scholarly journals Flow-Cytometry Based Detection of Any Minimal Residual Disease (FC-MRD) in Children with T-Acute Lymphoblastic Leukemias (T-ALL) Is a Powerful Indicator of Outcome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2585-2585 ◽  
Author(s):  
Prashant Tembhare ◽  
Gaurav Narula ◽  
Gaurav Chatterjee ◽  
Twinkle Khanka ◽  
Mahima Sanyal ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Risk Factor ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
High Dose ◽  
Free Survival ◽  
Post Induction ◽  
Minimal Residual ◽  
Risk Of Relapse

Background: Minimal Residual Disease (MRD) is a powerful predictor of event-free survival in acute lymphoblastic leukemia (ALL). However, as T-ALL is less common, MRD studies are limited, often with small cohorts, and even fewer have been done by flowcytometry-based MRD (FC-MRD). There have also been different time-points such as Post-Induction (PI-MRD), and late or Post-Consolidation (PC-MRD) that have shown significant correlation with overall, event, and relapse-free survival (OS, EFS & RFS). As the available literature is still not conclusive, we investigated the impact of FC-MRD on survival in childhood T-ALL at a large tertiary cancer care centre in India. Methods: Children less than 15-years age diagnosed with T-ALL from Jan-2014 to May 2018 were treated uniformly on a modified MCP-841 protocol that included a 4-drug induction (vincristine, prednisolone, l-asparaginase, daunomycin), and consolidation with high-dose cytarabine (24gm/m2 in 3 equal legs for children below 3-years, and 16gm/m2 in two equal legs, for 3 or more years age). Post-consolidation therapy followed the pattern of Interim Maintenance, two Delayed Intensification cycles, and 18 months of Maintenance. Central Nervous System (CNS)-directed therapy consisted of intrathecal methotrexate in all cycles, and those with CNS involvement received additional Cranial Radiation of 18Gy. In early-thymic-precursor (ETP-ALL) immunophenotype patients, dexamethasone replaced prednisolone in Induction. The protocol did not include High-Dose Methotrexate. FC-MRD was estimated by 10-color FC-MRD assay on Navios flow-cytometer (Beckman Coulter, Inc.) at Post-Induction(day-35), and Post-Consolidation(day-78) for those PI-MRD positive(+ve). FC-MRD was analyzed on Kaluza® software v-1.3. Any detectable value was taken as positive. Statistical analysis was performed using MedCalc Statistical Software®. Results: Of 368 eligible patients diagnosed at our centre in the study period, 81 did not undergo PI-MRD (14- Induction deaths, 13- treatment abandonment, 54- referral to other institute/ time-point missed/ did not consent/ other reasons). Another 18 abandoned treatment within 100 days of diagnosis and were also excluded. In the remaining 269, median age was 10-years (range:1-15), M:F-3.8:1. Median presenting WBC was 96.7 x 103/cmm (range:1.14-849), and thirteen patients had ETP. PI-MRD was positive in 125(46%) patients (median MRD -0.3%, range:0.0007-43.6%) of which 58(46.4%) developed medullary relapse, compared to 17 of 144(11.6%) for PI-MRD negative(-ve) patients, with Hazard Ratio (HR) for risk of medullary-relapse for PI-MRD+ve being 5.02(95% CI:3.16-7.96; p<0.0001). Median RFS was 20.5 months (95% CI:16.2-34.7) for PI-MRD+ve patients, while median was not-reached for PI-MRD-ve. PI-MRD+ve patients were at high risk for all events (medullary relapse, extramedullary relapse and death) with an incidence of 53.6% versus 27.8%; p<0.0001, and HR of 2.36 (95% CI:1.6-3.47; p<0.0001). Probability of EFS at 30 months was 68.9% for PI-MRD+ve and 41.1% for PI-MRD-ve patients(Fig-1), while there was no significant difference in 30-month OS, which were 78.7% and 77.9% respectively. Most relapsed/ refractory patients were unable to undergo intensive salvage regimens and/ or hematopoietic stem cell transplants due to socio-economic constraints. When their disease progressed, they were mostly sent home on palliative care on an oral metronomic chemotherapy protocol, on which they survived for varying periods of times. PC-MRD was available in 90 PI-MRD+ patients, and was positive in 28(31%), with median MRD level of 0.055% (range:0.0008-27.6%). PC-MRD+ve patients had significantly shorter RFS (median-14.3 months, 95% CI:7.1-49.7 months), with risk of relapse HR of 2.36 (95% CI:1.6-3.47; p<0.0001). Univariate and multivariate analysis using Cox-hazard model for age, hyperleukocytosis and ETP-immunophenotype showed that PI-MRD was the most significant and an independent high-risk factor for relapse with HR for multivariate analysis being 5.5(95% CI:2.85-11.45; p<0.0001). Conclusion: We conclude that 10-color FC-MRD done Post-Induction and Post-Consolidation detecting any residual disease reliably identifies those at highest risk of relapse and any other event. PI-MRD+ is an independent, and also the most important risk-factor for any event, and if PC-MRD is also positive, relapse occurs early. Figure 1 Disclosures No relevant conflicts of interest to declare.

