Minimal Residual Disease Monitoring by RQ-PCR in Core Binding Factor Positive AML Allows Risk-Stratification and Predicts Relapse: Results of the UK MRC AML-15 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 543-543
Author(s):  
John Ahman Liu-Yin ◽  
Sarah B. Daly ◽  
Michelle A. Sale ◽  
Stuart Green ◽  
Khalid Tobal ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Core Binding Factor ◽  
Transcript Levels ◽  
Log Reduction ◽  
Post Induction ◽  
Binding Factor ◽  
Relapse Rates ◽  
Minimal Residual

Abstract The clinical value of serial Minimal Residual Disease (MRD) monitoring in core binding factor (CBF) positive patients was prospectively assessed in the AML-15 Trial which opened in July 2002. The trial compared 3 induction regimens (DA V/S ADE V/S FLAG Ida), followed by randomisation in consolidation (courses 3 and 4) to either MACE or 2 doses of Ara-C (3g/m2 or 1.5g/m2) and to stop or have a 5th course (Ara-C 1.5g/m2). Patients were also randomised to receive Gemtuzumab Ozogamicin (3mg/m2) at induction and/or consolidation. Over 2500 patients have so far been recruited, with 271 CBF patients (155 t(8;21), 116 inv (16)). Complete remission (CR) and relapse rates (RR) at 4 years were 95% and 19% respectively. CBF transcripts (AML1-ETO for t(8;21), CBFB-MYH11 for inv(16)) from bone marrow (BM) and peripheral blood (PB) were measured by real-time quantitative PCR (RQ-PCR) on the 7900 HT ABI machine, at presentation, after each course of chemotherapy and 3 monthly during remission for 2 years. CBF copies were normalised to ABL gene and expressed per 105ABL. The sensitivity of the RQ-PCR assay was 10−5. Data were analysed in 47 relapsed patients and in 92 patients who were in remission for >1 year. In 66 patients, where the reduction of initial CBF transcript level in BM, following induction chemotherapy, was measured, only 1 of 32 patients with >3 log reduction at remission whereas 20/34 patients with <3 log reduction have relapsed, giving relapse rates of 3% and 61% respectively, (2p<0.00001). With respect to BM post induction transcript levels, in the t(8;21) group (n=50), patients with <500 AML1-ETO copies had a 18% RR compared to 62% for patients with >500 copies (2p=0.003) and in the inv (16) patients (n=38), the RR were 8% and 58% respectively for CBFB-MYH11 copies lower or higher than 100 (2p=0.004). After consolidation and during remission, BM and PB transcript levels were also highly predictive of relapse risk. In t(8;21) patients, all 7 with BM AML1-ETO level >500 copies but only 3/45 patients with <500 copies relapsed (RR 100% V/S 9%, 2p<0.0001). Moreover all 12 patients with PB level >50 copies and only 2/52 patients negative for or with <50 AML1-ETO copies relapsed (RR 100% V/S 4%, 2p <0.00001). In inv (16) patients, 13/13 with >100 CBFB-MYH11 copies in BM and 3/25 patients with <100 copies relapsed (RR 100% V/S 9%, 2p<0.00001). In PB, any positive level resulted in relapse in 18/18 patients compared to 2/29 (RR 7%) with a negative MRD for CBFB-MYH11 (2p<0.00001). The interval between molecular and clinical relapse was ≥3 months and there was a significant correlation between BM and PB MRD levels post induction and at first positivity after consolidation (r>0.40, p<0.05). We conclude that MRD monitoring in CBF AML allows risk stratification based on treatment response, and can predict relapse, thus opening the way to risk-directed or pre-emptive therapy. We propose that MRD monitoring by RQ-PCR should be an integral part of the management of CBF positive AML.

scholarly journals Minimal residual disease eradication with epigenetic therapy in core binding factor acute myeloid leukemia

2017 ◽  
Vol 92 (9) ◽  
pp. 845-850 ◽  
Author(s):  
Brittany Knick Ragon ◽  
Naval Daver ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Epigenetic Therapy ◽  
Core Binding Factor ◽  
Disease Eradication ◽  
Binding Factor ◽  
Minimal Residual ◽  
Acute Myeloid

Minimal Residual Disease Eradication by Azacitidine Maintenance in a Patient with Core-Binding Factor Acute Myeloid Leukemia

