Hematopoietic Stem Cell Transplantation Research Articles

Frontline combination of dasatinib and low-intensity chemotherapy in adults with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia

ABSTRACT Background Studies on dasatinib-based low-intensity induction regimens and post-remission strategies are limited in China. Therefore, we conducted a single-center phase 2 trial in newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) to establish the efficacy and safety of this treatment approach. Research design and methods Patients received one month of dasatinib plus low-intensity chemotherapy and two months of dasatinib monotherapy for induction, followed by a single course of high-dose methotrexate for consolidation. Subsequently, they underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) or tyrosine kinase inhibitor (TKI)-based treatment for maintenance therapy between October 2015 and August 2022. Results Twenty-two patients were enrolled. Median age was 45 years (range, 20–71). The rates of major and complete molecular responses in the third month were 18.2% and 40.9% respectively. With a median follow-up of 15 months (range, 5–89), the estimated 3-year disease-free survival (DFS) and overall survival (OS) were 52.4% and 73.2%, respectively. The TKI-based cohort had a significantly poorer DFS (p = 0.014) and OS (p = 0.008) than the allo-HSCT cohort. Conclusions Our results suggest that dasatinib-based low-intensity chemotherapy is safe and effective as an induction strategy in the Chinese population. Allo-HSCT plays a crucial role in the long-term outcomes of patients with Ph+ ALL. Clinical trial registration The trial was registered at ClinicalTrials.gov as NCT02690922.

[L-DEP regimen salvage therapy for refractory primary hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus infection in 4 children].

Objective: To analyze the efficacy and safety of the L-DEP regimen (asparaginase, liposome doxorubicin, etoposide and methylprednisolone) as a salvage therapy for the refractory primary hemophagocytic lymphohistocytosis triggered by Epstein-Barr virus infection (EBV-pHLH) in children. Methods: In this retrospective case study, clinical and laboratory data before and after L-DEP regimen of 4 children diagnosed with EBV-pHLH in Beijing Children's hospital between January 2016 and June 2022 were collected, and the efficacy and safety of L-DEP regimen for the treatment of EBV-pHLH were analyzed. Results: Among 4 patients, there were 3 females and 1 male with the age ranged from 0.8 to 7.0 years. Two of them showed compound heterozygous mutations of PRF1, one with a heterozygous mutation of UNC13D, one homozygous mutation of ITK. Before the L-DEP therapy, all of them had anemia and a soaring level of soluble CD25, 3 patients had neutropenia and thrombopenia, 3 patients had a high level of ferritin, 3 patients had hypofibrinogenemia and 1 patient had hypertriglyceridemia. After receiving 1 or 2 cycles of L-DEP treatment, three achieved remission, including complete remission (1 case) and partial remission (2 cases), and the other one had no remission. The levels of blood cell counts, soluble CD25, triglyceride, fibrinogen and albumin were recovered gradually in 3 patients who got remission. All four patients underwent hematopoietic stem cell transplantation (HSCT) after L-DEP regimen, and three survived. All patients had no severe chemotherapy related complications. The main side effects were bone marrow suppression, infection and pancreatitis, which recovered after appropriate treatments, apart from one who died from severe infection after urgent HSCT. Conclusion: L-DEP regimen could be served as an effective and safe salvage treatment for refractory pediatric EBV-pHLH, and also provide an opportunity for patients to receive HSCT.

[Analysis of efficacy and prognosis of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency].