Disease Response Guiding Therapy in Acute Lymphocytic Leukemia: Pivotal Role of Minimal Residual Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-34-SCI-34
Author(s):  
Michael A. Pulsipher
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Lower Risk ◽  
Residual Disease ◽  
Response To Therapy ◽  
Risk Patients ◽  
Very High ◽  
Minimal Residual ◽  
Risk Of Relapse

In spite of an explosion of data regarding mutations associated with childhood ALL, to date these key genetic changes rarely have been the driver of therapy. Clinical parameters at presentation (WBC, age, T- vs. B-lineage, etc.) have dictated initial risk stratification and induction approaches, followed by risk-adapted therapy based upon leukemic response measured by minimal residual disease (MRD, either PCR- or flow cytometry-based). With minor variations, rapid disappearance of peripheral MRD, followed by significant clearance from the marrow after induction, and most importantly, the level of MRD after consolidation have allowed clear distinctions in outcomes that have driven intensification or de-intensification of therapy resulting in improved outcomes. Although specific gene mutations have been associated with risk, MRD has further identified better risk patients within genetic subgroups. For patients noted to be very high risk who are candidates for hematopoietic cell transplantation (HCT), the presence of MRD both pre- and post-transplant has been associated with increased risk of relapse; the risk being modified by level of MRD, whether or not GVHD occurs after HCT, and timing after HCT when MRD is measured. In lower risk patients being treated with chemotherapy and higher risk patients eligible for HCT, more sensitive approaches to flow cytometry and PCR, as well as next-generation sequencing (NGS) MRD approaches (sensitive to 1/10^7 cells) are currently being tested. It is not clear yet whether NGS-MRD offers substantial improvements in patients treated with chemotherapy, as broad-based testing is underway; the latest comparative outcomes will be presented. There is evidence of a striking improvement in our ability to define patients who will do very will after transplant (not relapse), and preliminary evidence that post-HCT NGS MRD testing is more sensitive that other methodologies in defining risk of relapse after transplant. As the latest information about the ability of different approaches to MRD is shown in this session, we will also present how response to therapy based upon MRD interacts with various genetic subtypes (Ph+ ALL, extreme hypodiploidy, etc.). Even in subclasses that are considered very high risk based solely upon genetics, measurement of MRD can define higher and lower risk groups. Going forward, as more and different types of patients are subcategorized and treated with targeted agents based upon specific mutations, it is likely MRD response will continue to be important in mapping intensity of approach and defining children at highest risk of relapse who might benefit from HCT or other cellular therapeutic approaches. Disclosures Pulsipher: Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Post-Induction Undetectable Minimal Residual Disease at 10 -5 Sensitivity Level within Marrow and/or Stem Cell Graft Overrides Cytogenetic High Risk

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2909-2909
Author(s):  
Guldane Cengiz Seval ◽  
Klara Dalva ◽  
Dilek Oz ◽  
Sule Mine Bakanay ◽  
Ender Soydan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Post Induction ◽  
Sensitivity Level ◽  
Stem Cell Graft ◽  
The Impact ◽  
Minimal Residual

