MRD and Clinical Response Predictors of PFS in CLL

Summary

In chronic lymphocytic leukemia, progression-free survival in minimal residual disease–negative patients can be best predicted using a combination of minimal residual disease and the clinical response. The combination is more accurate than clinical response alone. Assessment using only splenomegaly has no influence on progression-free survival prediction.

  • progression-free survival
  • peripheral blood
  • prediction
  • fludarabine
  • cyclophosphamide
  • rituximab
  • bendamustine

Barbara Eichhorst, MD, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany, presented on behalf of the German CLL Study Group on the value of minimal residual disease (MRD) in combination with clinical response as a predictor of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL).

The study was based on previous observations that correlated PFS and overall survival (OS) with MRD level in patients with partial response (PR) and complete response (CR), with increasing MRD levels associated with increasingly worse outcomes in PFS and OS [Strati P et al. Blood. 2014; Boettcher S et al. J Clin Oncol. 2012]. To evaluate the relevance of MRD testing from peripheral blood with clinical response, 1378 patients treated with fludarabine/cyclophosphamide vs fludarabine/cyclophosphamide/rituximab (FCR) in 1 German CLL Study Group trial and with FCR vs bendamustine/rituximab in another trial were analyzed to identify the target population, composed of 555 patients who achieved CR or PR for whom MRD measurements from peripheral blood were available at the end of the trial. The target and nontarget populations were comparable at baseline (Table 1).

Table 1.

Baseline Characteristics and Prognostic Factors

MRD negativity was associated with significantly improved CR (median PFS, 68.9 vs 44.4 months; P = .004) and PR (median, 61.7 vs 28.1 months; P < .001). The improved MRD negativity–associated PR was significantly longer than the CR (P = .047). For OS, MRD positivity was associated with significantly worse PR. Multivariate analysis revealed significance between positive vs negative MRD status (HR, 3.487; 95% CI, 2.678 to 4.541; P < .001), PR vs CR (HR, 1.420; 95% CI, 1.075 to 1.876; P = .014), presence of del(17p) (HR, 9.082; 95% CI, 4.325 to 19.072; P < .001), and unmutated vs mutated immunoglobulin heavy chain variable (HR, 2.582; 95% CI, 1.930 to 3.455; P < .001).

The second portion of the study evaluated the MRD-negative target population for the clinical relevance of splenomegaly, lymph node enlargement, and bone marrow involvement at response assessment in MRD-negative patients. The analysis centered on patients with only lymphadenopathy (n = 25), only bone marrow involvement (n = 18), only splenomegaly (n = 78), and > 1 involvement (n = 40). The respective median PFSs were 38.7, 56.8, 72.0, and 51.8 months. The median PFS was significantly lower in patients with lymph node enlargement (P < .001; Table 2). No improvement in OS was evident.

Table 2.

PFS Grouped by MRD – PR Subgroups

Finally, PFS in MRD-negative patients displaying a PR was assessed using different cutoffs for normal spleen size on radiologic examination in the patients with only lymphadenopathy. PFS was not appreciably affected by use of a splenomegaly cutoff exceeding 12 cm in patients with only bone marrow involvement, only splenomegaly, lymph node enlargement, and > 1 involvement.

The data indicate that MRD and clinical response are strong predictors of PFS, with the 2 together providing a more accurate prediction of PFS than clinical response alone. Finally, splenomegaly as the only anomaly at the end of the trial had no influence on PFS in the MRD-negative patients who displayed PR.

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