Objective: To evaluate the efficacy of allogeneic hematopoietic stem cell transplantation for the treatment of combined immunodeficiency (CID) and explore prognostic risk factors. Methods: In this retrospective cohort study, clinical characteristics, laboratory tests and prognosis of 73 CID children who underwent allogeneic hematopoietic stem cell transplantation from February 2014 to April 2022 in the Children's Hospital of Fudan University were analyzed. Based on the subtypes of diseases, all patients were divided into severe combined immunodeficiency disease (SCID) group and other CID group. Based on the types of donors, all patients were divided into matched sibling donor group, matched unrelated donor group, unrelated cord blood group, and haploidentical donor group. Kaplan-Meier method and Log-Rank test were used to analyze the survival data. Cox regression was used to analyze prognostic factors. Results: Among the 73 patients, there were 61 (84%) males and 12 (16%) females. Fifty-five (75%) patients were SCID, and 18 (25%) patients were other CID. Donor source included 2 (3%) matched sibling donors (MSD), 3 (4%) matched unrelated donors (MUD), 64 (88%) unrelated cord blood (UCB), and 4 (5%) haploidentical donors. The age at transplant was 10.7 (5.9, 27.5) months, and the follow-up time was 36.2 (2.5, 62.9) months. The 3-year overall survival rate of 73 patients with CID was (67±6) %. No significant difference was found in the 3-year overall survival rates between patients with SCID (55 cases) and other CID (18 cases) ((64±7) % vs. (78±10) %, χ2=1.31, P=0.252). And no significant difference was found in the 3-year overall survival rates among patients who received MSD or MUD (5 cases), UCB (64 cases), and haploidentical donor (4 cases) transplant (100% (66±6)% vs. (50±25) %, χ2=2.30, P=0.317). Cox regression analysis showed that the medical history of sepsis (HR=2.55, 95%CI 1.05-6.20, P=0.039) and hypoalbuminemia at transplant (HR=2.96, 95%CI 1.14-7.68, P=0.026) were independent risk factors for the prognosis of allogeneic hematopoietic stem cell transplantation in pediatric patients with CID. Conclusions: Allogeneic hematopoietic stem cell transplantation is an effective treatment for CID. The medical history of sepsis and hypoalbuminemia at transplant were risk factors for prognosis. Enhancing infection prevention and nutritional intervention before transplant can improve patient prognosis.

A Multiplex Fluorescence of Loop Primer Upon Self-Dequenching Loop-Mediated Isothermal Amplification Assay for the Detection of Epstein-Barr Virus and Human Parvovirus B19 in Clinical Transplant Samples.

Viral infections are major causes of mortality in solid-organ and hematopoietic stem cell transplant recipients. Epstein-Barr virus (EBV) and Parvovirus B19 (B19V) are among the common viral infections after transplantation and were recommended for increased screening in relevant guidelines. Therefore, the development of rapid, specific, and cost-effective diagnostic methods for EBV and B19V is of paramount importance. We applied Fluorescence of Loop Primer Upon Self-Dequenching Loop-mediated Isothermal Amplification (FLOS-LAMP) for the first time to develop a novel multiplex assay for the detection of EBV and B19V; the fluorophore attached to the probe are self-quenched in unbound state. After binding to the dumbbell-shaped DNA target, the fluorophore is dequenched, resulting in fluorescence development. The novel multiplex FLOS-LAMP assay was optimized by testing various ratios of primer sets. This novel assay, with great specificity, did not cross-react with the common virus. For the detection of EBV and B19V, the limits of detection could reach 969 and 798 copies/μL, respectively, and the assay could be completed within 25 min. Applying this novel assay to detect 200 clinical transplant individuals indicated that the novel assay had high specificity and good sensitivity. We developed multiplex FLOS-LAMP assay for the detection of EBV and B19V, which has the potential to become an important tool for clinical transplant patient screening.

Serum Levels of miR-122-5p and miR-125a-5p Predict Hepatotoxicity Occurrence in Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation

Hepatic complications are an acknowledged cause of mortality and morbidity among patients undergoing hematopoietic stem cell transplantation. In this study, we aimed to evaluate the potential role in the prediction of liver injury of five selected microRNAs (miRNAs)—miR-122-5p, miR-122-3p, miR-15b-5p, miR-99b-5p, and miR-125a-5p—in the setting of autologous hematopoietic stem cell transplantation (ASCT). A total of 66 patients were included in the study: 50 patients (75.8%) with multiple myeloma (MM) and 16 (24.2%) with lymphoma. Blood samples were collected after the administration of the conditioning regimen, on the day of transplant (day 0). The expression levels of selected miRNAs were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using the miRCURY LNA miRNA Custom PCR Panels (QIAGEN). In a multivariate logistic regression analysis adjusted for age, sex, and the administered conditioning regimen, two miRNAs, hsa-miR-122-5p (odds ratio, OR 2.10, 95% confidence interval, CI: 1.29–3.42, p = 0.0029) and hsa-miR-125a-5p (OR 0.27, 95% CI: 0.11–0.71, p = 0.0079), were independent for hepatic toxicity occurrence during the 14 days after transplant. Our model in 10-fold cross-validation preserved its diagnostic potential with a receiver operating characteristics area under the curve (ROC AUC) of 0.75, 95% CI: 0.63–0.88 and at optimal cut-off reached 72.0% sensitivity and 74.4% specificity. An elevated serum level of miR-122-5p and decreased level of miR-125a-5p on day 0 are independent risk factors for hepatotoxicity in ASCT recipients, showing promise in accurately predicting post-ASCT complications. Identifying patients susceptible to complications has the potential to reduce procedure costs and optimize the selection of inpatient or outpatient procedures.

