–87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9–48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%).ConclusionsBelumosudil treatment demonstrated a favorable benefit–risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent.Trial registrationClinicalTrials.gov identifier NCT04930562.

The dynamics of B-cell reconstitution post allogeneic hematopoietic stem cell transplantation: A real-world study.

The immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is crucial for preventing infections and relapse and enhancing graft-versus-tumor effects. B cells play an important role in humoral immunity and immune regulation, but their reconstitution after allo-HSCT has not been well studied. In this study, we analyzed the dynamics of B cells in 252 patients who underwent allo-HSCT for 2 years and assessed the impact of factors on B-cell reconstitution and their correlations with survival outcomes, as well as the development stages of B cells in the bone marrow and the subsets in the peripheral blood. We found that the B-cell reconstitution in the bone marrow was consistent with the peripheral blood (p=0.232). B-cell reconstitution was delayed by the male gender, age >50, older donor age, the occurrence of chronic and acute graft-versus-host disease, and the infections of fungi and cytomegalovirus. The survival analysis revealed that patients with lower B cells had higher risks of death and relapse. More importantly, we used propensity score matching to obtain the conclusion that post-1-year B-cell reconstitution is better in females. Meanwhile, using mediation analysis, we proposed the age-B cells-survival axis and found that B-cell reconstitution at month 12 posttransplant mediated the effect of age on patient survival (p=0.013). We also found that younger patients showed more immature B cells in the bone marrow after transplantation (p=0.037). Our findings provide valuable insights for optimizing the management of B-cell reconstitution and improving the efficacy and safety of allo-HSCT.

Evaluating the Feasibility and Acceptability of a Psychosexual Intervention for Couples Post-allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) can have a long-term impact on patients' sexual functioning and consequently, their relationship satisfaction. This study aimed to examine the feasibility and acceptability of a 5-session psychosexual intervention for HSCT survivors and their partners. To be eligible patients were required to be more than 3 months post-allogeneic HSCT. The intervention comprised 2 components: (1) A psychosexual education session exploring medical/behavioral treatment options for sexual dysfunction, delivered by a specialist nurse; (2) A 4-session Emotionally-Focused Therapy-based relationship education program for couples delivered by a clinical psychologist. Measures assessing relationship quality, sexual functioning, anxiety, and depression were administered pre- and post-intervention. Feasibility was measured via participation rate, adherence and compliance with completing main measures. Acceptability of the intervention was assessed via patient/partner satisfaction surveys. Eight of 85 (9.4%) eligible patients and their partners participated in the study. Reasons for declining participation included: feeling uncomfortable due to sensitive nature of intervention; did not have any relationship/sexual function issues; and experiencing ongoing medical issues. Six of 8 couples (75%) attended at least 4 intervention sessions and 5 of 8 (62.5%) completed the main study measures post-intervention. Four couples reported that sexual satisfaction and relationship satisfaction was somewhat or much better post-intervention; 1 reported no change. Feasibility criteria were not met, with low enrolment rate, however the intervention was deemed acceptable. Couples who participated adhered to the intervention and considered it beneficial. Further strategies to identify and manage sexual concerns are required.

Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies.

The 5-azacytidine (AZA) and decitabine (DEC) are noncytotoxic, differentiation-inducing therapies approved for treatment of myelodysplastic syndrome, acute myeloid leukemias (AML), and under evaluation as maintenance therapy for AML postallogeneic hematopoietic stem cell transplant and to treat hemoglobinapathies. Malignant cell cytoreduction is thought to occur by S-phase specific depletion of the key epigenetic regulator, DNA methyltransferase 1 (DNMT1) that, in the case of cancers, thereby releases terminal-differentiation programs. DNMT1-targeting can also elevate expression of immune function genes (HLA-DR, MICA, MICB) to stimulate graft versus leukemia effects. In vivo, there is a large inter-individual variability in DEC and 5-AZA activity because of pharmacogenetic factors, and an assay to quantify the molecular pharmacodynamic effect of DNMT1-depletion is a logical step toward individualized or personalized therapy. We developed and analytically validated a flow cytometric assay for DNMT1 epitope levels in blood and bone marrow cell subpopulations defined by immunophenotype and cell cycle state. Wild type (WT) and DNMT1 knock out (DKO) HC116 cells were used to select and optimize a highly specific DNMT1 monoclonal antibody. Methodologic validation of the assay consisted of cytometry and matching immunoblots of HC116-WT and -DKO cells and peripheral blood mononuclear cells; flow cytometry of H116-WT treated with DEC, and patient samples before and after treatment with 5-AZA. Analysis of patient samples demonstrated assay reproducibility, variation in patient DNMT1 levels prior to treatment, and DNMT1 depletion posttherapy. A flow-cytometry assay has been developed that in the research setting of clinical trials can inform studies of DEC or 5-AZA treatment to achieve targeted molecular pharmacodynamic effects and better understand treatment-resistance/failure.

