Adult Acute Myeloid Leukemia Research Articles

Association of social deprivation with survival in younger adult patients with AML: an Alliance study

Survival of patients with acute myeloid leukemia (AML) is influenced by genetic factors, age, and race. Social deprivation is increasingly recognized as an important contributor to disparities in cancer outcomes, but studies of adult AML are lacking. We analyzed associations between social deprivation index (SDI) and outcome in 1,893 patients with AML treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology frontline protocols. Patients with low (first quartile, lowest deprivation) and high (quartiles 2-4) SDI were analyzed for associations with baseline clinical, cytogenetic and molecular features, and outcomes. Except for racial-ethnic identity, SDI was not associated with baseline clinical characteristics. Patients aged <60 years with high SDI harbored BCOR (3% vs 7%, P=.03), IDH1 (6% vs 11%, P=.03) and STAG2 (2% vs 5%, P=.02) mutations less often than patients with low SDI, suggesting possible differences in the underlying disease biology. High SDI patients had shorter disease-free (median: 1.5 vs 2.8 years, P=.02) and overall survival (OS; median: 1.9 vs 3.0 years, P=.005) than low SDI patients. In multivariable analysis, high SDI was associated with worse OS (HR: 1.28, 95% CI: 1.06-1.55, P=.001). Survival differences occurred mainly in the 2017 European LeukemiaNet favorable genetic-risk group. There were no significant associations between SDI and molecular features or survival among patients aged ≥60 years. We conclude that high SDI associated with worse survival, independent from other pretreatment prognostic factors, in younger AML patients. The role of socioeconomic factors in AML should be further investigated to overcome potentially avoidable survival disparities.

Clinical characteristics and prognosis analysis of patients with de novo ASXL1-mutated AML treated with the C-HUNAN-AML-15 protocol: A multicenter study by the South China Pediatric AML Collaborative Group.

ASXL1 mutation is an independent prognostic factor in adult acute myeloid leukemia (AML), but its effect on the prognosis of pediatric AML is poorly understood. This study aimed to investigate the clinical characteristics and prognostic factors of ASXL1-mutant pediatric AML from a large Chinese multicenter cohort. A total of 584 pediatric patients with newly diagnosed AML from 10 centers in South China were enrolled. The exon 13 of ASXL1 was amplified by polymerase chain reaction (PCR), and then analyzed the mutation status of the locus. (n = 59 for ASXL1-mut group, n = 487 for ASXL1-wt group). ASXL1 mutations were found in 10.81% of all patients with AML. A complex karyotype was significantly less common in the ASXL1-mut AML group than in the ASXL1-wt group (1.7% vs. 11.9%, p = 0.013). Furthermore, TET2 or TP53 mutations were predominantly found in the ASXL1+ group (p = 0.003 and 0.023, respectively). The 5-year overall survival (OS) and event-free survival (EFS) of the total cohort were 76.9% and 69.9%. In ASXL1-mut AML patients, a white blood cell (WBC) count ≥50 × 109 /L had significantly poorer 5-year OS and EFS than a WBC count <50 × 109 /L (78.0% vs. 44.6%, p = 0.001; 74.8% vs. 44.6%, p = 0.003, respectively), while receiving hematopoietic stem cell transplantation (HSCT) had a higher 5-year OS and EFS (84.5% vs. 48.5%, p = 0.024; 79.5% vs. 49.3%, p = 0.047, respectively). In the multivariate Cox regression analysis, patients with high-risk AML undergoing HSCT tended to have a better 5-year OS and EFS than those receiving chemotherapy as a consolidation (HR = 0.168 and 0.260, both p < 0.001), and WBC count ≥50 × 109 /L or failure to achieve complete response after the first course were independent adverse predictors of OS and EFS (HR = 1.784 and 1.870, p = 0.042 and 0.018; HR = 3.242 and 3.235, both p < 0.001). The C-HUANA-AML-15 protocol is a well-tolerated and effective in the treatment of pediatric AML. ASXL1 mutation is not an independent adverse prognosis predictor for survival in AML, whereas ASXL1-mut patients tend to have a poor prognosis if WBC count ≥50 × 109 /L, but they can benefit from HSCT.

