Investigations of the prognostic value of RUNX1 mutation in acute myeloid leukemia patients: Data from a real-world study.

RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML). Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML-RUNX1mut) was eliminated from the 2022 WHO classification system. To gain more insight into the characteristics of AML-RUNX1mut, we retrospectively analyzed 1065 newly diagnosed adult AML patients from the First Affiliated Hospital of Soochow University between January 2017 and December 2021. RUNX1 mutations were identified in 112 patients (10.5%). The presence of RUNX1 mutation (RUNX1mut) conferred a lower composite complete remission (CRc) rate (40.2% vs. 58.4%, P＜0.001), but no significant difference was observed in the 5-year overall survival (OS) rate (50.2% vs. 53.9%; HR=1.293; P=0.115) and event-free survival (EFS) rate (51.5% vs. 49.4%; HR=1.487, P=0.089), even within the same risk stratification. Multivariate analysis showed that RUNX1mut was not an independent prognostic factor for OS (HR=1.352, P=0.068) or EFS (HR=1.129, P=0.513). When patients were stratified according to induction regimen, RUNX1mut was an unfavorable factor for CRc both on univariate and multivariate analysis in patients receiving conventional chemotherapy, and higher risk stratification predicted worse OS. In those who received venetoclax plus hypomethylating agents, RUNX1mut was not predictive of CRc and comparable OS and EFS were seen between intermediate-risk and adverse-risk groups. The results of this study revealed that the impact of RUNX1mut is limited. Its prognostic value depended more on treatment and co-occurrent abnormalities. VEN-HMA may abrogate the prognostic impact of RUNX1, which merits a larger prospective cohort to illustrate.

Recent progress in chimeric antigen receptor therapy for acute myeloid leukemia.

Although CAR-T cell therapy has been particularly successful as a treatment for B cell malignancies, effectively treating acute myeloid leukemia with CAR remains a greater challenge. Multiple preclinical studies and clinical trials are underway, including on AML-related surface markers that CAR-T cells can target, such as CD123, CD33, NKG2D, CLL1, CD7, FLT3, Lewis Y and CD70, all of which provide opportunities for developing CAR-T therapies with improved specificity and efficacy. We also explored specific strategies for CAR-T cell treatment of AML, including immune checkpoints, suicide genes, dual targeting, genomic tools and the potential for universal CAR. In addition, CAR-T cell therapy for AML still has certain risks and challenges, including cytokine release syndrome (CRS) and haematotoxicity. Despite these challenges, as a new targeting method for AML treatment, CAR-T cell therapy still has great prospects. Ongoing research aims to further optimize this treatment mode.

Allogenic hematopoietic stem cell transplantation outcomes of patients aged ≥ 55 years with acute myeloid leukemia or myelodysplastic syndromes in China: a retrospective study.

BACKGROUND: Elderly patients with acute myeloid leukemia or myelodysplastic syndromes (AML/MDS) have historically had poor prognoses. However, there has been a recent increase in the use of allogenic hematopoietic stem cell transplantation (allo-HSCT) are in this patient population. Nevertheless, the optimal choice of donor type for the patients remains an unmet need. Limited data exist on the use of allo-HSCT in elderly patients with AML/MDS from China. To better understand and optimize the selection of donor type for the elderly patients, particularly for those with refractory or relapsed disease, in comparison with the previous studies in the US and Europe. METHODS: Our retrospective study enrolled 259 patients aged over 55 years who underwent their first allo-HSCT between April 2015 and August 2022. These patients were divided into three groups based on donor type: haploidentical related donor group (haploidentical related donor transplantation [HID], n = 184), matched sibling donor group (matched sibling donor transplantation [MSD], n = 39), and matched unrelated donor group (matched unrelated donor transplantation [MUD], n = 36). Statistics were performed with the chi-square test, the log-rank and Fine-Gray tests. RESULTS: The median age of the cohort was 57 years (range: 55-75) and 26.25% of patients were over 60 years old. Younger patients had a higher incidence of acute graft-versus-host disease (HR = 1.942, P = 0.035), faster neutrophil recovery (HR = 1.387, P = 0.012), and better overall survival (HR = 0.567, P = 0.043) than patients aged ≥ 60 years across the entire cohort. Patients with refractory or relapsed (R/R) diseases had delayed neutrophil engraftment (P = 0.010, HR = 0.752) and platelet engraftment (P < 0.001, HR = 0.596), higher incidence of relapses (HR = 2.300, P = 0.013), and inferior relapse-free survival (RFS) (HR = 1.740, HR = 0.016) regardless of donor type. When it came to graft-versus-host-disease-free, relapse-free survival (GRFS), MUDs turned out to be superior to HIDs (HR = 0.472, P = 0.026) according to the multivariable analysis. In contrast, we found MSDs had an inferior GRFS to HIDs in parallel (HR = 1.621, P = 0.043). CONCLUSION: The choice of donor type did not significantly affect the outcomes of allo-HSCT. However, when considering the quality of post-transplant life, MUDs or HIDs from younger donors may be the optimal choice for elderly patients.

