High-risk Adult Acute Myeloid Leukemia Research Articles

Peripheral blood stem cell transplantation from haploidentical related donor could achieve satisfactory clinical outcomes for intermediate- or high-risk adult acute myeloid leukemia patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most important curative method for intermediate- and high-risk adult acute myeloid leukemia (AML) patients. We aimed to identify the clinical outcomes of haploidentical related donor (HID) peripheral blood stem cell transplantation (PBSCT) who receiving peripheral blood (G-PB) harvest, and the patients receiving bone marrow (BM) plus G-PB harvest (BM + PB) as grafts were enrolled as control. The engraftments of neutrophil and platelet in G-PB group were both faster than those in BM + PB group. The cumulative incidences of grade II-IV acute graft-versus-host disease (aGVHD), and moderate to severe chronic GVHD (cGVHD) were all comparable between G-PB and BM + PB groups. The cumulative incidence of relapse and non-relapse mortality at 3 years after HID HSCT was 12.6% versus 13.7% (p = 0.899) and 3.6% versus 7.3% (p = 0.295), respectively, in G-PB and BM + PB group. While the probabilities of GVHD-free/relapse-free survival, leukemia-free survival, and overall survival at 3 years after HID HSCT were 60.6% versus 53.4% (p = 0.333), 83.8% versus 79.0% (p = 0.603), and were 87.3% versus 82.9% (p = 0.670), respectively. We confirmed the safety and efficacy of HID PBSCT in intermediate- and high-risk AML patients in a large cohort.

Acute myeloid leukemias with UBTF tandem duplications are sensitive to menin inhibitors

AbstractUBTF tandem duplications (UBTF-TDs) have recently emerged as a recurrent alteration in pediatric and adult acute myeloid leukemia (AML). UBTF-TD leukemias are characterized by a poor response to conventional chemotherapy and a transcriptional signature that mirrors NUP98-rearranged and NPM1-mutant AMLs, including HOX-gene dysregulation. However, the mechanism by which UBTF-TD drives leukemogenesis remains unknown. In this study, we investigated the genomic occupancy of UBTF-TD in transformed cord blood CD34+ cells and patient-derived xenograft models. We found that UBTF-TD protein maintained genomic occupancy at ribosomal DNA loci while also occupying genomic targets commonly dysregulated in UBTF-TD myeloid malignancies, such as the HOXA/HOXB gene clusters and MEIS1. These data suggest that UBTF-TD is a gain-of-function alteration that results in mislocalization to genomic loci dysregulated in UBTF-TD leukemias. UBTF-TD also co-occupies key genomic loci with KMT2A and menin, which are known to be key partners involved in HOX-dysregulated leukemias. Using a protein degradation system, we showed that stemness, proliferation, and transcriptional signatures are dependent on sustained UBTF-TD localization to chromatin. Finally, we demonstrate that primary cells from UBTF-TD leukemias are sensitive to the menin inhibitor SNDX-5613, resulting in markedly reduced in vitro and in vivo tumor growth, myeloid differentiation, and abrogation of the UBTF-TD leukemic expression signature. These findings provide a viable therapeutic strategy for patients with this high-risk AML subtype.

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.

Relationship between Quantitative Monitoring of WT1 Gene and Prognosis in Patients with Acute Leukemia

To investigate the exprassion of WT1 gene in patients with adult acute myeloid leukemia (AML) and its clinical significance. Sixty-three newly diagnosed patients with acute myeloid leukemia were selected. Quantitative RT-PCR was used to detect the expression of WT1 gene in the 63 AML patients and 20 non-AML controls. WT1 gene was highly expressed in AML patents and its expression in the low-risk group was significantly lower than that in middle-risk group and high-risk group (P<0.05), and no significant difference of WT1 gene expression between middle-risk and high-risk group was observed. In the patients of middle-risk and high-risk patients, the expression of WT1 gene in the remission group was significantly lower than that in the patients of non-remission after treatment (P<0.05). The non-remission patients after first treatment in middle-risk and high-risk group were treated with second induction therapy. After second induction therapy, the WT1 expression in remission patients was significantly decreased (P<0.05) in comparison with that in patients still in non-remission. There was a negative correlation between WT1 expression and the 2-year overall survival rate in the newly diagnosed middle and high-risk AML patients. The detection of WT1 gene expression can help to divide AML patients into low-/middle-/high-risk groups and to evaluate therapeutic response and clinical prognosis in middle and high-risk AML patients.

