scholarly journals Monitoring of post-transplant MLL-PTD as minimal residual disease can predict relapse after allogeneic HSCT in patients with acute myeloid leukemia and myelodysplastic syndrome

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Jun Kong ◽  
Meng-Ge Gao ◽  
Ya-Zhen Qin ◽  
Yu Wang ◽  
Chen-Hua Yan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Significant Difference ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background The mixed-lineage leukemia (MLL) gene is located on chromosome 11q23. The MLL gene can be rearranged to generate partial tandem duplications (MLL-PTD), which occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation. Methods We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People’s Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL > 0.08% was defined as MLL-PTD positive in this study. Results The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7 ± 5.2, 67.8 ± 6.9, 68.1 ± 6.8 and 20.3% ± 6.1%, respectively. ROC curve showed that post-transplant MLL-PTD ≥ 1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD ≥ 1.0% and MLL-PTD < 1.0% groups (3-year CIR: 75% ± 15.3% vs. 0%, P < 0.001; 3-year OS: 25.0 ± 15.3% vs. 80.7% ± 6.6%, P < 0.001; 3-year DFS: 25.0 ± 15.3% vs. 80.7 ± 6.6%, P < 0.001; 3-year TRM: 0 vs. 19.3 ± 6.6%, P = 0.277). However, whether MLL-PTD ≥ 1% or MLL-PTD < 1% before transplantation has no significant difference on the prognosis. Conclusions Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

scholarly journals Monitoring of Post-Transplant MLL-PTD as Minimal Residual Disease Can Predict Relapse After Allogeneic HSCT in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndrome

2021 ◽  
Author(s):  
Jun Kong ◽  
Meng-Ge Gao ◽  
Ya-Zhen Qin ◽  
Yu Wang ◽  
Chen-Hua Yan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Significant Difference ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: MLL-PTD is a special MLL rearrangement gene that occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, including AML and MDS, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation.Methods: We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People’s Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL>0.08% was defined as MLL-PTD positive in this study.Results: The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7%±5.2%, 67.8%±6.9%, 68.1%±6.8% and 20.3%±6.1%, respectively. ROC curve showed that post-transplant MLL-PTD≥1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD≥1.0% and MLL-PTD<1.0% groups (3-year CIR: 75%±15.3% vs. 0%, P<0.001; 3-year OS: 25.0±15.3% vs. 80.7%±6.6%, P<0.001; 3-year DFS: 25.0±15.3% vs. 80.7%±6.6%, P<0.001; 3-year TRM: 0 vs. 19.3±6.6%, P=0.277). However, whether MLL-PTD≥1% or MLL-PTD<1% before transplantation has no significant difference on the prognosis. Conclusions: Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

scholarly journals Minimal Residual Disease Diagnostics and Chimerism in the Post-Transplant Period in Acute Myeloid Leukemia

2011 ◽  
Vol 11 ◽  
pp. 310-319 ◽  
Author(s):  
Ulrike Bacher ◽  
Torsten Haferlach ◽  
Boris Fehse ◽  
Susanne Schnittger ◽  
Nicolaus Kröger
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Minimal Residual Disease ◽  
Real Time Pcr ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Quantitative Real Time Pcr ◽  
Post Transplant ◽  
Minimal Residual ◽  
Acute Myeloid

In acute myeloid leukemia (AML), the selection of poor-risk patients for allogeneic hematopoietic stem cell transplantation (HSCT) is associated with rather high post-transplant relapse rates. As immunotherapeutic intervention is considered to be more effective before the cytomorphologic manifestation of relapse, post-transplant monitoring gains increasing attention in stem cell recipients with a previous diagnosis of AML. Different methods for detection of chimerism (e.g., microsatellite analysis or quantitative real-time PCR) are available to quantify the ratio of donor and recipient cells in the post-transplant period. Various studies demonstrated the potential use of mixed chimerism kinetics to predict relapse of the AML. CD34+-specific chimerism is associated with a higher specificity of chimerism analysis. Nevertheless, a decrease of donor cells can have other causes as well. Therefore, efforts continue to introduce minimal residual disease (MRD) monitoring based on molecular mutations in the post-transplant period. TheNPM1(nucleophosmin) mutations can be monitored by sensitive quantitative real-time PCR in subsets of stem cell recipients with AML, but for approximately 20% of patients, suitable molecular mutations for post-transplant MRD monitoring are not available so far. This emphasizes the need for an expansion of the panel of MRD markers in the transplant setting.

