Minimal Residual Disease Status in CLL
Considering Minimal Residual Disease Status in CLL: An Emerging Measure to Help Gauge a Patient’s Disease
Demonstrating improvement in overall survival (OS) and progression-free survival (PFS) is an important goal of clinical trials in CLL.1
While OS has historically been considered the gold standard for measuring clinical efficacy, demonstrating significant difference in OS between comparators may require large clinical trials and extended periods of follow-up. As CLL is an indolent disease, endpoints such as PFS have been accepted as measures of clinical efficacy.1
Additional endpoints such as complete, partial, and overall response have also been used to assess patient outcomes. In particular, it is known from trial data that achieving a complete response (CR) in CLL is clinically meaningful.1-3
While these endpoints (OS, PFS, CR) continue to be the most relevant to clinical trials of CLL, achieving a CR may not necessarily mean that the patient is free of disease.1,2,4
Post-treatment minimal residual disease (MRD) status is emerging as an additional gauge of disease. In CLL, MRD is assessed in samples from the peripheral blood and/or bone marrow. While obtaining peripheral blood samples is less invasive, it may be important to assess MRD status in the bone marrow of some CLL patients.2,5
MRD is detected by polymerase chain reaction (PCR) or flow cytometry, which are highly sensitive laboratory testing techniques that can detect 1 leukemic cell in as many as 10,000 leukocytes. While the patient may not be free of disease, MRD negativity is achieved when no CLL cells are detected using these methods (this has also been referred to as a “molecular remission” in scientific literature).2,6,7
The FDA has held a workshop to further evaluate and define the potential role of MRD in CLL. Post-treatment MRD data contribute an additional testing metric to the understanding of disease status and are being included in CLL clinical trials.8,9
In summary, while endpoints such as OS, PFS, and CR continue to be the most relevant to clinical trials of CLL, post-treatment Minimal Residual Disease (MRD) status is emerging as an additional gauge of disease.1,2
- Beauchemin C, Johnston JB, Lapierre MÈ, Aissa F, Lachaine J. Relationship between progression-free survival and overall survival in chronic lymphocytic leukemia: a literature-based analysis. Curr Oncol. 2015;22:e148-156. doi:10.3747/co.22.2119.
- 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;111:5446-5456. doi:10.1182/blood-2007-06-093906.
- Lee L, Wang L, Crump M. Identification of potential surrogate end points in randomized clinical trials of aggressive and indolent non-Hodgkin’s lymphoma: correlation of complete response, time-to-event and overall survival end points. Ann Oncol. 2011;22:1392-1403. doi:10.1093/annonc/mdq615.
- Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26:v78-v84. doi:10.1093/annonc/mdv303.
- Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127:279-286. doi:10.1182/blood-2015-08-634816.
- Ritgen M, Stilgenbauer S, von Neuhoff N, et al. Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood. 2004;104:2600-2602. doi:10.1182/blood-2003-12-4321.
- 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;123:3727-3732. doi:10.1182/blood-2013-11-538116.
Food and Drug Administration.
http://www.fda.gov/Drugs/NewsEvents/ucm341421.htm, http://www.fda.gov/Drugs/NewsEvents/ucm294931.htm, http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm402038.htm. Accessed May 31, 2016.
- U.S. National Institutes of
https://clinicaltrials.gov/ct2/results?term=minimal+residual+disease+CLL&Search=Search. Accessed May 31, 2016.