scholarly journals Prognostic Impact of FLT3-ITD and DNMT3A R882 Double Mutations in Patients with Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5244-5244
Author(s):  
Shanhao Tang ◽  
Xiaowen Tang ◽  
Hongjie Shen ◽  
Shengli Xue ◽  
Tingjing Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Clinical Characteristics ◽  
Genetic Mutation ◽  
Prognostic Impact ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Double Mutation ◽  
Acute Myeloid

Abstract Background: FLT3-ITD and DNMT3A R882 mutations are both independent factors for poor prognosis of acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been confirmed to improve the outcome of AML with either of gene mutations. However, the clinical characteristics of AML with both of FLT3-ITD and DNMT3A R882 mutations and their outcome post allo-HSCT had been rarely evaluated. Objective: To investigate the clinical characteristics and transplantation outcomes of AML patients with the double mutations. Methods: A total of 241 patients were included in this retrospective analysis. Molecular genetic mutation sets in bone marrow (including FLT3-ITD, DNMT3A, C-kit, CEBPA, FLT3-TKD, and NMP1) of 241 AML patients were detected at diagnosis using direct sequencing method. And the clinical data of these patients were analyzed retrospectively. Results: (1)According to the genetic mutation types, the 241 AML patients were divided into four groups: FLT3-ITD+DNMT3A R882+, FLT3-ITD+DNMT3A R882-, FLT3-ITD-DNMT3A R882+ and FLT3-ITD-DNMT3A R882- groups, which consisted of 19, 38, 21 and 163 patients, respectively. (2) Patients with FLT3-ITD+DNMT3A R882+ have high white blood cell count and a low complete remission rate after first induction chemotherapy (52.6%), which are common in M5、M2、M4 with normal chromosome karyotype, higher early cumulative incidence of relapse(6m-CIR 36.8±1.3%、12m-CIR 49.7±1.6%) and cumulative mortality rate (6m-CMR 26.3±10.1%、12m-CMR 48.5±11.8%) . (3) 2-year CIR of the FLT3-ITD+DNMT3A R882+ was (72.2±2.7%), which was significantly higher than that of the FLT3-ITD+DNMT3A R882- group (38.6±0.7%) and FLT3-ITD-DNMT3A R882+ group (36.8±1.6%). While the 2-year overall survival (OS) rate and 2-year leukemia-free survival (LFS) rate of double mutation group were (30.9±13.3% ) and (11.3±10.2%), respectively, which were considerably lower than those of the FLT3-ITD+DNMT3A R882- and FLT3-ITD-DNMT3A R882+ groups (2y-OS: 67.5±7.8%, 61.4±12.4%: 2y-LFS: 47.9±8.4%, 56.8±12.5%). Meanwhile, the 2-year CIR rates of the FLT3-ITD+DNMT3A R882- and FLT3-ITD-DNMT3A R882+ groups were significantly higher than that of the FLT3-ITD-DNMT3A R882- group (16.3±0.1%), while their 2-year OS rate and 2-year LFS rate were significantly lower than those of the FLT3-ITD-DNMT3A R882- group (2y-OS: 82.5±3.1%、2y-LFS: 80.9±3.2%). (3) Univariate and multivariate analyses revealed that disease status prior to transplantation, grade III-IV aGVHD, FLT3-ITD, DNMT3A R882 and FLT3-ITD+DNMT3A R882+ were independent factors for poor prognosis post transplantation. Conclusion: AML patients with FLT3-ITD and DNMT3A R882 double mutations still present a very poor prognosis after transplantation with low OS and LFSas well as a high CIR rate. Therefore, it is necessary to explore prevention strategy for relapse post transplantation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Oral mucositis in patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation in relation to the conditioning used prior to transplantation

2021 ◽  
Author(s):  
Aleksandra Wysocka-Słowik ◽  
Lidia Gil ◽  
Zuzanna Ślebioda ◽  
Agnieszka Kręgielczak ◽  
Barbara Dorocka-Bobkowska
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Transplantation ◽  
Oral Mucositis ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Conditioning Regimen ◽  
World Health ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Acute Myeloid