Major breakthroughs in hematopoietic stem cell transplantation and future challenges in clinical implementation.

Major breakthroughs in hematopoietic stem cell transplantation and future challenges in clinical implementation.

Droplet digital PCR: An effective method for monitoring and prognostic evaluation of minimal residual disease in JMML.

Juvenile myelomonocytic leukaemia (JMML) is a rare myeloproliferative neoplasm requiring haematopoietic stem cell transplantation (HSCT) for potential cure. Relapse poses a significant obstacle to JMML HSCT treatment, as the lack of effective minimal residual disease (MRD)-monitoring methods leads to delayed interventions. This retrospective study utilized the droplet digital PCR (ddPCR) technique, a highly sensitive nucleic acid detection and quantification technique, to monitor MRD in 32 JMML patients. The results demonstrated that ddPCR detected relapse manifestations earlier than traditional methods and uncovered molecular insights into JMML MRD dynamics. The findings emphasized a critical 1- to 3-month window post-HSCT for detecting molecular relapse, with 66.7% (8/12) of relapses occurring within this period. Slow MRD clearance post-HSCT was observed, as 65% (13/20) of non-relapse patients took over 6 months to achieve ddPCR-MRD negativity. Furthermore, bone marrow ddPCR-MRD levels at 1-month post-HSCT proved to be prognostically significant. Relapsed patients exhibited significantly elevated ddPCR-MRD levels at this time point (p = 0.026), with a cut-off of 0.465% effectively stratifying overall survival (p = 0.007), event-free survival (p = 0.035) and cumulative incidence of relapse (p = 0.035). In conclusion, this study underscored ddPCR's superiority in JMML MRD monitoring post-HSCT. It provided valuable insights into JMML MRD dynamics, offering guidance for the effective management of JMML.

Fusarium, Scedosporium and Other Rare Mold Invasive Infections: Over Twenty-Five-Year Experience of a European Tertiary-Care Center

Invasive mold infections (IMD) are an emerging concern due to the growing prevalence of patients at risk, encompassing but not limited to allogeneic hematopoietic stem cell transplant recipients, hematological malignancies patients, solid organ transplant recipients and intensive care unit patients. In contrast with invasive aspergillosis and mucormycosis, other hyalohyphomycoses and phaeohyphomycoses remain poorly known. We conducted a retrospective analysis of the clinical, biological, microbiological and evolutive features of 92 IMD having occurred in patients in our tertiary-care center over more than 25 years. A quarter of these infections were due to multiple molds. Molds involved were Fusarium spp. (36.2% of IMD with a single agent, 43.5% of IMD with multiple agents), followed by Scedosporium spp. (respectively 14.5% and 26.1%) and Alternaria spp. (respectively 13.0% and 8.7%). Mortality at day 84 was higher for Fusarium spp., Scedosporium spp. or multiple pathogens IMD compared with Alternaria or other pathogens (51.7% vs. 17.6%, p < 0.05). Mortality at day 84 was also influenced by host factor: higher among hematology and alloHSCT patients than in other patients (30.6% vs. 20.9% at day 42 and 50.0% vs. 27.9% at day 84, p = 0.041). Better awareness, understanding and treatments are awaited to improve patient prognosis.

Prospective Association of Psychological Distress and Sexual Quality of Life Among Hematopoietic Stem Cell Transplant Survivors.

Sexual health concerns are one of the most common late effects facing hematopoietic stem cell transplant (HSCT) survivors. The current study tested whether self-reported depression and anxiety symptoms before transplant were associated with embedded items assessing two specific areas of sexual health-sexual interest and sexual satisfaction-one year post-HSCT. Of the 158 study participants, 41% were diagnosed with a plasma cell disorder (n = 60) and most received autologous transplantation (n = 128; 81%). At post-HSCT, 21% of participants reported they were not at all satisfied with their sex life, and 22% were not at all interested in sex. Greater pre-HSCT depressive symptomology was significantly predictive of lower sexual interest (β = -.27, p < .001) and satisfaction (β = -.39, p < .001) at post-HSCT. Similarly, greater pre-HSCT trait anxiety was significantly predictive of lower sexual interest (β = -.19, p = .02) whereas higher levels of state and trait anxiety were both predictive of lower satisfaction (β = -.22, p = .02 and β = -.29, p = .001, respectively). Participant sex significantly moderated the relationship between state anxiety and sexual satisfaction (b = -.05, t = -2.03, p = .04). Additional research examining the factors that contribute to sexual health post-HCST is needed to inform and implement clinical interventions to address these commonly overlooked survivorship concerns.