Members of the microRNA-106a-363 Cluster Associate with Unfavorable Outcome in Adult Acute Myeloid Leukemia Patients and Promote Leukemogenesis invivo through Increased Metabolic Activity

The miR-106a-363 cluster, encoding six miRNAs (miR-106a, miR-18b, miR-20b, miR-19b, miR-92a and miR-363), is a paralogue of the oncogenic miR-17-92a polycistron and its role in leukemia is at present largely unknown. We aimed to investigate the putative oncogenic role of the miR-106a-363 cluster in adult acute myeloid leukemia (AML) and to dissect the contributions of its individual members to disease formation and progression.First, we analyzed the expression of each miRNA in AML patient samples as well as their clinical relevance. To determine the association of the miR-106a-363 cluster in AML with active disease, we quantified all six miRNAs individually in AML patient samples at initial diagnosis (n=33) and in AML patients in complete remission after chemotherapy (n=6). Hereof, miR-106a-5p, miR-19b-3p and miR-92a-3p levels were significantly lower in remission samples (p=0.0015, p=0.0013 and p=0.0004, respectively), confirming that these miRNAs are upregulated in AML. Stratifying AML patients within the LAML miRNA-Seq dataset of The Cancer Genome Atlas (TCGA) Research Network (n=187) (Ley et al., NEJM, 2013) according to their cytogenetic risk group demonstrated that all members of the cluster, except for miR-18b-5p, significantly associated with adverse cytogenetics. In addition, with the exception of miR-18b-5p, all members associated with an inferior overall survival (OS) in AML patients within the TCGA-LAML dataset, further supporting a pro-leukemogenic role for the cluster. Of note, miR-106a-5p was the most abundantly expressed unique miRNA of the polycistron, both in the TCGA patient cohort and in 11 myeloid leukemia cell lines quantified by quantitative real-time PCR (qRT-PCR).Since the miR-106a-363 cluster is associated with high risk AML, we hypothesized that increased levels of the entire cluster as well as individual members would significantly shorten the survival time in a murine transplantation model mimicking aggressive AML. Therefore, we engineered transplantable, primary murine AML cell lines based on retroviral overexpression of Hoxa9 and Meis1 exhibiting a median disease latency of 39 days (n=14) after syngeneic transplantation in mice. Enforced lentiviral expression of miR-106a-363 (n=13, p<0.0001), miR-106a (n=15, p=0.0003), miR-18b (n=8, p<0.0001), miR-20b (n=13, p<0.0001) and miR-363 (n=13, p<0.0001) in Hoxa9/Meis1 cells significantly accelerated leukemogenesis compared to the control arm. The most pronounced anemia (p=0.03) and the most immature phenotype, based on a significantly higher proportion of c-kit+ (p=0.0147) and a concurrent lower percentage of Mac-1+ and Gr-1+ (p=0.0051) cells, were observed in mice transplanted with Hoxa9/Meis1/miR-106a cells.Based on these results, we focused on the mechanism by which miR-106a contributed to the pathogenesis of AML and performed a proteomics screen comparing Hoxa9/Meis1/miR-106a and Hoxa9/Meis1/control cells. In particular, mitochondrial respiration processes, such as oxidative phosphorylation and electron transport chain components were induced by miR-106a as shown by Gene Set Enrichment Analysis. Preliminary results using high-resolution respirometry further indicated an increased number of mitochondria in Hoxa9/Meis1/miR-106a cells, supporting these findings.In conclusion, we highlight the previously unrecognized oncogenic contribution of the miR-106a-363 polycistron in adult AML. Functional dissection of this cluster, in particular miR-106a, revealed a new therapeutic angle for high risk AML. DisclosuresDöhner:Astellas: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Celator: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Agios: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Molecular Profiling of High-Risk Pediatric Acute Myeloid Leukemia