Abstract Introduction: Post-induction minimal residual disease (MRD) within but not outside (peripheral blood/stem cell graft) of marrow among transplant eligible patients with multiple myeloma (MM) is currently recognized as poor-prognostic. Emerging number of studies are evaluating MRD within the context of cytogenetic risk. In this study we aimed to quantify circulating plasma cells (PCs) by flow in apheresis products (graft=gMRD) and compare with marrow MRD(mMRD) and outcome according to cytogenetics. Patients & Methods: Four hundred eleven subsequent newly diagnosed multiple myeloma (NDMM) patients transplanted (AHCT) between September 2006 - June 2021 were included prospectively. Standard-risk cytogenetics(SR) is defined as t(11;14), t(6;14), or a normal karyotype , whereas del(17p13), t(4;14), t(14;16), t(14;20), + 1q21 and complex findings are high-risk cytogenetics (HR). In the sample drawn for HPSC quantification of the graft and bone marrow, the number of clonal PCs were quantified by Flow. CD27 PC7 orCD27 A750, CD56 A700, CD19 ECD, CD38 FITC orCD38 A750, CD138 APC, CD45 KO, CD81 PE, CD117 PC7, polyclonal Rabbit Anti-Human Kappa or Lambda Chains /FITC antibodies and acquisition of at least 10 5 cells per tube Analysis was performed using the Navios Flow Cytometer (3L10C, Beckman Coulter) using the Kaluza software (Beckman Coulter, USA) according to the criteria defined by Montero et al and also abnormal distribution of kappa vs. Lambda expression. Undetectable MRD was defined as absence of clonal PCs at a sensitivity of 10 -4 prior to 2017(n=217) and 10 -5 after 2017(n=131). MRD assessment is similar in the graft and marrow. Impact of postinduction MRD analysis was performed in 131 patients with MRD data of 10 -5 sensitivity level. Results were reported in the intention-to-treat (ITT) population for mMRD. Results: Median follow-up after AHCT was 61.5 months (range:3.2-168) (prior to 2017) and 17.7 months (range: 3-47.4) (after 2017). Induction regimen consisted of bortezomib without or with immunomodulatory drug (IMID) 78.8%, 2.8% (prior to 2017) and 74.1%, 22.9% (after 2017). Consolidation 18% (n=39/217), 22.1% (n=29/131) (prior and after 2017) and maintenance 21.2% (n=46/217), 35.1% (n=46/131) (prior and after 2017) were administered based on the response to AHCT. Cytogenetically HR was observed 14.1% (n=47) (among total cohort) and 15.8% (n=19) (after 2017 cohort). Post-induction biochemical response distribution among patients with undetectable MRD are shown in Table-1. MRD assessments were performed at a sensitivity of 10 -4 and 10 -5 in graft (n=147 and 76), marrow (n=18 and 4) or both (n=52 and 51). A statistically significant correlation was detected between marrow and graft MRD only at sensitivity level 10 -5 (SE: 0.638, p&lt;0.001). Additionally, correlations between CR and gMRD (Kappa coefficient (SE): -0.284, p=0.03); CR and mMRD (SE: -0.452, p:0.001) were found. Since marrow and graft MRD results are correlated, all graft and marrow results were merged for the multivariate analysis (MVA) (Table-2). Having undetectable vs detectable MRD in either graft or marrow estimates a 2 years-PFS of 83.6% vs 46.5% (p=0.007). Among 42 MRD(-) patients, only four (two with HR)have relapsed. There is a tendency for better two year probability of PFS with undetectable mMRD vs gMRD at 10-5 ( not reached vs 84.7% ; ns)(Figure 1). The patients (after 2017) are divided into four groups according to MRD status and cytogenetic risk stratification: MRD(-)SR (n=35; 29.2%), MRD(-)HR (n=7; 5.8%), MRD(+)SR (n=66; 55%), MRD(+)HR (n=12; 10%). Kaplan-Meier curves revealed significant differences in PFS among these groups (p=0.03) (Figure-2). Conclusion: Our real-world triplet drug induction-based experience shows for the first-time post-induction mMRD and MRD to be correlated with each other and with PFS. PFS with MRD(-) at 10 -5 results have displayed a better outcome compared to 10 -4. MVA showed MRD and age to determine PFS, independent from post-induction CR, ISS and cytogenetic risk. Although observed less frequently, achieving post-induction MRD(-) either in graft or marrow may ameliorate the poor prognosis of HR. With improvement in induction it may be possible to achieve more frequent MRD(-) and thus analyze the impact of each cytogenetics risk group ie 1q amplification separately. Furthermore, MRD in graft may be a non-invasive therapeutic efficacy tool which is subject to less sampling variation. Figure 1 Figure 1. Disclosures Beksac: Amgen,Celgene,Janssen,Takeda,Oncopeptides,Sanofi: Consultancy, Speakers Bureau.