Zinc Status Affects T Cell Reconstitution in Patients Receiving Naïve T Cell Depleted Allogeneic HSCT

Delayed immune reconstitution (IR) is a major clinical problem contributing to post-allogeneic hematopoietic stem cell transplant (allo-HSCT) morbidity and mortality. Specifically, CD4 T cell reconstitution is linked with improved clinical outcomes. As the primary organ of T cell production, the thymus is a crucial contributor to T cell reconstitution after HSCT generating a broad T cell receptor (TCR) repertoire selected through central tolerance However, T cell reconstitution can be hindered by poor thymus function as a consequence of age, transplant conditioning, or graft versus host disease (GVHD). At present, no drugs are available to boost T cell recovery, while many of the factors limiting IR are still unknown. Zinc (Zn), the second most abundant trace element in our body, is important for normal T cell development. Zn deficiency (ZD) in humans and mice is characterized by poor circulating T cells and depressed thymic function, which are both restorable after reintroduction of Zn with the diet. Despite having multiple risk factors for ZD, there are no published data focusing on ZD prevalence among allo-HSCT recipients. Based on our previous observations, we hypothesized that peri-HSCT Zn levels correlate with IR. In this study, we analyzed serum Zn levels of allo-HSCT patients who received naïve T cell (T N) depleted grafts as a strategy to prevent aGVHD (Bleakley et al., 2022, NCT00914940). This population is particularly interesting for studying IR because in these patients, circulating T N at d+365 after HSCT will primarily be of donor hematopoietic stem cell origin generated in the recipient thymus. Samples and clinical data were prospectively collected. Fifty-two patients had peri-HSCT serum samples available for Zn measures, as pre-HSCT and/or day +80 samples. Zn measures were performed through mass-spectrometry at the University of Washington Hospital-Biochemistry Lab. ZD was defined for Zn<70ug/dL as defined by the WHO. T cell populations (CD4 +, CD8 +, T N CD4 + and CD8 +, T regulatory cells, NK cells, B cells) were analyzed by flow cytometry at day+365. DNA was extracted from PBMC pellets collected at d+365 and were analyzed in qPCR for the expression of signal-joint T cell receptor excision circles (sjTRECs), being the gold standard for measuring thymic-derived T cells. We studied the association between Zn levels at baseline and day+80 and parameters of IR through linear regression. Comparisons between two groups were analyzed by t-test. Median age at transplant was 47 (range 6-61). Twenty-eight patients received myeloablative conditioning with total body irradiation (TBI) of 13.2 Gy (53.8%) and 24 (46.2%) received an intermediate intensity conditioning regimen with 4Gy TBI. Forty-one patients (78.8%) had pre-HSCT and 46 (88.5%) had day+80 Zn measures; 38 patients (73.1%) had both pre-HSCT and day+80 Zn measures. Median pre-HSCT and day+80 Zn levels were, respectively, 71 (range 60-105) and 80 (range 36-112); at baseline, 13 patients (25%) had ZD (<70ug/dL, according to WHO), whereas seven (13.3%) were ZD at day+80. Median sjTRECs at day +365 were 3.33/mg of DNA (range 0.00-16,704.54). As expected, sjTRECs at day+365 significantly correlated with age at transplant (r 2=0,3824; p<0.0001), whereas Zn levels preHCT or day80 did not. The number of circulating CD4 + and CD8 + T N at day+365 showed significant correlation with age. Zinc levels did not correlate with IR of absolute CD4 +, CD8 +, NK, T regs, and B cells at day+365, although we observed a trend for lower CD4 + counts at day 365 with lower day+80 Zn levels. Day+80 serum Zn levels was associated with sjTRECs at day+365 (Figure 1A. r 2=0.2643; p=0.0019) and lower pre-HSCT Zn significantly correlated with worse CD8 +T N reconstitution at day+365 (Figure 1B. r 2=0.1433; p= 0.0327), with clear trends in the same direction also for pre-HSCT Zn and CD4 + T N and day+80 Zn and CD4 + T N. In conclusion, we found that a non-negligible population of patients undergo allo-HSCT with unrecognized ZD. Peri-transplant Zinc status negatively affects IR, especially on the thymic-derived T cell compartment. Early recognition of ZD and zinc supplementation might help prevent morbidity related to poor IR in a proportion of patients. A multivariable analysis looking at other clinical data and outcomes is ongoing. Validation of these findings is needed on a larger number of patients, including a cohort of patients receiving T N-replete HSCT.

