scholarly journals Harnessing Macrophages through the Blockage of CD47: Implications for Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6258
Author(s):  
Luciana Melo Garcia ◽  
Frédéric Barabé
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Surface Membrane ◽  
Regulatory Protein ◽  
Immune Surveillance ◽  
Poor Overall Survival ◽  
Phagocytic Capacity ◽  
Hematopoietic Stem ◽  
Acute Myeloid

CD47 is a surface membrane protein expressed by all normal tissues. It is the so-called “don’t eat me signal” because it protects the cells against phagocytosis. The CD47 interacts with the signal regulatory protein alpha (SIRPα) on the surface of macrophages, leading to downstream inhibitory signaling that dampens phagocytic capacity. Since macrophages exert immune surveillance against cancers, cancer cells overexpress CD47 to defend themselves against phagocytosis. Acute myeloid leukemia (AML) is a cancer of hematopoietic stem/progenitor cells (HSPC), and similar to other types of cancers, leukemic blasts show enhanced levels of CD47. In patients with AML, CD47 has been associated with a higher disease burden and poor overall survival. Blockage of CD47-SIRPα signaling leads to improved phagocytosis of AML cells and better overall survival in xenograft models. However, the introduction of a pro-phagocytic signal is needed to induce greater phagocytic capacity. These pro-phagocytic signals can be either Fc receptor stimulants (such as monoclonal antibodies) or natural pro-phagocytic molecules (such as calreticulin). Based on these pre-clinical findings, various clinical trials investigating the blockade of CD47-SIRPα interaction have been designed as monotherapy and in combination with other anti-leukemic agents. In this review, we will discuss CD47 biology, highlight its implications for AML pathophysiology, and explore the potential clinical translation of disrupting CD47-SIRPα to treat patients with AML.

Mitoxantrone, Etoposide, and Intermediate-Dose Cytarabine in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia : Single-Center Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4007-4007
Author(s):  
Hwa Jung Sung ◽  
Eui Bae Kim ◽  
Se Ryeon Lee ◽  
Hee Yun Seo ◽  
Kyong Hwa Park ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Salvage Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Relapsed Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract Background: The results of salvage chemotherapy for patient with refractory or relapsed acute myeloid leukemia(AML) have been generally disappointing with low response rates and occasional long-term survivors in most studies. Since therapeutic failure seems to be inevitable in the great majority of these patients, development of more effective salvage therapy is warranted. Recent approaches to the treatment of previously treated AML generally involved the use of cytarabine in intermediate or high-dose alone or in association with new intercalating agents, such as amsacrine, mitoxantrone or idarubicin, etoposide, or asparaginase. Methods: A single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for 1 hour, and cytarabine (Ara-C) 1g/m2 IV for 6 hours daily for 6 days (MEC), has been proposed as a salvage regimen. Between October 1998 and May 2005, thirty refractory/relapsed AML patients have been treated by MEC salvage chemotherapy. Twenty two patients were in relapse and eight patients were refractory after conventional induction chemotherapy including cytarabine and idarubicin or mitoxantrone. Two patient were in relapse after allogenous hematopoietic stem cell transplantation(SCT). Results: Complete remission(CR) was obtained in 12 of 30 patients(40%) and 3 of 30(10%) died during salvage treatment: 2 due to intracranial hemorrhage and 1 due to fungemia sepsis. After CR achievement, 5 patients received consolidation chemotherapy. Two patients with an HLA-identical sibling donor underwent allogeneic SCT, and one patient received autologous SCT. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 90% of patients. Nonhematologic toxicity was minimal. At the time of analysis, 9 of 11 patients who achieved CR have relapsed. Median disease-free survival was 12 months. Median overall survival was 13.5 months. There were only two longterm remitters. Several clinicolaboratory and treatment-related variables were analyzed to determine their prognostic significance for CR achievement, duration of CR, overall survival. Conclusions: Our results suggest that MEC combination chemotherapy might induce CR in a patient with refractory or relapsed AML, although new agents or new therapeutic strategies should be required for long term remission.