AbstractThis study was designed to investigate the frequency and severity of oral mucositis in patients with acute myeloid leukemia after allogeneic hematopoietic cell transplantation, in relation to the type of conditioning used. Eighty patients diagnosed with acute myeloid leukemia were assigned to two groups based on the conditioning regimen used before transplantation. The intensity of oral inflammatory lesions induced by chemotherapy (oral mucositis) was evaluated according to a 5-point scale recommended by World Health Organization. Oral mucosa was investigated in all patients before the transplantation and during two subsequent stages of the post-transplantation procedure in relation to the conditioning regimen used. Mucositis in the oral cavity was observed in the majority of patients (66%) in the first week after transplantation, whereas the largest percentage of patients suffering oral lesions (74%) occurred in the second week after transplantation. A significantly higher percentage of patients with mucositis was observed in the group which underwent myeloablation therapy (74% of MAC and 50% of RIC patients in the first week; 83% of MAC and 53% of RIC patients in the second examination).The severity of mucositis after transplantation was higher in the MAC patients compared to the RIC patients. The highest mean value of the mucositis index was recorded in the second week in the MAC group (1.59). In AML sufferers receiving allo-HSCT, oral mucositis is a significant complication of the transplantation. This condition is more frequent and more severe in patients after treatment with myeloablation therapy.

scholarly journals Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 9 (2) ◽  
pp. e001818 ◽  
Author(s):  
Chantal Saberian ◽  
Noha Abdel-Wahab ◽  
Ala Abudayyeh ◽  
Hind Rafei ◽  
Jacinth Joseph ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Checkpoint Inhibitors ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

BackgroundImmune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.MethodsA retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.ResultsFour patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).ConclusionsICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

The Influence of Monosomal Karyotype On Survival in Patients with Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Survey On Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 158-158 ◽  
Author(s):  
Angelique V.M. Brands-Nijenhuis ◽  
Myriam Labopin ◽  
Harry C. Schouten ◽  
Liisa Volin ◽  
Gérard Socié ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Complex Karyotype ◽  
Hematopoietic Stem ◽  
Monosomal Karyotype ◽  
Acute Myeloid

Abstract Abstract 158 Introduction: Monosomal karyotype (MK) has been shown to be associated with a very poor prognosis in AML patients (Breems, 2008). Whether allogeneic hematopoietic stem cell transplantation (alloHSCT) performed in an early phase can overcome the adverse prognosis in this cytogenetic patient category is currently unknown. To address this issue we performed a retrospective analysis on data from the registry of the EBMT among patients with primary AML who underwent alloHSCT in CR1. Patients and methods: A total of 4119 patients with primary AML and known cytogenetic abnormalities at diagnosis that underwent alloHSCT in CR1 were included in the analysis. Survival curves were calculated with Kaplan-Meier method. Log rank test and Cox regression analysis were used to determine statistical significance. Results: Median follow-up was 24 months (range 2–374). Overall, 171 patients (4.2%) fulfilled criteria for MK and 297 patients (7.2%) for complex karyotype (CK), with 115 patients fulfilling both conditions (MK and CK). Both the presence of a MK (2-yr OS: 35.5% versus 63.2%, p<0.0001) and CK (2-yr OS: 48.8% versus 61.9%, p<0.0001) were associated with a poorer outcome when compared with the remaining cytogenetics subtypes. Given the significant overlap between both categories, we further analyzed their prognostic impact after defining four subgroups of patients: MK but not CK (56 patients; MK+CK-), no MK but CK (180 patients; MK-CK+), MK and CK (115 patients; MK+CK+), and patients without either MK or CK (MK-CK-). Outcome of the MK-CK- subgroup did not differ according to cytogenetics. Patients harboring a MK, regardless concomitant presence of a CK, presented with a poorer OS after alloHSCT (2-yr OS: 31.7–43.0% versus 61.1%, p<0.0001). On the contrary patients with a CK but not MK showed a similar outcome than MK-CK- (2-yr OS: 61.1% versus 63.3%, p=0.170). Moreover, multivariate analysis confirmed the independent negative impact of MK (HR:1.90, range 1.5–2.4; p<0.0001) together with age, interval diagnosis-transplant, AML subtype, WBC at diagnosis, T-cell depletion, number of induction cycles and use of TBI during conditioning, whereas the presence of a CK did not retain its negative prognostic value. Conclusion: These results indicate that MK is a better indicator for poor outcome than CK after alloHSCT in patients with primary AML in CR1. Nonetheless, the potential curative role of alloHSCT for a subset of patients with MK should be further investigated. Reference: DA Breems, WLJ van Putten, GE de Greef, SL van Zelderen-Bhola, KBJ Gerssen-Schoorl, CHM Mellink, A Nieuwint et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008;26(29):4791–7. Disclosures: No relevant conflicts of interest to declare.

