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Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment; however, its efficacy remains limited, necessitating the development of alternative strategies. Here, we report that venetoclax, an FDA-approved BCL-2 inhibitor, directly activates NK cells, enhancing their cytotoxicity against acute myeloid leukemia (AML) both in vitro and in vivo, likely independent of BCL-2 inhibition. Through comprehensive approaches, including bulk and single-cell RNA sequencing, avidity measurement, and functional assays, we demonstrate that venetoclax increases the avidity of NK cells to AML cells and promotes lytic granule polarization during immunological synapse (IS) formation. Notably, we identify a distinct CD161 low CD218b + NK cell subpopulation that exhibits remarkable sensitivity to venetoclax treatment. Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, thereby facilitating IS formation in NK cells. Collectively, our findings establish venetoclax as a multifaceted immunometabolic modulator of NK cell function and provide a promising strategy for augmenting NK cell-based cancer immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: This study aimed to evaluate whether the addition of hypomethylating agents (HMA) to low-intensity chemotherapy can enhance the clinical efficacy of induction treatment for elderly acute myeloid leukemia (AML) patients who are unsuitable for standard induction therapy. Materials and Methods: This study retrospectively analyzed 117 patients over 60 years old who were initially diagnosed with AML and received low-intensity induction treatment in the Department of Hematology in Anhui provincial hospital from January 2015 to December 2020. Twenty-three patients were excluded, and the remaining 94 patients were divided into two groups according to the selection of induction regimens. Results: Forty-four patients received HMA combined with low-intensity chemotherapy, and the other 50 patients received only low-intensity induction chemotherapy. Forty-three patients (45.7%) obtained complete remission (CR) after the initial induction treatment. The CR rate in the HMA plus low-intensity chemotherapy group was 34.1% (15/44), and in the single low-intensity chemotherapy group was 56.0% (28/50) ( p = 0.04). The 30 days cumulative early death rates were 9.1% (95% CI: 3.5-22.4%) in the HMA plus low-intensity chemotherapy group and 6.0% (95% CI: 2.0-17.5%) in the single low-intensity chemotherapy group, respectively ( p = 0.59), and the one-year cumulative relapse rates were 21.1% (95% Cl: 9.8-41.9%) and 33.3% (95% Cl: 20.3-51.5%), respectively ( p = 0.80). The one-year overall survival (OS) rates for patients in the HMA plus low-intensity chemotherapy group and the single low-intensity chemotherapy group were 37.3% (95% Cl: 23.1-51.5%) and 55.4% (95% Cl: 40.5-67.9%), respectively ( p = 0.098), and the one-year event-free survival (EFS) rates were 8.5% (95% Cl: 2.2-20.6%) and 20.6% (95% Cl: 9.1-35.3%), respectively ( p = 0.058). Conclusions: This study showed that the addition of HMA to low-intensity induction chemotherapy does not improve prognosis in elderly AML patients who are unsuitable for standard induction chemotherapy.

Background: There is great uncertainty in the treatment of elderly patients with acute myeloid leukemia (AML), which leads to great challenges in treatment decision. The aim of this study is to find more suitable induction therapy and consolidation therapy for elderly AML patients., Methods: A total of 149 consecutive newly diagnosed elderly AML patients (aged ≥60 years) who received induction chemotherapy in our medical center from January 2015 to December 2019 were retrospectively analyzed., Results: After the first induction treatment, the complete remission/or complete remission with incomplete hematologic recovery (CR/CRi) rates in the standard-intensity chemotherapy group was significantly higher than that in the low-intensity chemotherapy group (58.2% vs 32.9%, p = 0.003). Compared with the low-intensity chemotherapy, the incidence of severe infection in the standard-intensity chemotherapy was significantly increased (p < 0.001), but the early mortality was comparable. One hundred and seven patients received minimal residual disease (MRD) examination after the first induction treatment; and MRD was negative accounting for 51.9% in the standard-intensity chemotherapy group, while only 32.7% in the low-intensity group (p = 0.05). The 2-year-overall survival (OS) of patients in standard-intensity induction chemotherapy group (37.2%) was slightly higher than that in low-intensity induction chemotherapy group (23.4%) (p = 0.075). Eighty-one CR/CRi patients received intermediate or high dose cytarabine (n = 35) or sequential chemotherapy regimens (n = 46) as consolidation treatment. The 2-year OS and event-free survival (EFS) of patients in the intermediate or high-dose cytarabine group were significantly higher than those in the sequential chemotherapy regimens group (73.0% vs 38.5%, p = 0.002; 54.8% vs 35.0%, p = 0.035)., Conclusion: Our results showed that standard-intensity induction chemotherapy can significantly improve the CR rate for elderly AML patients, and does not increase the early mortality; consolidation therapy with intermediate or high-dose cytarabine can significantly improve EFS and OS for elderly AML patients achieved CR., Competing Interests: The authors report no conflicts of interest., (© 2022 Wang et al.)