Oral Azacitidine for Maintenance Treatment of Acute Myeloid Leukaemia After Induction Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Celgene) of oral azacitidine (ONUREG), as part of the Single Technology Appraisal (STA) process, to submit evidence for the clinical effectiveness and cost-effectiveness of oral azacitidine for maintenance treatment of acute myeloid leukaemia (AML) after induction therapy compared with watch-and-wait plus best supportive care (BSC) and midostaurin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarises the company submission (CS), presents the ERG's critical review on the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations and describes the development of the NICE guidance by the Appraisal Committee. In the QUAZAR AML-001 trial, oral azacitidine significantly improved overall survival (OS) versus placebo: median OS gain of 9.9months (24.7months versus 14.8months; hazard ratio (HR) 0.69 (95% CI 0.55-0.86), p < 0.001). The median time to relapse was also better for oral azacitidine, and the incidences of TEAEs were similar for the two arms. The company excluded two of the comparators listed in the scope, low-dose cytarabine and subcutaneous azacitidine, informed only by clinical expert opinion, leaving only best supportive care (BSC) and midostaurin for the FLT3-ITD and/or FLT3-TKD (FLT3 mutation)-positive subgroup. An ITC comparing oral azacitidine to midostaurin as maintenance therapy in the appropriate subgroup demonstrated that the OS and relapse-free survival (RFS) HRs were favourable for oral azacitidine when compared with midostaurin. However, in the only available trial of midostaurin as maintenance treatment in AML that was used for this ITC, subjects were not randomised at the maintenance phase, but at induction, which posed a substantial risk of bias. The revised and final probabilistic incremental cost-effectiveness ratio (ICER) presented by the company, including a commercial arrangement, was £32,480 per quality-adjusted life year (QALY) gained for oral azacitidine versus watch-and-wait plus BSC. Oral azacitidine was dominant versus midostaurin in the FLT-3 subgroup. The ERG's concerns included the approach of modelling haematopoietic stem cell transplantation (HSCT), the generalisability of the population and the number of cycles of consolidation therapy pre-treatment in the QUAZAR AML-001 trial to UK clinical practice, and uncertainty in the relapse utility. The revised and final ERG base case resulted in a similar probabilistic ICER of £33,830 per QALY gained versus watch-and-wait plus BSC, but with remaining uncertainty. Oral azacitidine remained dominant versus midostaurin in the FLT-3 subgroup. After the second NICE appraisal committee meeting, the NICE Appraisal Committee recommended oral azacitidine (according to the commercial arrangement), within its marketing authorisation, as an option for maintenance treatment for AML in adults who are in complete remission, or complete remission with incomplete blood count recovery, after induction therapy with or without consolidation treatment, and cannot have or do not want HSCT.

Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis.

Obesity (body mass index [BMI] ≥30kg/m2 ) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60years or older). Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate-risk cytogenetics group (p=.008), poorer performance status (p=.01), and a trend toward older age (p=.06). Obesity was not associated with somatic mutations among a selected 18-gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high-dose (90mg/m2 ) daunorubicin arm (p=.002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90-2.13; p=.14). Obesity is associated with unique clinical and disease-related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area-based dosing is not necessary because dose adjustments do not affect outcomes.

UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18–60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4–78.5%) and 57.1% (95%CI: 39.5–82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

Abstract LB035: The role of nucleophosmin1 mediated caspase2 activation in acute myeloid leukemia cell death and cell survival