Post-transplant-cyclophosphamide and short-term Everolimus as graft-versus-host-prophylaxis in patients with relapsed/refractory lymphoma and myeloma-Final results of the phase II OCTET-EVER trial.

Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft-versus-tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti-cancer immune response. We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI-free approach consisting of post-transplant cyclophosphamide (PTCy) and short-term Everolimus after reduced-intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD. Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow-up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD-relapse-free-survival was 47% after 3 years. Using PTCy and short-term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non-relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies.

Risk stratification in multiple myeloma: Are we there yet?

The second revision of international staging system (R2-ISS) shows promise in patients with multiple myeloma treated with a regimen of novel agent-based induction therapy, autologous stem cell transplant and maintenance therapy, but challenges persist. This study by Alzahrani etal. underscores the importance of refining risk assessment tools for tailored treatment strategies. Commentary on: Alzahrani etal. Impact of revised international staging system 2 (R2-ISS) risk stratification on outcomes of patients with multiple myeloma receiving autologous hematopoietic stem cell transplantation. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19384.

T1 Mapping in Cardiovascular Magnetic Resonance—A Marker of Diffuse Myocardial Fibrosis in Patients Undergoing Hematopoietic Stem Cell Transplantation

Introduction: Hematopoietic stem cell transplantation (HSCT) recipients are at increased risk of cardiovascular diseases. In our study, we aimed to find subclinical changes in myocardial tissue after HSCT with the help of cardiovascular magnetic resonance (CMR) tissue imaging techniques. Methods: The data of 44 patients undergoing autologous and allogeneic HSCT in the Hospital of Lithuanian University of Health Sciences Kaunas Clinics from October 2021 to February 2023 were analyzed. Bioethics approval for the prospective study was obtained (No BE-2-96). CMR was performed two times: before enrolling for the HSCT procedure (before starting mobilization chemotherapy for autologous HSCT and before starting the conditioning regimen for allogeneic HSCT) and 12 ± 1 months after HSCT. LV end-diastolic volume, LV end-systolic volume, LV mass and values indexed to body surface area (BSA), and LV ejection fraction were calculated. T1 and T2 mapping values were measured. Results: There was a statistically significant change in T1 mapping values. Before HSCT, mean T1 mapping was 1226.13 ± 39.74 ms, and after HSCT, it was 1248.70 ± 41.07 ms (p = 0.01). The other parameters did not differ significantly. Conclusions: Increases in T1 mapping values following HSCT can show the progress of diffuse myocardial fibrosis and may reflect subclinical injury. T2 mapping values remain the same and do not show edema and active inflammation processes at 12 months after HSCT.

Assessment of Risk Factors for Acute Kidney Injury with Machine Learning Tools in Children Undergoing Hematopoietic Stem Cell Transplantation

Background: Although acute kidney injury (AKI) is a common complication in patients undergoing hematopoietic stem cell transplantation (HSCT), its prophylaxis remains a clinical challenge. Attempts at prevention or early diagnosis focus on various methods for the identification of factors influencing the incidence of AKI. Our aim was to test the artificial intelligence (AI) potential in the construction of a model defining parameters predicting AKI development. Methods: The analysis covered the clinical data of children followed up for 6 months after HSCT. Kidney function was assessed before conditioning therapy, 24 h after HSCT, 1, 2, 3, 4, and 8 weeks after transplantation, and, finally, 3 and 6 months post-transplant. The type of donor, conditioning protocol, and complications were incorporated into the model. Results: A random forest classifier (RFC) labeled the 93 patients according to presence or absence of AKI. The RFC model revealed that the values of the estimated glomerular filtration rate (eGFR) before and just after HSCT, as well as methotrexate use, acute graft versus host disease (GvHD), and viral infection occurrence, were the major determinants of AKI incidence within the 6-month post-transplant observation period. Conclusions: Artificial intelligence seems a promising tool in predicting the potential risk of developing AKI, even before HSCT or just after the procedure.

