Eradication of Minimal Residual Disease in B-Cell Chronic Lymphocytic Leukemia After Alemtuzumab Therapy Is Associated With Prolonged Survival

2005 ◽  
Vol 23 (13) ◽  
pp. 2971-2979 ◽  
Author(s):  
Paul Moreton ◽  
Ben Kennedy ◽  
Guy Lucas ◽  
Michael Leach ◽  
Saad M.B. Rassam ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Group Response ◽  
Minimal Residual ◽  
Cell Chronic Lymphocytic Leukemia

Purpose To test whether eradication of minimal residual disease (MRD) in B-cell chronic lymphocytic leukemia (CLL) by alemtuzumab is associated with a prolongation of treatment-free and overall survival. Patients and Methods Ninety-one previously treated patients with CLL (74 men and 17 women; median age, 58 years [range, 32 to 75 years]; 44 were refractory to purine analogs) received a median of 9 weeks of alemtuzumab treatment between 1996 and 2003. Regular bone marrow assessments by MRD flow cytometry were performed with the aim of eradicating detectable MRD (< 1 CLL cell in 105 normal cells). Results Responses according to National Cancer Institute-sponsored working group response criteria were complete remission (CR) in 32 patients (36%), partial remission (PR) in 17 patients (19%), and no response (NR) in 42 patients (46%). Twenty-two (50%) of 44 purine analog-refractory patients responded to alemtuzumab. Detectable CLL was eradicated from the blood and marrow in 18 patients (20%). Median survival was significantly longer in MRD-negative patients compared with those achieving an MRD-positive CR, PR, or NR. Patients achieving an MRD-negative CR had a longer treatment-free survival than patients with MRD-positive CRs, PR, or NR: MRD-negative CRs, not reached; MRD-positive CRs, 20 months; PRs, 13 months; NR, 6 months (P < .0001). Overall survival for the 18 patients with MRD-negative remissions was 84% at 60 months. Eight (47%) of the MRD-negative patients converted to MRD positivity at a median of 28 months. Conclusion MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.

Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia

2012 ◽  
Vol 153 (41) ◽  
pp. 1622-1628
Author(s):  
Márk Plander ◽  
Judit Skrapits ◽  
Tünde Bozsó ◽  
Tamás Szendrei ◽  
János László Iványi
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Single Agent ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Minimal Residual

Introduction: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. Aim: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. Methods: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. Results: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). Conclusion: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients. Orv. Hetil., 2012, 153, 1622–1628.

scholarly journals Highly Sensitive and Accurate Assessment of Minimal Residual Disease in Chronic Lymphocytic Leukemia Using the Novel CD160-ROR1 Assay

2020 ◽  
Vol 10 ◽  
Author(s):  
Timothy W. Farren ◽  
Kaushik S. Sadanand ◽  
Samir G. Agrawal
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Limit Of Detection ◽  
Lymphocytic Leukemia ◽  
Orphan Receptor ◽  
Research Initiative ◽  
Prognostic Outcome ◽  
Minimal Residual

Undetectable minimal residual disease (MRD) in Chronic Lymphocytic Leukemia (CLL) has a favorable prognostic outcome compared with MRD that can be detected. This study investigated a flow cytometric assay (CD160-ROR1FCA) targeting the tumor-specific antigens CD160 and receptor tyrosine kinase-like orphan receptor 1 (ROR1), along with CD2, CD5, CD19, CD45. CD160-ROR1FCA was compared with the originally published 8-colour European Research Initiative for CLL (ERIC) gold-standard assay for CLL MRD detection. CD160-ROR1FCA had a limit of detection of 0.001% and showed strong correlation with ERIC (R = 0.98, p &lt; 0.01) with negligible differences in MRD detection (bias -0.3152 95%CI 5.586 to -6.216). Using CD160-ROR1FCA, increased expression of both CD160 and ROR1 was found in Monoclonal B cell Lymphocytosis (MBL) compared to low-level polyclonal B-cell expansions (p &lt; 0.01). Patients in CR and with undetectable MRD had a longer EFS (not reached) than those in CR but with detectable MRD (756 days, p &lt; 0.01) versus 113 days in patients with partial remission (p &lt; 0.01). Patients with MRD levels of &gt;0.01 to 0.1% had a longer EFS (2,333 days), versus levels between 0.1 to 1% (1,049 days). CD160-ROR1FCA is a novel assay for routine CLL MRD measurement and for MBL detection. MRD status assessed by CD160-ROR1FCA after CLL treatment correlated with EFS.

