The FDA’s recent expanded approval of a targeted therapy for MRD-positive acute lymphoblastic leukemia marks the first time that MRD has been accepted as a primary endpoint for drug approval and in which patients’ treatment decisions were made based on their MRD status.6,8,9

The FDA’s approved label for a novel antibody therapy for patients with multiple myeloma (MM) includes MRD negativity rate as a secondary endpoint. Similarly, the FDA’s approved label of a targeted therapy for patients with chronic lymphocytic leukemia (CLL) was updated in 2018 to include rates of MRD negativity.11

The FDA currently recognizes MRD response rate as a surrogate endpoint in adult patients with ALL.7

Multiple myeloma (MM)

MM is a plasma cell disorder characterized by the proliferation of malignant plasma cells that infiltrate the bone marrow, peripheral blood, soft tissues, and organs.19,20

The role of MRD in the clinical management of MM

Studies in patients with MM have shown that MRD status is prognostic of clinical outcomes, inclusive of overall survival and progression-free survival, and may be used to inform treatment strategies.17,21,22 Furthermore, evidence supports the importance of deep MRD negativity in patients with MM, as deeper responses (below a 10-6 threshold) have been associated with improved clinical outcomes.23

Active Treatment

National Comprehensive Cancer Network (NCCN) guidelines and the International Myeloma Working Group (IMWG) criteria recommend MRD assessment after induction, and MRD is included as a component of response criteria.24

European Society for Medical Oncology guidelines include MRD as a component of response criteria.25

The FDA’s approved label for a novel antibody therapy for patients with MM includes MRD negativity rate as a secondary endpoint.26

NCCN guidelines and IMWG criteria recommend MRD assessment after high-dose therapy/autologous stem cell transplantation (ASCT).24 MRD negativity post ASCT is correlated with favorable progression-free survival and overall survival.27,28

MRD has been shown to be predictive of clinical outcomes regardless of patient cytogenetic profile.29

NCCN guidelines and IMWG criteria recommend MRD assessment after consolidation.24

Posttreatment

National Comprehensive Cancer Network Guidelines and the International Myeloma Working Group criteria recommend MRD assessment after maintenance.24

Disease Recurrence

Acute lymphoblastic leukemia (ALL)

ALL is an aggressive, fast-growing type of leukemia characterized by the progressive accumulation of lymphoid progenitor cells in the bone marrow and peripheral blood (PB).32

The role of MRD in the clinical management of ALL

Studies in both adult and pediatric ALL have demonstrated a correlation between MRD status and patient outcomes, and MRD negativity has been shown to be associated with improved event-free survival and overall survival.33-38 Sensitive testing techniques are able to detect MRD in PB of patients with ALL, and a correlation has been demonstrated between MRD measured in bone marrow and PB, although disease burden is typically lower in PB than in bone marrow.39-41

Diagnosis

Guidelines from College of American Pathologists and American Society of Hematology strongly recommend comprehensive molecular characterization at diagnosis to allow for subsequent MRD testing.42 Similarly, National Comprehensive Cancer Network (NCCN) Guidelines recommend baseline characterization of leukemic clone as part of the diagnostic work-up to facilitate subsequent MRD analysis.43

Active Treatment

National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology guidelines recommend MRD testing in patients who are in complete remission post induction.43,44

Peer-reviewed evidence

In a multicenter study of adult ALL, MRD negativity at the end of induction (below 10−4) was associated with a 3-year disease-free survival rate of 68.6%, compared with 37.8% for patients who were MRD positive.45

NCCN Guidelines use MRD status to guide selection of consolidation therapy and recommend a targeted therapy for patients with MRD after complete response.43

Posttreatment

MRD status impacts clinical outcomes, inclusive of event-free survival (EFS), overall survival (OS), and relapse rate.42

The National Comprehensive Cancer Network recommends considering periodic MRD monitoring guided by treatment regimen.43

Disease Recurrence

Chronic lymphocytic leukemia (CLL)

CLL is a slow-growing type of leukemia characterized by the progressive accumulation of lymphocytes in the blood, bone marrow, and lymphatic tissues.47,48