Long-Term Ovarian Function Assessment After Haematopoietic Stem Cell Transplantation in Female Sickle Cell Anaemia Survivors

Long-Term Ovarian Function Assessment After Haematopoietic Stem Cell Transplantation in Female Sickle Cell Anaemia Survivors

A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy.

CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.

Recent Advances in Material Technology for Leukemia Treatments.

Leukemia is a widespread hematological malignancy characterized by an elevated white blood cell count in both the blood and the bone marrow. Despite notable advancements in leukemia intervention in the clinic, a large proportion of patients, especially acute leukemia patients, fail to achieve long-term remission or complete remission following treatment. Therefore, leukemia therapy necessitates optimization to meet the treatment requirements. In recent years, a multitude of materials have undergone rigorous study to serve as delivery vectors or direct intervention agents to bolster the effectiveness of leukemia therapy. These materials include liposomes, protein-based materials, polymeric materials, cell-derived materials, and inorganic materials. They possess unique characteristics and are applied in a broad array of therapeutic modalities, including chemotherapy, gene therapy, immunotherapy, radiotherapy, hematopoietic stem cell transplantation, and other evolving treatments. Here, an overview of these materials is presented, describing their physicochemical properties, their role in leukemia treatment, and the challenges they face in the context of clinical translation. This review inspires researchers to further develop various materials that can be used to augment the efficacy of multiple therapeutic modalities for novel applications in leukemia treatment.

A retrospective study of intravenous pentamidine for PCP prophylaxis in adult patients with hematological malignancies – its utility during respiratory virus pandemics

BackgroundIn Haematology, prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is recommended for patients undergoing hematopoietic stem cell transplantation and in selected categories of intensive chemotherapy for hematological malignancies. Trimethoprim–sulfamethoxazole (TMP-SMX) is the recommended first-line agent, but its use is not straightforward. Inhaled pentamidine is the recommended second-line agent but aerosolized medications were discouraged during respiratory virus outbreaks, especially during the COVID-19 pandemic, in view of potential contamination risks. Intravenous (IV) pentamidine is a potential alternative agent. AimWe evaluated the effectiveness and tolerability of IV pentamidine use for PCP prophylaxis in adult allogeneic HSCT recipients and patients with hematological malignancies during COVID-19. FindingsA total of 202 unique patients who received 239 courses of IV pentamidine, with a median of 3 doses received (1-29). The largest group of the patients (49.5%) who received IV pentamidine were undergoing or had received a hematopoietic stem cell transplant. The commonest reason for not using TMP-SMX prophylaxis was cytopenia (34.7%). We have no patients who had breakthrough PCP infection while on IV pentamidine. None of the patients develop an infusion reaction or suffer adverse effects from IV pentamidine Conclusion: Pentamidine administered IV monthly is safe and effective.

Loss of NLRP6 expression increases the severity of intestinal injury after syngeneic hematopoietic stemcell transplantation.

NLRP6 plays a crucial role in maintaining intestinal homeostasis by regulating the interaction between the intestinal mucosa and the microbiota. However, the impact of NLRP6 deficiency on intestinal damage following hematopoietic stem cell transplantation (HSCT) remains poorly understood. In this study, we established a syngeneic HSCT mouse model using C57BL/6 mice as donors and NLRP6-/- or C57BL/6 mice as recipients. Our findings revealed that NLRP6 deficiency had minimal influence on peripheral blood cell counts and splenic immune cell proportions in transplanted mice. However, it exacerbated pathological changes in the small intestine on day 14 post-transplantation, accompanied by increased proportions of macrophages, dendritic cells, and neutrophils. Furthermore, the NLRP6 deficiency resulted in elevated expression of MPO and CD11b, while reducing the levels mature caspase-1 and mature IL-1β in the intestine. Moreover, the NLRP6 deficiency disturbed the expression of apoptosis-related molecules and decreased the tight junction protein occludin. Notably, recipient mice with NLRP6 deficiency exhibited lower mRNA expression levels of antimicrobial genes, such as Reg3γ and Pla2g2a. The short-term increase in inflammatory cell infiltration caused by NLRP6 deficiency was associated with intestinal damage, increased apoptosis, reduced expression of antimicrobial peptides, and impaired intestinal repair. Taken together, our findings demonstrate that the loss of NLRP6 exacerbates post-transplantation intestinal damage in recipient mice.

Upfront allogeneic hematopoietic stem cell transplantation for adult T-cell acute lymphoblastic leukemia/lymphoma in first complete remission: a single-center study.