Background: Several landmark genomic profiling studies have dramatically advanced our understanding of the origin, progression and clonal evolution of adult acute myeloid leukemia (AML) and directly impacted clinical care. However, very little is known about the mutational landscape of pediatric AML, a distinct entity that shares few genetic and clinical characteristics with adult AML. To investigate potential drivers of high-risk pediatric AML, comprehensive genomic profiling was performed on high-risk AML samples as part of a prospective clinical next-generation sequencing program.Methods:Samples obtained from patients with known high-risk features at diagnosis or with refractory or relapsed AML were selected for molecular profiling. Comprehensive testing included whole-exome sequencing (WES) of matched tumor (bone marrow or chloroma tissue) and normal tissue (peripheral blood or buccal swab) samples and transcriptome analysis (RNAseq). Targeted sequencing of 467 cancer-associated genes was used when tumor tissue was limited. Sequencing was performed on Illumina's HiSeq 2500 with 150X and 500X average coverage for WES and targeted sequencing, respectively. Variants were filtered to select alterations in cancer-related genes or genes relevant for patient care.Results:Fifteen patients with AML (mean age 7.7 yrs; range 0.75-19 yrs) met high-risk criteria (high-risk features at diagnosis = 4, relapsed disease = 8, refractory disease = 3) and were selected for profiling. WES and RNAseq were performed on 11 samples, WES only on 3 samples and targeted DNA sequencing on 1 sample. The median number of variants was 60 (range 14- 5950) per case. After filtering, 54 mutations were identified in 35 genes with a mean of 3.6 mutated genes per patient sample (range 0-14); two samples only carried a fusion gene with no other genetic alterations. At least one driver genetic alteration was detected in each patient sample. Thirteen samples carried mutations in at least one gene known to be altered in AML (e.g. IDH1, WT1, TP53, NRAS) (mean, 2; range, 1-6) and 5 samples carried novel mutations in 15 genes not previously implicated in AML (e.g. CARD9, CHD9, Axin1). Mutations in 11 AML related genes were detected in more than one sample including NRAS in 4, TP53 in 3 and KRAS, PTPN11 PHF6, JAK3 in 2 samples each; genes not previously implicated in AML were only mutated in single patients. Of note, mutations in genes encoding members of the RAS pathway occurred in 60% of cases (9/15 samples). RNAseq identified gene fusions in 7/11 samples (63%). Four fusions involving KMT2A and core binding factor genes were also detected by FISH while three fusions were detected by RNAseq only: NUP98-NSD1 in two patients and CBFA2T3-GLIS2 in one patient. Samples carrying driver gene fusions had the lowest number of mutated genes (0-1) compared to samples lacking a gene fusion (1-5 mutated genes), with one exception of a patient with history of infant ALL who later developed KMT2A-AFF1AML with the highest number of mutated genes (n=14). There was no correlation between the number of mutated genes and age, clinical characteristics, initial risk classification at diagnosis or intensity of therapy prior to sequencing.Conclusion:Our study provides an initial overview of the genetic alterations that characterize high-risk, chemo-resistant pediatric AML. Analysis of the data highlights the overall low genetic complexity of high-risk AML despite the aggressive clinical behavior and exposure to intense chemotherapy, including stem cell transplant. Of interest, similar to adult AML, we found that mutations leading to aberrant activation of the RAS pathway were also very frequent in our cohort of pediatric high-risk AML, while genes typically mutated early in the process of leukemogenesis in adult AML, such as NPM1, DNMT3A, FLT3, IDH1, IDH2 were not affected. Such findings suggest that distinct, age-specific mechanisms of leukemogenesis might exist. Furthermore, our data also highlights the important role of RNA sequencing in complementing current standard diagnostic tools, allowing the identification of driver fusion genes in samples for which no other driver event is detected. Larger studies, preferably including diagnostic samples and utilizing broader approaches, are needed to better understand the mechanisms responsible for the initiation and progression of childhood AML. DisclosuresNo relevant conflicts of interest to declare.

Feasibility of Allogeneic Hematopoietic Cell Transplantation Among High-Risk AML Patients in First Complete Remission: Results of the Transplant Objective from the SWOG (S1203) Randomized Phase III Study of Induction Therapy Using Standard 7+3 Therapy or Idarubicin with High-Dose Cytarabine (IA) Versus IA Plus Vorinostat