Minimal residual disease at end of induction and consolidation remain important prognostic indicators for newly diagnosed children and young adults with very high-risk (VHR) B-lymphoblastic leukemia (B-ALL): Children’s Oncology Group AALL1131.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10004-10004
Author(s):  
Wanda L. Salzer ◽  
Michael James Burke ◽  
Meenakshi Devidas ◽  
Yunfeng Dai ◽  
Nyla A. Heerema ◽  
...  
Keyword(s):  
Young Adults ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Post Induction ◽  
Children And Young Adults ◽  
Very High ◽  
Minimal Residual

10004 Background: Children and young adults with very high risk (VHR) B-acute lymphoblastic leukemia (B-ALL) [13-30 years of age with any features or 1-30 years of age with adverse prognostic features including KMT2A rearrangements, iAMP21, hypodiploidy (<44 chromosomes/DNA index < 0.81), central nervous system disease, end of induction (EOI) minimal residual disease (MRD) >0.01%, or induction failure] collectively have a predicted 4-year disease free survival (DFS) of approximately 70%. Whether patients with VHR B-ALL who are MRD positive at EOI and become MRD negative at the end of consolidation (EOC) will have improved survival versus patients remaining MRD positive at EOC is unknown. Methods: Patients with newly diagnosed NCI high risk B-ALL enrolled on AALL1131 or NCI standard risk B-ALL enrolled on AALL0932 and classified as VHR at EOI were treated on the VHR stratum of AALL1131 which sought to improve DFS with intensive post-Induction therapy using fractionated cyclophosphamide (CPM), etoposide (ETOP) and clofarabine (CLOF).Patients were randomly assigned post-Induction to Control Arm (CA) with modified augmented BFM CPM + fractionated cytarabine + mercaptopurine, Experimental Arm 1 (Exp1) with CPM + ETOP, or Experimental Arm 2 (Exp2) with CLOF + CPM + ETOP during Part 2 of Consolidation and Delayed Intensification. Doses of vincristine and pegaspargase were identical on all arms. Exp2 was permanently closed September 2014 due to excessive toxicities, and these patients are excluded from this report. MRD was measured by 6-color flow cytometry at EOI and for those who consented at the EOC. Results: 4-yr DFS for all patients (n=823) with VHR B-ALL was 76.8 ± 2.0%. As we reported previously, 4-year DFS was not significantly different between CA and Exp 1 (85.5 ± 6.8% versus 72.3 ± 6.3%; p=0.76; Burke, Haematologica 2019). 4-yr DFS for patients who were EOI MRD <0.01%, (n=325) versus >0.01 (n=498) was 83.3% ± 2.6% vs 72.0% ± 2.8%, p=0.0013. 4-Year DFS of Patients EOI MRD > 0.01%. Conclusions: MRD is a powerful prognostic indicator in VHR B-ALL with inferior outcomes in patients who are EOI MRD positive. Among patients who were EOI MRD positive treated on Exp1, outcomes were similar for EOC MRD negative and EOC MRD positive, though numbers were small. In contrast, patients who were EOI MRD positive treated on CA that were EOC MRD negative had significantly improved DFS compared to those that were EOC MRD positive. The CA remains the standard of care for COG ALL trials. With this therapy, patients with VHR B-ALL that are EOI MRD positive and EOC MRD negative have significantly improved DFS compared to those that remain MRD positive at EOC. Clinical trial information: NCT02883049. [Table: see text]