Abstract Nucleophosmin 1 (NPM1) mutation is the primary genetic lesion in adult acute myeloid leukemia (AML). Typically, a nucleolar protein, NPM1 mutations cause cytoplasmic delocalization of NPM1(NPM1c+), triggering leukemogenesis. Interestingly, NPM1c+ mutation confers enhanced chemosensitivity. However, the mechanism underlying NPM1c+ mutation-induced oncogenesis or chemosensitivity remains unclear. We previously reported that, in response to genotoxic stimuli, NPM1 forms a platform for caspase-2 activation in the nucleolus. Caspase-2 is a pro-apoptotic protein and a known tumor suppressor. Our results indicate that nucleolar caspase-2 activation is specific to NPM1wt cells. In the NPM1c+ cells, caspase-2 activation is exclusively cytosolic, suggesting that caspase-2 is activated in the same sub-cellular compartment as NPM1 localization. Loss of caspase-2 rescued the increased sensitivity of NPM1c+ cells to apoptotic cell death. This is accompanied by reduced cleavage of the apoptotic substrate, caspase-3. Notably, caspase-2 deficient NPM1wt cells showed no significant difference in the percentage of apoptotic cell death or endogenous substrate cleavage compared to its caspase-2 wild-type counterpart. This suggests that caspase-2 may contribute to the chemosensitivity of NPM1c+ cells. Strikingly, in unstimulated cells, loss of caspase-2 leads to prolonged G1 arrest and progressive loss of cell viability. Immunophenotyping of NPM1c+ cells revealed a remarkable increase in the CD14+population representing monocyte/macrophage-like features, suggesting that loss of caspase-2 results in terminal differentiation. Exogenous expression of NPM1c+ in caspase-2 deficient NPM1wt cells impaired viability, confirming that NPM1c+ cells require caspase-2 for its growth and proliferation. Transcriptomic analysis revealed that loss of caspase-2 significantly downregulates pathways involved in stem cell pluripotency. In particular, FGF2, IGFR, WNT, LIF, and one of the core members of the self-renewal transcription factor, OCT 4, were downregulated in the absence of caspase-2 in NPM1c+ cells. This reveals a novel role for caspase-2 in maintaining NPM1c+ AML stemness. Taken together, our study shows that NPM1c+ mediated caspase-2 activation regulates AML cell death and survival cascades, a key determinant of chemosensitivity and leukemogenesis. Citation Format: Dharaniya Sakthivel, Alexandra Brown-Suedel, Francesca Keane, F. Kenneth McSherry, Chloe I. Charendoff, Kevin Dunne, Dexter Robichaux, Jonathan M. Flanagan, Lisa Bouchier-Hayes. The role of nucleophosmin1 mediated caspase2 activation in acute myeloid leukemia cell death and cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB035.

Impact of disease burden on clinical outcomes of AML patients receiving allogeneic hematopoietic cell transplantation: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47-2.24) p < 0.001 and HR = 1.54 (95% CI: 1.34-1.77), p < 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p < 0.001 and HR = 1.71 (95% CI: 1.51-1.94), p < 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.

Changing the strategic paradigm for the treatment of adult acute myeloid leukemia

Background: Acute myeloid leukemia (AML) is a representative blood cancer, accounting for most adult leukemia cases in Korea. Until recently, intensive chemotherapy and hematopoietic stem cell transplantation were the only curative treatment options for AML. However, the recent introduction of new drugs is bringing about changes in the strategic paradigm for the treatment of AML.Current Concepts: Along with the clinical eligibility for receiving intensive treatment and hematopoietic stem cell transplantation, the most critical determinants in treating AML are precise classification and risk stratification based on cytogenetic and molecular information. The recently revised World Health Organization classification, newly proposed International Consensus Classification, and the latest version of the European LeukemiaNet risk stratification reflect the importance of cytogenetic and molecular information. Although there have been no significant changes for a long time in the landscape of AML, especially in the field of treatment, the treatment paradigm has started to evolve with the introduction of new drugs. This evolution is led by FLT3 inhibitors, Bcl-2 inhibitors, isocitrate dehydrogenase inhibitors, target agents against CD33 antigens, and liposomal formulations of chemotherapeutics.Discussion and Conclusion: Successful initial treatment to induce complete remission followed by post-remission treatment to remove residual disease can lead to the achievement of long-term survival and cure goals in AML. We hope that new drugs will markedly improve the treatment outcomes for patients with AML.

High trophinin-associated protein expression predicts good survival in acute myeloid leukemia with normal cytogenetics.

