EHA 2019 round up — MRD

Approximately 50% of patients with AML will relapse after achieving complete remission (CR) with induction chemotherapy.¹ Even small amounts of residual tumor cells after chemotherapy induction predispose to relapse. Measurable (minimal) residual disease (MRD), referred to as submicroscopic disease during or after therapy, has recently received lots of attention.

Accumulating evidence has shown that MRD is a strong prognostic marker for relapse and patient outcomes in various hematological malignancies. It is evident that MRD has a strong clinical value for all AML patient populations, and it helps clinicians decide between the use of further treatment or transplant in patients with AML who relapse after initial treatment.

The MRD topic featured in many reports presented during the last year’s annual meeting of the European Hematology Association (EHA). With the next annual EHA meeting fast approaching, we are going to see more reports on this topic, including updates on results from the phase IB/II study investigating ivosidenib with venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies, phase 1B results of magrolimab combined with azacitidine, and an update on the NCRI AML18 trial.

In this article we have created a summary of the highlights on this topic, with expert interviews and articles we have covered since the last EHA meeting.

The EHA annual meeting

What impact does MRD status have on the outcomes of patients with AML undergoing allo-HSCT?

Richard Dillon from King's College, London, UK, talked about the impact of MRD status on the outcomes of patients with AML undergoing allogeneic stem cell transplantation (allo-HSCT).

Dr. Dillon explained that patients who have a stem cell transplant for AML, and then relapse, have very poor outcomes with fewer than 20% of patients achieving long-term survival. He emphasized that there is a lot of interest in trying to identify patients who are at high-risk of relapse after transplant, so that physicians can intervene and improve survival rates.

Over the years a lot of studies looked at MRD pretransplantion, and when this is measured using flow cytometry. The studies have found that patients who test positive have an extremely high-risk of relapse. Another method used to measure MRD, that Dr. Dillon explained, is polymerase chain reaction (PCR), which has been used to test 107 patients in the UK, in the AML17 trial. This trial assessed the MRD status of patients by PCR prior to transplant; this was important because the PCR test is more sensitive than MRD testing by flow cytometry.

The study found that a group of patients who had MRD+ that have levels below a defined threshold; therefore, identifying patients who do not need any interventions. On the other hand, Dr. Dillon and his colleagues identified another group of patients who had high-levels of MRD, and patients with FLT3 mutations with any level of MRD, who had extremely poor outcomes after transplant, with only 17% of survival at 2 years after transplant.

Dr. Dillon and his team were able to define a population of patients that were at high-risk of relapse, which can lead physicians to test for interventions that will ultimately reduce the risk of patients relapsing.

Another study presented during the meeting was the AMLSG study, which aimed to correlate the molecular MRD status with outcome. They studied patients with AML featuring recurrent genetic abnormalities (RUNX1-RUNX1T1 fusion gene), quantifying RUNX1-RUNX1T1 transcription levels (TL) in bone marrow (BM) and peripheral blood (PB), at various treatment stages.

The results from these studies suggest that a refined practical guideline for MRD assessment in AML is needed. The AM17 study demonstrated that in patients with NPM1-mutant AML, MRD negativity prior to transplant predicted the outcome, with above 200 copies/10⁵ of Abelson murine leukemia viral oncogene homolog gene (ABL) in the PB, or 1,000 copies in the BM, indicating an adverse outcome. Below this level, FLT3-ITD and postinduction PB status were strongly associated with a poor outcome. T-cell depletion was also associated with an adverse outcome in patients who were MRD-positive.

In RUNX1-RUNX1T1-positive AML, MRD monitoring allows for the discrimination of patients at high- and low-risk of relapse. Therefore, MRD in BM and PB should be analyzed after each treatment cycle and in the follow-up according to MRD status, as below:

• MRD-negative: PB monthly
• MRD-positive (TL < 150 in BM and < 50 in PB): BM 3-monthly, and PB monthly
• MRD-positive (TL > 150 in BM and/or > 50 in PB) or increase of MRD > 1-log, or conversion from MRD-negative to MRD-positive: BM and PB monthly

This study also noted very short latency from molecular to morphologic relapse, indicating that MRD assessment at shorter intervals during the first-year posttreatment is indispensable.

More details about the studies are available in an article here.

1st NCRI AML academy meeting

Prof. David Grimwade was one of the pioneers establishing the value of MRD for treatment management. He was one of the first experts to extend the use of MRD from other malignancies, like acute promyelocytic leukemia to AML. His belief in tailoring therapy in AML had a global impact, and provided a prime example advancing basic science that could rapidly be applied to clinical practice. Today, multiple clinical investigations are underway to determine the exact MRD protocols needed to successfully guide posttreatment therapeutic strategies in AML. You can watch the lecture here.