Identification of Post-Induction Minimal Residual Disease by Multidimensional Flow Cytometry Identifies Patients with AML at High Risk of Relapse and Poor Outcome- a Report From the Children's Oncology Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1702-1702
Author(s):  
Soheil Meshinchi ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Phoenix A. Ho ◽  
Alan S. Gamis ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Patient Specific ◽  
Intermediate Risk ◽  
Oncology Group ◽  
Childhood All ◽  
Post Induction ◽  
Minimal Residual

Abstract Abstract 1702 Multidimensional flow cytometry (MDF) is used to identify risk in childhood ALL; however, its utility in AML has been limited. We used 4-color MDF with standard (rather than patient-specific) panels to evaluate diagnostic and postinduction bone marrow specimens from patients treated on Children's Oncology Group (COG) study AAML03P1 for evidence of minimal residual disease (MRD). A total of 254 patients submitted marrow specimens for MRD assessment at the end of induction I, the end of induction II, and the end of therapy. Of the 222 patients with evaluable specimens at the end of induction I, 191 (86%) were in morphologic remission, and 27 (12.2%) had persistence of morphologic disease, 3 had persistent CNS disease and 1 was not evaluable for response. Of those with morphologic disease, 15 were in partial remission (PR, 5%-20% blasts), and 12 had refractory disease (RD, >20% blasts). MDF of specimens showing morphologic disease revealed that 7 (26%) did not have evidence of disease; thus, MDF identified patients with reported morphologic disease who did not have immunophenotypic evidence of disease. Overall, in 222 patients with evaluable marrow at the end of induction I, 69 (31%) had evidence of various levels of MRD by MDF (% blast range, 0.02%-43%, median, 1.5%). For the 208 patients with known cytogenetic data, the presence of MRD was evaluated in the following cytogenetic subgroups: favorable risk, defined as t(8;21) or inv(16) (the Core Binding Factor leukemias); unfavorable risk, defined as –5/del(5q) or –7; and intermediate risk, defined as all other cytogenetic subtypes. MRD prevalence at the end of Induction I in patients with favorable, intermediate-risk, or high-risk cytogenetics was 13%, 36%, and 67%, respectively. Prevalence of MRD at the end of induction I was 50% (10/20) in patients with FLT3/ITD, 40% (4/10) in patients with CEBPA mutations, and 0% (0/5) in patients with NPM1 mutations. Of the 222 patients with evaluable specimens at the end of induction I, 191 had morphologic response to the initial chemotherapy. Of those, 57 (28%) had evidence of disease by MDF. Cumulative relapse risk (RR) and disease-free survival (DFS) was assessed in those with or without MRD. Those with MRD at the end of induction I had a RR at 3 years from the end of induction of 60% vs. 29% for those without MRD (p <0.001). DFS was 32% for those with MRD and 65% for those without MRD (p<0.001). In a multivariate analysis, which included cytogenetic and molecular risk factors, the presence of MRD was highly associated with outcome and was an independent predictor of relapse (p<0.001) and worse survival (p<0.001). We further evaluated the significance of clearance of residual disease. Of the 91 patients evaluated for MRD at the end of therapy, 7 (8%) were MRD-positive (6 of whom relapsed). Of the 84 patients who were MRD-negative, 22 (26%) had previously documented MRD. For those with a history of MRD, RR from the end of therapy was 64%, and for those without previous MRD, it was 25% (p<0.001). Therefore, despite clearance of MRD, patients with previous MRD had a high RR. Given the high correlation of MRD with RR, MDF assessment of post-induction response should be incorporated into AML clinical trials for risk identification and assignment to the appropriate risk-based therapy. Disclosures: No relevant conflicts of interest to declare.

