Post-allogeneic Hematopoietic Stem Cell Transplantation Research Articles

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.

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.

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.

The Presence of Somatic Mutation in Donor Does Not Affect Long-Term Outcomes in 339 Patients Following Allogeneic Hematopoietic Stem Cell Transplantation Using Uniform Fludarabine/Busulfan Myeloablative Conditioning and Cyclosporine/Methotrexate and ATG Gvhd Prophylaxis

Introduction: Clonal hematopoiesis with indeterminate potential (CHIP) constitutes a part of the biological aging process and comprises the acquisition of somatic mutations in hematopoietic stem cells (HSCs). In the context of allogeneic hematopoietic stem cell transplantation (HCT), the potential transfer of CHIP from donor to recipient may raise concerns on HCT-related complications. There are contradictory data on donor CHIP's impact on long-term transplant outcomes using very diverse conditioning regimen as well as various graft-versus-host disease (GVHD) prophylaxis. This study aims to evaluate the impact of donor CHIP on allogeneic HCT outcomes in a cohort of the patients transplanted using a uniform, myeloablative intensity conditioning of Fludarabine-Busulfan (4 days) as well as Cyclosporine/Methotrexate with 4.5 mg/kg rabbit antithymocyte globulin (ATG) over 3 days for GVHD prophylaxis. Patients and methods: Peripheral blood samples were obtained from recipients and their corresponding donors who underwent allogeneic HCT at Tom Baker Cancer Centre, Calgary, Canada. Samples were archived from 339 patients and 255 donors prior to HCT, and additional patient sampling was done on day 28 (D28), day 56 (D56), or day 84 post allogeneic HCT (D84). As a result, paired recipient-donor samples were available for 255 HCTs. This study was approved by the institutional review boards of Princess Margaret Cancer Centre, Toronto, and Tom Baker Cancer Centre, Calgary. For the detection of CHIP, we have applied a bar-coded error-corrected sequencing protocol, a single-molecule molecular inversion probe capture protocol (NAR Genom Bioinform, 2022), which was performed at Wiesmann Institute of Science (Rehovot, Israel). We designed probes targeting 34 genes covering CHIP mutations along with other AML related mutations. Bar-coded NGS library was generated and processed. All statistical analyses were performed using R statistical software 3.5.0 and EZR version 1.41. Results: Sixty-seven clonal mutations in 56 recipients (18.2%) and 22 clonal mutations in 18 donors (7.1%) were detected prior to HCT. For recipients, TET2, JAK2, RUNX1, PPM1D, and DNMT3A were detected in at least 2 patients or more. For donors, the most frequently mutated gene was TET2 (3.1%), and the seconds were DNMT3A and PTPN11 (1.2% for both). Baseline characteristics of 255 patient-donor pairs did not show any difference between D-CHIP and no D-CHIP groups except donor age. Donor CHIP status was distributed evenly throughout most of the demographics of recipients, type of disease, pre-transplant status, and transplant procedure. Most of the pts received peripheral blood stem cells (97%). With a median follow up duration 6.02 years, the 5-year OS rates tend to be higher in no D-CHIP group than D-CHIP group (63.1% vs 42.8%) with a HR of 1.73 (95% CI [0.90-3.35]), although it was not statistically significant (p=0.096). The cumulative incidence of relapse for both groups were not different in 5 years (28.1% vs. 28.4%, p=0.849). The cumulative incidence of NRM within 5 years in D-CHIP group was slightly higher than no D-CHIP group (28.4% vs 17.5%), but it was not statistically significant (p=0.250). Neutrophil engraftment by day 28 was 99.1% vs. 100%, without statistical difference between the two groups (p=0.785). The cumulative incidence of grade II-IV acute GVHD within day+100 seemed to be higher in D-CHIP group compared to no D-CHIP group, but it was not statistically significant (24.8% vs. 34.5%, p=0.148; Figure A). In terms of chronic GVHD, cumulative incidence of moderate to severe GVHD was significantly higher in 5 years after transplant (29.4% vs. 58.8%; HR 2.55 [1.331-4.96], p=0.006; Figure B). Even when we set the cut off level of donor CHIP positivity up to >1% or >10%, the association between donor CHIP and risk of chronic GVHD remained significant. The impact of donor CHIP on the cumulative incidence of moderate to severe GVHD was confirmed in multivariate analysis (HR 2.3 [1.3-4.1], p=0.003). Other factors associated with moderate to severe chronic GVHD were previous history of grade II-IV acute GVHD (p=0.008) and donor type (p=0.054). Conclusion: Under clinical setting of uniform conditioning regimen and GVHD prophylaxis incorporating ATG (4.5mg/kg), donor CHIP was found to be associated with higher risk of moderate to severe chronic GVHD, while it does not affect other allogeneic HCT outcomes.

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.

