PB1866: IS ALLO-HSCT IN CR1 NECESSARY FOR AML PATIENTS WITH MRD NEGATIVITY ACHIEVED AFTER THE FIRST INDUCTION COURSE? RUSSIAN PROSPECTIVE MULTICENTER RANDOMIZED TRIAL IN AML PATIENTS UNDER THE AGE OF 60
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SUBMITTER: Parovichnikova E
PROVIDER: S-EPMC10430313 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:The benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) aged >60 years remains a matter of debate, notably when performed in first complete remission (CR1). To clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN) 2010 classification. The impact of allo-HSCT was analyzed through three models: (1) time-dependent Cox; (2) multistate for dynamic prediction; and (3) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR patients with AML, 203 of whom received an allo-HSCT. Classical multivariate analysis showed that allo-HSCT significantly improved relapse-free survival (RFS; hazard ratio [HR] [95% confidence interval (CI)], 0.47 [0.35-0.62]; P < .001) and overall survival (OS; HR [95% CI], 0.56 [0.42-0.76]; P < .001), independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without allo-HSCT continue to relapse over time. Finally, the super landmark model showed that allo-HSCT significantly improved RFS (HR [95% CI], 0.47 [0.36-0.62]; P < .001) and OS (HR [95% CI], 0.54 [0.40-0.72]; P < .001). allo-HSCT in CR1 is reported here as significantly improving the outcome of fit older patients with AML. Long-term RFS without allo-HSCT is very low (<10%), supporting allo-HSCT as being the best curative option for these patients.
| S-EPMC8941467 | biostudies-literature
Project description:Multiple studies have demonstrated that patients with acute myeloid leukemia (AML) who have measurable residual disease (MRD) detected during or after treatment have higher relapse rates and worse survival than similar patients testing negative. Updated response criteria for AML reflect the understanding that achievement of complete remission (CR) with no detectable MRD using high-sensitivity tests represents a superior response over conventional cytomorphological CR alone. Potential use cases for AML MRD testing are diverse and include patient selection for clinical trials and therapeutic assignment, early relapse detection and intervention during sequential monitoring, and drug development, including deep quantification for antileukemia efficacy and as a surrogate endpoint for overall survival in regulatory approvals. Testing for AML MRD has not, however, been harmonized, and many technical and clinical questions remain. The implications of MRD test results for specific therapeutic combinations, molecular subsets, test types, treatment time points, sample types, and patient characteristics remain incompletely defined. No perfect AML MRD test or testing strategy currently exists, and the evidence basis for clinical recommendations in this rare disease is sparse but growing. It is unproven whether conversion of an MRD test result from positive to negative by additional therapeutic intervention improves relapse risk and survival. Several national- and international-level consortia have recently been initiated to advance the generation and collection of evidence to support the use of AML MRD testing in clinical practice, drug development, and regulatory approvals.
| S-EPMC9820122 | biostudies-literature
Project description:In relapsed/refractory acute myeloid leukemia (AML), the prognostic impact of complete remission (CR) and measurable residual disease (MRD) negativity is not well established. We retrospectively analyzed 141 patients with relapsed/refractory AML who received first salvage therapy and had MRD assessed by multiparameter flow cytometry at the time of response. Patients who achieved CR with full hematologic recovery as best response vs those with incomplete hematology recovery had lower cumulative incidence of relapse (P = .01) and better relapse-free survival (P = .004) but not overall survival (P = .15); a similar trend was observed in patients who achieved MRD negativity vs those who were MRD positive (P = .01, P = .05, and P = .21, respectively). By multivariate analysis, CR and MRD negativity were each independently associated with lower cumulative incidence of relapse (P = .001 and P = .003, respectively) and better relapse-free survival (P < .001 and P = .02) but not overall survival. Patients who achieved CR with MRD negativity had the lowest rates of relapse and best survival (2-year overall survival rate, 37%), which was driven largely by lower rates of early relapse and an increased ability in this group to undergo hematopoietic stem cell transplantation (HSCT); however, post-HSCT outcomes were similar regardless of response to salvage chemotherapy. Overall, in patients with relapsed/refractory AML, CR with MRD negativity was associated with the best outcomes, supporting it as the optimal response in this setting.