Nearly half of adult acute myeloid leukemia (AML) patients were classified into cytogenetic normal acute myeloid leukemia (CN-AML). The expression level of Trophinin associated protein (TROAP) was proven to be associated with the prognosis of several cancers, but it is still unclear in the prognosis of patients with CN-AML. We integrated CN-AML patients samples from 4 datasets to analyze the relationship between TROAP expression and the survival of CN-AML. In addition, we investigated 92 AML patients of The Cancer Genome Atlas (TCGA) database to analyze the relationship between TROAP expression and the survival of AML patients received chemotherapy. We investigated the relationship between the expression of TROAP and drug sensitivity in AML cell lines. CN-AML patients with high TROAP expression were related to good event-free survival (EFS) and overall survival (OS). In AML patients received chemotherapy, high TROAP expression was associated with good survival prognosis. Additionally, the expression of TROAP gene in leukemia stem cells (LSC) + group was lower. Among multiple drugs, the lower the expression of TROAP, the lower the IC50. TROAP could serve as an independent predictor of CN-AML patients and could act as a potential biomarker for the prognosis of CN-AML. TROAP expression levels were closely correlated with the drug sensitivity of multiple drugs.

The effect of viral hepatitis B and C on the outcome of allogenic bone marrow transplantation of patients with adult acute myeloid leukemia (Egyptian sample)

Abstract Background Hematopoietic stem cell transplantation is now established as a standard therapeutic modality for different malignant and benign diseases. Hematopoietic stem cell transplantation has many complications. Infection and graft-versus-host disease (GVHD) remain the major source of morbidity and mortality in patients who undergo BMT. Aim The aim of this work was to investigate the effect of hepatitis B and hepatitis C (HCV) viral infection on the outcome of fully matched sibling donor peripheral blood stem cell transplantation in patients with acute myeloid leukemia (AML). Patients and methods A total of 328 patients with AML who received allogeneic PBSC transplantation using BU/CY or FLU/BU conditioning regimen after the consent of the Ethical Committee of Nasser Institute Hospital during the period from 1997 to December 2016 were included in this study with a follow-up of 12 months. Results In seropositive patients, neutrophil engraftment was reached at a median of 14.57 days and platelet engraftment was reached at a median of 12.7. However, in seronegative patients, neutrophil engraftment was reached at a median of 14.3 (P=0.287) and platelet engraftment was reached at a median of 12.66 (P=0.917). In seropositive patients, the incidence of SOS was 2.1%, acute GVHD grades 2–4 was reported in eight patients, whereas chronic GVHD was reported in nine patients. In seronegative patients, the incidence of SOS was 0.70% (P=0.33), acute GVHD grades 2–4 was reported in 30 patients (P=0.184), whereas chronic GVHD was reported in 45 patients (P=0.54). Overall survival for HCV seronegative and seropositive patients was 58.4 and 44.6%, respectively (P=0.001), whereas disease-free survival for HCV seronegative and seropositive patients was 56.9 and 43.4%, respectively (P=0.0001). Conclusion Analysis of 46 HCV-positive adult AML patients and 282 HCV seronegative patients who had peripheral blood stem cell transplantation shows that HCV infection does not affect platelet or neutrophil engraftment or the incidence of SOS. HCV viremia did not show a significant effect on the incidence of acute and chronic GVHD. We also documented that there is a significant effect of HCV on both the disease-free survival and overall survival.

Bax, Bcl-2, and Bax/Bcl-2 as prognostic markers in adults Acute myeloid Leukemia Patients

Bax, Bcl-2, and Bax/Bcl-2 as prognostic markers in adults Acute myeloid Leukemia Patients

Molecular Alterations in IDH 1/2 Genes among Iraqi Adult Acute Myeloid Leukemia Patients