Hematopoietic Stem Cell Transplantation (HSCT) Benefits the Survival of Acute Myeloid Leukemia (AML) Patients with IDH1, NRAS and DNMT3A Mutations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1981-1981
Author(s):  
Yang Xu ◽  
Zhen Yang ◽  
Hong Tian ◽  
Huiying Qiu ◽  
Aining Sun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Newly Diagnosed ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 1981 Background: Gene mutations may serve as potential markers to extend the prognostic parameters in acute myeloid leukemia (AML) patients. In this study, we detected distribution of mutations in the nucleophosmin gene (NPM1), C-KIT, the fms-related tyrosine kinase 3 gene (FLT3), Isocitrate dehydrogenase gene 1 and 2 (IDH1, IDH2), the neuroblastoma RAS viral oncogene homolog (NRAS) and DNA methyltransferase 3A gene (DNMT3A) in 442 newly diagnosed AML patients (none-APL). Associations of gene mutations with clinical outcomes in these patients followed HSCT treatment or chemotherapy were further evaluated. Methods: Between February 2005 and December 2011, 442 newly diagnosed AML (none-APL) patients in our centre were retrospectively analyzed. There are 248 males and 194 females, and the median ages were 40 (16–60) years. 393 patients (88.9%) of patients were with single or normal karyotype and 49 patients (11.1%) were with complex abnormal karyotype. In addition to MICM examination, direct sequencing was employed to access the distribution of mutations in of FLT3-ITD (exon14), FLT3-TKD (exon 20), NPM1 (exon12), C-KIT (exon8, 17), IDH2 (exon 4), NRAS (exon1, 2), DNMT3A (exon23) of 445 AML patients. Complete remission (CR) was achieved in 258 patients (58.4%) followed the standard induction therapy, 128 patients received HSCT (Allo-HSCT: 121 vs. Auto-HSCT: 7) therapy after first remission or second remission while 258 patients received consolidation chemotherapy contained 4–6 cycles high dose Ara-C (HD-Ara-C). Overall survival (OS) and Event-free survival (EFS) were measured at last follow-up (censored), and Kaplan-Meier analysis was used to calculate the distribution of OS and EFS. Results: In 442 AML (None-APL) patients, 44 patients (9.7%) had C-KIT mutations, 97 patients (21.9%) had NPM1 mutations, 95 patients (21.5%) had FLT3-ITD mutations, 26 patients (5.9%) had FLT3-TKD mutations, 23 patients (5.2%) had IDH1 mutations, 48 patients (10.9%) had IDH2 mutations, 31 patients (7.0%) had DNMT3A mutations, and 40 patients (9.0%) had NRAS mutations. Using COX regression, we found that mutations in FLT3-ITD (HR:2.113; 95%CI: 1.1420 to 3.144),IDH1 (HR:3.023; 95%CI: 1.055 to 3.879), NRAS (HR:1.881; 95%CI: 1.021 to 2.945), and DNMT3A (HR: 2.394; 95%CI: 1.328 to 4.315) were independent unfavorable prognostic indicators of overall survival of AML patients. We further compared the outcomes of AML patients with such gene mutations followed different therapy (HSCT vs. HD Ara-C), and results shown that patients with mutations in IDH1, NRAS and DNMT3A received HSCT therapy had better survival. The median OS and EFS of patients with FLT3-ITD, IDH1, NRAS and DNMT3A in the two groups (HSCT vs. HD Ara-C) were as follows: IDH1 (OS: 35 months vs. 11 months, p=0.016; EFS: 34 months vs. 8 months, p=0.012), NRAS (OS: 27months vs. 8 months, p=0.008; EFS: 23 months vs. 4 months, p=0.049), DNMT3A (OS: 66 months vs. 19 months, p=0.008; EFS: 54 months vs. 13 months, p=0.002). Conclusions: Taken together, our data proved that mutant FLT3-ITD, IDH1, NRAS, and DNMT3A might serve as poor prognostic markers and hematopoietic stem cell transplantation as first-line treatment could favor the outcome of AML patients carrying IDH1, NRAS, and DNMT3A mutations. Disclosures: No relevant conflicts of interest to declare.

