KIT Mutation Versus MRD, Which Is More Important To Predict Relapse Of Acute Myeloid Leukemia With t (8; 21)?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1309-1309 ◽  
Author(s):  
Hong-Hu Zhu ◽  
Daihong Liu ◽  
Hao Jiang ◽  
Ya-Zhen Qin ◽  
Lan-Ping Xu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Relapse Rate ◽  
Subgroup Analysis ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Kit Mutation ◽  
Very High ◽  
Acute Myeloid

Abstract Background Although acute myeloid leukemia (AML) with t (8; 21) translocation generally belongs to the favorable-risk AML subtypes, relapse occurs in about 40% of cases and long-term (>5years) survival less than 50%. KIT-mutation (KIT+) and minimal residual disease (MRD) levels have been demonstrated as two most important risk factors in several retrospective studies. Until now, only two prospective studies (Our AML05 trial; French CBF-2006 trial) have assessed their respective prognostic values (Zhu HH, et al. Blood 2013; 121:4056; Jourdan E, et al. Blood 2013; 121:2213). We found both KIT+ and MRD were independent risk factors for relapse, but Joundan et al found only MRD rather than KIT+ was sole prognostic factor for relapse in multivariate anaysis. Both studies did not perform a comprehensive subgroup analysis combining the two factors, and risk-adopt postremission treatment might also affect this assessment. Therefore, we performed a subgroup analysis combining KIT mutation and MRD in a prospective protocol AML05 to answer which is more important to predict outcomes of t(8;21)AML. Methods From July, 2005, to Jan, 2013, 114 patients with t (8; 21) AML after achieving complete remission were included in this analysis. KIT mutations in exons 17 and 8 were screened using the direct sequencing method. MRD was detected using quantitative PCR to detect the RUNX1/RUNX1T1 transcript. MRD-positive (MRD+) was defined as < 3 log reduction of RUNX1/RUNX1T1 transcript from baseline after second consolidation therapy. Sixty-two patients received high-dose cytarabine-based consolidation chemotherapy (CT) or autologous hematopoietic stem-cell transplantation (auto-HSCT), and 52 patients received allogeneic HSCT (allo-HSCT). Results When receiving CT/auto-HSCT as postremission treatment, KIT+ patients (n=19) had a higher 3 year cumulative incidence of relapse (CIR) than KIT-patients (n=43) (94.4% vs. 38.2%, p<0.0001). Similar results also found in MRD+ (n=19) and MRD- (n=43) patients (CIR 92.9% vs. 46.6%, p<0.0001). Among KIT+ patients, a very high relapse rate was found in both MRD+ and MRD-patients (CIR, 100% vs.88.9%). However, among KIT-patients, MRD+ patients had a significant higher relapse rate than MRD-patients (CIR, 84.4% vs.26.3%, p=0.0006). When pooling KIT+ and or MRD+ into one group (KIT+/MRD+), this group had a significant higher relapse rate than KIT-MRD- group ( 94.4% vs. 26.3%, p<0.0001), However, the prognostic values of KIT and MRD was lost when patients received allo-HSCT (CIR of KIT+/MRD+ and KIT-MRD-, 23.8% vs. 15.6%, p=0.47). Similar results were also been found in disease-free survival (DFS) and overall-survival (OS). Multivariate analysis revealed that KIT+, MRD+, and treatment (allo-HSCT or CT/auto-HSCT) were three independent prognostic factors for relapse (all p<0.0001), DFS (all p<0.0001) and OS (p<0.0001, p<0.0001, p=0.007). Conclusions Both KIT status and MRD level were important to predict relapse of t (8;21) AML. KIT+ patients hold a very high relapse risk. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1–RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1–RUNX1T1

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 336
Author(s):  
Byung-Sik Cho ◽  
Gi-June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Young-Woo Jeon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Poor Survival ◽  
Hematopoietic Stem ◽  
Kit Mutation ◽  
Time Points ◽  
Post Transplant ◽  
Acute Myeloid

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

Donor Lymphocyte Infusion in the Treatment of First Hematological Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by the EBMT Acute Leukemia Working Party