Allogeneic Hematopoietic Stem Cell Transplantation Overcomes the Adverse Prognostic Impact of Minimal Residual Disease in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2027-2027
Author(s):  
Betul Oran ◽  
Timothy Singleton ◽  
Pablo A. Ramirez ◽  
Ryan Shanley ◽  
Claudio Brunstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Hematopoietic Stem ◽  
Disease Outcomes ◽  
The Impact ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 2027 BACKGROUND: The identification of minimal residual disease (MRD) can predict impending relapse in acute myeloid leukemia (AML) patients. Little data exists evaluating the prognostic impact of MRD, as determined by multiparametric flow cytometry (MFC), at the time of allogeneic (allo-HCT). Although disease outcomes may be worse for MRD positive (MRD+) patients, MRD is often associated with other adverse risk factors leaving it unclear whether MRD is an independent risk factor for relapse or a surrogate marker for underlying poor risk disease features. METHODS: We retrospectively analyzed 97 consecutive AML patients in complete morphological remission (CR) who underwent allo-HCT with a matched related donor (MRD, n=30, 31%), matched unrelated donor (MUD, n=4, 4%) or umbilical cord blood (UCB, n=63, 65%) at the University of Minnesota between January 2005 and June 2009. Presence of MRD at allo-HCT was determined by MFC. Analyses were done separately for myeloablative (MAC) and reduced intensity conditioning (RIC) patients, testing the impact of MRD along with conditioning intensity, age, donor type and disease status on allo-HCT outcomes. RESULTS: Of 97 patients, 41 (42%) had MAC; 57 (58%) had RIC. Sixty-six were in first CR (CR1) with the rest in CR2 or later remission (CR2+). MRD at allo-HCT was detected in 7 patients after MAC (17%) and 7 after RIC (12.5%); and this frequency was similar in patients in CR1 and CR2+ (13% vs. 16%, p=0.7). MRD+ and MRD- patients had similar median age (40 vs. 44 yrs), gender, donor source (MSD or MUD vs. UCB), CMV serostatus and diagnostic cytogenetic risk group. Six of 40 (15%) intermediate and 5 of 39 (13%) high risk cytogenetics patients had MRD+ (p=0.8). Only 3 of 53 patients with a cytogenetic abnormality at diagnosis had it detected prior allo-HCT and 1 of 3 had MRD. The median follow-up of survivors was 25 months. Two-year probabilities for MAC and RIC patients were similar: Overall survival (OS), 48% and 47 % and leukemia free survival (LFS) 43% and 41% respectively. When disease outcomes were analyzed separately by MRD status (table), OS and LFS were markedly worse in MRD+ patients receiving RIC, but this difference was not statistically significant. In multivariate analysis, MRD+ was not an independent prognostic factor for OS and LFS. Although we identified no adverse prognostic factors for MAC patients, patient with RIC in CR2+ had worse OS and LFS vs. CR1 (HR 2.6, p=0.04 and HR 2.7, p=0.04 respectively). CONCLUSION: The negative prognostic impact of MRD was overcome by allo-HCT with MAC, but outcomes with MRD+ were suggestively inferior after RIC. However due to limited sample size, MRD in patients with RIC should be further investigated. Disclosures: Weisdorf: Genzyme: Consultancy, Research Funding.