Inotuzumab Ozogamicin in Lymphoid B Cell Malignancy：a Single Center Analysis in the Real World

Background : Recent developments in immunoconjugate usage has changed the landscape of lymphoid B-cell malignancy therapy. Historically, those who relapse from this condition have a dismal prognosis and limited treatment options. One recent development is the inotuzumab ozogamicin (INO), a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, which has the potential to reduce the overall toxicity of intensive regimens for ALL, as well as to show therapeutic effects in lymphoid B-cell malignancy. Aims and Methods: The study included B cell-acute lymphoblastic leukemia (B-ALL) (n=23), B/ myeloid mixed phenotype acute leukemia (MPAL) (n=1) and B-cell lymphoblastic lymphoma (B-LBL) (n=3) adult patients who received INO in our center from June 2022 to June 2023. Intravenous INO was given 1 or more doses at the dose of 0.6mg/m2, its clinical efficacy and adverse reactions were explored. Results: In our center, INO was strategically employed in various therapeutic scenarios: induction (n=2), maintenance/consolidation (n=6), minimal residual disease (MRD) clearance (n=5), and the management of relapsed/refractory lymphoid B-cell malignancies (n=14). Of the 27 patients, 14 were subjected to a combination regimen of INO and chemotherapy for recurrent and refractory lymphoid B-cell malignancy. The composition of these patients comprised of 4 individuals who experienced a relapse post-standard chemotherapy, 1 patient with a relapse post-allogeneic hematopoietic stem cell transplantation (allo-HSCT), 4 patients with a relapse post-autologous hematopoietic stem cell transplantation (auto-HSCT), and the remaining 5 patients were categorized as refractory cases. The median number of doses administered was 2 (1-3). Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was observed in 9 out of 14 patients (64.3%) within a median duration of 30 (16-78)days. Partial response (PR) was noted in 2 of the 14 patients (14.3%), rendering the overall response rate (ORR) to be 78.6%. Negative MRD was observed in 7 out of 14 patients (50.0%). Of the 9 patients who achieved CR/CRi, 4 (44.4%) relapsed again with 2 fatalities. The remaining 2 patients attained negative MRD following a second allo-HSCT or INO retreatment. The two patients who achieved PR proceeded to receive chimeric antigen receptor T cell (CART) treatment, with one of them subsequently undergoing allo-HSCT after achieving CR. For the three non-responders (NR), one patient unfortunately passed away while the other two patients remained alive and were either participating in clinical trials or undergoing allo-HSCT after CART. For MRD clearance, it was successfully achieved in 4 out of 5 patients (80.0%)treated with INO within a median period of 45 (28-52)days. However, 2 patients reverted to MRD positivity and 1 died. The other four patients underwent allo-HSCT with neither mortality nor recurrence observed. Moreover, two patients (100%) were treated with a VICLP induction regimen combined with INO, with MRD negativity observed post-treatment. Regarding the remaining six patients, three patients were treated with INO as consolidation therapy due to high-risk factors or the intention to undergo auto-HSCT. Another 3 B-ALL patients treated with INO as maintenance therapy after auto-HSCT or after the remission of recurrence after transplantation. One patient unfortunately experienced a second recurrence four months following INO maintenance. The remaining five patients achieved and have since sustained negative MRD status, preceding INO treatment. Fortunately, no treatment-related fatalities or treatment discontinuation due to adverse events were observed. Notably, 19 out of 27 patients (70.4%) experienced Grade 3-4 hematological toxicity, while 1 out of 24 patients (4.2%) exhibited Grade 3 alanine aminotransferase (ALT) elevation. Veno-occlusive disease (VOD) was not observed. Furthermore, two patients developed septicemia, one each from Escherichia coli and Klebsiella pneumoniae, respectively. Conclusions: Given the well tolerance and improvement in response rates, InO may be an important treatment option not only for patients with relapsed/refractory lymphoid B-cell malignancy, but also for induction, maintenance and MRD clearance treatment. Key words: inotuzumab ozogamicin, acute lymphoblastic leukemia, hematopoietic stem cell transplantation, CD22