This is a retrospective study comparing the effectiveness of umbilical cord blood transplantation (UCBT) and chemotherapy for patients in the first complete remission period for acute myeloid leukemia with KMT2A-MLLT3 rearrangements. A total of 22 patients were included, all of whom achieved first complete remission (CR1) through 1-2 rounds of induction chemotherapy, excluding patients with an early relapse. Twelve patients were treated with UCBT, and 10 patients were treated with chemotherapy after 2 to 4 courses of consolidation therapy. The 3-year overall survival (OS) of the UCBT group was 71.3% (95% CI, 34.4-89.8%), and that of the chemotherapy group was 10% (95% CI, 5.89-37.3%). The OS of the UCBT group was significantly higher than that of the chemotherapy group (P = 0.003). The disease-free survival (DFS) of the UCBT group was 60.8% (95% CI, 25.0-83.6%), which was significantly higher than the 10% (95% CI, 5.72-35.8%) of the chemotherapy group (P = 0.003). The relapse rate of the UCBT group was 23.6% (95% CI, 0-46.8%), and that of the chemotherapy group was 85.4% (95% CI, 35.8-98.4%), which was significantly higher than that of the UCBT group (P < 0.001). The non-relapse mortality (NRM) rate in the UCBT group was 19.8% (95% CI, 0-41.3%), and that in the chemotherapy group was 0.0%. The NRM rate in the UCBT group was higher than that in the chemotherapy group, but there was no significant difference between the two groups (P = 0.272). Two patients in the UCBT group relapsed, two died of acute and chronic GVHD, and one patient developed chronic GVHD 140 days after UCBT and is still alive, so the GVHD-free/relapse-free survival (GRFS) was 50% (95% CI, 17.2-76.1%). AML patients with KMT2A-MLLT3 rearrangements who receive chemotherapy as their consolidation therapy after CR1 have a very poor prognosis. UCBT can overcome the poor prognosis and significantly improve survival, and the GRFS for these patients is very good. We suggest that UCBT is a better choice than chemotherapy for KMT2A-MLLT3 patients.