The role of MRD in the clinical management of CLL

Studies in CLL have shown that MRD is highly prognostic of progression-free survival and overall survival. In fact, MRD in CLL may represent an endpoint that more accurately describes the depth of remission than endpoints such as complete response.18,49-52 Sensitive testing techniques are able to detect MRD in peripheral blood of patients with CLL, and in most cases results are comparable to those seen with bone marrow.53,54

Active Treatment

MRD-negative status in peripheral blood (PB) correlates with improved progression-free survival (PFS). Evidence indicates that splenomegaly has no clinical significance if PB is MRD negative.55

In CLL, MRD may represent an endpoint that more accurately describes the depth of remission than endpoints such as CR.52

Posttreatment

The National Comprehensive Cancer Network Guidelines use MRD status to help guide considerations in post–first-line maintenance therapy.56

Peer-reviewed evidence

A retrospective analysis of patients with CLL treated between 1996 and 2007 found that achieving MRD negativity was associated with a 10-year progression-free survival (PFS) of 65% vs 10% for MRD positivity and a 10-year overall survival of 70% vs 30% for MRD positivity.18

Non-Hodgkin’s lymphoma (NHL)

NHL is an umbrella term for lymphomas that affect either B or T cells. The most common type of NHL is diffuse large B-cell lymphoma, a fast-growing lymphoma that accounts for approximately 1 in 3 of the lymphomas that are diagnosed in the United States.57 Mantle cell lymphoma is another fast-growing, rarer subtype of NHL that affects B cells, accounting for approximately 4% of lymphomas.58

The role of MRD in the clinical management of NHL

Studies in NHL subtypes have shown that MRD negativity is correlated with improved progression-free survival, overall survival, and time to disease progression.59-61

Active Treatment

In addition to evidence supporting the value of MRD assessment in bone marrow, advances in molecular assessment of MRD now make it possible to test blood samples and detect cell-free tumor DNA.62 Cell-free tumor DNA levels have been shown to enable early prediction of relapse in patients with certain types of NHL (eg, diffuse large B-cell lymphoma), compared with traditional techniques such as imaging.59

Posttreatment

NCCN Guidelines®

MM: The National Comprehensive Cancer Network (NCCN) Guidelines for patients with MM use MRD status to define response criteria, and MRD testing is recommended in patients with a complete response at multiple time points during treatment and maintenance.24

ALL: The NCCN Guidelines recommend baseline characterization of leukemic clone as part of the diagnostic work-up to facilitate subsequent MRD analysis and MRD testing for adult patients with ALL upon completion of initial induction, with additional time points for MRD testing guided by the regimen used. Additionally, NCCN recommends the use of MRD testing to identify patients in complete response who are MRD positive and thus should be treated with a targeted therapy, as well as to describe MRD as an essential component of patient evaluation in ALL.43

CLL: The NCCN Guidelines for patients with CLL recommend post–first-line maintenance therapy options for high-risk patients based on MRD status.56

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CAP and ASH Guidelines®

ALL: Guidelines from the College of American Pathologists (CAP) and the American Society of Hematology (ASH) strongly recommend that for patients with suspected or confirmed ALL, diagnostic work-up ought to be comprehensive enough to allow for subsequent MRD testing.42

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ESMO clinical practice guidelines

MM: The European Society for Medical Oncology (ESMO) clinical practice guidelines recommend measuring MRD as a part of response criteria for patients with MM.25

ALL: The European Society for Medical Oncology (ESMO) clinical practice guidelines include MRD as part of response parameters for patients with ALL, as well as recommend quantification of MRD in patients whenever possible.44

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IMWG consensus criteria

MM: The International Myeloma Working Group (IMWG) recommend measuring MRD as a part of response assessment in both clinical practice and clinical trials.63

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References

ALL, acute lymphoblastic leukemia; ASH, American Society of Hematology; ASCT, autologous stem cell transplantation; CAP, College of American Pathologists; CI, confidence interval; CLL, chronic lymphocytic leukemia; CR, complete response; DFS, disease-free survival; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; ESMO, European Society for Medical Oncology; FDA, Food and Drug Administration; HR, hazard ratio; IMWG, International Myeloma Working Group; MCL, mantle cell lymphoma; MM, multiple myeloma; MRD, measurable residual disease; NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin’s lymphoma; OS, overall survival; PB, peripheral blood; PFS, progression-free survival; PR, partial response; TTP, time to progression.

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