The Relation of Clinical Response and Minimal Residual Disease and Their Prognostic Impact On Outcome in Acute Myeloid Leukemia

Presence of minimal residual disease (MRD) after induction therapy predicts risk of relapse in AML (San Miguel JF et al 2001). Furthermore, achievement of complete remission (CR) rather than CR with incomplete platelet recovery (CRp) (defined using standard morphologic criteria) after induction therapy is independently associated with shorter relapse-free survival (Walter RB et al 2010). These results suggest a correlation between peripheral blood count recovery at the time of morphologic remission and MRD; however, this has not been documented. Here we address this question and examine whether response and MRD have independent effects on relapse.

We retrospectively analyzed data from 340 adults with AML who achieved CR, CRp or CRi (CR with incomplete peripheral count recovery; cellular marrow with <5% blasts but neutrophil count < 1,000/mL) after induction therapy at University of Washington/Fred Hutchinson Cancer Research Center since 2008. The bone marrows were collected on or closest to the first date of response and MRD was determined by ten-color multiparametric flow cytometry. The impact of MRD and response on relapse was analyzed using Cox proportional regression models. Cytogenetics were classified according to SWOG criteria.

Among the 340 patients, 23% of the 247 with CR, 37% of the 65 with CRp and 50% of the 28 with CRi had MRD (p =0.002). Amounts of MRD differed among the 3 groups (p=0.015) and in particular was higher with CRi median 2.6 (interquartile range [IQR] 1.3–3.4), than with CRp median 0.7 (IQR 0.3–1.3) and CR median 0.7 (IQR 0.3–2.4). By univariable Cox proportional regression analysis with death before relapse considered a competing risk, patients with MRD were more likely to relapse than patients without MRD regardless of whether MRD was considered as 0 vs. > 0 (hazard ratio [HR] 1.85; 95% CI 1.25–2.72; p=0.002) or as a numerical variable (HR 1.15 for each 1% increase; 95% CI 1.06–1.25; p <0.001). As expected, the risk of relapse was also higher in patients achieving only CRi (vs. CR: HR 2.95; 95% CI 1.63–5.36; p <0.001) or CRp (vs. CR: HR 2.17; 95% CI 1.37–3.42; p<0.001). In multivariable Cox proportional regression analyses including cytogenetic risk factors, MRD 0 vs. >0 (HR 1.50; 95% CI 1.00–2.23; p=0.047), response (CR vs. CRp and CRi: HR 2.11; 95% CI 1.40–3.17; p<0.001), and cytogenetic factors (intermediate vs. favorable: HR 4.67; 95% CI 1.13–19.2; p=0.033 or unfavorable/unknown prognostic significance vs. favorable: HR 4.59; 95% CI 1.11–19.0; p=0.035) were each independently associated with relapse.

CRp and CRi are associated with increased frequency of MRD (0 vs. >0) in comparison to CR while CRi is characterized by higher levels of MRD than CRp or CR. This indicates that failure of blood count recovery is often due to persistent AML rather than toxic effects on normal progenitors and thus should often call for further therapy rather than delay. Clinical response, MRD and cytogenetic factors are independent predictors for relapse in AML patients achieving remission.

No relevant conflicts of interest to declare.