Minimal Residual Disease–Directed Therapy for Childhood Acute Myeloid Leukemia: Results of the AML02 Multicenter Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 16-16
Author(s):  
Jeffrey Rubnitz ◽  
Hiroto Inaba ◽  
Gary Dahl ◽  
W. Paul Bowman ◽  
Jeffrey Taub ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Supportive Care ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Hematopoietic Stem ◽  
Cns Relapse ◽  
Cure Rates ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 16 With improvements in risk-directed therapy and supportive care, cure rates for children with acute lymphoblastic leukemia are now approaching 90%. In contrast, little progress has been made for children with acute myeloid leukemia (AML). We designed a multicenter treatment protocol for children with newly diagnosed AML that used sequential minimal residual disease (MRD) assessment for risk assignment. Patients (n = 230) with AML were randomized to receive daunorubicin and etoposide plus high-dose cytarabine (HD-ADE, n = 113) or low-dose cytarabine (LD-ADE, n = 117) as Induction I. Induction II consisted of LD-ADE with or without gemtuzumab ozogamicin (GO), depending on the level of MRD after Induction I. The remaining treatment was based on presenting features and MRD levels, and included hematopoietic stem cell transplantation (HSCT) for high-risk patients. The protocol underwent 2 treatment changes. First, LD-ADE + GO was initially given only to patients with MRD more than 25%, but was later extended to patients with MRD more than 1% because the combination was found to be safe and effective at reducing MRD. Of the 30 patients who received LD-ADE + GO, 27 (90%) had a reduction in MRD and 13 (43%) became MRD negative, with a median overall MRD reduction of 98%. CNS-directed therapy initially consisted of intrathecal (IT) cytarabine alone. However, because 3 of the first 33 patients enrolled on AML02 developed CNS relapse, subsequent patients were treated with triple IT therapy consisting of methotrexate, hydrocortisone, and cytarabine. The cumulative incidence of CNS relapse decreased from 9% to 2% after this treatment change (P = 0.004). Of the 212 (92%) evaluable patients, 80% became MRD negative and 95% achieved clinical complete remission (CR) after 2 courses of therapy; overall 3-year event-free survival (EFS) and overall survival (OS) rates were 60% ± 5% and 70% ± 4%, respectively. Patients on the HD-ADE and LD-ADE treatment arms had similar MRD-negative rates after 1 (66% vs. 58%, P = 0.17) and 2 courses of therapy, as well as similar CR, EFS (59% vs. 61%, P = 0.79), and OS rates (68% vs. 73%, P = 0.41). Multipredictor logistic regression modeling indicated that the odds of having detectable MRD after 1 course of therapy was significantly lower for patients with core binding factor (CBF) leukemia [t(8;21) or inv(16)] (P <0.0001), and significantly greater for those with FLT3-ITD-positive leukemia (P = 0.0007). Despite treatment intensification for MRD-positive patients, presence of MRD after Induction I remained a significant adverse predictor: 3-year EFS rates were 72% for MRD-negative patients and 41% for MRD-positive patients (P<0.0001). We also observed significant differences in 3-year EFS rates between patients with and without FLT3-ITD (37% vs. 65%, P = 0.003) and between patients with and without CBF leukemia (82% vs. 53%, P = 0.0003). By Cox proportional hazard modeling, EFS was significantly associated with MRD on day 22 (P = 0.009) and CBF leukemia (P=0.04). Only 8 of the 230 patients enrolled had infection-related deaths: 1 patient died during induction, 4 in CR during or after completing chemotherapy, and 3 in CR after HSCT. As previously reported, use of the prophylactic vancomycin, ciprofloxacin, and voriconazole contributed to this low rate of toxic death. In conclusion, risk-adapted therapy, incorporation of GO, and excellent supportive care contributed to a CR rate of 95%, low mortality, and an overall 3-year OS rate of 70% for children with AML enrolled on AML02. Although this is substantially higher than rates reported in our previous studies, it should be possible to further increase cure rates by additional refinements in risk assignment, as well as by introducing novel agents that can bypass drug resistance. To this end, our current AML08 protocol has incorporated newly discovered molecular predictors, highly sensitive MRD tests, and natural killer cell therapy. Disclosures: No relevant conflicts of interest to declare.

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