Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia

Sakaguchi, Masahiro; Yamaguchi, Hiroki; Najima, Yuho; Usuki, Kensuke; Ueki, Tomoyuki; Oh, Iekuni; Mori, Sinichiro; Kawata, Eri; Uoshima, Nobuhiko; Kobayashi, Yutaka; Kako, Shinichi; Takagi, Kenji; Gomi, Seiji; Shono, Katsuhiro; Kayamori, Kensuke; Hagihara, Masao; Kanda, Junya; Uchiyama, Hitoji; Kuroda, Junya; Uchida, Naoyuki; Kubota, Yasushi; Kimura, Shinya; Kurosawa, Saiko; Nakajima, N.; Marumo, Atsushi; Omori, Ikuko; Fujiwara, Y.; Yui, Shunsuke; Wakita, Satoshi; Arai, Kohei; Kitano, Tomoaki; Kakihana, Kazuhiko; Kanda, Yoshinobu; Ohashi, Kazuteru; Fukuda, Takahiro; Inokuchi, Koiti

doi:10.1182/bloodadvances.2018020305

Cited by 111 publications

(75 citation statements)

References 35 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Besides, some studies indicated that allo-HSCT improves the prognosis in NPM1 mutated AML with FLT3-ITD low AR. [19][20][21] Moreover, Patel et al 23 reported that high variant allele frequency of NPM1 predict poor outcomes in de novo AML, even after undergoing hematopoietic stem cell transplantation. And the effect of high NPM1 variant allele frequency on prognosis was not affected by the level of FLT-ITD AR.…”

Section: Discussionmentioning

confidence: 99%

“…However, this risk classification on FLT3-ITD and NPM1 double mutated AML was not accepted by some clinicians, and several studies provided evidence that this type of AML is with unfavorable risks. [16][17][18][19][20][21] What is the optimal treatment for AML FLT3-ITD+/NPM1+ patients is also under investigation. In this study, we retrospectively analyzed the clinical features and risk factors of AML FLT3-ITD+/NPM1+ , and discussed whether hematopoietic stem cell transplantation is necessary after complete remission (CR).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis

Huang¹,

Hu²,

Lu³

et al. 2019

CMAR

View full text Add to dashboard Cite

Background: According to the recent National Comprehensive Cancer Network (NCCN) guidelines, the risk level in acute myeloid leukemia (AML) patients with FLT3-ITD and NPM1 double mutation (AML FLT3-ITD+/NPM1+) depends on the allelic ratio of FLT3-ITD. But despite a low or high allelic ratio of FLT3-ITD, AML FLT3-ITD+/NPM1+ patients belong to the favorable or intermediate risk, for whom allogeneic stem cell transplantation is not obligated. However, some latest studies pointing out that NPM1 and FLT3-ITD double mutation patients showed an inferior prognosis, which have raised concern about the risk categorization and more effective treatment of AML FLT3-ITD+/NPM1+ patients. Methods: A total of 76 patients were selected for coexisting FLT3 and NPM1 mutations with normal cytogenetics. The prognostic risk factors were analyzed, and treatment strategies including allogeneic stem cell transplantati1on and chemotherapy were compared. Results: In 76 AML FLT3-ITD+/NPM1+ patients, 36.8% of patients had hyperleukocytosis (HL) and DNMT3A R882 mutation was the most common concomitant gene (23.7%). For 53 patients in the complete remission (CR), 22 had received allogeneic hematopoietic stem cell transplantation (allo-HSCT) on first complete remission (CR1). Patients in transplantation group had better overall survival (OS) and disease-free survival (DFS) than chemotherapy only (P=0.002 and 0.001, respectively). In multivariable Cox model analyses, HL and DNMT3A R882 mutation were independent adverse prognostic factors (all P<0.05) for AML FLT3-ITD+/NPM1+ patients. Nevertheless, allo-HSCT was an independent good factor of OS and DFS (P=0.001 and 0.000; HR =0.173 and 0.138; 95% CI were 0.062-0.483 and 0.049-0.389). And allo-HSCT could moderately improve the poor prognosis of AML FLT3-ITD+/NPM1+/DNMT3A R882+. Conclusion: Although, AML FLT3-ITD+/NPM1+ patients are categorized as favorable or intermediate risk levels according to recent NCCN and ELN guidelines, these patients should receive allo-HSCT in CR1 for a longer survival. AML FLT3-ITD+/NPM1+ patients with DNMT3A R882 mutation had a very poor prognosis, and allo-HSCT could moderately improve their survival.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acute myeloid leukemia patient with FLT3-ITD and NPM1 double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis

Huang¹,

Hu²,

Lu³

et al. 2019

CMAR

View full text Add to dashboard Cite

show abstract

“…Therefore, the ELN‐2017 system includes CN‐AML patients with mutated NPM1 and FLT3 ‐ITD low in addition to those with mutated NPM1 and wild‐type FLT3 . However, we and others reported that FLT3 ‐ITD low has an impact on the long‐term prognosis, as for FLT3 ‐ITD high , in Japanese AML patients …”

