Measurable residual disease status and FLT3 inhibitor therapy in patients with FLT3-ITD mutated AML following allogeneic hematopoietic cell transplantation

2021 ◽  
Author(s):  
Emily C. Liang ◽  
Connie Chen ◽  
Rong Lu ◽  
Gabriel N. Mannis ◽  
Lori Muffly
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Disease Status ◽  
Hematopoietic Cell ◽  
Inhibitor Therapy ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Flt3 Inhibitor ◽  
Measurable Residual Disease

scholarly journals Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML

Blood ◽  
2018 ◽  
Vol 132 (16) ◽  
pp. 1703-1713 ◽  
Author(s):  
Felicitas Thol ◽  
Razif Gabdoulline ◽  
Alessandro Liebich ◽  
Piroska Klement ◽  
Johannes Schiller ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Somatic Gene Mutation ◽  
Measurable Residual Disease

Abstract Molecular measurable residual disease (MRD) assessment is not established in approximately 60% of acute myeloid leukemia (AML) patients because of the lack of suitable markers for quantitative real-time polymerase chain reaction. To overcome this limitation, we established an error-corrected next-generation sequencing (NGS) MRD approach that can be applied to any somatic gene mutation. The clinical significance of this approach was evaluated in 116 AML patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) in complete morphologic remission (CR). Targeted resequencing at the time of diagnosis identified a suitable mutation in 93% of the patients, covering 24 different genes. MRD was measured in CR samples from peripheral blood or bone marrow before alloHCT and identified 12 patients with persistence of an ancestral clone (variant allele frequency [VAF] >5%). The remaining 96 patients formed the final cohort of which 45% were MRD+ (median VAF, 0.33%; range, 0.016%-4.91%). In competing risk analysis, cumulative incidence of relapse (CIR) was higher in MRD+ than in MRD− patients (hazard ratio [HR], 5.58; P < .001; 5-year CIR, 66% vs 17%), whereas nonrelapse mortality was not significantly different (HR, 0.60; P = .47). In multivariate analysis, MRD positivity was an independent negative predictor of CIR (HR, 5.68; P < .001), in addition to FLT3-ITD and NPM1 mutation status at the time of diagnosis, and of overall survival (HR, 3.0; P = .004), in addition to conditioning regimen and TP53 and KRAS mutation status. In conclusion, NGS-based MRD is widely applicable to AML patients, is highly predictive of relapse and survival, and may help refine transplantation and posttransplantation management in AML patients.

scholarly journals Measurable residual disease affects allogeneic hematopoietic cell transplantation in Ph+ ALL during both CR1 and CR2

2021 ◽  
Vol 5 (2) ◽  
pp. 584-592
Author(s):  
Satoshi Nishiwaki ◽  
Yu Akahoshi ◽  
Shuichi Mizuta ◽  
Akihito Shinohara ◽  
Shigeki Hirabayashi ◽  
...  
Keyword(s):  
Risk Factor ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Survival Rates ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Prognostic Impact ◽  
Significant Difference ◽  
Measurable Residual Disease

Abstract Although measurable residual disease (MRD) at the time of allogeneic hematopoietic cell transplantation (allo-HCT) has been reported to be an important prognostic factor for Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) during first complete remission (CR1), the prognostic impact of MRD is unclear during second CR (CR2). To clarify the impact of MRD for both CR1 and CR2, we analyzed data from a registry database including 1625 adult patients with Ph+ ALL who underwent first allo-HCT during either CR1 or CR2 between 2002 and 2017. Adjusted overall and leukemia-free survival rates at 4 years were 71% and 64%, respectively, for patients undergoing allo-HCT during CR1 with MRD−, 55% and 43% during CR1 with MRD+, 51% and 49% during CR2 with MRD−, and 38% and 29% during CR2 with MRD+. Although survival rates were significantly better among patients with CR1 MRD− than among patients with CR2 MRD−, no significant difference was observed in survival rate between patients with CR1 MRD+ and CR2 MRD−. Relapse rates after 4 years were 16% in patients with CR1 MRD−, 29% in CR1 MRD+, 21% in patients with CR2 MRD−, and 46% in patients with CR2 MRD+. No significant difference was identified in relapse rate between patients with CR1 MRD− and CR2 MRD−. CR2 MRD− was not a significant risk factor for relapse in multivariate analysis (hazard ratio, 1.26; 95% confidence interval, 0.69-2.29; P = .45 vs CR1 MRD−). MRD at time of allo-HCT was an important risk factor in patients with Ph+ ALL during both CR1 and CR2.

scholarly journals Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lymphoblastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Jiří Pavlů ◽  
Myriam Labopin ◽  
Riitta Niittyvuopio ◽  
Gerard Socié ◽  
Ibrahim Yakoub-Agha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Registry Study ◽  
The Impact ◽  
Measurable Residual Disease

Abstract Background Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. Methods In this retrospective registry study, we explored whether measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia is associated with different outcomes in recipients of myeloablative total body irradiation (TBI)-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18–72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated donors. Results In 1816 of patients, no disease was detectable, and in 964 patients, MRD was positive. Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02–1.39), 1.26 (1.1–1.44), and 1.51 (1.26–1.8). TBI was associated with a higher OS, LFS, and lower RI with HR of 0.75 (0.62–0.90), 0.70 (0.60–0.82), and 0.60 (0.49–0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS and LFS and higher RI in the TBI group, and with higher RI in the chemotherapy group. TBI-based conditioning was associated with improved outcomes in both MRD-negative and MRD-positive patients. Conclusions In this large study, we confirmed that patients who are MRD-negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI-based conditioning in the myeloablative setting.

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