Yield of Repeat Blood Cultures in Acute Myeloid Leukemia Patients Following Allogeneic Hematopoietic Stem Cell Transplantation

Introduction: Unnecessary repeat blood culture collection has been demonstrated to increase health care costs, length of stay, duration of antimicrobial exposure, and risk of anemia and result in unnecessary removal of vascular catheters. The aim of this study was to characterize the yield of new pathogen identification in acute myeloid leukemia (AML) patients with known bacteremia in the post-allogeneic hematopoietic stem cell transplant (HSCT) period. Methods: This was a retrospective study of AML patients who underwent allogeneic HSCT at Taussig Cancer Center from January 1 st 2019 to December 31 st 2022. Patients who experienced an occurrence of febrile neutropenia (FN) within 35 days of date of HSCT and had positive initial blood cultures within 24 hours of diagnosis of FN were included in the study. Patients who had at least 1 additional set of repeat cultures drawn following initial blood cultures were included in the study. Blood cultures were collected through a peripheral site via venipuncture or through a central line. The study was approved by the Institutional Review Board. Data were collected on baseline patient characteristics, AML disease characteristics, HSCT characteristics, and infection characteristics. Febrile neutropenia was defined as recorded temperature ≥ 100.4°F with concurrent ANC <1500 cells/uL. Each patient day with a recorded temperature ≥100.4°F and ANC <1500 cells/μL was considered as a day of FN. An episode of FN was considered to be resolved following 72 hours of defervescence. Cultures drawn within 24 hours of onset of FN were considered the initial blood cultures. All subsequent sets of blood cultures were considered repeat blood cultures. A positive set of blood culture was defined as >50% of all blood cultures in that set growing an organism. Cultures drawn from all peripheral and central sites on the same day of FN were considered as one set of blood cultures. All patients received post-HSCT anti-bacterial prophylaxis with bactrim or ciprofloxacin. Results: A total of 154 AML patients who underwent HSCT at Taussig Cancer Center were screened for the study. 50/154 (32.5%) of those patients met inclusion criteria and were included in the study. Among the 50 patients included in the study, there were 50 episodes of FN with positive initial blood cultures that were diagnosed within 35 days of HSCT. There were 120 total days of FN among the 50 episodes of FN with an average of 2.4 days per episode. 50 initial sets of blood cultures and 96 sets of repeat blood cultures were drawn between the 50 episodes of FN with an average of 2.9 total sets of blood cultures per episode. 12/96 (12.5%) of repeat blood cultures sets were positive for a pathogen. 3/96 (3.1%) of repeat blood cultures sets grew a pathogen that differed from the pathogen which grew in the preceding positive blood culture. The median duration of febrile neutropenia at time of repeat positive culture was 3.5 days. 30-day mortality rate from infection was 6.0% (3/50). Conclusion: Even amongst bacteremic AML patients in the post-HSCT period, the yield of repeat blood cultures was low for detecting new pathogen identification. Repeat blood cultures should be guided by thorough evaluation of emerging clinical signs and symptoms.