Although previous studies have demonstrated improved outcomes in umbilical cord blood transplantation (UCBT) by omitting antithymocyte globulin (ATG) in the conditioning regimen, this approach has not been comparatively studied in unrelated peripheral blood stem cell transplantation (UPBSCT). To compare the risks and benefits between UCBT without ATG and UPBSCT in patients with acute leukemia (AL), we conducted a multicenter retrospective study of 79 patients who underwent UCBT (myeloablative conditioning without ATG) and 96 patients who underwent UPBSCT (myeloablative conditioning with ATG). The outcomes were graft failure, neutrophil engraftment, platelet engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), transplantation-related mortality (TRM), relapse, overall survival (OS), and leukemia-free survival (LFS). Follow-up was censored on October 31, 2016. Engraftment was similar between the 2 groups but granulocyte and platelet recovery were slower in the UCBT group (both P < .001). The incidences of aGVHD, TRM, OS, and LFS were similar between the 2 groups (all P > .05). Without ATG, the UCBT group displayed less cGVHD and less moderate and severe cGVHD (P < .001 and P = .004). The incidences of Epstein-Barr virus viremia and post-transplantation lymphoproliferative disease were significantly lower in the UCBT group (P < .001 and P = .037). UCBT recipients had higher activity Karnofsky performance scores and 3-year GVHD-free/relapse-free survival than the UPBSCT group (P = .03 and P = .04). We observed similar survival when comparing UCBT without ATG and UPBSCT, but we also observed better quality of life in patients undergoing UCBT without ATG. We can therefore conclude that patients with primary AL for whom an appropriate HLA-matched sibling donor is not available could select either UCBT or UPBSCT., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The aim of this study is to investigate the impact of pre-engraftment bloodstream infections (BSIs) on the outcomes in acute leukemia patients undergoing myeloablative cord blood transplantation (CBT). A total of 226 acute leukemia patients who received unrelated CBT were enrolled in this study, and all these patients received an intensified myeloablative conditioning without ATG. Pre-engraftment BSIs occurred in 72 patients (31.9 %), and the median time of onset was 4.5 days after cord blood infusion, BSIs of gram-negative bacilli, and gram-positive cocci comprised of 63.8 and 36.2 %, respectively. The cumulative incidences of neutrophil and platelet engraftment, acute or chronic graft versus host disease (GVHD) were comparable among the non-BSI, gram-negative bacilli BSI, and gram-positive cocci BSI groups. The cumulative incidence of transplant-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) was similar between the non-BSI and the BSI groups. For subgroups analysis, TRM was lower in gram-positive cocci BSI patients compared with that of gram-negative bacilli BSI patients (8.3 vs 39.3 %) (p = 0.01) (HR = 0.39, p = 0.034), and the 5-year OS was higher in gram-positive cocci BSI cohort (79.1 vs 44.2 %) (p = 0.01) (HR = 0.36, p = 0.046). Our study demonstrated that, for acute leukemia patients who received CBT after myeloablative conditioning that omitted ATG, pre-engraftment BSI had no impact on engraftment, GVHD, TRM, relapse, and long-term survival. Due to the fact that gram-negative bacilli BSI was associated with poor outcomes compared with gram-positive cocci BSI, appropriate early empirical antimicrobial management strategies and better supportive care are required to decrease the gram-negative bacilli BSI-related mortality.

No clinical studies have investigated the role of decitabine as a part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL in patients in NR status. The aim of this study was to identify the potential benefits of decitabine as a prior therapy before salvaged unrelated UCBT for refractory or relapsed childhood AL. Eight consecutive patients with childhood refractory/relapsed AL were enrolled in our study between 2013 and 2014. All patients were in NR status before the time of transplant and had features associated with poor outcomes, such as CNSL, MDS-AML, high WBC count at diagnosis, and hypodiploid status (FLT3+/ITD+). Additionally, all patients had one of the following disease statuses: PIF, multiple relapse, or early relapse. All transplants were performed with decitabine as part of the myeloablative conditioning regimen, which was decitabine+Flu/Bu/CY±BCNU or decitabine+Ara-c/BU/CY2±BCNU. A total of seven patients (7 of 8) achieved neutrophil engraftment and platelet engraftment, and one patient experienced primary graft failure. All eight patients (100%) developed PES at a median of 7 days. Three patients developed stage II-IV acute GVHD at a median of 18 days. Additionally, three patients developed chronic GVHD, but it was not extensive in any of those three patients. The median follow-up time after CBT was 19.9 months (range, 9.2-30.7 months). The estimated probability of OS was 75%. Two patients (2 of 8) experienced a testis relapse, and two patients (2 of 8) died. Our experience suggests that the additional application of decitabine as part of the myeloablative conditioning regimen prior to UCBT for refractory or relapsed childhood AL among patients who are not in remission is safe and might be an effective treatment option., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The impact of pretransplant minimal residual disease (MRD) on outcome of myeloablative cord blood transplant (CBT) for acute myeloid leukemia (AML) in complete remission (CR) has not been reported. Seventy-two AML patients were assessed for MRD before CBT, and the majority (84.7%) of these patients received single-unit CBT. All patients received intensified myeloablative conditioning with BUCY2 or TBICY plus high-dose cytarabine, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The cumulative incidences of neutrophil and platelet engraftment, acute or chronic GVHD were comparable between MRD-negative and MRD-positive groups. The cumulative incidence of transplant-related mortality (TRM) and relapse did not differ significantly between the two cohorts (25.6% vs. 32.5%, 16.1% vs. 19.2%; p = 0.52, 0.61). There were no apparent differences in 3-year overall survival (OS) (68.9% in MRD-negative group and 57.9% in MRD-positive group, p = 0.31) and 3-year leukemia-free survival (LFS) (62.5% in MRD-negative group and 52.7% in MRD-positive group, p = 0.42) between both groups. The current study suggests that AML patients in morphological CR1 or CR2 who have detectable MRD might benefit from unrelated CBT with intensified myeloablative conditioning.