Poor Prognosis With Different Induction Rate Was Observed In Children With Acute Myeloid Leukemia and FLT3-ITD According To The ITD/WT Allelic Ratio: A Result From The Japanese Pediatric Leukemia/Lymphoma Study Group

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3891-3891
Author(s):  
Akira Shimada ◽  
Yuka Yamashita ◽  
Daisuke Tomizawa ◽  
Akio Tawa ◽  
Tomoyuki Watanabe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Pediatric Leukemia ◽  
Hematopoietic Stem ◽  
Allelic Ratio ◽  
Induction Rate ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia harboring internal tandem duplication of fms-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis, but the previous studies have reported that the inferior outcome is only confined to those with high allelic ratio (AR) of ITD/wild type (WT). In our previous AML99 study (2000-2002), AMLFLT3-ITD showed a poor outcome compared to the WT cases (5-year OS; 35% vs. 84%, P<0.0001). We, therefore, assigned all the patients with AMLFLT3-ITD to receive hematopoietic stem cell transplantation (HSCT) in first remission (1CR) in the JPLSG AML-05 study. Patients & Methods AML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a Japanese nation-wide multi-institutional study for children (age<18 years) with de novo AML and enrolled 443 eligible patients from Nov. 2006 to Dec. 2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. FLT3-ITD was examined centrally for all the patients. After the 2 consecutive induction chemotherapies [(ECM: etoposide, Ara-C, and mitoxantrone) and (HCEI: HD Ara-C, etoposide, and idarubicin)], all the AMLFLT3-ITD patients were allocated to the high risk group and further received intensification therapy including HD Ara-C followed by HSCT in 1CR. All DNA samples were extracted from the first diagnostic bone marrow or peripheral blood and subjected to PCR and direct sequencing. AR of FLT3-ITD/WT was examined by GeneScan, and defined AR >0.4 as high and AR ≤ 0.4 as low as previously reported (Meshinchi S. Blood2006). Results We found 47 patients (10.6%) with AMLFLT3-ITD in this study (30 males, 17 females, and median age of 11 years at diagnosis). The median WBC count was 65,300/ml (3,690 - 522,050/mL). FAB classification included M1 (n=10), M2 (n=9), M4 (n=9), and M5 (n=11), and AML with normal karyotype was dominant (19/47, 40.4%). Of the 29 patients (61.7%) who achieved CR, twenty-seven received HSCT in 1CR and 19 patients survived (19/27, 70.4%). On the other hand, 14/16 non-CR patients received HSCT, but only 4 survived. The only demographic difference between the 29 CR and 16 non-CR cases was the median WBC count at diagnosis (19,000 vs. 124,000/μL, P<0.001), and rapid clearance of bone marrow blasts after single induction course was observed in the CR group (median blast percentage dropped from 73% to 1.1% in the CR group, while that was 85% to 30.6% in the non-CR group). Finally, five-year OS, DFS and EFS for all 47 AMLFLT3-ITD patients were 41.3%, 58.4% and 36.1%, respectively. AR was analyzed in 44 patients with median ratio of 0.68 (range, 0.11 to 4.47). Median AR was not different between CR vs. non-CR cases (0.53 vs. 0.72). There were no difference in 5-year OS (52.8% vs. 42.5%, P=0.302), DFS (54.5% vs. 64.5%, P=0.524), and EFS (50.0% vs. 34.4%, P=0.283) between patients with low (n=12) and high AR (n=32), however, induction rate was significantly higher in the low AR patients (91.7% vs. 53.1%, P=0.018). It was rather surprising that all FLT3-ITDs were found only in JM domain and not in TKI domain in the current trial. In addition, six of 47 (12.8%) AMLFLT3-ITD patients had NPM1mutation simultaneously, and all received HSCT at 1CR and survived. Discussion and Conclusion We observed a different induction rate between AMLFLT3-ITD patients with low and high AR, but poor final outcomes in both. Regardless of the level of AR, patients with AMLFLT3-ITD, especially who fail to achieve remission, have dismal outcome and effective therapy combined with novel FLT3 inhibitor is urgently needed to overcome the disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeted Treatment of FLT3 -Overexpressing Acute Myeloid Leukemia with MiR-150 Nanoparticles Guided By Conjugated FLT3 Ligand Peptides

