Debating the Significance of MRD in Blood Cancers vs Initial Patient Characteristics

In the myeloma space, minimal residual disease negativity is prognostic of progression-free survival in relapsed or refractory patients. In leukemia, the biomarker combined with other prognostication techniques provides complex information that is clinically relevant.

Oncologists know that minimal residual disease (MRD) is a prognostic marker in leukemia, lymphoma, and myeloma. In some diseases, MRD testing has become standard practice for predicting outcomes. In other diseases, research is ongoing to determine if MRD-positive or MRD-negative status affects outcomes.

In non-Hodgkin lymphoma, MRD could transform treatment paradigms by allowing intensification of treatment in at-risk patients or early intervention for impending relapse, as predicted by Chase et al in a 2017 paper published in the British Journal of Haematology.1 Recent research also shows that using circulating tumor DNA may enhance MRD detection in patients with non-Hodgkin lymphoma.2,3

In the myeloma space, MRD negativity is prognostic of progression-free survival in relapsed or refractory patients.4 In leukemia, MRD combined with other prognostication techniques provides complex information that is clinically relevant.5

MRD is just 1 of many tools used to provide individualized patient care. There is a lingering question among investigators: Is MRD a better prognostic indicator than initial patient characteristics? This question will be debated during the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022) at 4:01 pm on September 28, 2022, during the Acute Myeloid Leukemia session.

Michael Heuser, MD, Chair for Hematology, Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, at Hannover Medical School in Germany, will present an argument in favor of MRD. R. Coleman Lindsley, MD, PhD, a physician at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, will argue in favor of initial patient characteristics.

Heuser discussed the importance of MRD testing and his expectations for the SOHO 2022 debate during an interview with The SOHO Daily News.

The SOHO Daily News: What is the topic of the debate?

Heuser: MRD is a diagnostic technology used to refine the prognosis of the patients and is also helpful to predict which treatment will work best at a certain timepoint. This technology is also developed as a surrogate end point for a later outcome for overall survival in clinical trials. The main points are the prognostic and predictive role of MRD. It’s well established that MRD is prognostic, but it’s less well established that it’s predictive for the outcome of a certain treatment. There are now claims that MRD testing before the treatment is sufficient so that you don’t need MRD assessment later.

Please expand on the role of MRD testing in hematologic malignancies.

The role of MRD testing in the hematologic malignancies space is increasing in significance. On the other hand, it’s very important to be aware that the technology for each disease and for certain subtypes are different. Although we struggle with standardization, the prognostic power is well established.

The goal of this technology is to assign the best treatment to each individual patient, and that is especially important as we face an increasingly individualized treatment approach. We cannot rely so much on our previous knowledge of prognostic markers. Therefore, I expect that the significance of MRD will even increase in the future.

What is your opinion on the prognostic value of MRD compared with initial presentation characteristics in patients with hematologic malignancies?

To answer this question, we should look at genetically defined subgroups of AML patients with favorable or intermediate risk genetics, who are treated with standard induction and consolidation chemotherapy. For example, MRD has been studied extensively in CBFB-MYH11 AML.6

Within this subgroup, MRD is independently prognostic apart from the pretreatment characteristics. There are several other genetic subgroups in which we observe a strong prognostic impact of MRD as well. Although further work needs to be done, we already have ample evidence for the value of MRD beyond the initial presentation characteristics.

Models that rely on initial presentation characteristics should be validated in independent cohorts and should not include post-therapeutic information like remission status. However, MRD assessment currently adds little to the management of patients with adverse risk genetics or limited therapeutic options.

How do you think MRD will be used in the future?

MRD has become standard in several subgroups of AML patients. I expect that we will use well standardized assays and increasingly transition to next-generation flow-cytometry and next-generation sequencing. I also expect that we will use MRD more selectively depending on the treatment, genetic subgroup and time point during treatment or follow-up.

Looking beyond MRD, what other prognostic tests are important to perform for patients with hematologic malignancies?

What’s important currently are the molecular analysis at diagnosis and the cytogenetic profile. These tests are essential to assign the right diagnosis to the patient. In order to choose the appropriate treatment intensity, we need a thorough assessment of the patient’s fitness, organ function, and comorbidities. After that, the next most important assessment is MRD.

REFERENCES:

1. Chase ML, Armand P. Minimal residual disease in non-Hodgkin lymphoma – current applications and future directions. Br J Haematol. 2018;180(2):177-188. doi:10.1111/bjh.14996

2. Garg S, Kumar A, Gupta R. Stance of MRD in Non-Hodgkin’s Lymphoma and its upsurge in the novel era of cell-free DNA. Clin Transl Oncol. 2021;23(11):2206-2219. doi:10.1007/s12094-021-02635-4

3. Kurtz DM, Soo J, Keh LCT, et al. Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nat Biotechnol. 2021;39(12):1537-1547. doi:10.1038/s41587-021-00981-w

4. Cavo M, San-Miguel J, Usmani SZ. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood. 2022;10;139(6):835-844. doi:10.1182/blood.2021011101

5. Aitken MJL, Ravandi F, Patel KP, Short NJ. Prognostic and therapeutic implications of measurable residual disease in acute myeloid leukemia. J Hematol Oncol. 2021;14(1):137. doi:10.1186/s13045-021-01148-5

6. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 ELN recommendations from an international expert panel. Blood. Published online July 7, 2022. doi:10.1182/blood.2022016867