IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients

Abstract

Key Points• IgH-V(D)J NGS-MRD detection pretransplant identifies a cohort at low risk for relapse, for which treatment modification could be considered.• Positive NGS-MRD was highly predictive of relapse and survival as early as 30 days after HCT.Positive detection of minimal residual disease (MRD) by multichannel flow cytometry (MFC) prior to hematopoietic cell transplantation (HCT) of patients with acute lymphoblastic leukemia (ALL) identifies patients at high risk for relapse, but many pre-HCT MFC-MRD negative patients also relapse, and the predictive power MFC-MRD early post-HCT is poor. To test whether the increased sensitivity of next-generation sequencing (NGS)-MRD better identifies pre-and post-HCT relapse risk, we performed immunoglobulin heavy chain (IgH) variable, diversity, and joining (V[D]J) DNA sequences J NGS-MRD on 56 patients with B-cell ALL enrolled in Children's Oncology Group trial ASCT0431. NGS-MRD predicted relapse and survival more accurately than MFC-MRD (P < .0001), especially in the MRD negative cohort (relapse, 0% vs 16%; P 5 .02; 2-year overall survival, 96% vs 77%; P 5 .003). Post-HCT NGS-MRD detection was better at predicting relapse than MFC-MRD (P < .0001), especially early after HCT (day 30 MFC-MRD positive relapse rate, 35%; NGS-MRD positive relapse rate, 67%; P 5 .004). Any post-HCT NGS positivity resulted in an increase in relapse risk by multivariate analysis (hazard ratio, 7.7; P 5 .05). Absence of detectable IgH-V(D)J NGS-MRD pre-HCT defines good-risk patients potentially eligible for less intense treatment approaches. Post-HCT NGS-MRD is highly predictive of relapse and survival, suggesting a role for this technique in defining patients early who would be eligible for post-HCT interventions. The trial was registered at www.clinicaltrials.gov as #NCT00382109. (Blood. 2015;125(22):3501-3508)

Next-Generation Sequencing in Adult B Cell Acute Lymphoblastic Leukemia Patients

“…This is consistent with a recent report suggesting any amount of MRD detected after stem cell transplantation increases relapse risk 25 . If these data are confirmed in larger studies, NGS will be useful to fine tune criteria for transplantation in adult ALL patients, as the excellent outcome of patients with no disease detectable by NGS could favor a less aggressive treatment path.…”

Clinical utility of next‐generation sequencing‐based minimal residual disease in paediatric B‐cell acute lymphoblastic leukaemia

“…Wu et al (2014) defined a frequency of >10% of all sequences as a threshold for leukaemia-specific sequences. Pulsipher et al (2015) compared the predictive powers of NGS and FCM in 56 patients with B-cell ALL who underwent HSCT. In contrast, other investigators set a cut-off of level of 5% (Faham et al, 2012;Ladetto et al, 2014;Pulsipher et al, 2015).…”

Molecular detection of minimal residual disease in multiple myeloma

“…Finally, the copy number is normalized by the number of total cells, measured by standard PicoGreen methods and RQ-PCR of control genes, and the MRD level is expressed as the number of cancer-derived molecules per million cell equivalents (Faham et al, 2012;Martinez-Lopez et al, 2014). For the immunoSEQ platform, more than 100 VH FR2 forward primers and nine JH reverse primers are adopted to amplify IGH VDJ rearrangements in a single reaction (Pulsipher et al, 2015).…”