Objective: To evaluate the therapeutic efficacy and related risk factors of acute myelogenous leukemia （AML） patients treated with unrelated cord blood transplantation （UCBT）., Methods: A retrospective analysis was performed on the clinical data of 58 AML patients that consisted of 1 case of M0, 1 case M1, 35 cases M2, 3 cases M4, 14 cases M5, 3 cases M6, and 1 case acute mixed leukemia, respectively. Of them, 1 case AML secondary to myelodysplastic syndrome, and 36 in first complete remission （CR1）, 14 in second complele remission （CR2）, 8 in non- remission （NR）, 43 cases were refractory or high-risk patients（70.1%）. The median age was 14.5 years with the median weight of 45 kg, 49 patients received sUCBT and 9 dUCBT. All the patients conditioned with intensified myeloablative regimen and received a combination of Cyclosporine A（CsA）and mycophenolate mofetil（MMF）to prevent graft- versus- host disease（GVHD）., Results: 56 out of 58 patients achieved engraftment with implantation rate 96.6%. The median time of ANC≥0.5×10⁹/L was 17（12-37）days, and that of PLT≥20× 109/L 33（17-140）days respectively. 24 cases developed acute GVHD（aGVHD）, the incidence rate of grade Ⅱ to Ⅳ aGVHD was 30.4%. The chronic GVHD（cGVHD）was occured in 7 patients of the 49 evaluable patients, all were limited. The estimated 3-year overall survival（OS）and disease-free survival （DFS）were（60.3±6.4）% and（60.1±6.5）% respectively. And the cumulative incidences of 3-year nonrelapse mortality（NRM）and relapse were 33.3% and 9.1% respectively. The 3- year OS rates of AML patients were（66.0 ± 6.7）% for CR and（25.0 ± 15.3）% for NR, differences were statistical significance., Conclusion: For AML patients, UCBT was conducive to improve outcome with lower incidences of cGVHD and relapse, the patients after transplantation could obtain high quality of life.

The aim of this report was to present a clinical comparison of unrelated cord blood transplantation (CBT) and human leukocyte antigen (HLA)-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) in children with high-risk or advanced acute leukemia. A total of 115 consecutive pediatric patients received unrelated CBT (n = 90) or sibling allo-PBSCT/BMT (n = 25) between 2000 and 2012. Neutrophil and platelet recovery were significantly delayed after CBT compared to allo-PBSCT/BMT. There was no difference in the incidence of acute graft-versus-host disease (GVHD) or chronic GVHD between the two groups. The cumulative incidence of transplant-related mortality (TRM) was higher in the CBT group than in the allo-PBSCT/BMT group (32.5 vs 12.8 %) (p = 0.03). The cumulative incidence of relapse was 13.1 % after CBT, which was significantly lower than that of after allo-PBSCT/BMT (45.3 %) (p = 0.015). The overall survival (OS) and leukemia-free survival (LFS) in the CBT group were similar to those of the allo-PBSCT/BMT group; however, for acute myeloid leukemia (AML) patients, the 5-year LFS in the CBT group was slightly better than the allo-PBSCT/BMT group (55.7 % for CBT and 32.7 % for allo-PBSCT/BMT) (p = 0.08). Our comparisons suggest that for high-risk or advanced childhood acute leukemia, unrelated CBT has a higher TRM and similar long-term survival, but better antileukemia effect than HLA-matched sibling PBSCT/BMT. New strategies and better supportive care are required to decrease the TRM of CBT.

Objectives: The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML)., Methods: Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation., Results: The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6∼60.8 × 10(9)/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 × 10(9)/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P < 0.001, 0.005). Twenty-four out of 34 patients (70.6%) with CNS recurrence achieved CNS complete remission at a median of 58 days (range, 30-120). The 3-year disease-free survival and overall survival estimates for all CNS recurrence patients were 21.6 and 25.3%, respectively., Discussion: This report indicates that the tailored CNS-directed strategy is an effective modality to treat CNS recurrence in adult AML, but further studies are needed to improve the long-term survival.