The first of a series of patient case studies incorporating MRD monitoring Case 1: Normal karyotype AML, NPM1-mutated and FLT3-ITD positive

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.

Patient details

• 45-year-old female, diagnosed in May 2015
• No co-morbidity
• Normal karyotype, NPM1-mutated, FLT3­‑ITD positive (risk stratification according to European LeukemiaNet [ELN] guidelines: intermediate²)
• Randomized to induction: daunorubicin and gemtuzumab ozogamicin (DAGO)
• Neutrophil recovery: Day 27
• Morphology: complete response (CR)

Patient response assessment

The audience voted on how they would assess response:

1. Flow MRD: 16%
2. Molecular MRD for NPM1 mutation: 71%
3. Molecular MRD for FLT3-ITD: 11%
4. MRD is of limited clinical value: 1%

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).

Patient management plan

The audience was asked to select their choice of further consolidation for the patient:

1. No further therapy: 2%
2. 1# cytarabine 1.5 g/m²: 5%
3. 1# cytarabine 3.0 g/m²: 14%
4. 2# cytarabine 1.5 g/m²: 11%
5. 2# cytarabine 3.0 g/m²: 25%
6. Amsacrine, cytarabine and etoposide (MACE) / mitoxantrone and cytarabine (MidAC): 7%
7. Allograft: 15%
8. Fludarabine, idarubicin, granulocyte-colony stimulating factor and cytarabine (FLAG-IDA) then allograft: 22%

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.

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.

Patient management plan

The audience was asked for their opinion on further management:

1. Recheck at Day 60: 14%

2. Reduce immunosuppression: 52%

3. Azacitidine: 14%

4. 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

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.

Patient management plan

The audience was asked for their opinion on further management:

1. Re-check at Day +100: 7%
2. Reduce immunosuppression: 9%
3. Azacitidine: 12%
4. Azacitidine – lenalidomide: 5%
5. Midostaurin: 16%
6. Donor lymphocyte infusion: 46%
7. Second transplant: 5%

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.