Minimal Residual Disease Assessment by Flow Cytometry In AML Patients at Time of Aplasia Post-Induction Is Highly Predictive of Outcome and Strongly Correlates with Molecular MRD In a Subgroup of NPM1 Positive Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1723-1723 ◽  
Author(s):  
Daniela Sauter ◽  
Katharina Ringel ◽  
Jan Braess ◽  
Wolfgang Hiddemann ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Induction Therapy ◽  
Residual Disease ◽  
Therapeutic Strategies ◽  
Initial Diagnosis ◽  
Relapse Free Survival ◽  
Prognostic Information ◽  
Free Survival ◽  
Post Induction ◽  
Minimal Residual

Abstract Abstract 1723 Background: Quantification of minimal residual disease (MRD) by multiparameter flowcytometry (MFC) in patients with acute myeloid leukemia (AML) provides significant prognostic information. Previous analyses have shown that positivity of leukemia-associated aberrant immunophenotype (LAIP) after induction and consolidation therapy is a risk factor concerning relapse and reflects over-all survival and relapse-free survival. Albeit molecular MRD monitoring has translated into therapeutic strategies in certain AML subgroups, e.g. APL, flowcytometric MRD assessment is still not integrated into therapeutic strategies. Methods: We performed a retrospective analysis of flowcytometric MRD data of 201 adult patients with AML. Patients were treated within the clinical study of the German AML cooperation group (AMLCG99 or sHAM); patients with APL were excluded. 165 patients were in the intermediate risk group according to karyotype; NPM1 and Flt3 positivity was present in 80 and 59 patients, respectively. 51% of patients relapsed in the course of disease, the median overall survival (OS) and relapse-free survival (RFS) were 518 and 292 days, respectively. MRD assessment by 3-color-flowcytometry was performed at initial diagnosis, during bone marrow aplasia (day 16 – 18 of induction therapy), after induction, after consolidation and at time of relapse. MRD flow was compared to molecular MRD assessment in patients with mutated NPM1. Results: Data on flowcytometric MRD assessment were available in 99% of patients at initial diagnosis, 74% on day16 of induction therapy, 80% post-induction, 42% post-consolidation and 62% at time of relapse. MRD positivity was defined as percentage of LAIP positive cells > 0,15%. In addition, the post-therapeutic degree of LAIP reduction compared to initial diagnosis was assessed: an indequate degree of LAIP reduction was set at a log difference (initial diagnosis/ day16) < 2. We could confirm that flowcytometric MRD predicts OS and RFS. The absolute level of MRD as well as the relative degree of MRD reduction on day16 of induction therapy defined significantly distinct risk groups concerning OS and RFS (OS: p = 0,03, RFS: p = 0,002). Discriminating the different types of LAIPs, we could demonstrate that cross-lineage phenotypes have the best sensitivity and specificity for predicting relapse (sensitivity 64%, specificity 88% on day16). The course of LAIP and NPM1 as assessed by rtPCR, highly correlates on day16 (correlation coefficient 0,84). Conclusion: Flowcytometric MRD assessment provides significant prognostic information at a very early point in induction therapy. In a subpopulation of NPM1+ AML patients we found a strong correleation of flowcytometric MRD and molecular MRD assessment. LAIP reduction on day 16 post-induction could therefore be integrated into prognostic models and can improve risk stratification especially in the absence of molecular MRD markers. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clearance of Somatic Mutations at Remission and the Risk of Relapse in Acute Myeloid Leukemia

2018 ◽  
Vol 36 (18) ◽  
pp. 1788-1797 ◽  
Author(s):  
Kiyomi Morita ◽  
Hagop M. Kantarjian ◽  
Feng Wang ◽  
Yuanqing Yan ◽  
Carlos Bueso-Ramos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Residual Disease ◽  
Event Free Survival ◽  
Free Survival ◽  
Minimal Residual ◽  
Risk Of Relapse ◽  
Acute Myeloid

Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5%; MC1.0: if the VAF was < 1%; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75% v 61% in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77% v 60% in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26% v 46% in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24% v 46% in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry–based minimal residual disease revealed that patients with CMC had significantly better event-free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.