Treatment of Refractory Adenovirus (ADV) Infections Using Adv-Specific Cytotoxic T-Lymphocytes (CTLs) in Children, Adolescents and Young Adults (CAYA) Post Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT), Solid Organ Transplantation (SOT), or with Primary Immunodeficiency (PID)

Background: AlloHSCT induces long-term, cure in CAYA with malignant and non-malignant disorders, including those with primary immunodeficiencies (PID). However, post-transplant complications secondary to immunosuppression and slow or delayed immune reconstitution remains a cause of morbidity and mortality amongst AlloHSCT recipients (Satwani/Cairo, BBMT, 2009). Major complications include refractory viral infections, most importantly adenovirus (ADV), which is secondary to absent or decreased adenovirus specific T-cell immunity which occurs due to delayed immune reconstitution and/or continued immunosuppression (George/Cairo, BJH, 2012). The use of virus-specific (vs) CTLs in immunocompromised patients offer an opportunity to restore temporary virus specific immunity. From the Viral Cytotoxic T-Lymphocyte Consortium (VIRCTLC), we present safety and efficacy results on immune compromised, AlloHSCT, or SOT patients treated with familial ADV specific CTLs. Objective: Determine the safety and efficacy of familial ADV specific CTLs for the treatment of refractory systemic ADV infections. Design/Methods: Patient were deemed eligible if they had a history of AlloHSCT, SOT, or PID and had evidence of ADV infections refractory to anti-viral agents. Refractory ADV infection was defined by increasing serum RT-PCR DNA (by 1 log) after 7 days or persistent quantitative RT-PCR DNA copies after 14 days of appropriate anti-viral therapy, and/or known resistance/intolerance to anti-viral agents. Related donors were required to be matched ≥3 HLA (A, B, or DRB1) loci and have an adequate T-cell response to viral specific MACS ADV PepTivators®. We chose a direct selection method to facilitate more rapid generation of cellular products in a point of care setting (and with 14 hrs eligibility determination). Peripheral blood mononuclear cells were collected from eligible family donors using non-mobilized apheresis. vsCTLs were isolated using the CliniMACS ® Prodigy following stimulation with viral specific MACS® GMP PepTivator® AdV5 Hexon, generously provided by Miltenyi Biotec®. ADV specific CTLs were enriched using a Cytokine Capture System (CCS). CD4+ and CD8+ vsCTLs were quantified by flow cytometry (Feuchtinger et al, Blood, 2010). The target cell dose was 0.5x10 4 CD3+ cells/kg (recipient weight) for haploidentical related donors and 2.5x10 4 CD3+ cells/kg for matched related donors. Repeated doses were permitted every 2 weeks to a maximum of doses in the absence of a complete response (CR) and adverse events. The following were used to define response: CR - undetected ADV PCR, partial response (PR) - at least one log decrease from baseline, progressive disease (PD) - at least one log increase from baseline, and patients with stable disease. Results: Fifteen patients were enrolled: 10 females and 5 males; aged 1-19 years. All patients were post-AlloHSCT. All vsCTL donors were haploidentical: 8 were the original HSCT donors and 7 were third party donors (5 maternal, 2 paternal). The mean number of ADV CTL infusions was 3.7 (range: 1-16). One patient with underlying aplastic anemia had progressive disease complicated by increased adenoviral load despite 5 infusions of vsCTLs. Patient received FDA approval for additional CTLs, totaling 16 doses. Thirteen patients achieved CR as defined and 2 achieved PR. The overall response (OR) was 100% and the CR was 88%. The average time to OR was 33 days (range 6-112 days) and time to CR was 34 days (range 6-112 days). Day 100 and 365 overall survival (OS) post-HSCT was 86.1% (CI95: 49.4-95.7) and 70.5% (CI95: 38.9-87.8), respectively (Figure 1). For patients who achieved CR, the Day 100 OS post AlloHSCT was 83.9% (CI95: 55.0-94.3) and Day 365 post AlloHSCT was 74.6% (CI95: 39.8-91.1). Day 100 and 365 probability of ADV related mortality was 0% (Figure 2). One patient developed acute grade 2 skin GVHD possibly related to infusion, which resolved. Conclusion: Our preliminary data demonstrate that haploidentical ADV specific CTLs manufactured by direct selections using the CCS with the CliniMACS® Prodigy and ADV specific peptivators are safe, well-tolerated, and efficacious in patients with refractory/persistent ADV infections after AlloHSCT. Manufacturing is rapid, reproducible, and effective. Accrual is ongoing. This research is supported by FDA RO1006301A1.