MIRROS: An ongoing randomized phase 3 trial of idasanutlin + ARA-C in patients with relapsed or refractory acute myeloid leukemia.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7063-TPS7063 ◽  
Author(s):  
Pau Montesinos ◽  
Jordi Esteve ◽  
Marina Konopleva ◽  
Giovanni Martinelli ◽  
Oliver Ottmann ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
Randomized Study ◽  
Data Monitoring Committee ◽  
Development Program ◽  
Phase 3 ◽  
Hematopoietic Stem ◽  
Acute Myeloid

TPS7063 Background: The prognosis for patients (pts) with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with 3-year overall survival rates ~10–30% after intensive chemotherapy-based approaches. Despite the advent of targeted therapies, considerable unmet medical need remains in this population. Idasanutlin (RG7388; RO5503781) is an orally available small molecule that binds to the murine double minute 2 (MDM2) protein and blocks MDM2 interaction with p53. This stabilizes and activates p53 and facilitates cell cycle arrest and apoptosis, preventing tumor growth. A phase 1b study of idasanutlin + ARA-C in pts with R/R AML, irrespective of TP53 mutation status (NCT01773408), has shown a composite complete remission (CR) rate (CR plus CR with incomplete platelet or hematologic recovery) of 29% (Martinelli et al. 2016). Methods: MIRROS (NCT02545283; WO29519) is an international, phase 3, double-blind, randomized study comparing idasanutlin (300 mg bid) + ARA-C (1 g/m2 qd) days 1–5 versus placebo + ARA-C in 440 pts with first or second R/R AML, with or without TP53 mutation. The primary endpoint is overall survival in pts with wild-type (WT) TP53. Secondary endpoints include CR, overall remission rates, event-free survival (EFS) and percentages of pts undergoing hematopoietic stem cell transplantation. MIRROS integrates phase 2 trial methodology into the phase 3 design by incorporating an interim analysis (IA) in 120 pts with WT TP53, using a high bar on the odds ratio for durable CR and EFS to assess for futility. Stop/go gating criteria for safety were also implemented. The IA was performed by an independent data monitoring committee and study continuation criteria were successfully met in mid-2017. This innovative strategy has allowed acceleration of the idasanutlin development program while maintaining a robust trial design. As of December 31 2018, 351 pts had been enrolled. The MIRROS study is ongoing and its results will inform the potential role of idasanutlin and MDM2 inhibition in the treatment of R/R AML. Clinical trial information: NCT02545283; WO29519.

scholarly journals SMPDL3B Predicts Poor Prognosis and Contributes to Development of Acute Myeloid Leukemia

2021 ◽  
Vol 8 ◽  
Author(s):  
Huiqing Qu ◽  
Ye Zhu
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Human Cancer ◽  
Negative Regulator ◽  
Poor Overall Survival ◽  
Clinicopathologic Characteristics ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML), characterized by the low cure rate and high relapse, urgently needs novel diagnostic or prognostic biomarkers and potential therapeutic targets. Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) is a negative regulator of Toll-like receptor signaling that plays important roles in the interface of membrane biology and innate immunity. However, the potential role of SMPDL3B in human cancer, especially in AML, is still unknown.Methods: The expression of SMPDL3B in AML samples was investigated through data collected from Gene Expression Omnibus (GEO). Association between SMPDL3B expression and clinicopathologic characteristics was analyzed with the chi-square test. Survival curves were calculated by the Kaplan–Meier method. Cox univariate and multivariate analyses were used to detect risk factors for overall survival. The biological functions of SMPDL3B in human AML were investigated both in vitro and in vivo.Results: Expression of SMPDL3B mRNA was significantly upregulated in human AML samples and closely correlated to cytogenetics risk and karyotypes. Elevated expression of SMPDL3B was associated with poor overall survival and emerged as an independent predictor for poor overall survival in human AML. Blocked SMPDL3B expression inhibited AML cells growth both in vitro and in vivo via promoting cell apoptosis.Conclusion: Taken together, our results demonstrate that SMPDL3B could be used as an efficient prognostic biomarker and represent a potential therapeutic target for human AML.

