Minimal residual disease in patients with diffuse large B-cell lymphoma undergoing autologous stem cell transplantation

Abstract

Improved biomarkers are needed to guide the optimal use of autologous stem cell transplantation (ASCT) for patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples or post-ASCT peripheral blood mononuclear cell (PBMC) and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, p<0.001) and inferior overall survival (52% vs 68%, p=0.05). The sensitivity and specificity of ASC MRD positivity for progression or death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in a multivariable analysis (hazard ratio [HR] 3.7, p<0.001). Post-ASCT surveillance MRD testing from plasma, but not PBMC samples, reliably identified patients with impending relapse. A positive plasma MRD result was associated with inferior PFS (HR 3.0, p=0.016) on a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range 0-518 days). In conclusion, detection of MRD in ASC samples is associated with a very high relapse risk, justifying alternative treatment strategies or trials of novel consolidation options in those patients. Furthermore, post-ASCT MRD monitoring may facilitate trials evaluating early initiation of treatment at molecular relapse. This trial is registered at www.clinicaltrials.gov as NCT02362997.

2024 Update: Advances in the risk stratification and management of large B‐cell lymphoma

“…Early and major molecular responses appear to be predictive of 24‐month event‐free survival (EFS) and OS in the frontline and salvage settings independent of the IPI 41 . Further, ctDNA appears to be effective in predicting progression‐free survival (PFS) and OS in response to polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola‐R‐CHP) (PFS HR 3.0, 95% CI 1.53–5.80; OS HR 2.7, 95% CI 1.07–7.02), axicabtagene ciloleucel (median PFS 3 months vs. NR, median OS 19 months vs. NR, p = .008), and ASCT (5‐year PFS and OS: 52% vs. 13% and 68% vs. 52% for undetectable and detectable ctDNA) 42–45 …”

“…In a study of 107 patients achieving a CR in response to R‐EPOCH, all those who developed reproducible ctDNA positivity during surveillance developed disease progression with a median lead‐time of 1.6 months and 7.4 months among those with early and late relapse (HR 228, p < .0001) 40 . Similarly, 91% of patients who developed reproducible ctDNA positivity following ASCT relapsed with a median lead‐time of 62 days 45 …”

Comparison of whole‐genome and immunoglobulin‐based circulating tumor DNA assays in diffuse large B‐cell lymphoma

“…Plasma samples were previously analyzed using the IgHTS ClonoSEQ® assay (Adaptive Biotechnologies), and ctDNA was found to be a significant predictor of progression‐free survival (PFS). 9 Among 31 enrolled patients, nine had leftover genomic DNA (gDNA) from tissue samples and sufficient post‐ASCT plasma samples. These patients were selected for additional analysis (Figure 1A ).…”

Specificity of immunoglobulin high-throughput sequencing minimal residual disease monitoring in non-Hodgkin lymphomas

“…Several important prior studies have evaluated the performance of Ig-HTS techniques for MRD detection. 14 , 15 , 16 , 17 , 18 However, these studies have focused primarily on sensitivity and have not assessed performance when separately considering the heavy and light chains, which substantially differ not only in theoretical diversity (∼20-40×, as detailed above), but also in their observed junctional mutation and somatic hypermutation rates as paired clonotypes in B-cell malignancies. 11 , 19 We therefore sought to empirically evaluate the clinical specificity of Ig-HTS for heavy-chain and light-chain MRD measurement in mature B-cell lymphomas.…”