SOHO 2019

During the annual meeting of the Society of Hematologic Oncology (SOHO), held in Houston, US, Pau Montesinos, Hospital La Fe, ES, discussed the latest data regarding the use of MRD in AML.

Although many trials have confirmed that CR with detectable MRD is not better than partial remission, Dr Montesinos pointed out that there is currently no gold standard for the use of MRD in the treatment of AML. To date, MRD has only formed an exploratory endpoint for clinical trials. Currently, Dr Montesinos’s recommendation is to use MRD in well-defined interventional trials, and for research purposes. You can access the article here.

MRD-driven treatment in patients with newly diagnosed intermediate-risk AML

The GIMEMA AML1310 trial was the first study that attempted to apply a prospective program of risk-adapted, MRD-driven treatment in patients with newly diagnosed intermediate-risk AML, that integrated genetics and post-consolidation assessment of MRD status. The data demonstrated that allo-HSCT can be avoided in patients who tested MRD-negative after induction therapy. In contrast, in patients who were MRD-positive, allo-HSCT improved overall survival and prolonged disease-free survival, to comparable levels as those of patients in the favorable-risk group. More details about the study design and results are available here.

MRD detection methods

Part of the MRD debate is about the sensitivity of the detection methods used to detect remaining leukemic cells, which varies between technologies and at the threshold to define MRD-negativity; which can help to predict the risk of relapse. During the European School of Hematology Translational Research Conference on AML, we interviewed two experts about new developments in the techniques used for MRD detection. Jacqueline Cloos, VU University Medical Center, NL, gave an update on what is new in the flow cytometry assessment of MRD. She discussed how clinically validated MRD can be improved to act as a surrogate endpoint in clinical trials.

What's new in flow cytometry assessment of MRD?

Paresh Vyas, University of Oxford, UK, gave his opinion on when to use single-cell MRD assessment in AML. He discussed the role of MRD monitoring in informing clinical practice, and reviewed different approaches such as next-generation sequencing, flow cytometry, and single-cell measurement of disease.

When do you use single-cell MRD assessment in AML?

A review of the latest developments in the technologies used for MRD detection, and MRD guided timing of allogenic transplantation for AML, is available here.

MRD monitoring can predict treatment outcomes

The presence of MRD after induction chemotherapy is a strong and independent prognostic marker of increased risk of relapse and shorter survival in patients with AML, and can be used to stratify risk and assess treatment response. In two of the latest studies, presented at the 61st American Society of Hematology Annual Meeting & Exposition, US, in December 2019, MRD was used to predict the relapse after HSCT. 

The summary of risk-adapted post-remission treatment allocation in the AML12 trial, and MRD monitoring being able to predict relapse after allo-HSCT, is available here.

Earlier this year, a study found that the MRD status could also predict outcome in patients with NPM1-mutated AML. You can read the whole article here.

Clonal hematopoiesis and monitoring treatment effect using MRD

The persistence of certain mutations after treatment can be difficult to interpret with regard to the likelihood of disease recurrence, as some mutations occur as either a somatic mutation in an AML clone or as a germline mutation. While successful treatment would eliminate an AML clone with a somatic mutation, germline mutations would persist. Exploring the clinical implications of detectable mutations in treated AML is further impeded by the lack of consistency in the terminology used.

In a perspective recently published by Robert Hasserjian and colleagues, discuss the types of clonal hematopoiesis (CH) detected posttreatment in patients with AML , including the molecular markers associated with true residual AML disease. The authors also proposed a standardized terminology for distinct types of CH. You can read more here.

Conclusion

Despite its advantages, the adoption of MRD assessments in standard clinical practice has been slow so far, partly due to a lack of standards regarding the use of various techniques, the source of cells, and the best time-points for assessment, among others. The most commonly used methods to detect MRD are multiparameter flow cytometry (MPFC) and real-time quantitative polymerase chain reaction (qPCR). Two other methods are emerging: digital PCR, and next-generation sequencing. Each methodology has its advantages and disadvantages and needs to be standardized, validated, and improved to be used to guide clinical decision making.

In recent years, a growing interest in MRD determination is raising and this is not surprising, since MRD assessments may help to inform prognosis and treatment decisions. A large number of published studies have shown that patients with MRD-positive AML are at higher risk of relapse, and experience shorter overall survival, compared with MRD-negative patients. Latest data from clinical studies provide exciting prospects for the use of MRD in a more personalized approach to allo-HSCT, in patients with AML.

However, many questions remain. The topic will be discussed during the EHA meeting this year, and we will report any new updates as they become available, so stay tuned.