Moving toward a conceptualization of measurable residual disease in myelodysplastic syndromes

Abstract

Approximately 90% of patients with myelodysplastic syndromes (MDS) have somatic mutations in the malignant cells that are known or suspected to be oncogenic. The genetic risk-stratification of MDS has evolved substantially by the introduction of the clinical-molecular International Prognostic Scoring System (IPSS-M) that establishes next-generation sequencing at diagnosis as a standard of care. Furthermore, the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias has refined MDS diagnostic criteria with the introduction of a new myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) category. Monitoring measurable residual disease (MRD) has historically been used to define remission status, improve relapse prediction, and determine the efficacy of antileukemic drugs in patients with acute and chronic leukemias. However, in contrast to leukemias, assessment of MRD including tracking of patient-specific mutations has not yet been formally defined as a biomarker for MDS. This article summarizes current evidence and challenges, and provides a conceptual framework for incorporating MRD into the treatment of MDS and future clinical trials.

Identification and surveillance of rare relapse-initiating stem cells during complete remission after transplantation

“…However, aberrant phenotypes were distinctly present in multiple (nontransplanted) high-risk MDS/AML BM samples included as controls ( Figure 5 A-D; supplemental Table 1 ), although not for all aberrant phenotypes investigated, in agreement with other studies. 11 , 41 , 42 , 43

Figure 5. FCM–based leukemic stem cell and aberrant antigen expression analysis.

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“…However, MRD-positive results after transplantation in patients who later do not relapse are not uncommon, 11 , 22 representing a significant limitation when deciding whether, how, and when to start preemptive relapse treatment based on a reliable MRD-positive finding while patients remain in clinical CR after transplantation, and also for assessment of effects of such treatments. Whether or not an MRD-positive finding in HSPCs might predict a relapse not only earlier but potentially also more reliably than in whole BM will require prospective studies of much larger cohorts of patients, because in 12 of 13 patients in this study remaining in continuous-CR ≥66 months after allo-HSCT, no clonal involvement was observed in MNCs nor HSPCs in multiple sequential BM samples after transplantation.…”

“… 22 However, 20% of mutation-negative cases later progressed, and 30% of mutation-positive cases did not experience subsequent disease progression. 22 Other MDS/AML MRD studies assessing post–allo-HSCT persistence of recurrent driver mutations had similar sensitivity and specificity limitations regarding predicting relapse after allo-HSCT, 11 , 23 , 24 , 25 , 26 highlighting the need for the development of MRD screening platforms with higher sensitivity and relapse predictive value.…”

“… 8 , 9 , 10 However, to explore this, it is critical to establish more sensitive and specific biomarkers for measurable residual disease (MRD) and early prediction of relapse after allo-HSCT. 11 , 12 Platforms used to assess MRD in MDS and AML include sequencing-based tracking of recurrent mutations and flow cytometry (FCM) tracking of aberrant cell surface phenotypes 11 , 12 , 13 , 14 but in particular FCM platforms have not been extensively validated in MDS after allo-HSCT.…”