Real-world data on outcomes of upfront allogeneic hematopoietic stem cell transplantation (allo-HCT) for adult T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) patients in first complete remission (CR1) is still lacking. A single center retrospective study was conducted from 94 consecutive patients received their first allo-HCT between 2010 and 2021, which include 76 patients received upfront allo-HCT and 18 patients received allo-HCT in non-upfront settings. There were no significant differences in most variables. In the upfront allo-HCT group, 52 (68%) patients achieved CR1 with one cycle of induction regimen. 24 (32%) patients achieved CR1 with more than one cycle. In the non-upfront group, there were 14 patients with active disease and 4 patients in second CR before transplant. The majority of patients received antithymocyte globulin-based graft-versus-host disease prophylaxis. Median follow-up time was 51 months for both groups. 5-year overall survival (OS) was 54% in the upfront allo-HCT group. While, in the non-upfront group, 5-year OS were 19% (P = 0.013). 5-year progression free survival in the upfront group was higher than that in the non-upfront group (50% versus 20%, P = 0.02). 5-year cumulative incidence relapse rate was significantly higher in non-upfront group (64% vs. 32%, P = 0.006). While, there was no difference in the 5-year non-relapse mortality (NRM) rate (19% versus 16%, P = 0.56). The most common cause of death was disease progression. In multivariable analysis, non-upfront allo-HCT (hazard ratios (HR) 2.14, P = 0.03) and HCT-CI (≥ 2) (HR 6.07, P = 0.002) were identified to be associated with worse OS. Non-upfront allo-HCT and HCT-CI (≥ 2) were also found to be independent risk factors for higher relapse rate. While, haploidentical-HCT was found to be associated with increased NRM. Our study indicated that allo-HCT remains an important curative treatment for adult patients with T-ALL, especially when it was performed in the upfront setting.

Mitoxantrone Versus Liposomal Daunorubicin in Induction of Pediatric AML With Risk Stratification Based on Flow Cytometry Measurement of Residual Disease.

Measurable residual disease (MRD) by using flow cytometry after induction therapy is strongly prognostic in pediatric AML, and hematopoietic stem-cell transplant (hSCT) may counteract a poor response. We designed a phase III study with intensified response-guided induction and MRD-based risk stratification and treated poor induction response with hSCT. The efficacy of liposomal daunorubicin (DNX) in induction was compared with mitoxantrone. The study planned to randomly assign 300 patients, but the production of DNX ceased in 2017. One hundred ninety-four patients were randomly assigned to mitoxantrone or experimental DNX in induction 1. Ninety-three non-randomly assigned patients served as an observation cohort. Primary end point was fraction of patients with MRD <0.1% on day 22 after induction 1. Patients with MRD ≥15% after induction 1 or ≥0.1% after induction 2 or FLT3-ITD with NPM1 wildtype were stratified to high-risk therapy, including hSCT. Outcome for all 287 children was good with 5-year event-free survival (EFS5y) 66.7% (CI, 61.4 to 72.4) and 5-year overall survival (OS5y) 79.6% (CI, 75.0 to 84.4). Overall, 75% were stratified to standard-risk and 19% to high-risk. There was no difference in the proportion of patients with MRD <0.1% on day 22 after induction 1 (34% mitoxantrone, etoposide, araC [MEC], 30% DNX, P = .65), but the proportion increased to 61% for MEC versus 47% for DNX (P = .061) at the last evaluation before induction 2. EFS5y was significantly lower, 56.6% (CI, 46.7 to 66.5) versus 71.9% (CI, 63.0 to 80.9), and cumulative incidence of relapse (CIR) was higher, 35.1% (CI, 25.7 to 44.7) versus 18.8% (CI, 11.6 to 27.2) for DNX. The inferior outcome for DNX was only in standard-risk patients with EFS5y 55.3% (CI, 45.1 to 67.7) versus 79.9% (CI, 71.1 to 89.9), CIR 39.5% (CI, 28.4 to 50.3) versus 18.7% (CI, 10.5 to 28.7), and OS5y 76.2% (CI, 67.2 to 86.4) versus 88.6% (CI, 81.4 to 96.3). As-treated analyses, including the observation cohort, supported these results. For all high-risk patients, 85% received hSCT, and EFS5y was 77.7 (CI, 67.3 to 89.7) and OS5y was 83.0 (CI, 73.5 to 93.8). The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.