BACKGROUND: The recurrent somatic variations in IDH1/2 genes in AML play imperative roles in epigenetic dysregulation and the pathogenesis of AML, which could be useful prognostic markers for risk stratification. AIM: The aim of the study was to detect the frequency of R132 mutations in the IDH1 gene and R140Q mutation in the IDH2 gene with their treatment outcomes. PATIENTS, MATERIALS AND METHODS: IDH molecular alterations were detected by high-resolution-melting (HRM)-based real-time PCR assay in 56 newly diagnosed AML patients. RESULTS: IDH molecular alterations were identified in 39.3% of AML patients; IDH1 R132 and IDH2 R140Q mutations were present in 32.1% and 12.5% of patients, respectively. The mean age of patients with mutant IDH (52±14.87 years) is higher than in wild type (41.68±20.4 years), P = 0.041. Females were seen in 53% of mutant IDH patients while in the wild-type 73.3% were males (P = 0.038). There were significantly lower mean levels of hemoglobin, absolute neutrophil count, and platelet count in mutant IDH than in wild-type (P = 0.015, 0,.03 and 0.01, respectively). After induction remission therapy, 68.2% of mutated IDH and 64.7% of unmutated IDH patients didn't achieve complete remission (P &gt; 0.05). After 6 months; 59.1% of mutated IDH and 64.7% of unmutated IDH had unfavorable outcomes (P &gt; 0.05). CONCLUSIONS: IDH mutations are common in Iraqi adult AML patients and present in older age and females predominance with lower Hb level, WBC count, absolute neutrophil count, platelet count, and less extramedullary involvement. There is an insignificant association with treatment outcomes.

Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia.

Preferentially Expressed Antigen in Melanoma (PRAME), a cancer-testis antigen, provides an ideal target for immunotherapy in acute myeloid leukemia (AML). We have shown expression of PRAME in a significant subset of childhood and adult AML and lack of expression in normal hematopoiesis. Although an intracellular antigen, we developed a novel approach to target PRAME using a chimeric antigen receptor (CAR) construct encoding a targeting domain based on T-cell receptor (TCR) mimic antibodies that target the peptide-HLA complex. We used the antibody sequence from a previously designed TCR mimic (mTCR) antibody, Pr20, that recognizes the PRAME ALY peptide in complex with HLA-A∗02 and verified expression of PRAME in AML cell lines and primary AML blasts. Using the Pr20 antibody sequence, we developed CAR T cells (PRAME mTCRCAR T) to be tested against primary samples from patients with AML and AML cell lines that express the PRAME antigen in the context of HLA-A2 expression. In contrast to appropriate controls, PRAME mTCRCAR T cells demonstrate target-specific and HLA-mediated invitro activity in OCI-AML2 and THP-1 cell lines, HLA-A2 cell lines expressing the PRAME antigen, and against primary AML patient samples. Invivo cell-derived xenograft models treated with PRAME mTCRCAR T cells demonstrated potent leukemia clearance and improved survival compared with unmodified T-cell controls. Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with interferon gamma, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.

Validation of National Early Warning Score and Quick Sequential (sepsis-related) Organ Failure Assessment in acute myeloid leukaemia patients treated with intensive chemotherapy.

Chemotherapy-induced neutropenia in acute myeloid leukaemia (AML) is a risk factor for life-threatening infections. Early diagnosis and prompt interventions are associated with better outcomes, but the prediction of infection severity remains an open question. Recently, National Early Warning Score (NEWS) and quick sequential organ failure assessment (qSOFA) scores were proposed as warning clinical instruments predicting in-hospital mortality, but their role in the haematological context is still unknown. We retrospectively assess the predictive role of NEWS and qSOFA in a large and homogeneous cohort of adult AML patients treated with intensive chemotherapy. In a total of 1048 neutropenic episodes recorded in 334 consecutive patients, the scores were applied to predict outcomes on the same day of fever onset, and after 24 and 48 h from score calculation. Both NEWS and qSOFA significantly predicted death, with more accuracy on the same day (NEWS AUROC 0.984 and qSOFA AUROC 0.969) and after 24 h (NEWS AUROC 0.928 and qSOFA AUROC 0.887), while remained moderately accurate after 48 h. Furthermore, also ICU admission was accurately predicted at fever onset and after 24 h. Both scores were useful tools in the management of post chemotherapy neutropenic febrile AML patients.

