In younger, fitter MCL patients eligible for high-dose therapy followed by autologous stem cell transplantation, presence of minimal residual disease (MRD) has been shown to be an independent adverse prognostic factors for progression-free survival (PFS) and overall survival (OS) when detected either after induction therapy but before transplant, or after transplant.1-6 In elderly patients receiving immunochemotherapy followed by maintenance treatment, presence of MRD after induction or during maintenance was also shown to be predictive of PFS.4, 5
Most studies of MRD in MCL have utilized allele-specific oligonucleotide PCR (ASO-PCR), with a sensitivity of 10-4-10-5. The clonoSEQ MRD test, which has a sensitivity of 10-6, has been shown to be concordant with and more sensitive than ASO-PCR in MCL.7, 8
Clinical Validation Data
The clonoSEQ MRD Test is Highly Concordant with Traditional MRD Detection Methods in MCL
- In 114 samples from 22 MCL patients, sequencing-based MRD detection was highly concordant with ASO-PCR (r2 = 0.61, Figure 1).8
- Higher sensitivity of the sequencing-based method was demonstrated by its detection of MRD in 14 samples with disease present at or below 10-5, below the detection limit of ASO-PCR (Figure 1, red box).8
MRD Dynamics as Measured by the clonoSEQ MRD Test Correlate with Clinical Outcome
- Serial bone marrow samples obtained at pre-induction, post-induction and three months post-transplant for 13 MCL patients were assessed for MRD using sequencing. As anticipated, MRD levels were markedly reduced as patients received induction treatment and transplant (Figure 2).8
- 2/13 patients (15%) were MRD negative at the post-induction time point
- 11/13 patients (85%) were MRD negative three months post-transplant
- In one illustrative patient, six bone marrow samples were available spanning from 1.2 months pre-transplant through 18.7 months post-transplant. A rise in MRD level was observed prior to clinical relapse (Figure 3).8
Comparison between sequencing and ASO-PCR
MRD dynamics in MCL patients following standard therapy
MRD positivity predicts clinical relapse
MRD decreased following chemotherapy, remained low for approximately 300 days, and then became positive approximately 1 year prior to clinical relapse
- Cowan AJ, Stevenson PA, Cassaday RD, et al. Pretransplantation Minimal Residual Disease Predicts Survival in Patients with Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplantation in Complete Remission. Biol Blood Marrow Transplant. 2015.
- Geisler CH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008;112(7):2687-2693.
- Liu H, Johnson JL, Koval G, et al. Detection of minimal residual disease following induction immunochemotherapy predicts progression free survival in mantle cell lymphoma: final results of CALGB 59909. Haematologica. 2012;97(4):579-585.
- Pott C. Minimal residual disease detection in mantle cell lymphoma: technical aspects and clinical relevance. Seminars in hematology. 2011;48(3):172-184.
- Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood. 2010;115(16):3215-3223.
- Pott C, Schrader C, Gesk S, et al. Quantitative assessment of molecular remission after high-dose therapy with autologous stem cell transplantation predicts long-term remission in mantle cell lymphoma. Blood. 2006;107(6):2271-2278.
- Ladetto M, Bruggemann M, Monitillo L, et al. Next-generation sequencing and real-time quantitative PCR for minimal residual disease detection in B-cell disorders. Leukemia. 2013.
- Malnassy G, Geyer S, Fulton N, et al. Comparison Of Deep Sequencing and Allele-Specific Oligonucleotide PCR Methods For MRD Quantitation In Acute Lymphoblastic Leukemia and Mantle Cell Lymphoma: CALGB 10403 and CALGB 59909 (Alliance). Blood. 2013;122(21):2547.