Venetoclax and hypomethylating agents in critically ill patients with newly diagnosed acute myeloid leukaemia.

Venetoclax (VEN) in combination with hypomethylating agents (HMAs) is considered the standard of treatment for individuals with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. We conducted a retrospective analysis that encompassed 16 critically ill patients newly diagnosed with AML who were admitted to the intensive care unit (ICU) and received the VEN and HMA regimen. Among them, 13 were primary AML, and three were MDS-transformed AML. The mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 18.9, and the mean sepsis-related organ failure assessment score (SOFA) was 6.2. The average length of the ICU stay was 27.3 days. The median duration of VEN administration was 16 days. After the first course of VEN + HMA, 12 cases (75%) achieved complete remission (CR) or CR with incomplete haematological recovery (CRi). Among the five patients harbouring TP53 mutations, the overall response rate (ORR) was 90%. All patients experienced grade 3-4 haematological adverse events (AEs). With a median follow-up of 9.5 months (range: 0.5-23), the overall survival (OS) rate was 43.75%. TP53-wild patients and CR state after the first course of VEN-HMA indicated better survival. The combination of VEN and HMA has demonstrated a significantly elevated therapeutic response rate in newly diagnosed AML patients with critical illness.

Preemptive inotuzumab ozogamicin eradicated measurable residual disease in Ph-negative acute lymphoblastic leukemia relapsed post CD19 CART therapy.

There are no reports of application of inotuzumab ozogamicin (InO) for the treatment of MRD in r/r B-ALL. We firstly report the efficacy of InO for a patient experienced morphological relapse after HSCT and molecular relapse after CART therapy.

Development of a scoring system for predicting primary resistance to venetoclax plus hypomethylating agents (HMAs) in acute myeloid leukemia patients.

In recent years, one of the most promising advances in the treatment of acute myeloid leukemia (AML) is the combination of a hypomethylating agent (HMA) with the BCL2 inhibitor venetoclax (VEN). To better understand the key factors associated with the response of VEN plus HMA, 212 consecutive AML patients were retrospectively recruited to establish and validate a scoring system for predicting the primary resistance to VEN-based induced therapy. All AML patients were divided randomly into a training set (n = 155) and a validation set (n = 57). Factors were selected using a multivariate logistic regression model, including FAB-M5, myelodysplastic syndrome-secondary acute myeloid leukemia (MDS-sAML), RUNX1-RUNX1T1 and FLT3-ITD mutation (FLT3-ITDm). A nomogram was then constructed including all these four predictors. The nomogram both presented a good performance of discrimination and calibration, with a C-index of 0.770 and 0.733 in the training and validation set. Decision curve analysis also indicated that the nomogram was feasible to make beneficial decisions. Eventually a total scoring system of 8 points was developed, which was divided into three risk groups: low-risk (score 0-2), medium-risk (score 3-4), and high-risk (score 5-8). There was a significant difference in the nonremission (NR) rate of these three risk groups (22.8% vs. 60.0% vs. 77.8%, p < 0.001). After adjustment of the other variables, patients in medium- or high-risk groups also presented a worse event-free survival (EFS) than that in the low-risk group (hazard ratio [HR] = 1.62, p = 0.03). In conclusion, we highlighted the response determinants of AML patients receiving a combination therapy of VEN plus HMAs. The scoring system can be used to predict the resistance of VEN, providing better guidance for clinical treatment.

Combination of venetoclax with BCR-ABL tyrosine kinase inhibitor as a therapeutic strategy for Philadelphia chromosome-positive leukemias.

OBJECTIVES: Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKIs) in preclinical studies for patients with Philadelphia chromosome-positive (Ph+) leukemias. This combination may suggest a novel treatment strategy for Ph + leukemias. METHODS: We conducted a retrospective study to summarize the activity of combining venetoclax and BCR-ABL1 TKI-based therapies in Ph + leukemias. RESULT: A total of 18 patients with Ph + leukemias were enrolled in this study. At the time of venetoclax and TKI-based therapy, 5 patients were initially diagnosed, with Ph + acute myeloid leukemia (AML) (n = 1) and mixed phenotype acute leukemia (MPAL) (n = 4), 7 patients had chronic myeloid leukemia at blastic phase (CML-BP), and the remaining 6 patients had relapsed or refractory to prior therapy. The overall response rate (ORR) was 88.9% (9 CR, 2 CRi, 4 MLFS, 1 PR), and a major molecular response (MMR) (or better) was achieved in 7 (38.8%) of all patients. With a median follow-up of 7.0 months (range, 2.3-15.6), 15 (83.3%) were in continuous CR at the time of this analysis, with a 1-year OS of 85.6%, 1-year LFS of 76.7%, and 1-year CIR of 22.4%. Moreover, 10 of 18 patients were treated with venetoclax, TKI and hypomethylating agent (HMA) regimens, which also associated with a high ORR rate (6 CR, 1 CRi, 3 MLFS), and can be used for induction or salvage therapy. CONCLUSION: Venetoclax and TKI-based combination regimens may be a feasible approach for Ph + leukemias, and prospective studies are needed to properly assess the safety, tolerability and efficacy of this regimen.