Background: Adult acute myeloid leukemia (AML) patients with high-risk cytogenetics have a significantly worse survival compared to similarly treated intermediate- or favorable-risk patients. Although prior studies suggest better outcome in high-risk AML patients in first complete remission (CR1) who undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy, only 40% of patients proceed to HCT. The lack of a matched sibling donor (available in about 33%) should not be a barrier to HCT since alternative donors are available for the large majority of high-risk AMLpatients and recent data suggest outcomes after allogeneic HCT from fully matched unrelated donors are similar to those following matched related donor transplantation. We sought to determine if a prospective organized effort could rapidly identify alternative donors to improve the historical 40% allogeneic HCT rate in high-risk CR1 AML patients ≤ age 61. Secondly, we hypothesized that transplanting significantly more adults with high-risk AML in CR1 would lead to an improved outcome compared with the historical relapse-free survival (RFS) of 22%. Patients and Methods: Adult patients between ages 18 and 60 years with untreated AML were randomized to receive induction therapy with standard cytarabine plus daunorubicin (7+3; n=261), idarubicin with high-dose cytarabine (IA; n=261), or IA with vorinostat (IA+V; n=216). Conventional cytogenetics were obtained at time of enrollment and used to determine risk classification by standard criteria. All patients with high-risk cytogenetics underwent expedited HLA-typing. High-risk patientswere encouraged tobe referred for consultation with a transplant team with the goal of conducting an allogeneic HCT in CR1. Results: Of 738 eligible patients (median age, 49 years; range, 18-60), 159 (22%) had high-risk cytogenetics, of whom 60 (38%), 61 (38%), and 38 (24%) received induction with 7+3, IA, or IA+V, respectively. A total of 107 of the 159 high-risk patients achieved CR/CRi (67%). HCT was performed in 317 of all 738 patients (43%) and 68 (64%) of the high-risk patients received a transplant in CR1 (p Conclusions: In newly diagnosed adults with AML age 18-60, early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donorled to a CR1 transplant rate of 64% in the high-risk group, which in turn led to a significant improvement in RFS over historical controls. Better outcomes in poor prognosis AML patients may be achieved simply by rapidly finding unrelated donors and performing allogeneic HCT in CR1 as soon as possible. Clinical Trials Registry: NCT #0180233; Support: NIH/NCI grants: CA180888, CA180819, CA18020, CA180821, CA180863, CA077202; CCSRI #021039 Disclosures Othus:Glycomimetics: Consultancy; Celgene: Consultancy. Radich:Novartis: Consultancy, Other: laboratory contract; ARIAD: Consultancy; Pfizer: Consultancy; TwinStrand: Consultancy; Bristol-MyersSquibb: Consultancy. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Savoie:AbbVie: Consultancy; Lundbeck: Consultancy; BMS: Consultancy, Honoraria; Velgene: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Jazz: Consultancy. Sekeres:Millenium/Takeda: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees. Stone:Amgen: Consultancy; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Xenetic Biosciences: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Agios: Consultancy; Novartis: Consultancy; Celator: Consultancy; Karyopharm: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Celator: Research Funding; Ariad: Consultancy; Agios: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Gylcomimetics: Other: DSMB; Sunesis: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Research Funding.

Fractionated Gemtuzumab Ozogamicin Combined with Intermediate-Dose Cytarabine and Daunorubicin As Salvage Therapy in Very High Risk AML Patients: A Bridge to Reduced Intensity Conditioning Transplant?