2007 ◽  
Vol 25 (31) ◽  
pp. 4938-4945 ◽  
Author(s):  
Christoph Schmid ◽  
Myriam Labopin ◽  
Arnon Nagler ◽  
Martin Bornhäuser ◽  
Jürgen Finke ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Tumor Burden ◽  
Donor Lymphocyte Infusion ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Purpose To evaluate the role of donor lymphocyte infusion (DLI) in the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). Patients and Methods We retrospectively analyzed the data of 399 patients with AML in first hematological relapse after HSCT whose treatment did (n = 171) or did not (n = 228) include DLI. After correction for imbalances and established risk factors, the two groups were compared with respect to overall survival. Further, a detailed analysis of risk factors for survival among DLI recipients was performed. Results Median follow-up was 27 and 40 months, respectively. Estimated survival at 2 years (± standard deviation) was 21% ± 3% for patients receiving DLI and 9% ± 2% for patients not receiving DLI. After adjustment for differences between the groups, better outcome was associated with age younger than 37 years (P = .008), relapse occurring more than 5 months after HSCT (P < .0001), and use of DLI (P = .04). Among DLI recipients, a lower tumor burden at relapse (< 35% of bone marrow blasts; P = .006), female sex (P = .02), favorable cytogenetics (P = .004), and remission at time of DLI (P < .0001) were predictive for survival in a multivariate analysis. Two-year survival was 56% ± 10%, if DLI was performed in remission or with favorable karyotype, and 15% ± 3% if DLI was given in aplasia or with active disease. Conclusion Although further evidence for a graft-versus-leukemia effect by DLI is provided, our results confirm, that the clinical benefit is limited to a minority of patients. Strategies to reduce tumor burden before DLI, as well as alternative treatment options should be investigated in adults with relapsed AML after HSCT.

Dose-related mucositis with hydroxyurea for cytoreduction in acute myeloid leukemia

2018 ◽  
Vol 25 (4) ◽  
pp. 801-805 ◽  
Author(s):  
Morgan L Trepte ◽  
Jessica J Auten ◽  
Stephen M Clark ◽  
Hendrik W van Deventer
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Medical Center ◽  
Prescribing Patterns ◽  
High Dose ◽  
Dosing Strategies ◽  
Safety And Toxicity ◽  
Dosing Strategy ◽  
Acute Myeloid

Hyperleukocytosis occurs in 15–20% of all newly diagnosed acute myeloid leukemia patients and requires emergent treatment with leukapheresis or hydroxyurea when accompanied by signs or symptoms of leukostasis. Currently, there is no standardized hydroxyurea dosing strategy, although usual dosing ranges from 50 to 150 mg/kg/day, and prescribing patterns vary significantly among oncologists and institutions. In addition to other hematologic and dermatologic toxicities, the use of hydroxyurea may be associated with significant mucositis and mucositis-related pain. The purpose of this study was to compare mucositis-related pain between two different hydroxyurea dosing strategies in patients who received hydroxyurea for cytoreduction during induction. A retrospective chart review of adult patients with acute myeloid leukemia treated with chemotherapy at UNC Medical Center from April 2014 to April 2016 who received at least one dose of hydroxyurea for cytoreduction was conducted. This study compared the safety and toxicity profiles of hydroxyurea in patients who received high-dose hydroxyurea (≥75 mg/kg/day) versus low-dose hydroxyurea (<75 mg/kg/day). Safety and toxicity were evaluated based on indicators of mucositis and cumulative intravenous narcotic requirements following induction chemotherapy. Data collection included baseline demographics, mucositis risk factors, baseline laboratory values, hydroxyurea dosing, mucositis indicators, and pain indicators. A total of 55 patients were included in the study, 21 patients (38.2%) received the high-dose hydroxyurea dosing strategy. The high-dose hydroxyurea dosing strategy had a significantly higher white blood cell count at diagnosis, increased duration of hydroxyurea, and received a higher cumulative dose of hydroxyurea. Additionally, the high-dose hydroxyurea dosing strategy patients were associated with significantly more grade 3 or 4 mucositis requiring a formulation change (0% versus 28.6%, p = 0.002) and significantly higher cumulative intravenous narcotic requirements during induction (p = 0.019). No significant differences in baseline demographics or mucositis risk factors between dosing strategies were identified. The high-dose hydroxyurea dosing strategy patients had a significant increase in cumulative intravenous narcotic requirements and formulation changes, both common interventions made for the treatment of mucositis. Additional studies are needed to further elucidate the safety and toxicity profiles of hydroxyurea dosing strategies and to explore the correlation between total cumulative hydroxyurea dose and total cumulative narcotic requirements.