Outcomes of adult patients with type 1 primary refractory acute myeloid leukemia: a single center experience.

Adult patients with newly diagnosed de novo acute myeloid leukemia (AML), who had less than a 50% reduction in blast numbers and with > 15% residual blasts after first cycle of induction chemotherapy, defined as type 1 primary refractory (REF1), have grave prognosis. We retrospectively analyzed the data of 58 patients with REF1 who received salvage treatments with curative intension to evaluate the impact of salvage regimens with regard to response and overall survival (OS). Seventeen patients received intermediate- or high-dose cytarabine (ID/HD Ara-C) based intensive salvage chemotherapy, 36 patients received G-CSF primed less intensive chemotherapy and 5 patients received novel targeted drugs based low intensive therapy. The CR/CRi and MLFS rate was 6/17 and 2/17, 14/36 and 3/36, 3/5 and 0/5, respectively. The median OS for the whole cohort was 20.3 months. Median OS was comparable between the 3 arms. Overall, 42 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), 14 patients in the intensive arm, 24 patients in the less intensive arm and 4 patients in the low intensive arm. Median survival for allo-HSCT patients was significantly longer than for non-allo-HSCT patients (38.8 months vs. 2.1 months, p < 0.001). In multivariate analysis, achievement of CR/CRi after the salvage regimen were predictive of OS. We conclude that no significant difference in outcome among traditional salvage regimens in patients with REF1. G-CSF primed less intensive chemotherapy could serve as an alternative of ID/HD Ara-C based intensive chemotherapy and allo-HSCT is indispensable for long-term survival.

Targeted therapy and immunotherapy for T cell acute lymphoblastic leukemia/lymphoma.

T cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is an aggressive malignancy of progenitor T cells. Despite significant improvements in survival of T-ALL/LBL over the past decades, treatment of relapsed and refractory T-ALL (R/R T-ALL/LBL) remains extremely challenging. The prognosis of R/R T-ALL/LBL patients who are intolerant to intensive chemotherapy remains poor. Therefore, innovative approaches are needed to further improve the survival of R/R T-ALL/LBL patients. With the widespread use of next-generation sequencing in T-ALL/LBL, a range of new therapeutic targets such as NOTCH1 inhibitors, JAK-STAT inhibitors, and tyrosine kinase inhibitors have been identified. These findings led to pre-clinical studies and clinical trials of molecular targeted therapy in T-ALL/LBL. Furthermore, immunotherapies such as CD7 CAR T cell therapy and CD5 CAR T cell therapy have shown profound response rate in R/R T-ALL/LBL. Here, we review the progress of targeted therapies and immunotherapies for T-ALL/LBL, and look at the future directions and challenges for the further use of these therapies in T-ALL/LBL.

The Use of SARS-CoV-2-Positive Donors in Hematopoietic Stem Cell Transplantation.

BACKGROUND: Since 2019, the SARS-CoV-2 pandemic has become a global issue due to its high fatality rate. Over time, the characteristics of the virus have evolved and led to the creation of an omicron strain with higher infectivity but a significantly decreased fatality rate. For patients in urgent need of hematopoietic stem cell transplantation (HSCT), whether the SARS-CoV-2 infection status of donors has a significant impact on HSCT recipients should be clarified. METHODS: To estimate the transplantation risk of SARS-CoV-2-positive donors, 24 patients who underwent HSCT from December 1, 2022 to January 30, 2023 were retrospectively included. The ratio of the observation group (SARS-CoV-2-positive donors, n = 12) to the control group (SARS-CoV-2-negative donors, n = 12) was 1:1. We observed the time of hematopoietic reconstruction, donor chimerism, severe infection, acute graft vs host disease, and hepatic vein occlusion disease during hematopoietic reconstruction. RESULTS: In the observation group, the average time of myeloid hematopoietic reconstruction was 11.58 days, and in the control group, it was 12.17 days (P = .3563 [>.05]). On average, all patients achieved a 90% donor chimerism rate of +13.58 (±4.5) days (P = .5121 [>.05]). The average percentage of patients that achieved successful hematopoietic reconstruction was 96.75% in the observation group and 96.31% in the control group (P = .7819 [>.05]). A total of 6 adverse events occurred during this study: 3 in the observation group and 3 in the control group. CONCLUSIONS: Our preliminary results showed favorable short-term outcomes in recipients of SARS-CoV-2-positive HCST donors.