Allogeneic hematopoietic stem cell transplantation to improve survival in acute myeloid leukemia patients with FLT3 internal tandem duplication.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e17014-e17014
Author(s):  
Po-Han Lin ◽  
Hwai-I Yang ◽  
Li-Yuan Bai ◽  
Su-Peng Yeh ◽  
Chang-Fang Chiu
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Internal Tandem Duplication ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Fab Classification ◽  
Acute Myeloid

e17014 Background: Fms-like tyrosine kinase (FLT3) gene with internal tandem duplication (ITD) is a poor prognostic factor in patients with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is considered as an effective treatment for AML patients with poor risk. However, the efficacy of allogenic HSCT in the treatment of AML patients with FLT3-ITD was not clear. Methods: A total of 122 patients, who were newly diagnosed as de novo AML and received intensive chemotherapy at China Medical University Hospital between 2003 January and 2010 December, were retrospectively analyzed. At diagnosis, all patients received French-American-British (FAB) classification, cytogenetic analyses and immunophenotyping. The HSCT was performed on the basis of the consensus of the hematologists in this institute, mainly according to the two factors: unfavorable karyotype and suitable donor availability. The FLT3-ITD was detected by polymerase chain reaction and confirmed by direct sequencing. The Cox proportional hazards regression analysis was used to estimate the hazards ratios of the overall survival and corresponding 95% confidence interval (CI) for various combinations of FLT3-ITD and HSCT status. Results: An FLT3-ITD was detected in 34 patients (27.9%). The allogeneic HSCT was performed in 39 patients; 29 patients with wild type (wt)-FLT3 and 10 patients with FLT3-ITD. The number of death/number of patients (medium overall survival) of wt-FLT3/HSCT(+), wt-FLT3/HSCT(-), FLT3-ITD/HSCT(+) and FLT3-ITD/HSCT(-) was 12/29 (53.4 months), 25/59 (40.7 months), 3/10 (medium not reached) and 17/24 (12.0 months), respectively (p=0.014). Comparing with wt-FLT3/HSCT(-) patients, the hazard ratio (95% CI) of overall survival for wt-FLT3/HSCT(+), FLT3-ITD/HSCT(+) and FLT3-ITD/HSCT(-) was 1.39 (0.61-3.18), 0.40 (0.11-1.49), and 3.57 (1.58-8.09), respectively, after adjustment of age, sex, WBC, LDH, karyotype and FAB classification. Conclusions: AML patients without FLT3-ITD had better survival than those with FLT3-ITD regardless of the allogeneic-HSCT. The allogeneic HSCT may improve overall survival in AML patients with FLT3-ITD.

scholarly journals P09.12 Bifunctional SIRPα-CD123 fusion antibody for the elimination of acute myeloid leukemia stem cells

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A58.1-A58
Author(s):  
S Tahk ◽  
SM Schmitt ◽  
B Vick ◽  
C Augsberger ◽  
L Pascual Ponce ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Escape ◽  
Nk Cell ◽  
Regulatory Protein ◽  
Target Antigen ◽  
Hematopoietic Stem ◽  
Acute Myeloid