Improved Outcome of Adult Acute Lymphoblastic Leukemia Treated with Individualized Protocol Adjusted to the Status of Minimal Residual Disease and Age. Interim Analysis of PALG ALL 5–2007 Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2138-2138
Author(s):  
Sebastian Giebel ◽  
Jerzy Holowiecki ◽  
Malgorzata Krawczyk-Kulis ◽  
Krystyna Jagoda ◽  
Jaroslaw Piszcz ◽  
...  
Keyword(s):  
High Risk ◽  
Minimal Residual Disease ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Minimal Residual ◽  
Improved Outcome

Abstract Abstract 2138 In a previous study by the Polish Adult Leukemia Group (PALG 4–2002) we demonstrated that status of minimal residual disease (MRD) during induction-consolidation is the most important factor predicting long-term outcome of adult ALL (Br J Haematol 2008). In a new PALG 5–2007 protocol the treatment was intensified for patients with MRD level >0.1% of bone marrow cells and adjusted to age. Induction consisted of Epirubicine(4×), Vincristine(4×), Prednisone and PEG-asparaginase. Patients with complete remission (CR) but MRD >0.1% obtained additional 2nd phase of induction: AraC+Cyclophosphamide(Ctx) + 6MP. Consolidation consisted of 2 courses of Methotrexate(Mtx) + Etoposide + Dexamethasone and subsequent 2 cycles of Ctx + high dose AraC, asparaginase, intrathecal prophylaxis and CNS irradiation. Doses of Mtx were 500 mg/m2 for patients with MRD<0.1%, aged >35y and 1500 mg/m2 for all remaining ones. For Ph+ ALL imatinib 600 mg/d was administered in parallel to chemotherapy. Patients with standard risk disease continued with 2 years maintenance while those with high-risk were referred for alloHSCT. High risk was defined as the presence of at least one of: initial WBC >30×10e9/L, age >35y, pro-B, early-T, mature-T, late CR, t(9;22), t(4;11) or MRD >0.1% at any time during induction-consolidation. Results of PALG 5–2007 protocol (N=108, median age 32y, range 16–55y) were compared to PALG 4–2002 (N=253, age 28y, range 16–55y), in which MRD status was not taken into account for treatment decisions. CR rate was 92% for PALG 5–2007 compared to 89% for PALG 4–2002. The probability of the overall survival at 36 months was 56% vs. 33% (p=0.02), while leukemia-free survival was 53% vs. 28% (p=0.04), respectively. The probability of relapse decreased from 54% in PALG 4–2002 to 16% in PALG 5–2007 (p=0.002). In a multivariate analysis adjusted to age, initial WBC and the presence of t(9;22) treatment according to PLAG 5–2007 protocol was associated with decreased risk of mortality (HR=0.57, p=0.02), relapse (HR=0.37, p=0.006) and treatment failure (HR=0.64, p=0.049). We conclude that individualized therapeutic approach with treatment intensity adjusted to MRD status and age may result in improved outcome of adults with ALL. *This multi-institutional study was supported by Polish Ministry of Sciences Grant NN-402366433 Disclosures: Off Label Use: Dasatinib as first line therapy in Ph ALL.

scholarly journals Early Detection of WT1 Measurable Residual Disease Identifies High-Risk Patients Independently of Transplantation in AML

2021 ◽  
Author(s):  
Juliette Lambert ◽  
Jerome Lambert ◽  
Xavier Thomas ◽  
Alice MARCEAU-RENAUT ◽  
Jean-Baptiste Micol ◽  
...  
Keyword(s):  
High Risk ◽  
Prognostic Value ◽  
Residual Disease ◽  
Free Survival ◽  
High Risk Patients ◽  
Post Induction ◽  
Potential Marker ◽  
Risk Patients ◽  
Measurable Residual Disease ◽  
Risk Of Relapse