| S-EPMC7757010 | biostudies-literature
Project description:Using targeted exome sequencing, we studied correlations between mutations at diagnosis and transplant outcomes in 332 subjects with acute myeloid leukemia (AML) receiving allotransplantation. A total of 299 patients (299/332, 90.1%) had at least one oncogenic point mutation. In multivariable analyses, pretransplant disease status, minimal residual disease (MRD) before transplantation (pre-MRD), cytogenetic risk classification, and TP53 and FLT3-ITD high ratio mutations were independent risk factors for AML recurrence after allotransplantation (p < 0.05). A nomogram for the cumulative incidence of relapse (CIR) that integrated all the predictors in the multivariable model was then constructed, and the concordance index (C-index) values at 6, 12, 18, and 24 months for CIR prediction were 0.754, 0.730, 0.715, and 0.690, respectively. Moreover, calibration plots showed good agreements between the actual observation and the nomogram prediction for the 6, 12, 18, and 24 months posttransplantation CIR in the internal validation. The integrated calibration index (ICI) values were 0.008, 0.055, 0.094, and 0.136 at 6, 12, 18, and 24 months posttransplantation, respectively. With a median cutoff score of 9.73 from the nomogram, all patients could be divided into two groups, and the differences in 2-year CIR, disease-free survival (DFS), and overall survival (OS) between these two groups were significant (p < 0.05). Taken together, the results of our study indicate that gene mutations could help to predict the outcomes of patients with AML receiving allotransplantation.
| S-EPMC8503644 | biostudies-literature
Project description:Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow-derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor β1 (TGF-β1) were associated with impaired effector function of BMNK cells in these AML patients. TGF-β1 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-β1 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-β1 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-β1 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-β1 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell-based immunotherapy.
| S-EPMC10653097 | biostudies-literature
Project description: Not available
| S-EPMC10632351 | biostudies-literature
Project description:BackgroundConsolidative allogeneic hematopoietic stem cell transplantation is a controversial option for patients with relapsed/refractory acute lymphoblastic leukemia after chimeric antigen receptor T cell (CAR-T) therapy. We performed a multicenter retrospective study to assess whether patients can benefit from haploidentical hematopoietic stem cell transplantation after CAR-T therapy.MethodsA total of 122 patients after CAR-T therapy were enrolled, including 67 patients without subsequent transplantation (non-transplant group) and 55 patients with subsequent haploidentical hematopoietic stem cell transplantation (transplant group). Long-term outcome was assessed, as was its association with baseline patient characteristics.ResultsCompared with the non-transplant group, transplantation recipients had a higher 2-year overall survival (OS; 77.0% versus 36.4%; P < 0.001) and leukemia-free survival (LFS; 65.6% versus 32.8%; P < 0.001). Multivariate analysis showed that minimal residual disease (MRD) positivity at transplantation is an independent factor associated with poor LFS (P = 0.005), OS (P = 0.035), and high cumulative incidence rate of relapse (P = 0.045). Pre-transplant MRD-negative recipients (MRD- group) had a lower cumulative incidence of relapse (17.3%) than those in the non-transplant group (67.2%; P < 0.001) and pre-transplant MRD-positive recipients (MRD+ group) (65.8%; P = 0.006). The cumulative incidence of relapse in MRD+ and non-transplant groups did not differ significantly (P = 0.139). The 2-year LFS in the non-transplant, MRD+, and MRD- groups was 32.8%, 27.6%, and 76.1%, respectively. The MRD- group had a higher LFS than the non-transplantation group (P < 0.001) and MRD+ group (P = 0.007), whereas the LFS in the MRD+ and non-transplant groups did not differ significantly (P = 0.305). The 2-year OS of the MRD- group was higher than that of the non-transplant group (83.3% versus 36.4%; P < 0.001) but did not differ from that of the MRD+ group (83.3% versus 62.7%; P = 0.069). The OS in the non-transplant and MRD+ groups did not differ significantly (P = 0.231).ConclusionHaploidentical hematopoietic stem cell transplantation with pre-transplant MRD negativity after CAR-T therapy could greatly improve LFS and OS in patients with relapsed/refractory acute lymphoblastic leukemia.Trial registrationThe study was registered in the Chinese clinical trial registry (ChiCTR1900023957).
| S-EPMC7199358 | biostudies-literature
Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also mediated by these cells. Here, we assessed the effect of attenuating TCR-mediated SLP76:ITK interaction in GVL vs. GVHD effects after allo-HSCT. CD8+ and CD4+ donor T cells from mice expressing a Y145F mutation in SLP-76 did not cause GVHD but preserved GVL effects against B-ALL cells. SLP76Y145FKI CD8+ and CD4+ donor T cells also showed less inflammatory cytokine production and migration to GVHD target organs. We developed a novel peptide to specifically inhibit SLP76:ITK interactions, resulting in decreased phosphorylation of PLCγ1 and ERK, decreased cytokine production in human T cells, and separation of GVHD from GVL effects. Altogether, our data suggest that inhibiting SLP76:ITK interaction could be a therapeutic strategy to separate GVHD from GVL effects after allo-HSCT treatment.
| S-EPMC8024657 | biostudies-literature
