A measure of whether cancer cells have survived therapeutic intervention, measurable residual disease (MRD) is the presence of leukemic cells below the threshold of detection when using conventional morphologic methods. In acute myeloid leukemia (AML), achieving MRD negativity (MRD-) has been correlated with improved relapse and survival outcomes for patients, making it a key prognostic factor in the field.
Kelly Norsworthy, MD, Johns Hopkins Medicine, US Food & Drug Administration, Baltimore, MD, commented at iwAL 2022, “The FDA is open to the use of complete remission (CR) with MRD negativity as an endpoint, provided the test is adequately validated, sufficiently sensitive and there is data demonstrating a correlation with event-free survival (EFS) or overall survival (OS) in independent data.”
She added that the FDA is aware that “patients with AML who achieve MRD- have improved OS and relapse-free survival (RFS), compared to patients who remain MRD positive (MRD+), therefore the FDA has been encouraging sponsors to measure MRD- remissions in clinical trials of AML drugs.”
Additionally, Dr Norsworthy explained that MRD has been utilized to support acute lymphoblastic leukemia (ALL) drug approvals, using marrow MRD <0.01% to support evidence of efficacy; however, with its measurement being much more complicated for AML, Dr Norsworthy recommended that sponsors seeking to use MRD for patient selection, risk-based treatment assignment or as a surrogate endpoint, engage with the FDA early in development.
For additional information on the FDA’s thinking around the use of MRD in AML, Dr Norsworthy pointed towards a guidance document that presents information on tools for MRD assessment, disease-specific indications and pathways for surrogate endpoint validation.
Andrew Wei, MBBS, PhD, of the Alfred Hospital and Monash University, Melbourne, Australia, noted that “the recent ELN [guidelines] does formally recognize that MRD at the end of treatment and MRD relapse are clinically definable and relevant endpoints.”
Dr Wei discussed an example of MRD being applied for regulatory filing by Kronos Bio. The Phase III trial (NCT05020665) is evaluating the efficacy of entospletinib when added to chemotherapy in previously untreated nucleophosmin-1 mutated (NPM1mut) AML. However, Dr Wei expressed concern with the measurement timepoint of 42 days, as research conducted at his center has demonstrated that MRD status takes around 12 months to level out.1
Beyond measuring MRD as an efficacy endpoint, Dr Wei emphasized the potential benefit of treating patients at MRD relapse (molecular failure) before they develop full clinical (morphologic) relapse. He noted that if you have an MRD relapse, defined as a 1log increase in MRD, then your chance of clinical progression within three or four months is almost 100%.2 Dr Wei therefore questioned whether shifting the treatment paradigm from waiting for patients to have a clinical relapse to treating patients on the upswing of the MRD could achieve better results, as patients would be fitter and healthier without cytopenia and concomitant medications.
Dr Wei described a small prospective study (VALDAC) in which researchers had, in response to MRD relapse, treated older adult AML patients with NPM1mut MRD with off-label venetoclax (ven) in combination with low-dose cytarabine or azacitidine (LDAC).3,4 Dr Wei noted that after one cycle, 50% had an MRD response with at least 1log reduction. After four cycles, MRD clearance was 67%,4 which he said was “competitive with intensive chemotherapy without all the toxicity,” adding that as yet unpublished data suggests this may work in multiple genetic scenarios aside from NPM1mut.
The INTERCEPT platform trial (ACTRN12621001265864P) has been established to examine whether patients with various genetic factors treated in response to MRD relapse, will have a higher chance of achieving MRD response and thus a better quality of remission (longer RFS). The endpoint is a 1log reduction in MRD within 100 days.
As you may have noted above, Dr Wei described the use of a low-intensity regimen for the treatment of MRD relapse; however, according to Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center, Houston, TX, the majority of trials that have shown MRD to be able to predict disease-free survival (DFS) and OS have been in higher intensity regimens.
To overcome the lack of studies looking at the role of MRD assessment in lower-intensity therapies, Dr Ravandi’s team retrospectively looked at their patients with AML treated with single-agent hypomethylating agents (HMAs; either decitabine or azacitidine). They excluded those treated with ven and found that, in those that had achieved a response and had a flow cytometry MRD assessment, achieving an MRD- status “was associated with a reduced cumulative incidence of relapse but this did not translate to better survival.”
In a further assessment, achievement of CR and MRD- when ven was added to decitabine was associated with a significant improvement in OS (25.1 months for MRD- versus 11.6 months for MRD+). This was corroborated by the Phase III VIALE-A trial (NCT02993523) in which 41% of patients on ven plus azacitidine who had CR and MRD- had significantly improved OS versus those who had CR and MRD+.5 “On multivariate analysis, achieving MRD- status as well as cytogenetic risk groups were the predictors of outcomes,” stated Dr Ravandi.
Further emphasizing the importance of MRD in AML, he discussed two examples in which multivariate analysis revealed that it was MRD status, along with ELN 2017 risk classification and type of remission, that were the predictors of OS in AML, rather than whether the treatment course was intensive or low intensity.6,7
Despite the benefits outlined above, Catherine Smith, MD, of the University of California, San Francisco, CA, outlined notable limitations with existing MRD measurement tools. She explained that, since MRD is treatment-resistant cancer left following therapy, understanding its nature beyond what current measures are capable of could help guide treatment and enhance therapeutic outcomes. To potentially overcome the limitations, Dr Smith presented the use of single-cell DNA sequencing (SCS) in combination with multi-omic analysis to characterize both the immunophenotype and genotype of MRD cells.
“SCS can distinguish disease response, such as clonal hematopoiesis or differentiation, from true relapse. It can precisely identify the MRD clone as well as co-mutations, and this can impact selection of therapy, and there actually may be increased sensitivity compared to standard MRD detection methods such as flow,” she stated. “However, the assessment of MRD at a single timepoint is inadequate [to predict relapse clones]… continued and subsequent therapy may impact the clonal selection and we really need to look at serial MRD assessment, ideally in a clinical trial setting, to properly apply these next-generation sequencing techniques.”
Despite its promise, a key concern of SCS is that running a single sample currently costs ~$3500, without considering many additional costs, including that of running the machine. “These are really well beyond the cost of a clinical sequencing assay at this point and it’s really going to require significant strategies for cost savings to make this a clinically applicable strategy,” Dr Smith concluded.
View Dr Norsworthy, Dr Wei and Dr Ravandi’s presentations at iwAL here.
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