BackgroundDespite advances in the development of novel strategies against acute myeloid leukemia (AML), treatment options are limited and most patients relapse. Relapse occurs due to the persistence of chemotherapy-resistant leukemic stem cells (LSCs), which re-initiate the outgrowth of the disease, highlighting the need of targeting LSCs to improve patient survival. LSCs are characterized by the expression of the interleukin-3 receptor α, also known as CD123. CD123 is expressed on AML blasts and LSCs, and shows a moderate expression on normal hematopoietic stem cells, claiming CD123 as a suitable target antigen. CD47 is a ubiquitously expressed immune checkpoint upregulated on LSCs where it acts as an immune escape mechanism. CD47 transmits a ‘don’t eat me’ signal upon its interaction with the signal regulatory protein alpha (SIRPα) receptor on macrophages, thus inhibiting phagocytosis. In order to efficiently eliminate LSCs, we have designed a bifunctional antibody that specifically targets CD123 and simultaneously blocks CD47. Importantly, our strategy restricts the benefits of the CD47 blockade to CD123+ AML cells. Thus, we hypothesize a lower risk for on-target off-leukemia toxicity.Materials and MethodsThe bifunctional SIRPα-CD123 antibody was generated by fusing an extracellular domain of the SIRPα receptor, which functions as the CD47 blocking domain, to the CD123 antibody. The biological activity of the SIRPα-CD123 antibody was examined using AML-derived MOLM-13 cells, primary AML patient material and patient-derived xenografted (PDX) AML cells with NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ (NSG) mice.ResultsThe SIRPα fusion improved the binding of the bifunctional SIRPα-CD123 antibody to AML cells compared to a conventional CD123 antibody. The SIRPα-CD123 antibody enhanced the elimination of the AML-derived MOLM-13 cells by antibody-dependent cellular cytotoxicity via NK cells. Additionally, the cytotoxicity was confirmed using primary patient-derived AML cells. Furthermore, an improved cytotoxicity towards leukemia initiating AML PDX cells was observed with the SIRPα-CD123 antibody using luciferase bioluminescence in vivo imaging. With regards to the inhibition of CD47 signaling, we were able to show a blockade of CD47 on CD123+CD47+ cells by the SIRPα-CD123 antibody. Correspondingly, a significant increase in phagocytosis of primary patient-derived AML cells mediated by monocyte-derived macrophages was observed in both allogenic and autologous setting. We were also able to show a preferential binding to MOLM-13 in the presence of a 20-fold excess of red blood cells indicating a potential low on-target off-leukemia toxicity.ConclusionsThe bifunctional SIRPα-CD123 fusion antibodies target the CD123+CD47+ cells and stimulate their phagocytosis by blocking the inhibitory CD47 signal. The dual mode of action of the SIRPα-CD123 has the potential to deplete the AML LSCs through NK cell cytotoxicity and macrophage-mediated phagocytosis while restricting the CD47 related on-target off-leukemia toxicity.SupportH2020-EU grant agreement no 641549Disclosure InformationS. Tahk: None. S.M. Schmitt: None. B. Vick: None. C. Augsberger: None. L. Pascual Ponce: None. I. Jeremias: None. G. Wittmann: None. M. Subklewe: None. N.C. Fenn: None. K. Hopfner: None.

scholarly journals Redirecting the Immune Microenvironment in Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1423
Author(s):  
Stephanie Sendker ◽  
Dirk Reinhardt ◽  
Naghmeh Niktoreh
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Immune Surveillance ◽  
Success Rates ◽  
Hematopoietic Stem ◽  
Immune Mediated ◽  
Life Threatening ◽  
Pediatric Aml ◽  
Immunosuppressive Microenvironment ◽  
Acute Myeloid

Acute myeloid leukemia is a life-threatening malignant disorder arising in a complex and dysregulated microenvironment that, in part, promotes the leukemogenesis. Treatment of relapsed and refractory AML, despite the current overall success rates in management of pediatric AML, remains a challenge with limited options considering the heavy but unsuccessful pretreatments in these patients. For relapsed/refractory (R/R) patients, hematopoietic stem cell transplantation (HSCT) following ablative chemotherapy presents the only opportunity to cure AML. Even though in some cases immune-mediated graft-versus-leukemia (GvL) effect has been proven to efficiently eradicate leukemic blasts, the immune- and chemotherapy-related toxicities and adverse effects considerably restrict the feasibility and therapeutic power. Thus, immunotherapy presents a potent tool against acute leukemia but needs to be engineered to function more specifically and with decreased toxicity. To identify innovative immunotherapeutic approaches, sound knowledge concerning immune-evasive strategies of AML blasts and the clinical impact of an immune-privileged microenvironment is indispensable. Based on our knowledge to date, several promising immunotherapies are under clinical evaluation and further innovative approaches are on their way. In this review, we first focus on immunological dysregulations contributing to leukemogenesis and progression in AML. Second, we highlight the most promising therapeutic targets for redirecting the leukemic immunosuppressive microenvironment into a highly immunogenic environment again capable of anti-leukemic immune surveillance.