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3784-3784
Author(s):  
Xi Jiang ◽  
Jason Bugno ◽  
Chao Hu ◽  
Yang Yang ◽  
Tobias Herold ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Impact ◽  
Dependent Manner ◽  
Flt3 Ligand ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematopoietic malignancies. With standard chemotherapies, only 30-50% of younger (aged <60) and 5-10% of older patients with AML survive longer than 5 years. Aberrancy of FMS-like tyrosine kinase 3 (FLT3) occurs in the majority cases of AML. Two major classes of constitutively activating mutations of FLT3, i.e. internal-tandem duplications (ITDs) and tyrosine kinase domain (TKD) point mutations are found in more than 30% of AML cases and usually predict poor prognosis. Overexpression of FLT3 has also been reported in more than 70% of AML cases with a variety of AML subtypes, e.g. MLL (Mixed Lineage Leukemia)-rearranged or FLT3 -ITD AML, and may be associated with poor survival in AML patients. Given the disappointing results with FLT3 tyrosine kinase inhibitors (TKIs) in clinical trials in the past decade, decreasing the overall abundance of FLT3 at the RNA and protein levels would be an alternative strategy to treat AMLs with FLT3 overexpression and/or FLT3 -ITD/TKD mutations. MicroRNAs (miRNA) are a class of small, non-coding RNAs that play important roles in post-transcriptional gene regulation. We recently reported that miR-150 functions as a pivotal tumor-suppressor gatekeeper in MLL-rearranged and other subtypes of AML, through targeting FLT3 and MYB directly, and the MYC/LIN28/HOXA9/MEIS1 pathway indirectly. Our data showed that MLL-fusion proteins up-regulate FLT3 level through inhibiting the maturation of miR-150. Therefore, our findings strongly suggest a significant clinical potential of restoration of miR-150 expression/function in treating FLT3 -overexpressing AML. In the present study, we first analyzed FLT3 expression patterns and prognostic impact in a large cohort of AML patients (n=562). We found that FLT3 is aberrantly highly expressed in FAB M1/M2/M5 AML or AML with t(11q23)/MLL -rearrangements, FLT3 -ITD or NPM1 mutations, and that increased expression of FLT3 is an independent predictor of poor prognosis in patients with FLT3 -overexpressing AML. To treat FLT3 -overexpressing AML, we developed a novel targeted nanoparticle system consisting of FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) dendriplexes encapsulating miR-150 oligos (see Figure 1A). In FLT3 -overexpressing cell lines, the uptake ratios of the G7-FLT3L dendrimers were much higher (50.3~97.1%) than the G7-histone 2B (H2B) control nanoparticles (4.3~33.2%). And the uptake only took minutes. By integrating the miR-150 oligo with G7-FLT3L dendrimers, we constructed the G7-FLT3L-miR-150 dendriplexes, which significantly reduced the viability and increased the apoptosis of MONOMAC-6 cells carrying t(9;11) in a dose-dependent manner. To increase the stability of miR-150 oligos, we incorporated a 2'-o -methyl (2'-O Me) modification into the miRNA oligos. Indeed, the G7-FLT3L nanoparticles carrying 2'-O Me modified miR-150 exhibited a more sustained inhibition on cell growth. In order to further investigate the in vivo therapeutic effects of the miR-150 nanoparticles, we used a MLL -rearranged leukemia model. We transplanted wild-type recipient mice with primary mouse leukemic cells bearing the MLL-AF9 fusion. After the onset of leukemia, the mice were treated with G7-Flt3L or G7-NH2 control nanoparticles complexed with 2'-O Me-modified miR-150 oligos. In these treated animals, G7-Flt3L-miR-150 nanoparticles tended to be enriched in the bone marrow. The G7-Flt3L-miR-150 nanoparticles showed the best therapeutic effect (with median survival of 86 days), as compared with the control group (Ctrl; PBS treated; with median survival of 54 days) or the G7-NH2-miR-150 treated group (with median survival of 63 days). Nanoparticles carrying miR-150 mutant oligos showed no anti-leukemia effect at all. Notably, the G7-Flt3L-miR-150 treatment almost completely blocked MLL-AF9 -induced leukemia in 20% of the mice (Fig. 1B). Furthermore, the G7-Flt3L-miR-150 nanoparticles showed a synergistic effect with JQ1, a small-molecule inhibitor of the MYC pathway, in treating AML in vivo (Fig. 1C). Collectively, we have developed a novel targeted therapeutic strategy to treat FLT3-overexpressing AML, such as MLL-rearranged leukemias, which are resistant to currently available therapies, with both high specificity and efficacy. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document