Economic analysis of allogeneic hematopoietic stem cell transplantation in the Bone Marrow Transplant Center of Tunisia

ABSTRACT Introduction: New procedures and diagnostic tests in hematopoietic stem cell transplantation (HSCT) are associated with a significant increase in costs. The last cost estimate of allogeneic HSCT done in Tunisia was in 1996 and concerned only direct medical costs. Therefore, an updated cost analysis is needed. Objective: Analysis of direct costs during the first-year post-allogeneic HSCT in two groups of patients: Bone Marrow Transplant (Allo-BMT) and Peripheral Blood Stem Cell Transplant (Allo-PBSCT) and identification of factors leading to interindividual variations in costs in order to compare these costs with the budget allocated by the payer (CNAM). Methods: Pharmacoeconomic retrospective study, concerning patients who underwent allogeneic HSCT in 2013. Clinical and unit cost data were obtained from medical and administration records. Results:This study showed that the average direct cost of allogeneic HSCT in the population during the first year reached 56 638€. The average cost of Allo-BMT was 63 612€, and Allo-PBSCT was 45 966€ (p > 0.05). The initial hospitalization counted for 88% of total direct cost with an average cost of 41 441€ in Allo-BMT and 24 672€ in Allo-PBSCT (p < 0.05). Direct medical costs represented more than 70% of total direct costs, drugs, and laboratory tests occupied the largest share. Antifungals, antitumors, and antiviral drugs were the most expensive pharmaceutical classes with a mean cost, respectively, of 4 526€; 3 737€ and 3 268€. Some clinical criteria were significantly related to total direct costs like length of aplasia (p < 0.01) and GVHD (p < 0.05). However, the type of blood disease, its risk, length of mucositis, and the treatment protocol have no effect on the costs for all allogeneic patients. Conclusion: Our results showed that the costs of Allo HSCT have exceeded by far the budget allocated by the CNAM to the center, since the 90s to this day. That’s why the total reimbursement mechanism should be revised.

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&gt;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.

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

Acute kidney injury after allogeneic hematopoietic stem cell transplantation – Predictors and survival impact: A single center retrospective study

Introduction and objectivesAcute kidney injury (AKI) is a frequent complication of hematopoietic stem cell transplantation (HSCT) and appears to be linked to increased morbidity and mortality. The aim of this study was to evaluate the incidence, etiology, predictors and survival impact of early AKI in the post-allogeneic HSCT setting. Patients and methodsWe performed a retrospective single center study that included 155 allogeneic transplant procedures from June 2017 through September 2019. ResultsAKI was observed in 50 patients (32%). In multivariate analysis, age (OR 31.55, 95% CI [3.42; 290.80], p=0.002), evidence of disease at the time of transplant (OR 2.54, 95% CI [1.12; 5.75], p=0.025), cytomegalovirus reactivation (OR 5.77, 95% CI [2.43; 13.72], p<0.001) and hospital stay >35 days (OR 2.66, 95% CI [1.08; 6.52], p=0.033) were independent predictors for AKI. Increasing age (HR 1.02, 95% CI [1.00; 1.04], p=0.029), increasing length of hospital stay (HR 1.02, 95% CI [1.01; 1.03], p=0.002), matched unrelated reduced intensity conditioning HSCT (HR 1.91, 95% CI [1.10; 3.33], p=0.022), occurrence of grade III/IV acute graft-versus-host disease (HR 2.41, 95% CI [1.15; 5.03], p=0.019) and need for mechanical ventilation (HR 3.49, 95% CI [1.54; 7.92], p=0.003) predicted an inferior survival in multivariate analysis. Early AKI from any etiology was not related to worse survival. ConclusionPatients submitted to HSCT are at an increased risk for AKI, which etiology is often multifactorial. Due to AKI incidence, specialized nephrologist consultation as part of the multidisciplinary team might be of benefit.

Estimating the Incidence-Based Cost of Illness Due to Hematopoietic Stem Cell Transplantation Using One-Year Insurance Claim Data in Korea.

Long-term follow-up data are required for incidence-based cost-of-illness (COI) studies, and it is difficult to carry out such assessments. To overcome this limitation, we estimated the acute and maintenance-state costs of hematopoietic stem cell transplantation (HSCT) using 1-year claim data. Using Korean National Health Insurance (NHI) data from 2016, 2017, and 2018, we identified patients receiving HSCT based on the procedure code "X5*" (i.e., HSCT). The post-HSCT group was defined as patients without the "X5*" code, but with the code "Z948 (other transplanted conditions)" and indications of HSCT (referring to those who had received HSCT). Mean annual medical use and costs were computed using the monthly values available for each patient. The mean number of hospitalizations/year, outpatient visits per year, hospitalization days/year, and length of stay (LOS)/hospitalization were 8.14, 35.80, 97.16, and 14.72, respectively, for allogeneic HSCT patients (n = 56); 8.08, 33.58, 73.04, and 10.63, respectively, for autologous HSCT patients (n = 89); 2.93, 29.40, 50.95, and 20.84, respectively, for post-allogeneic HSCT patients (n = 40); and 1.72, 16.38, 30.11, and 19.29, respectively, for post-autologous HSCT patients (n = 252). The estimated annual NHI-covered medical costs (US dollars) were $38,833-$40,876 for the allogeneic HSCT group, $1749-$6744 for the post-allogeneic HSCT group, $21,231-$22,863 for the autologous HSCT group, and $3954-$5352 for the post-autologous HSCT group. This study describes an alternative method for conducting incidence-based COI studies using cross-sectional claims data.

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.

Pediatric Vulvovaginal Graft-Versus-Host Disease: A Retrospective Cohort Study and Literature Review

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