High Expression Levels of Iaps Predict Poor Overall Survival in Childhood De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4396-4396
Author(s):  
Ingo Tamm ◽  
Stephan Richter ◽  
Doreen Oltersdorf ◽  
Ursula Creutzig ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
High Expression ◽  
Prognostic Impact ◽  
Poor Overall Survival ◽  
Expression Levels ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. Using flow cytometry and western blot analysis, we therefore investigated 45 leukemic cell samples of children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins (CD95, Bcl-2, Bax, Bcl-xL, Procaspase-3, XIAP, cIAP-1, Survivin). XIAP (p<0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by FAB morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (p<0.01) and Bcl-xL (p<0.01) expression was lower in patients with favorable than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP {30 (n=10) vs. 41 months (n=34); p<0.05} and Survivin {27 (n=10) vs. 41 months (n=34); p<0.05}. We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics and poor overall survival should be confirmed within prospective pediatric AML trials.

High Disease-Free and Overall Survival Rate Following Allogeneic Hematopoietic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia Even in Non-Remission Status

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2283-2283 ◽  
Author(s):  
Aya Nishida ◽  
Mitsuhiro Yuasa ◽  
Kosei Kageyama ◽  
Kazuya Ishiwata ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Poor Prognosis ◽  
Hematopoietic Stem ◽  
Remission Status ◽  
Disease Free ◽  
Acute Myeloid

Abstract [Background] FMS like tyrosine kinase 3 (FLT3) mutations occur in about 30% of patients with acute myeloid leukemia (AML). Patients with FLT3-mutated AML have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). So far, there is still limited data available on allo-HSCT for FLT3-mutated AML in non-remission status. [Objective and method] To assess the clinical features and outcome of allo-HSCT for FLT3-mutated AML, we retrospectively analyzed patients underwent first allo-HSCT for FLT3-mutated AML excluding acute promyelocytic leukemia (FAB M3) from January 2011 to March 2016. [Result] During the study period, 332 patients received first allo-HSCT for AML in our institute. One hundred and thirty-eight were tested for the presence of FLT3-mutation and 35 showed positive results and were subjected to the analysis. The median follow-up day of survivors was 602 (101-1867). The median age of the patients was 55 years (range, 21-72). Twenty-one patients had de novo AML, 12 had AML with myelodysplasia related changes, and 2 had therapy related AML. Eighteen had normal karyotype, 4 had complex, and 13 had others. Seven were in remission (5 in CR1, and 2 in CR2), and 28 were in non-remission (8 in primary induction failure, 13 in relapse 1, and 7 in chemo naïve status). Twenty-nine patients used unrelated cord blood, 2 did unrelated bone marrow, and 4 did related peripheral blood stem cell as grafts. All but 1 received myeloablative pretransplant conditionings. At 2 years after transplantation, overall survival (OS), disease free survival (DFS), relapse rate (RR), and non-relapse mortality (NRM) of whole studied population were 65.9%, 50.2%, 28.4%, and 21.4%, respectively. Among those in non-remission before transplantation, OS, DFS, RR, and NRM at 2 years post-transplant were 62.2% (Figure 1A), 49.9%(Figure 1B), 24.3%, and 25.8%, respectively. Only younger age (<55 years) was the factor associated with better OS with statistical significance in multivariate analysis. [Conclusion] Our data indicated that allo-HSCT could overcome the poor prognosis of FLT3-mutated AML even for those in non-remission status, despite the profound chemo-resistant character of FLT3-mutated AML. Figure 1A Figure 1A. Figure 1B Figure 1B. Disclosures Izutsu: Abbvie: Research Funding; Gilead: Research Funding; Celgene: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Mundipharma KK: Research Funding.

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