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During the 1st NCRI AML academy meeting, Dr Richard Dillon from King's College, London, UK, delivered an interactive presentation on measurable residual disease (MRD) implementation through a series of patient case studies.1
Here we present the first case study from a participant in the AML17 trial (EudraCT Number: 2007-003798-16).
Further case studies, from both the clinical trial setting and routine clinical practice, will be published on the AML Global Portal in due course.
The audience voted on how they would assess response:
Dr Dillon highlighted that NPM1 mutations are an ideal MRD target for PCR tracking because they are always located in exon 12 of the NPM gene. The patient’s MRD profile was shown to the audience and after 2 cycles of induction, there was 2–3-log reduction in MRD level in the bone marrow (BM) and >3- log reduction in the peripheral blood (PB).
The audience was asked to select their choice of further consolidation for the patient:
Molecular MRD status provides powerful prognostic information in NPM1-mutated AML.3 Analysis of the AML 17 trial data showed that persistence of NPM1-mutated transcripts in peripheral blood after the second chemotherapy cycle was associated with a significantly higher risk of relapse at 3 years than was the absence of such transcripts (82% vs. 30%; hazard ratio [HR], 4.80; 95% confidence interval [CI], 2.95– 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; HR for death, 4.38; 95% CI, 2.57–7.47; P<0.001).3 |
Another study assessed the prognostic impact of post-induction NPM1-mutated MRD assessment in patients enrolled in the Acute Leukemia French Association 0702 (ALFA-0702) trial.4 The results of the study supported the early monitoring of MRD in NPM1-mutated AML and its use as a treatment decision factor for allogeneic stem cell transplant (allo-SCT). |
With the above studies in mind, it was decided that the patient, who was MRD-positive, would likely benefit from allo-SCT. The next consideration was whether the patient should proceed straight to allo-SCT or receive further therapy prior to transplant.
Patients with high levels of MRD pre-transplant have a poor outcome compared with patients who are MRD negative pre-transplant who have a favourable outcome. However, for patients with low levels of MRD pre-transplant, outcomes are dependent on the FLT3-ITD mutational status: patients without the mutation have a relatively favourable outcome in contrast to FLT3-ITD-mutated patients who have a poor outcome.5 |
In the present case study, although the patient had a low level of MRD, she had the FLT3-ITD mutation at diagnosis, so the decision was made to deliver further therapy (FLAG-IDA) prior to transplant. The patient’s MRD status at Day 30 post-transplant revealed an almost 1-log increase in transcript levels and the peripheral blood remained positive.
The audience was asked for their opinion on further management:
Recheck at Day 60: 14%
Reduce immunosuppression: 52%
Azacitidine: 14%
Sorafenib: 21%
Dr Dillon emphasized the difficulty in clinical decision making in this situation with persistent molecular relapse. He highlighted two studies, the RELAZA2 study and the SORMAIN study which used MRD-guided preemptive therapy in order to prevent or delay relapse in patients.6,7
RELAZA2 (previously reported by the AML Global Portal) was an open-label, multicentre, phase 2 study at nine university health centres in Germany.6 Patients aged ≥18 years with advanced myelodysplastic syndrome or AML, who had achieved a CR after conventional chemotherapy or allo-SCT, were prospectively screened for MRD over 24 months from baseline. MRD-positive patients in confirmed CR received azacitidine 75 mg/m2 per day subcutaneously on days 1–7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. Relapse rates differed significantly depending on whether patients had previously received allo-SCT. Only 8/24 (33%) patients with previous allo-SCT relapsed during the study period compared to 18/29 (62%) patients without previous allo-SCT. However, this result did not translate into a significant difference in RFS (HR 0·5, 95% CI 0·2–1·1, P=0·072) or OS (1·9, 0·6–6·6, p=0·28) between these groups of patients. |
The phase II SORMAIN study (EudraCT 2010-018539-16; previously reported by the AML Global portal) was a randomized, double-blind, placebo-controlled study, evaluating sorafenib – a tyrosine kinase inhibitor – as maintenance therapy after allo-SCT in patients with FLT3-ITD–positive AML. In total, 83 patients (median age 54.0 years; range 18.6–75.6) with FLT3-ITD AML who underwent allo-SCT and were in confirmed complete hematological remission at the time of screening between day +30 and day +100 post-allo-SCT were included. Patients were randomized to receive sorafenib (n = 43; starting dose: 2 x 1 tbl. [2 x 200mg] QD, increasing every 14 days to up to 2 x 2 tbl. [2 x 400mg] QD according to tolerability) or placebo (n = 40) for up to 24 months. After a median follow-up of 41.8 months, 2-year RFS in patients in the sorafenib arm was 85.0% (95% CI, 69.5–93.0) versus 53.3% (95% CI, 36.5–67.5) in the placebo arm (HR = 0.39; 95% CI, 0.183–0.848; P=0.013). After a median follow-up of 55.4 months, OS was significantly longer in patients in the sorafenib arm compared to the placebo arm: HR = 0.447 (95% CI, 0.20–0.97), P=0.03. This was the first study to demonstrate that FLT3 inhibition after allo-SCT was feasible and significantly reduced the risk of relapse and death in patients with FLT3-ITD AML. |
The patient was treated with sorafenib and had a reduction in immunosuppression. Subsequent MRD testing revealed a further 1-log increase in disease-related transcripts.
The audience was asked for their opinion on further management:
Dr Dillon confirmed that the patient received a donor lymphocyte infusion based on the rising MRD titer. The patient then had a complete metabolic response and is still alive in complete medical remission, three years later.
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