The presence of minimal residual disease (MRD) has been shown to be an independent adverse prognostic factor for both progression-free survival (PFS) and overall survival (OS) in patients with CLL treated with chemoimmunotherapy in the first-line or relapsed/refractory settings.1-9
In high-risk patients who have relapsed or had early treatment failure and undergone allogeneic hematopoietic cell transplantation (HCT), detection of MRD one-year post-transplant has been shown to predict relapse. The relevance of ongoing MRD-monitoring in this population has been suggested by the demonstration that MRD kinetics (e.g., doubling time) are also associated with relapse risk.10, 11
Current international guidelines arbitrarily set the threshold for MRD-positivity in CLL at 10-4, primarily due to the technical limitations of the most often used measurement techniques, flow cytometry and allele-specific oligonucleotide PCR (ASO-PCR).2, 12 The clonoSEQ MRD Test has been shown to be concordant with both of these techniques in CLL, with most discordances attributable to the ability of the next-generation sequencing based technique to detect MRD down to the level of 10-6.11, 13
The impact of reaching levels of disease below the 10-4 threshold has not been proven, but is suggested by results demonstrating that different quantitative levels within the current range of MRD-positivity are at least as prognostic as the distinction between MRD-negativity and -positivity.3
Clinical Validation Data
The clonoSEQ® MRD Test Predicts Relapse in the Post-Transplant CLL Setting
- Twelve-month landmark analysis of 31 post-transplant patients found that disease-free survival was significantly longer in those patients deemed MRD-negative by sequencing (at a level of 1 cell/million) compared to those who were MRD-positive, with a median follow-up of 50 months for non-relapse patients (Figure 1).11
- Testing of serial samples allows monitoring of the trajectory of disease burden, which has been shown to trend upward prior to clinical relapse (Figure 2).14
At 12 months post-transplant, MRD-negative CLL patients had significantly longer disease-free survival compared to MRD-positive patients (93.5% vs. 37.5%; HR=7.9, 95% CI 2.3-26; p=0.0002)
Results of serial MRD assessment for two patients is shown:
- Patient 1 was relapse-free 4.3 years (1579 days) post-transplant
- Patient 2 relapsed 2.7 years (985 days) post-transplant
- Bottcher S. Paving the road to MRD-guided treatment in CLL. Blood. 2014;123(24):3683-3684
- Bottcher S, Hallek M, Ritgen M, Kneba M. The role of minimal residual disease measurements in the therapy for CLL: is it ready for prime time? Hematology/oncology clinics of North America. 2013;27(2):267-288.
- Bottcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(9):980-988.
- Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012;30(26):3209-3216.
- Ghia P. A look into the future: can minimal residual disease guide therapy and predict prognosis in chronic lymphocytic leukemia? Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. 2012;2012:97-104.
- Maloum K, Settegrana C, Chapiro E, et al. IGHV gene mutational status and LPL/ADAM29 gene expression as clinical outcome predictors in CLL patients in remission following treatment with oral fludarabine plus cyclophosphamide. Ann Hematol. 2009;88(12):1215-1221.
- Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2005;23(13):2971-2979.
- Santacruz R, Villamor N, Aymerich M, et al. The prognostic impact of minimal residual disease in patients with chronic lymphocytic leukemia requiring first-line therapy. Haematologica. 2014;99(5):873-880.
- Strati P, Keating MJ, O'Brien SM, et al. Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood. 2014;123(24):3727-3732.
- Bottcher S, Ritgen M, Dreger P. Allogeneic stem cell transplantation for chronic lymphocytic leukemia: lessons to be learned from minimal residual disease studies. Blood Rev. 2011;25(2):91-96.
- Logan AC, Zhang B, Narasimhan B, et al. Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia. 2013;27(8):1659-1665.
- Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
- Rawstron A. A complementary role of multiparameter flow-cytometry and high-throughput sequencing for Minimal Residual Disease (MRD) detection in Chronic Lymphocytic Leukemia (CLL): an European Research Initiative on CLL (ERIC) study. Blood. 2015;In press
- Unpublished analysis of Logan AC, Zhang B, Narasimhan B, et al. Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia. 2013;27(8):1659-1665.