Real-World Effectiveness and Safety of Hetrombopag for Delayed Platelet Engraftment Post-Allogeneic Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) serves as a critical therapeutic approach for various malignant and non-malignant hematopoietic disorders. Notwithstanding successful hematopoietic recovery in most patients following allo-HSCT, a subset may encounter delayed platelet engraftment (DPE), a prevalent and potentially serious complication that stems from myeloablative conditioning. Occurring in approximately 5%-37% of allo-HSCT recipients, DPE is a known harbinger of increased transplant-related mortality and diminished quality of survival. Despite its clinical significance, a well-established standard treatment protocol for post-allo-HSCT DPE remains elusive. Multiple platelet transfusions, often administered in such cases, not only exacerbate the economic burden but also induce toxicities, thereby undermining the patient's quality of life. An alternative to platelet transfusion lies in the utilization of thrombopoietin-receptor agonists (TPO-RAs), advocated for enhancing platelet engraftment. These agents interact with the thrombopoietin receptor, stimulating intracellular signaling pathways inclusive of JAK/STAT, PI3K/AKT, and ERK1/2, which in turn, promote megakaryocyte proliferation and differentiation, thereby augmenting platelet production. Hetrombopag, a novel, orally administered, non-peptide, small-molecule TPO-RA, has been validated to effectively boost platelet engraftment and reduce the necessity for platelet transfusions post-allo-HSCT in a pilot study. Our study sought to investigate the effectiveness and safety of hetrombopag in treating DPE following allo-HSCT within a real-world setting. Methods: In this retrospective study, we evaluated adult patients with hematopoietic disorders who underwent allo-HSCT and subsequently experienced DPE in our center, treated with hetrombopag between March 2022 and April 2023. Given the lack of a consensus definition, we deemed DPE as a platelet count (PLT) < 20 × 10 9/L or a significant and rapid decreasing trend past day 28 post-allo-HSCT. Hetrombopag dosages of 2.5 mg, 5 mg, or 7.5 mg/day were prescribed based on individual patient conditions. Response criteria post-treatment were as follows: complete response: PLT > 50 × 10 9/L without platelet transfusion; partial response: PLT between 20 and 50 × 10 9/L without platelet transfusion; no response: PLT < 20 × 10 9/L. Results: A total of 20 patients were included in the analysis, with a median age of 52, and 60% of them were male. Hetrombopag administration commenced at a median of 58 days following allo-HSCT at a median dose of 5 mg/day, with a median treatment duration of 44 days. The initial platelet count was 24.5 × 10 9/L and serum ferritin levels stood at 3351.1 ng/mL. Post-hetrombopag treatment, platelet counts escalated to 67.5 × 10 9/L while serum ferritin levels decreased to 2726.0 ng/mL. Of the 20 patients, 13 patients (65%) exhibited a complete response, 6 patients (30%) achieved a partial response, and 1 patient (5%) displayed no response. Hetrombopag was well tolerated with only 5 patients reporting increased alanine aminotransferase/aspartate aminotransferase or total bilirubin levels (all grade 1 or 2), and the association with hetrombopag was undetermined. Conclusion: Our findings suggest that hetrombopag yields a sustained response with acceptable tolerability in patients who experienced DPE following allo-HSCT, and could potentially offer a novel approach for managing such patients. Future large-scale, prospective studies are warranted to further assess the potential benefits of hetrombopag for improving patient outcomes following allo-HSCT.

Post Allogeneic Stem Cell Transplant Outcomes Following Response to Hypomethylating Agent Therapy in Myelodysplastic Syndromes Are Predicted By Persistent International Prognostic Scoring System-Molecular Risk