Section: Clinical Significance Of Flt3 Mutationsmentioning

confidence: 99%

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

2019

View full text Add to dashboard Cite

FMS‐like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that plays an important role in hematopoietic cell survival, proliferation and differentiation. The most clinically important point is that mutation of the FLT3 gene is the most frequent genetic alteration and a poor prognostic factor in acute myeloid leukemia (AML) patients. There are two major types of FLT3 mutations: internal tandem duplication mutations in the juxtamembrane domain (FLT3‐ITD) and point mutations or deletion in the tyrosine kinase domain (FLT3‐TKD). Both mutant FLT3 molecules are activated through ligand‐independent dimerization and trans‐phosphorylation. Mutant FLT3 induces the activation of multiple intracellular signaling pathways, mainly STAT5, MAPK and AKT signals, leading to cell proliferation and anti–apoptosis. Because high‐dose chemotherapy and allogeneic hematopoietic stem cell transplantation cannot sufficiently improve the prognosis, clinical development of FLT3 kinase inhibitors expected. Although several FLT3 inhibitors have been developed, it takes more than 20 years from the first identification of FLT3 mutations until FLT3 inhibitors become clinically available for AML patients with FLT3 mutations. To date, three FLT3 inhibitors have been clinically approved as monotherapy or combination therapy with conventional chemotherapeutic agents in Japan and/or Europe and United states. However, several mechanisms of resistance to FLT3 inhibitors have already become apparent during their clinical trials. The resistance mechanisms are complex and emerging resistant clones are heterogenous. Further basic and clinical studies are required to establish the best therapeutic strategy for AML patients with FLT3 mutations.

show abstract

“…FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) or tyrosine kinase domain (FLT3-TKD) gene mutations are encountered in around 30% of acute myeloid leukemia (AML) Japanese study reported that performing allo-SCT in CR1 significantly improves the outcome in these patients, irrespective of the FLT3-ITD allele ratio [12]. Unfortunately, patients with FLT3-ITD mutation still carry a poor prognosis after allo-SCT because of higher rates of early relapse and the lack of response to chemotherapy in the salvage setting [13,14].…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia: In vivo T-Cell Depletion and Posttransplant Sorafenib Maintenance Improve Survival. A Retrospective Acute Leukemia Working Party-European Society for Blood and Marrow Transplant Study

Bazarbachi¹,

Labopin

Battipaglia³

et al. 2019

CHI

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) with FLT3-mutation carries a poor prognosis, and allogeneic stem cell transplantation (allo-SCT) is recommended at first complete remission (CR1). We assessed 462 adults (median age 50 years) with FLT3-mutated AML allografted between 2010 and 2015 from a matched related (40%), unrelated (49%), or haploidentical donor (11%). The median follow-up of alive patients was 39 months. Day-100 acute graft versus host disease (GVHD) grades II-IV and III-IV were encountered in 26% and 9%, whereas the 2-year incidence of chronic and extensive chronic GVHD were 34% and 16%, respectively. The 2-year incidences of relapse and nonrelapse mortality were 34% and 15%, respectively. The 2-year leukemia-free survival, overall survival (OS), and GVHD relapse-free survival (GRFS) were 51%, 59%, and 38%, respectively. In multivariate analysis, NPM1-mutation, transplantation in CR1, in vivo T-cell depletion, and posttransplant sorafenib improved OS, whereas more than one induction (late CR1) negatively affected OS. Similarly, NPM1-mutation, a haploidentical donor, T-cell depletion, and sorafenib maintenance improved GRFS, whereas late CR1 or persistent disease negatively affected it. In conclusion, FLT3mutated AML remains a challenge even following allo-SCT. In vivo T-cell depletion and posttransplant sorafenib significantly improve OS and GRFS, and may be considered as standard of care.

show abstract

Prognostic impact of low allelic ratio FLT3-ITD and NPM1 mutation in acute myeloid leukemia

Cited by 111 publications

References 35 publications

<p>Acute myeloid leukemia patient with <em>FLT3-ITD</em> and <em>NPM1</em> double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis </p>

<p>Acute myeloid leukemia patient with <em>FLT3-ITD</em> and <em>NPM1</em> double mutation should undergo allogeneic hematopoietic stem cell transplantation in CR1 for better prognosis </p>

FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development

Allogeneic Stem Cell Transplantation for FLT3-Mutated Acute Myeloid Leukemia: In vivo T-Cell Depletion and Posttransplant Sorafenib Maintenance Improve Survival. A Retrospective Acute Leukemia Working Party-European Society for Blood and Marrow Transplant Study

Contact Info

Product

Resources

About