WT1 overexpression is frequently identified in acute myeloid leukemia (AML) and has been reported as a potential marker for measurable residual disease (MRD) monitoring. Here, we evaluated the value of post-induction WT1 MRD level as a prognostic factor, as well as the interaction between post-induction WT1 MRD response and the effect of allogeneic stem cell transplantation (allo-SCT) in first complete remission (CR). In the ALFA-0702 trial, AML patients aged 18 to 59 years had a prospective quantification of WT1 MRD. Occurrence of a WT1 MRD ratio &gt;2.5% in bone marrow or &gt;0.5% in peripheral blood was defined as MRDhigh, while ratio under these thresholds was defined as MRDlow. The prognostic value of MRD after induction chemotherapy was assessed in 314 patients in first CR by comparing the risk of relapse, the relapse-free survival (RFS) and the overall survival (OS). Interaction between MRD response and allo-SCT effect was evaluated in patients by comparing the influence of allo-SCT on the outcomes of patients with MRDhigh and MRDlow. We showed that MRDhigh patients after induction had a higher risk of relapse and a shorter RFS and OS. MRD response remained of strong prognostic value in the subset of 225 patients with intermediate/unfavorable-risk AML, eligible for allo-SCT, since MRDhigh patients had a significantly higher risk of relapse resulting in worse RFS and OS. Effect of allo-SCT was higher in MRDlow patients than in MRDhigh patients but not statistically different. Early WT1 MRD response highlight a population of high-risk patients in need of additional therapies.

scholarly journals Quantitation of Minimal Residual Disease in Acute Myeloid Leukemia by Tryptase Monitoring Identifies a Group of Patients with a High Risk of Relapse

2005 ◽  
Vol 11 (18) ◽  
pp. 6536-6543 ◽  
Author(s):  
Wolfgang R. Sperr ◽  
Margit Mitterbauer ◽  
Gerlinde Mitterbauer ◽  
Michael Kundi ◽  
Ulrich Jäger ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Minimal Residual ◽  
Risk Of Relapse ◽  
Acute Myeloid

Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML to reduce risk of relapse.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7018-7018
Author(s):  
Prajwal Boddu ◽  
Jeffrey L. Jorgensen ◽  
Hagop M. Kantarjian ◽  
Gautam Borthakur ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Cumulative Risk ◽  
Detection Sensitivity ◽  
Hypomethylating Agents ◽  
Color Flow ◽  
Free Survival ◽  
Minimal Residual ◽  
Risk Of Relapse

7018 Background: Persistence of minimal residual disease (MRD) post therapy is a powerful predictor of outcome in patients with AML treated with traditional cytarabine and anthracycline based regimens. The clinical relevance of MRD in the context of hypomethylating agents has not been evaluated extensively. Methods: Among 194 patients with AML treated with single agent azacytidine, decitabine, or gaudecitabine, 116 (median age 76, range 60 - 92) had MRD analysis performed on bone marrow specimens obtained at time of assessment of response or thereafter; among them 69 (59%) achieved either morphologic complete remission (CR) or CR with incomplete recovery of platelets (CRp) or counts (CRi), and 61 (53%) had evaluable MRD data; MRD was assessed using an 8-color flow panel, with a detection sensitivity of 0.01%. Results: Median cycles to achieving response was 2 (range, 1-6). Sixty one patients had evaluable MRD data at the time of response, of whom 19 (28%) became MRD negative (-). This was associated with a reduced cumulative risk of relapse (p = 0.012) but did not translate to an improved relapse-free survival (RFS; p = 0.17) or overall survival (OS; p = 0.79) due to high frequency of non-relapse deaths (attributable to comorbidities and infections) in the MRD- group. Patients who achieved a MRD- state at the time of achieving response had a higher mortality [5/8 (62%)] when compared with those who achieved a MRD- state in subsequent cycles [1/13 (7.6%); p = 0.01], resulting in an inferior OS (6.2 months (mo) vs 20 mo, p = 0.012). Similarly, achieving negative MRD at CR and at any time up to 3 months post response was not associated with improved RFS or OS despite a lower cumulative risk of relapse (p = 0.045). There was no impact of MRD, on OS, whether the MRD- state was achieved after 1st, 3rd or 6thcycle of therapy. Association between depth of MRD response at time of remission and RFS was borderline significant (p = 0.08). On multivariate analysis, response (CR vs CRi/CRp), but not a negative MRD, was predictive for RFS or OS. Conclusions: In this cohort of older AML patients treated with hypomethylating agents, achieving a MRD- state was associated with a reduced risk of relapse but not improved RFS or OS.

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