Introduction: The International Prognostic Scoring System-Molecular (IPSS-M) ( Bernard NEJM Evidence 2022) and the 2023 International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) ( Zeidan Blood 2023) are used to more accurately assess prognosis and therapeutic response in MDS. However, it is unknown if these tools can be used to predict outcomes post-allogeneic hematopoietic stem cell transplant (HCT). We sought to understand the impact of pre-HCT IPSS-M on post-HCT outcomes in patients (pts) with MDS who responded to hypomethylating agent (HMA) therapy. Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT post-HMA at Dana-Farber Cancer Institute from January 2014 to December 2020 were included. Response to HMA was assessed by 2023 IWG response criteria and was defined as complete remission (CR) + CR with bi-lineage blood count recovery (CRbi) + CR with uni-lineage blood count recovery (Cruni) + CR with partial hematological recovery (CRh). Combined clinical and molecular risk was assessed by IPSS-M at times of diagnosis and of HCT, the latter using the bone marrow biopsy and sequencing data collected closest to HCT. High risk was defined as IPSS-M moderately high, high, and very high, whereas low risk was defined as IPSS-M very low, low, and moderately low. Results: A total of 148 pts with MDS who received HMA and underwent subsequent HCT were included. Median age was 64 years (range 26-79) and 61.5% were men. Pts were diagnosed with MDS-EB1 (26.4%), MDS-EB2 (45.3%), and other MDS subtypes (28.3%). IPSS-M at time of diagnosis was very low (2%), low (10.1%), moderate low (6.1%), moderate high (8.8%), high (31.8%), and very high (22.3%). IPSS-M pre-HCT was very low (12.8%), low (8.8%), moderate low (10.8%), moderate high (12.8%), high (20.3%), and very high (10.8%). IPSS-M at diagnosis and pre-HCT could not be calculated because of missing molecular data in 18.9% and 23.6% of pts, respectively. Pts received a median of 4 HMA cycles (range 1-20) and were treated with azacitidine for 7 days (54.1%), decitabine for 5 days (39.2%), and other schedules (6.7%). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), partial remission (PR: 1.4%), hematological improvement (HI: 9.5%), and no response (38.5%). Most pts received HCT from either a matched unrelated (60.8%) or matched related donor (18.2%) with reduced intensity conditioning (74.3%). Pts received graft versus host disease prophylaxis with tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), post-transplant cyclophosphamide/mycophenolate mofetil/tac (15.5%), tac/sirolimus (8.1%), other (2%). Median HCT-comorbidity index (CI) was 2 (range 0-13) and 48.6% pts had HCT-CI ≥ 3. For the entire cohort, the median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). Among pts who responded to HMA per IWG 2023 criteria (CR/CRbi/CRuni/CRh), those who had high risk by IPSS-M prior to HCT had significantly shorter median overall survival (OS) (27 months; 95% CI 7.5-51) compared to pts with a low risk by IPSS-M (not reached; p=0.016) ( Figure A). Cumulative incidence of relapse (CIR) at 4 years was 66% for pts with high risk and 31% for low risk (p=0.034) ( Figure B). Pts with response to HMA with high risk by IPSS-M had lower OS (4-year OS: 27% versus 53%; p=0.016) and progression-free survival (4-year PFS: 19% versus 50%; p=0.018) but similar non-relapse mortality (NRM) (4-year NRM: 16% vs. 19%; p=0.66) post-HCT compared to pts with low risk at time of HCT. Conclusion: For pts with MDS who achieve a response to HMA prior to HCT, combined clinical/molecular risk, as assessed by IPSS-M, has an important prognostic impact on post-HCT outcomes. Pre-HCT risk should be evaluated for prognostication and to guide patient care, including future prospective studies evaluating novel agents for post-HCT therapy.

Novel Approaches to Treatment of Acute Myeloid Leukemia Relapse Post Allogeneic Stem Cell Transplantation.

The management of patients with acute myeloid leukemia (AML) relapsed post allogeneic hematopoietic stem cell transplantation (HSCT) remains a clinical challenge. Intensive treatment approaches are limited by severe toxicities in the early post-transplantation period. Therefore, hypomethylating agents (HMAs) have become the standard therapeutic approach due to favorable tolerability. Moreover, HMAs serve as a backbone for additional anti-leukemic agents. Despite discordant results, the addition of donor lymphocytes infusions (DLI) generally granted improved outcomes with manageable GvHD incidence. The recent introduction of novel targeted drugs in AML gives the opportunity to add a third element to salvage regimens. Those patients harboring targetable mutations might benefit from IDH1/2 inhibitors Ivosidenib and Enasidenib as well as FLT3 inhibitors Sorafenib and Gilteritinib in combination with HMA and DLI. Conversely, patients lacking targetable mutations actually benefit from the addition of Venetoclax. A second HSCT remains a valid option, especially for fit patients and for those who achieve a complete disease response with salvage regimens. Overall, across studies, higher response rates and longer survival were observed in cases of pre-emptive intervention for molecular relapse. Future perspectives currently rely on the development of adoptive immunotherapeutic strategies mainly represented by CAR-T cells.