Chemotherapy ◽  
2020 ◽  
pp. 1-5
Author(s):  
Orhan Kemal Yucel ◽  
Mustafa Serkan Alemdar ◽  
Unal Atas ◽  
Levent Undar
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
High Sensitivity ◽  
Core Binding Factor ◽  
Hematopoietic Stem ◽  
Real Time Quantitative Pcr ◽  
End Of Treatment ◽  
Binding Factor ◽  
Minimal Residual

Although core-binding factor AML (CBF-AML) has a favorable outcome, disease relapses occur in up to 35% of patients. Minimal residual disease (MRD) monitoring is one of the important tools to enable us to identify patients at high risk of relapse. Real-time quantitative PCR allows MRD to be measured with high sensitivity in CBF-AML. If the patient with CBF-AML is in complete morphologic remission but MRD positive at the end of treatment, what to do for those is still uncertain. Preemptive intervention approaches such as allogeneic hematopoietic stem cell transplantation or intensive chemotherapy could be an option or another strategy might be just follow-up until overt relapse developed. Although using hypomethylating agents as a maintenance therapy has not been widely explored, here, we report a case with CBF-AML who was still positive for MRD after induction/consolidation therapies and whose MRD was eradicated by azacitidine maintenance.

scholarly journals Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial

Blood ◽  
2012 ◽  
Vol 120 (14) ◽  
pp. 2826-2835 ◽  
Author(s):  
John A. Liu Yin ◽  
Michelle A. O'Brien ◽  
Robert K. Hills ◽  
Sarah B. Daly ◽  
Keith Wheatley ◽  
...  
Keyword(s):  
United Kingdom ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Preemptive Therapy ◽  
Rt Pcr ◽  
Core Binding Factor ◽  
The United Kingdom ◽  
Binding Factor ◽  
Minimal Residual

AbstractThe clinical value of serial minimal residual disease (MRD) monitoring in core binding factor (CBF) acute myeloid leukemia (AML) by quantitative RT-PCR was prospectively assessed in 278 patients [163 with t(8;21) and 115 with inv(16)] entered in the United Kingdom MRC AML 15 trial. CBF transcripts were normalized to 105ABL copies. At remission, after course 1 induction chemotherapy, a > 3 log reduction in RUNX1-RUNX1T1 transcripts in BM in t(8;21) patients and a > 10 CBFB-MYH11 copy number in peripheral blood (PB) in inv(16) patients were the most useful prognostic variables for relapse risk on multivariate analysis. MRD levels after consolidation (course 3) were also informative. During follow-up, cut-off MRD thresholds in BM and PB associated with a 100% relapse rate were identified: for t(8;21) patients BM > 500 copies, PB > 100 copies; for inv(16) patients, BM > 50 copies and PB > 10 copies. Rising MRD levels on serial monitoring accurately predicted hematologic relapse. During follow-up, PB sampling was equally informative as BM for MRD detection. We conclude that MRD monitoring by quantitative RT-PCR at specific time points in CBF AML allows identification of patients at high risk of relapse and could now be incorporated in clinical trials to evaluate the role of risk directed/preemptive therapy.

Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia

Blood ◽  
2013 ◽  
Vol 121 (12) ◽  
pp. 2213-2223 ◽  
Author(s):  
Eric Jourdan ◽  
Nicolas Boissel ◽  
Sylvie Chevret ◽  
Eric Delabesse ◽  
Aline Renneville ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Gene Mutations ◽  
Prospective Evaluation ◽  
Core Binding Factor ◽  
Binding Factor ◽  
Key Points ◽  
Postremission Therapy ◽  
Minimal Residual

Key Points In adult patients with core binding factor AML, intensified induction is not associated with a better outcome in the context of intensive postremission therapy. Minimal residual disease, rather than KIT or FLT3 gene mutations, should be used to identify core binding factor AML patients at higher risk of relapse.

Minimal Residual Disease Assessed by WT1 Expression and NPM1 Mutations Specific RQ-PCR Assays Identifies Patients with Distinct Outcomes in the ALFA 0701 Trial and Is Decreased by Treatment with Gemtuzumab Ozogamicin

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 659-659 ◽  
Author(s):  
Juliette Lambert ◽  
Jerome Lambert ◽  
Olivier Nibourel ◽  
Cécile Pautas ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Statistical Significance ◽  
Prognostic Significance ◽  
Gemtuzumab Ozogamicin ◽  
Poor Responders ◽  
Prognostic Impact ◽  
Transcript Levels ◽  
Post Induction ◽  
Minimal Residual