Introduction: Despite recent improvements in the treatment of adult acute myeloid leukemia (AML), many patients still fail to achieve complete remission (CR) or relapse early after response to initial induction chemotherapy. Outcome of patients with primary refractory/relapsed (R/R) acute myeloid leukemia (AML) remains dismal. Nevertheless, most of these patients undergo salvage chemotherapy. Gemtuzumab ozogamicin (GO) is an antibody-targeted chemotherapy agent consisting of a humanized murine anti-CD33 monoclonal antibody linked to calicheamicinϒ1, a potent antitumor antibiotic. Binding of GO induces cell death in CD33-positive cells by internalization of the calicheamicin drug and toxin release intracellulary leading then to then cleavage of double-stranded DNA. In relapsed AML, GO used alone with an unfractionated dose of 9 mg/m² on days 1 and 14 resulted in 13% of CR and a median OS of 5 months. Combined with intermediate-dose cytarabine and mitoxantrone, unfractionated dose of GO gave 50% of CR in patients with R/R AML, and a 2-year OS of 41%. However, early toxic deaths were reported related to sinusoidal obstruction syndrome (SOS). These results were confirmed by subsequent studies evaluating unfractionated GO combined with various agents in patients with R/R AML. The main objective of the present retrospective study was to evaluate the efficacy of the combination of fractionated GO with intermediate-dose cytarabine and daunorubicin in very high-risk patients with AML, and its potential use as bridge to transplant in this patient population.Methods: Herein we present a retrospective monocentric study of 24 very high-risk AML patients who received a combination of fractionated gemtuzumab ozogamicin (GO) with intermediate-dose cytarabine and daunorubicin as salvage therapy.Results: Median age was 55.3 years. Diagnoses were secondary AML for 33% of them. Seven patients had favorable, 8 had intermediate-1 or intermediate-2 and 6 unfavorable-risk AML according to the European LeukemiaNet prognostic index. Complete remission rate was achievied in 50% of cases (46% in refractory and 55% in relapsed AML) without excessive toxicity. Only allogeneic hematopoietic stem cell transplantation provided a benefit in this patient cohort with a one-year overall survival of 50.7% versus 18.1% in the absence of transplantation. Patients treated with reduced intensity conditioning (RIC) showed a higher survival as compared to those undergoing myeloablative conditioning regimen. CD33 expression was not associated with survival. In multivariate analysis in a model including the age older than 60 years, allo-HSCT, refractory AML and achievement of CR after GO, only the performance of allo-HSCT predicts patients' outcome with a Hazard Ratio (HR) of 0.25 (95% CI 0.07-0.86), p=0.02.Conclusions: Our data suggest that salvage therapy with fractionated GO combined with intermediate-dose cytarabine and daunorubicin in very high-risk patients may serve as a potential bridge therapy to RIC transplant. Data from studies published after withdraw of GO from the market, of which our present study, suggest that the licence status of GO might be reviewed, at least for certain subtypes of patients and certain situations of which R/R AML patients. [Display omitted] [Display omitted] DisclosuresNicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles:Gilead: Honoraria, Research Funding; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Thomas:Pfizer: Consultancy.

Comparison of Allogeneic Hematopoietic Stem Cell Transplant from HLA-Matched Related Donors and from Unrelated Donors for Intermediate- to High-Risk Adult Acute Myeloid Leukemia in Remission

Introduction: Allogeneic hematopoietic stem cell transplant (allo-HSCT) is currently the most powerful method to treat intermediate- to high-risk acute myeloid leukemia (AML). Human leukocyte antigen (HLA) matched related donors (MRD) are considered the best donors in allo-HSCT, but they are only available for a small proportion of patients. With the progress of transplant skills over decades, outcome of unrelated donor (URD) HSCT has improved significantly, and the difference between MRD and URD HSCT has been steadily declining. But the role of URD HSCT has still not been well defined in AML, especially for different risk groups. We therefore compared the results of URD HSCT with MRD HSCT in adult AML patients with intermediate- to high-risk in our center.Methods: During January 2005 to December 2012, 108 adult patients with intermediate- or high-risk AML receiving allo-HSCT in complete remission (CR) in our center were admitted in this study. All patients received a standard-dose cytarabine with anthracycline or homoharringtonine as induction therapy. Consolidation courses include high-dose cytarabine or standard-dose cytarabine with anthracycline, homoharringtonine, or mitoxantrone. After consolidation, all patients received allo-HSCT in CR. High resolution DNA typing for HLA-A, -B, -C, -DRB1, and -DQB1 was performed during CR. Patients with HRD would receive HRD HSCT; while for those without HRD, URD with at least 8/10 locus match were selected as donor source. Among the 108 patients, 51 received grafts from HRD and 62 from URD. The conditioning regimen mainly involved BuCy without total body irradiation. All patients received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine A, methotrexate and low-dose mycophenolate mofetil. Rabbit antithymocyte globulin (Thymoglobulin, IMTIX-SangStat, Lyon, France) was also administered to some patients receiving URD HSCT (4.5–6 mg/kg total dose).Results: Most of the baseline characteristics were well balanced between two groups. However, The interval from diagnosis to transplantation differed significantly between two groups, with a median interval of 7 months for HRD group versus 10 months for URD group (P=0.008). Bone marrow was used as graft source in 100% and 80.7% of patients in HRD and URD groups, respectively. Another 19.3% of patients in URD group received peripheral blood stem cell as graft source. The median follow-up was 37.5 months in the whole cohort.The cumulative incidence of acute grade 2 to 4 GVHD was significantly higher in URD group compared with HRD group (40.3% vs. 13.8%, P=0.002). Chronic GVHD and extensive chronic GVHD were also significantly more frequent in URD group (chronic GVHD: 49.2% vs. 29.6%, P=0.037; extensive chronic GVHD: 22.0% vs. 3.7%, P=0.005). The treatment-related mortality (TRM) was significantly higher in the URD group (17.9% vs. 4.3%, P=0.015). While the overall survival (OS), relapse-free survival (RFS), and relapse rate were comparable between two groups (OS at 3 years: HRD 79.9% vs. URD 70.3%, P=0.146; RFS at 3 years: HRD 73.1% vs. URD 66.7%, P=0.239; relapse rate at 3 years: HRD 23.5% vs. URD 18.0%, P=0.643). Clinical characteristics were subjected into univariate and multivariate Cox analysis for OS to find prognostic factors. Cytogenetics, status at transplant (CR1 vs. CR2 to CR3), and MRD levels at transplant were identified as factors that were significantly associated with OS, whereas donor type had no significant impact.When the analysis was done in patients divided by risk stratification, we found that for intermediate-risk patients, the HRD group had a 3-year improved survival rate than URD group (RFS: 85.2% vs. 70.5%, P=0.043; OS: 85.2% vs. 72.7%, P=0.062) with a significantly reduced TRM rate (3.8% vs. 18%, P=0.025). The relapse rate were comparable between two groups (HRD 11.3% vs. URD 12.7%, P=0.649). While for high-risk patients, no differences were observed between two groups in terms of OS, RFS, TRM and relapse rate.Conclusions: For intermediate-risk AML patients, compared with URD HSCT, the results from HRD HSCT were better with improved survival rate and reduced TRM; while for high-risk AML patients, donor types had no effect on transplant outcome. Cytogenetics, status at transplant, and MRD levels at transplant were found to be independent prognostic factors for OS. DisclosuresNo relevant conflicts of interest to declare.