A direct comparison, and prioritisation, of the antigens ex-pressed in adult and paediatric acute myeloid leukaemia: a systematic review and meta-analysis

A direct comparison, and prioritisation, of the antigens ex-pressed in adult and paediatric acute myeloid leukaemia: a systematic review and meta-analysis

Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia

The possibility that HLA mismatches could reduce relapse after alternative HLA-mismatched allogeneic hematopoietic cell transplantation (HCT) is an attractive concept for treating acute myeloid leukemia (AML). However, it remains unclear whether the prognostic effect of graft-versus-host disease (GVHD) on survival differs between recipients of single-unit cord blood transplantation (CBT) and recipients of haploidentical HCT using post-transplantation cyclophosphamide (PTCy-haplo-HCT) for AML. The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT. We retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n=1981) between 2014 and 2020 using a Japanese registry database. In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD (P < .001, log-rank test) and limited chronic GVHD (P < .001, log-rank test) among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT, .73, 95% confidence interval [CI], .60 to .87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI, .70 to 1.64; P for interaction=.038). Our data demonstrate that grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.

Human leukocyte antigens and adult acute myeloid leukemia: A first report from Lebanon

IntroductionAcute Myeloid Leukemia (AML) represents the most common type of acute leukemia in adults and the second most common form of leukemia in general. AML has been associated with HLA alleles and these correlations have been widely investigated worldwide. ObjectiveThe aim of this study is to analyze the antigen frequency of HLA Class I (HLA-A, HLAB, and HLAC) and Class II (HLA-DRB1 and HLA-DQB1) among AML Lebanese adult patients. MethodsThis is a retrospective study reviewing all the HLA results of 121 adult patients admitted to the American University of Beirut Medical Center (AUBMC) from January 2017 to May 2022. Comparison of HLA frequency in AML patients to frequency in general Lebanese population published in previous studies was done. ResultsIn HLA class I, an increased frequency of HLA-A*03 (OR, 1.61; 95% CI, 1.10 to 2.37; P = 0.02), HLA-A*25 (OR, 6.69; 95% CI, 1.78 to 25.07; P = 0.01), HLA-A*74 (OR, 8.33; 95% CI, 1.67 to 41.51; P = 0.02) was found in the AML group, whereas decreased frequency of HLA-B*15 (OR, 0.22; 95% CI, 0.05 to 0.93; P = 0.03) was noted. In HLA class II, DRB1*03 (OR, 0.27; 95% CI, 0.14 to 0.50; P < 0.001) was higher among the control group and DRB1*12 (OR, 15.71; 95% CI, 1.88 to 131.20; P = 0.01) among the AML group. ConclusionFindings revealed that three class I HLA antigens are predisposing to AML (HLA-A*03; HLA-A*25; HLA-A*74) and one class I HLA antigen is protective (HLA-B*15). Regarding class II HLA antigens, DRB1*03 was found to be protective whereas DRB1*12 was found to be predisposing to AML.

Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) in second complete remission (CR2) transplanted from unrelated donors with post-transplant cyclophosphamide (PTCy). A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Post-transplant cyclophosphamide (PTCy) is being increasingly used as graft-versus-host disease (GVHD) prophylaxis post allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) transplanted in first complete remission (CR1). However, results may differ in patients transplanted in CR2. We retrospectively evaluated transplant outcomes of adult AML patients transplanted between 2010-2019 from 9-10/10 human leukocyte antigen (HLA)-matched unrelated donor (UD) in CR2. In total, 127 patients were included (median age 45.5 years, 54% male). Median follow-up was 19.2 months. Conditioning was myeloablative (MAC) in 50.4% and the graft source was peripheral blood in 93.7% of the transplants. Incidence of acute (a)GVHD II-IV and III-IV was 26.2% and 9.2%. Two-year total and extensive chronic (c)GVHD were 34.3% and 13.8 %, respectively. Two-year non-relapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were 17.2%, 21.1%, 61.7, %, 65.2%, and 49.3%, respectively. Time from diagnosis to transplant (>18 months) was a favorable prognostic factor for RI, LFS, OS, and GRFS while favorable risk cytogenetics was a positive prognostic factor for OS. The patient's age was a poor prognostic factor for NRM and cGVHD. Finally, the female-to-male combination and reduced intensity conditioning (RIC) were poor and favorable prognostic factors for cGVHD, respectively. We conclude that PTCy is an effective method for GVHD prophylaxis in AML patients undergoing allo-HCT in CR2 from UD.