Novel therapies for graft versus host disease with a focus on cell therapies.

Graft versus host disease (GVHD) can occur at any period post allogeneic hematopoietic stem cell transplantation as a common clinical complication contributing to significant morbidity and mortality. Acute GVHD develops in approximately 30-50% of patients receiving transplants from matched related donors. High doses of steroids are used as first-line treatment, but are unsuccessful in around 40% of patients, resulting in the diagnosis of steroid-refractory acute GVHD. Consensus has yet to develop for the management of steroid-refractory acute GVHD, and prognosis at six months has been estimated at around 50%. Thus, it is critical to find effective treatments that increase survival of steroid-refractory acute GVHD. This article describes the currently known characteristics, pathophysiology, and treatments for GVHD, with a special focus on recent advances in cell therapies. In particular, a novel cell therapy using decidua stromal cells (DSCs) was recently shown to have promising results for acute GVHD, with improved effectiveness over previous treatments including mesenchymal stromal cells. At the Karolinska Institute, severe acute GVHD patients treated with placenta-derived DSCs supplemented with either 5% albumin or 10% AB plasma displayed a one-year survival rate of 76% and 47% respectively. Furthermore, patients with steroid-refractory acute GVHD, displayed survival rates of 73% with albumin and 31% with AB plasma-supplemented DSCs, compared to the 20% survival rate in the mesenchymal stromal cell control group. Adverse events and deaths were found to be attributed only to complications of hematopoietic stem cell transplant and GVHD, not to the study intervention. ASC Therapeutics, Inc, in collaboration with the Karolinska Institute, will soon initiate a phase 2 multicenter, open-label study to further assess the efficacy and safety of intravenous DSC treatment in sixty patients with Grade II-IV steroid-refractory acute GVHD. This novel cell therapy represents a promising treatment to combat the poor prognosis that steroid-refractory acute GVHD patients currently face.

Efficacy and safety of venetoclax combined with hypomethylating agents for relapse of acute myeloid leukemia and myelodysplastic syndrome post allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis

BackgroundCurrently, there is no standard treatment for managing relapse in patients with acute myeloid leukemia and myelodysplastic syndrome (AML/MDS) after allogeneic hematopoietic cell transplantation. Venetoclax-based therapies have been increasingly used for treating post-transplantation relapse of AML. The aim of this systematic review and meta-analysis was to evaluate the efficacy and adverse events of Venetoclax combined with hypomethylating agents (HMAs) for AML/MDS relapse post-transplantation.MethodsWe searched PubMed, Web of Science, Excerpta Medica Database, Cochrane Library, and Clinical. gov for eligible studies from the inception to February 2022. The Methodological Index for Non-Randomized Studies was used to evaluate the quality of the included literatures. The inverse variance method calculated the pooled proportion and 95% confidence interval (CI).ResultsThis meta-analysis included 10 studies involving a total of 243 patients. The pooled complete response and complete response with incomplete blood count recovery rate of Venetoclax combined with HMAs for post-transplantation relapse in AML/MDS was 32% (95% CI, 26-39%, I2 = 0%), with an overall response rate of 48% (95% CI, 39-56%, I2 = 37%). The 6-month survival rate was 42% (95% CI, 29-55%, I2 = 62%) and the 1-year survival rate was 23% (95% CI, 11-38%, I2 = 78%).ConclusionThis study demonstrated a moderate benefit of Venetoclax in combination with HMAs for patients with relapsed AML/MDS post-transplantation (including those who have received prior HMAs therapy), and may become one of treatment options in the future. Large-scale prospective studies are needed to confirm the potential benefit from venetoclax combined with HMAs.

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.