Abstract Abstract 659 Background: NPM1 mutations and WT1 expression are frequently identified in acute myeloid leukemia (AML). Both markers have been reported as suitable molecular target for minimal residual disease (MRD) monitoring. Recently, Gemtuzumab Ozogamicin (GO) has been shown to improve event free survival and overall survival in adult AML. Aims: To follow MRD in AML patients with NPM1 mutations (NPM1mut) and/or WT1 expression (WT1+) and treated in the randomized ALFA 0701 GO trial conducted by the Acute Leukemia French Association (Castaigne et al, Lancet 2012), in order to validate their prognostic significance and to evaluate the effect of GO on MRD response. Methods: The ALFA 0701 trial included 278 patients aged 50–70 years with newly-diagnosed de novo AML, randomized to receive or not five doses of 3 mg/m2 GO, on day 1, 4 and 7 of standard induction chemotherapy and on day 1 of two consolidation chemotherapy courses, respectively. A total of 77 NPM1mut (35 in control arm, 42 in GO arm) and 178 WT1+ (87 in control arm, 91 in GO arm) AML patients were studied. WT1 + at diagnosis was defined as a ratio WT1/ABL transcript above 25% in bone marrow (BM) or 5% in peripheral blood (PB) samples. PB and BM samples were collected at diagnosis, after induction and after each consolidation course. MRD levels were assessed using cDNA-based real-time quantitative PCR (RQ-PCR) and reported as the ratio NPM1mut or WT1 transcript/100 ABL transcript. Occurrence of a MRD level below the threshold (NPM1mut <0.1% and WT1 transcript < 0.5% in PB) was defined here as a good MRD response. The prognostic value of MRD was assessed by comparing the outcome of good versus poor MRD responders after induction in terms of cumulative incidence of relapse (CIR) at 18 months. Effect of GO was then evaluated by comparing MRD response in both treatment arms. Results: 178 patients (favorable cytogenetics: 4%, intermediate: 69%, unfavorable: 27%) were WT1+. WT1 transcript levels at diagnosis had no prognostic impact on complete remission (CR) rate or CIR. In the 104 patients who achieved CR, post-induction WT1 MRD level was predictive of relapse: 18-month CIR was 70% (95%CI: [49% - 84%]) in poor responders (n=31) versus 38% [26% - 50%] in good responders (n=73) (p=0.0001). When adjusted on cytogenetics, randomization arm and FLT3-ITD status, WT1 MRD remained independently associated with relapse (HR: 2.43, [1.25 – 4.75], p=0.009). Similarly, NPM1mut transcript levels at diagnosis had no prognostic impact on CR rate or CIR. Among the 67 NPM1mut patients who achieved CR, post-induction NPM1mut MRD level was predictive of relapse: 18-month CIR was 64% [45% – 70%] in poor responders (n=50) versus 25% [10% – 42%] in good responders (n=17) (p=0.0007). When adjusted on randomization arm and FLT3-ITD status, NPM1 MRD remained independently associated with relapse (HR: 4.2, [1.2 – 14.3], p=0.02). We were able to evaluate both MRD markers in 53 patients after induction (NPM1+/WT1+ n=16, NPM1+/WT1- n=24, NPM1-/WT1- n= 13). 18-month CIR was significantly different in the 3 groups (respectively 69% [38% - 87%], 40% [19% - 60%] and 25% [5% - 51%], p=0.008). In patients with poor MRD response assessed by NPM1mut, the presence of a positive WT1 MRD level was associated with a higher CIR. NPM1 MRD good response was more frequently observed in GO arm as compared to control arm (OR: 4.38 [2.12 – 9.03], p<0.0001). The rate of good NPM1 MRD response was 41% versus 7% after induction, 76% versus 35% and 93% versus 62% after first and second consolidation in GO and control arms respectively. WT1 MRD good response was more frequently observed in GO arm, although not reaching statistical significance (OR: 1.84 [0.89 – 3.77] p=0.098). The rate of good WT1 MRD response was 76% versus 65% after induction, 87% versus 66% and 87% versus 80% after first and second consolidation, respectively in GO and in control arms (figure 1). Conclusion: Our study confirms the predictive value of MRD based on NPM1 mutations and WT1 expression in patients treated in the ALFA 0701 randomized trial. In multivariate analysis, WT1 and NPM1 MRD levels remained independent prognostic factors for relapse. We showed that treatment with GO significantly improved MRD response in adult AML. Disclosures: Castaigne: Wyeth: Consultancy.

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