Long Noncoding RNA Expression Independently Predicts Outcome in Pediatric Acute Myeloid Leukemia.

Optimized strategies for risk classification are essential to tailor therapy for patients with biologically distinctive disease. Risk classification in pediatric acute myeloid leukemia (pAML) relies on detection of translocations and gene mutations. Long noncoding RNA (lncRNA) transcripts have been shown to associate with and mediate malignant phenotypes in acute myeloid leukemia (AML) but have not been comprehensively evaluated in pAML. To identify lncRNA transcripts associated with outcomes, we evaluated the annotated lncRNA landscape by transcript sequencing of 1,298 pediatric and 96 adult AML specimens. Upregulated lncRNAs identified in the pAML training set were used to establish a regularized Cox regression model of event-free survival (EFS), yielding a 37 lncRNA signature (lncScore). Discretized lncScores were correlated with initial and postinduction treatment outcomes using Cox proportional hazards models in validation sets. Predictive model performance was compared with standard stratification methods by concordance analysis. Training set cases with positive lncScores had 5-year EFS and overall survival rates of 26.7% and 42.7%, respectively, compared with 56.9% and 76.3% with negative lncScores (hazard ratio, 2.48 and 3.16; P < .001). Pediatric validation cohorts and an adult AML group yielded comparable results in magnitude and significance. lncScore remained independently prognostic in multivariable models, including key factors used in preinduction and postinduction risk stratification. Subgroup analysis suggested that lncScores provide additional outcome information in heterogeneous subgroups currently classified as indeterminate risk. Concordance analysis showed that lncScore adds to overall classification accuracy with at least comparable predictive performance to current stratification methods that rely on multiple assays. Inclusion of the lncScore enhances predictive power of traditional cytogenetic and mutation-defined stratification in pAML with potential, as a single assay, to replace these complex stratification schemes with comparable predictive accuracy.

Investigation of distinct gene expression profile patterns that can improve the classification of intermediate-risk prognosis in AML patients.

Background: Acute myeloid leukemia (AML) is a heterogeneous type of blood cancer that generally affects the elderly. AML patients are categorized with favorable-, intermediate-, and adverse-risks based on an individual's genomic features and chromosomal abnormalities. Despite the risk stratification, the progression and outcome of the disease remain highly variable. To facilitate and improve the risk stratification of AML patients, the study focused on gene expression profiling of AML patients within various risk categories. Therefore, the study aims to establish gene signatures that can predict the prognosis of AML patients and find correlations in gene expression profile patterns that are associated with risk groups. Methods: Microarray data were obtained from Gene Expression Omnibus (GSE6891). The patients were stratified into four subgroups based on risk and overall survival. Limma was applied to screen for differentially expressed genes (DEGs) between short survival (SS) and long survival (LS). DEGs strongly related to general survival were discovered using Cox regression and LASSO analysis. To assess the model's accuracy, Kaplan-Meier (K-M) and receiver operating characteristic (ROC) were used. A one-way ANOVA was performed to assess for differences in the mean gene expression profiles of the identified prognostic genes between the risk subcategories and survival. GO and KEGG enrichment analyses were performed on DEGs. Results: A total of 87 DEGs were identified between SS and LS groups. The Cox regression model selected nine genes CD109, CPNE3, DDIT4, INPP4B, LSP1, CPNE8, PLXNC1, SLC40A1, and SPINK2 that are associated with AML survival. K-M illustrated that the high expression of the nine-prognostic genes is associated with poor prognosis in AML. ROC further provided high diagnostic efficacy of the prognostic genes. ANOVA also validated the difference in gene expression profiles of the nine genes between the survival groups, and highlighted four prognostic genes to provide novel insight into risk subcategories poor and intermediate-poor, as well as good and intermediate-good that displayed similar expression patterns. Conclusion: Prognostic genes can provide more accurate risk stratification in AML. CD109, CPNE3, DDIT4, and INPP4B provided novel targets for better intermediate-risk stratification. This could enhance treatment strategies for this group, which constitutes the majority of adult AML patients.