Minimal disease assessment in the treatment of children and adolescents with intermediate-risk (Stage III/IV) B-cell non-Hodgkin lymphoma: a children's oncology group report

Abstract

Children/adolescents with mature B-cell non-Hodgkin lymphoma (B-NHL) have an excellent prognosis but relapses still occur. While chromosomal aberrations and/or clonal immunoglobulin (Ig) gene rearrangements may indicate risk of failure, a more universal approach was developed to detect minimal disease (MD). Children/adolescents with intermediate-risk B-NHL were treated with French-British-American/Lymphome Malins de Burkitt 96 (FAB/LMB96) B4 modified chemotherapy and rituximab. Specimens from diagnosis, end of induction (EOI), and end of therapy (EOT) were assayed for MD. Initial specimens were screened for IGHV family usage with primer pools followed by individual primers to identify MD. Thirty-two diagnostic/staging specimens screened positive with primer pools and unique IGHV family primers were identified. Two patients relapsed; first relapse (4 months from diagnosis) was MD-positive at EOI, the second (36 months from diagnosis) was MD-positive at EOT. At EOI, recurrent rates were similar between the MRD-positive and MRD-negative patients (P = 0·40). At EOT, only 13/32 patients had MRD data available with one relapse in the MRD-positive group and no recurrences in the MRD-negative group (P = 0·077). The study demonstrated molecular-disseminated disease in which IgIGHV primer pools could be used to assess MD. This feasibility study supports future investigations to assess the validity and significance of MD screening in a larger cohort of patients with intermediate-risk mature B-NHL.

Figure 1

Minimal Disease (MD) Assay Time Points. At diagnosis, 32 subjects had specimens available for MD analysis, which were all MD-positive. At end of induction (EOI), 7 of 33 specimens were MD-positive; of which 6 became MD-negative at end of therapy (EOT); the other patient with the MD-positive EOI specimen relapsed at 4 months and did not have an EOT specimen available. Only 13 EOT specimens were available for MD assessment, of which 1 was MD-positive and this patient had a clinical relapse at 36 months.

Figure 2

Histology and Minimal Disease (MD) Melt Curves and Associated Amplified Products from a patient with Stage III/ Diffuse Large B-cell Lymphoma (DLBCL). Panel A: Haematoxylin and eosin stain of DLBCL tissue at diagnosis. Original magnification ×400; Panel B: Amplified product and positive-melt curve from diagnostic blood; Panel C: Negative-melt curve of from blood specimen at end of induction (EOI); Panel D: Positive melt curve of amplified product from blood specimen at end of therapy (EOT).