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

2012 ◽  
Vol 30 (9) ◽  
pp. 980-988 ◽  
Author(s):  
Sebastian Böttcher ◽  
Matthias Ritgen ◽  
Kirsten Fischer ◽  
Stephan Stilgenbauer ◽  
Raymonde M. Busch ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Surrogate Marker ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
High Level ◽  
Minimal Residual

Purpose To determine the clinical significance of flow cytometric minimal residual disease (MRD) quantification in chronic lymphocytic leukemia (CLL) in addition to pretherapeutic risk factors and to compare the prognostic impact of MRD between the arms of the German CLL Study Group CLL8 trial. Patients and Methods MRD levels were prospectively quantified in 1,775 blood and bone marrow samples from 493 patients randomly assigned to receive fludarabine and cyclophosphamide (FC) or FC plus rituximab (FCR). Patients were categorized by MRD into low- (< 10−4), intermediate- (≥ 10−4 to <10−2), and high-level (≥ 10−2) groups. Results Low MRD levels during and after therapy were associated with longer progression-free survival (PFS) and overall survival (OS; P < .0001). Median PFS is estimated at 68.7, 40.5, and 15.4 months for low, intermediate, and high MRD levels, respectively, when assessed 2 months after therapy. Compared with patients with low MRD, greater risks of disease progression were associated with intermediate and high MRD levels (hazard ratios, 2.49 and 14.7, respectively; both P < .0001). Median OS was 48.4 months in patients with high MRD and was not reached for lower MRD levels. MRD remained predictive for OS and PFS in multivariate analyses that included the most important pretherapeutic risk markers in CLL. PFS and OS did not differ between treatment arms within each MRD category. However, FCR induced low MRD levels more frequently than FC. Conclusion MRD levels independently predict OS and PFS in CLL. Therefore, MRD quantification might serve as a surrogate marker to assess treatment efficacy in randomized trials before clinical end points can be evaluated.

Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group

2016 ◽  
Vol 34 (31) ◽  
pp. 3758-3765 ◽  
Author(s):  
Gabor Kovacs ◽  
Sandra Robrecht ◽  
Anna Maria Fink ◽  
Jasmin Bahlo ◽  
Paula Cramer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Clinical Response ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Study Group ◽  
Minimal Residual

Purpose To determine the value of minimal residual disease (MRD) assessments, together with the evaluation of clinical response in chronic lymphocytic leukemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia criteria. Patients and Methods Progression-free survival (PFS) and overall survival of 554 patients from two randomized trials of the German CLL Study Group (CLL8: fludarabine and cyclophosphamide [FC] v FC plus rituximab; CLL10: FC plus rituximab v bendamustine plus rituximab) were analyzed according to MRD assessed in peripheral blood at a threshold of 10−4 and clinical response. The prognostic value of different parameters defining a partial response (PR) was further investigated. Results Patients with MRD-negative complete remission (CR), MRD-negative PR, MRD-positive CR, and MRD-positive PR experienced a median PFS from a landmark at end of treatment of 61 months, 54 months, 35 months, and 21 months, respectively. PFS did not differ significantly between MRD-negative CR and MRD-negative PR; however, PFS was longer for MRD-negative PR than for MRD-positive CR ( P = .048) and for MRD-positive CR compared with MRD-positive PR ( P = .002). Compared with MRD-negative CR, only patients with MRD-positive PR had a significantly shorter overall survival (not reached v 72 months; P = .001), whereas there was no detectable difference for patients with MRD-negative PR or MRD-positive CR ( P = 0.612 and P = 0.853, respectively). Patients with MRD-negative PR who presented with residual splenomegaly had only a similar PFS (63 months) compared with patients with MRD-negative CR (61 months; P = .354), whereas patients with MRD-negative PR with lymphadenopathy showed a shorter PFS (31 months; P < .001). Conclusion MRD quantification allows for improved PFS prediction in both patients who achive PR and CR, which thus supports its application in all responders. In contrast to residual lymphadenopathy, persisting splenomegaly does not impact outcome in patients with MRD-negative PR.

scholarly journals Orphan receptor ROR1 for detection of minimal residual disease in chronic lymphocytic leukemia

2020 ◽  
pp. 19-24
Author(s):  
Yu. V. Mirolyubova ◽  
N. S. Timofeeva ◽  
V. A. Bart ◽  
V. M. Solovyov ◽  
E. V. Tolstopyatova ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Color Flow ◽  
B Cell Precursors ◽  
Minimal Residual

Background and Aims. The detection of minimal residual disease (MRD) of chronic lymphocytic leukemia (CLL) using multicolor flow cytometry has been widely used in clinical studies to evaluate the effectiveness of treatment. The method is being improved by searching for the most sensitive and specific markers for use in panels for 6–8 color cytometers. According to published data, ROR1 shows high expression on CLL cells, and lack of expression on mature lymphocytes, which distinguishes it from other markers used to detect MRD in CLL.Aim: to determine a significance of ROR1 for detection of MRD CLL by flow cytometry in a 4-color panel.Materials and Methods. We analyzed 64 bone marrow samples of 37 patients with a verified diagnosis of CLL after the 3rd and 6th cycles of therapy according to bendamustine and rituximab (BR) regimen – 15 MRD-negative and 49 MRD-positive. Quantitative determination of MRD was carried out by the standardized method of 4-color flow cytometry according to the recommendations of ERIC (European research initiative on CLL) with the inclusion of ROR1 in the diagnostic panel. A discriminatory analysis of the differentiating properties of diagnostic markers was performed using Statistica 10.Results. ROR1 has demonstrated high differentiating properties on CLL cells and mature lymphocytes. All the analyzed samples showed a bright monomorphic expression of ROR1 on CLL cells and B-cell precursors, and the absence of its expression on mature lymphocytes.Conclusion. ROR1 is a highly specific and sensitive marker for the detection of CLL cells among mature lymphocytes. The high expression of ROR1 on normal B-cell precursors requires the use of ROR1 in combination with a marker that differentiates CLL cells from progenitor cells (CD81).

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