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.

scholarly journals Risk factors affect accurate prognosis in ASXL1-mutated acute myeloid leukemia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yi Fan ◽  
Linxiao Liao ◽  
Yajun Liu ◽  
Zhenzhen Wu ◽  
Chong Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Primary Data ◽  
Hematopoietic Stem ◽  
Mutational Spectrum ◽  
Double Hit ◽  
Acute Myeloid

Abstract Background The epigenetic regulator additional sex combs-like 1 (ASXL1) is an adverse prognostic factor in acute myeloid leukemia (AML). However, the mutational spectrum and prognostic factors of ASXL1-mutated (ASXL1+) AML are largely unknown. We aim to evaluate the risk factors influencing the prognosis of ASXL1+ AML. Methods We performed next-generation sequencing (NGS) in 1047 cases of de novo AML and discovered 91 ASXL1+ AML (8.7%). The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis. Results In a total of 91 ASXL1+ AML, 86% had one or more co-mutations. The factors that had adverse impact on overall survival (OS) and event-free survival (EFS) are defined as high risk factors, including age ≥ 60 years, WBC count ≥ 50 × 109/L, FLT3-ITD mutations, RUNX1 mutations, and absence of AML1-ETO fusion gene. ASXL1 mutations without any risk factor were classified as single-hit ASXL1+ AML; ASXL1 mutations accompanied with one of the risk factors was referred to as double-hit ASXL1+ AML; ASXL1 mutations with two or more of the risk factors were designated as triple-hit ASXL1+ AML. The combination of these risk factors had a negative influence on the prognosis of ASXL1+ AML. The median OS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 6.67 months in triple-hit ASXL1+ AML (P = 0.003). The median EFS was not attained in single-hit ASXL1+ AML, 29.53 months in double-hit ASXL1+ AML, and 5.47 months in triple-hit ASXL1+ AML (P = 0.002). Allogenic hematopoietic stem cell transplantation (allo-HSCT) improved the prognosis of double/triple-hit ASXL1+ AML patients. Conclusions Our study provided new insights into the mutational spectrum and prognostic factors of ASXL1+ AML patients. Our primary data suggest that the risk factors in ASXL1+ AML contribute to the poor outcome of these patients. The management of ASXL1+ AML patients should be based on the risk factors and allo-HSCT is highly recommended for consolidation.

scholarly journals A Retrospective Observation of Treatment Outcomes Using Decitabine-Combined Standard Conditioning Regimens Before Transplantation in Patients With Relapsed or Refractory Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuhang Li ◽  
Longcan Cheng ◽  
Chen Xu ◽  
Jianlin Chen ◽  
Jiangwei Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Hematopoietic Reconstitution ◽  
Conditioning Regimens ◽  
Refractory Acute Myeloid Leukemia ◽  
Acute Myeloid ◽  
Refractory Aml

Hypomethylating agents, decitabine (DAC) and azacitidine, can act as prophylactic and pre-emptive approaches after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and a non-intensive bridging approach before allo-HSCT. However, they are rarely used as a part of conditioning regimens in patients with relapsed or refractory acute myeloid leukemia (AML). This retrospectively study included a total of 65 patients (median, 37; range, 13–63) with relapsed or refractory AML who were treated by allo-HSCT after myeloablative conditioning regimens without or with DAC (high-dose DAC schedule, 75 mg/m2 on day −9 and 50 mg/m2 on day −8; low-dose DAC schedule, 25 mg/m2/day on day −10 to −8). DAC exerted no impact on hematopoietic reconstitution. However, patients who were treated with the high-dose DAC schedule had significantly higher incidence of overall survival (OS, 50.0%) and leukemia-free survival (LFS, 35.0%), and lower incidence of relapse (41.1%) and grade II–IV acute graft versus host disease (aGVHD, 10.0%) at 3 years, when compared with those treated with standard conditioning regimens or with the low-dose DAC schedule. In conclusion, high-dose DAC combined with standard conditioning regimens before allo-HSCT is feasible and efficient and might improve outcomes of patients with relapsed or refractory AML, which provides a potential approach to treat these patients.

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