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Minimal residual disease at induction shows value for acute myeloid leukemia
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Identification of minimal residual disease using multiparameter flow cytometry following the first treatment cycle may improve outcome stratification among patients with acute myeloid leukemia and predict which patients with NPM1 wild-type standard-risk disease will benefit from transplant, study data showed.
“Studies have shown the prognostic value of minimal residual disease [MRD] monitoring by polymerase chain reaction for patients with validated molecular targets, usually after two courses of chemotherapy,” Sylvie D. Freeman, MD, PhD, clinical senior lecturer in immunohematology and consultant hematologist at Birmingham Medical School in the U.K., and colleagues wrote. “Multiparametric flow cytometry MRD may identify, as early as after course 1, patients with a [worse] response despite achieving complete remission and is an assay that can be applied across AML genetic subgroups.”
However, insufficient data exists to identify the prognostic effect of multiparametric flow cytometry MRD positivity when patients are in complete remission following the first course compared with morphologic active disease.
“It is feasible that the outcomes of patients with detectable MRD resemble those of refractory patients who achieve the cytoreduction criteria for a morphologic partial response,” Freeman and colleagues added. “Evaluating this will help refine which response categories are the most useful prognostic surrogate endpoints to assess effectiveness of the first induction course.”
The researchers prospectively evaluated 6,539 bone marrow samples from 2,450 patients with AML or high-risk myelodysplastic syndrome between 2009 and 2014 as part of the NCRI AML17 trial.
Following the first course of treatment, Freeman and colleagues categorized patient responses as resistant disease, partial remission, complete remission, or complete remission with absolute neutrophil count of less than 1,000/µL or thrombocytopenia of less than 100,000/µL (CRi). Researchers further subdivided complete remission and CRi as being either multiparameter flow cytometric MRD positive or negative.
Patients who did not have high-risk factors — based on white blood cell count, secondary disease, morphologic response to course 1, and FLT3 internal tandem duplication/NPM1 mutation status — underwent a second induction with daunorubicin or cytosine arabinoside.
Patients with high-risk factors received an intensified second course.
Five-year OS appeared similar among patients who achieved partial remission or were MRD positive following the first course of treatment. This appeared particularly true when researchers excluded poor-risk subgroups (5-year OS, 27% for resistant disease; 46% for partial remission; 51% for MRD positive; 70% for MRD negative; P < .001).
Adjusted analyses showed significant OS differences between patients who demonstrated resistant disease after one course of induction compared with those with partial remission or MRD-positive disease (HR = 2.28; 95% CI, 1.38-3.75), but not between patients in partial remission compared with those who were MRD positive (HR = 1.32; 95% CI, 0.65-2.68).
Achievement of CRi after course 1 was associated with poorer 5-year OS overall (39% vs. 53%; P = .002) and among MRD-positive patients (19% vs. 45%; P = .001), but not among MRD-negative patients. This effect persisted, but less so, after course 2.
Multiparameter flow cytometric MRD status appeared more prognostic after course 2 (HR for relapse = 1.88; 95% CI, 1.5-2.36; HR for survival = 1.77; 95% CI, 1.41-2.22) than after course 1 (HR for relapse = 1.7; 95% CI, 95% CI, 1.4-2.06; HR for survival = 1.5; 95% CI, 1.23-1.84), but this difference lessened when researchers restricted the course 1 analysis to patients who received course 2 and survival at least 30 afterward.
MRD positivity vs. negativity after course 2 appeared significantly associated with worse 5-year OS among patients in the NPM1 wild-type subgroup (33% vs. 63%; P = .003). Relapse incidence reached 89% for this subgroup when MRD was 0.1% or greater.
The benefit of transplant appeared greater among patients who were MRD positive (HR = 0.72; 95% CI, 0.31-1.69) than those who were MRD negative (HR = 1.68; 95% CI, 0.75-3.85).
“Despite the relatively large and overlapping CIs, the authors suggest that a positive MRD test may identify patients with intermediate-risk AML who might benefit from allogeneic [hematopoietic stem cell transplant] while in first morphologic remission,” Ronald B. Walter, MD, PhD, associate professor at Fred Hutchinson Cancer Researcher Center and University of Washington, Seattle, wrote in an accompanying editorial.
Walter noted that other studies have drawn similar conclusions.
“However, because the decision to subject a patient to allogeneic [HSCT] was made informally in all these studies, potential biases are important to consider and findings need to be interpreted with great caution,” Walter wrote. “Thus, rather than considering available data conclusive regarding value of MRD-directed treatment decision-making in AML, they should stimulate additional efforts to test this concept in a controlled manner.” – by Andy Polhamus
Disclosures: Freeman reports no relevant financial disclosures. Please see the study for a list of all other authors’ relevant financial disclosures. Walter reports no relevant financial disclosures.
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