Wilms’ tumor protein and FLT3‐internal tandem duplication expression in patients with de novo acute myeloid leukemia

Bone marrow samples of 30 patients with de novo adult acute myeloid leukemia (AML) were analyzed for Wt1 and FLT3‐internal tandem duplication (FLT3‐ITD) expression measured by western blot and reverse transcription‐polymerase chain reaction analysis, respectively. Wt1 was detected in 53·3% of AML patients (16/30), while FLT3‐ITD in 23·3% (7/30). The high Wt1 expression correlated with the presence of FLT3‐ITD (P = 0·014) and lower rate of complete remission (P = 0·023). The cumulative survival in AML patients was affected significantly by the presence of FLT3‐ITD, being lower in the FLT3‐ITD (+) group (6·0±2·4 months) compared to the FLT3‐ITD (−) patients (17·9±3·3; P = 0·04). The expression of FLT3‐ITD could probably activate Wt1 expression in AML blast cells and thus might contribute to its oncogenic function to provide cells with survival advantages in vivo. The detection of both molecular markers (Wt1 and/or FLT3‐ITD) may be helpful in defining high risk AML patients that need special therapeutic strategies.

Haplotype mismatched transplantation using high doses of peripheral blood CD34+ cells together with stratified conditioning regimens for high-risk adult acute myeloid leukemia patients: a pilot study in a single Korean institution

A total of 11 high-risk Korean acute myeloid leukemia (AML) patients received stem cell transplantation from human leukocyte antigen (HLA) haploidentical donors. Specifically, for eight patients with 2-3 mismatched antigens and bidirectional vectors, we used a newly designed conditioning regimen that consists of total body irradiation, busulfex, ATG, and fludarabine. The median number of CD34+ cells infused was 15.4 x 10(6)/kg (range, 8-21.2). These patients received neither graft-versus-host disease (GvHD) prophylaxis nor post transplantation G-CSF. All of the patients who were followed up for a median of 6 months (range, 17 days-28 months) showed stable primary engraftment and had no acute GvHD or transplant-related mortality for 100 days post transplant. Three patients with high-risk or refractory disease eventually died in relapse, even with GvH-directed NK alloreactivity. However, the patients in complete remission (CR), with the exception of one patient who is alive at 18 months EFS, died at 4, 6, and 8 months post transplantation due to infections that were associated with delayed immune recovery. Our findings suggest that haploidentical transplantation represents a feasible treatment for patients with high-risk AML in CR, provided that a plan for the enhancement of immune recovery is implemented.