Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group (COG)

Abstract

Minimal residual disease (MRD) after initial therapy is integral to risk stratification in B- and T-precursor acute lymphoblastic leukemia (B-ALL, T-ALL). While MRD determines depth of remission, remission remains defined by morphology. We determined the outcomes of children with discordant assessments of remission by morphology vs. flow cytometry using patients age 1–30.99 years enrolled on Children’s Oncology Group ALL trials who underwent bone marrow assessment at the end of induction (N=9 350). Morphologic response was assessed locally as M1 (<5% lymphoblasts; remission), M2 (5–25%), or M3 (>25%). MRD was centrally measured by flow cytometry. 19.8% of patients with M2/M3 morphology had MRD<5%. M1 with MRD≥5% was less common in B-ALL (0.9%) than T-ALL (6.9%; p<0.0001). In B-ALL, M1/MRD≥5% was associated with superior 5-year event-free survival (EFS) than M2/MRD≥5% (59.1%±6.5% vs. 39.1%±7.9%; p=0.009), but was inferior to M1/MRD<5% (87.1%±0.4%; p<0.0001). MRD levels were higher in M2/MRD≥5% than M1/MRD≥5% patients. In T-ALL, EFS was not significantly different between M1/MRD≥5% and M2/MRD ≥5%. Patients with morphologic remission but MRD ≥5% have outcomes similar to those who fail to achieve morphological remission, and significantly inferior to those with M1 marrows and concordant MRD, suggesting that flow cytometry should augment the definition of remission in ALL.

Disease detection methodologies in relapsed B‐cell acute lymphoblastic leukemia: Opportunities for improvement

“…In both cases, while flow and aspirate were relatively concurrent, the biopsy was essential to determining the extent of disease involvement can be complicated by multiple factors including hypocellularity and confusion with hematogones that can be present in increased numbers in a regenerative marrow. 21,22 Additionally, these techniques lack the sensitivity of multiparametric FC to find rare, minimal levels of leukemic blasts. Combining multiple methods provides comprehensive data to more fully assess response to leukemia-directed therapy.…”

“…Though each study provides complementary information, and in theory, a uniform assessment of disease status, we have observed numerous cases in the relapsed/refractory setting where the multiparametric FC results are discrepant from the concurrent morphologic assessment of BM aspirate and/or biopsy. Very few studies have evaluated the additive value that BM aspirate morphology 1,2 or routine BM biopsy may provide in disease assessment. 1,3 Given the prognostic role of disease detection in ALL, 4,5 having an accurate and complete assessment of disease is essential.…”

“…Very few studies have evaluated the additive value that BM aspirate morphology 1,2 or routine BM biopsy may provide in disease assessment. 1,3 Given the prognostic role of disease detection in ALL, 4,5 having an accurate and complete assessment of disease is essential. Minimal residual disease (MRD) assessment by FC, which is usually based on a single BM aspirate sample, is subject to variability in specimen collection techniques and/or sampling error, and could be inaccurate due to a dilute sample or if there is nonuniform distribution of disease involvement in the BM.…”

“…Recent data indicate that even low-level disease may impact outcomes 7 and utilization of FC for disease evaluation in the CNS may increase the diagnostic yield. [8][9][10] With the dual objectives in this study to (1) identify the role of BM biopsy in conjunction with BM aspirate and FC and (2) evaluate the role of CSF FC alongside cytopathology, we performed a systematic retrospective analysis on patients with relapsed/refractory ALL treated in the Pediatric Oncology Branch (POB) at the National Cancer Institute (NCI). We report the frequency and degree of discrepancies in disease burden based on methodologies of BM and CSF assessments and strongly suggest a role for incorporating routine utilization of BM biopsies and CSF FC to augment current disease detection modalities, particularly in those with multiply relapsed disease.…”

Stage at diagnosis for children with blood cancers in Australia: Application of the Toronto Paediatric Cancer Stage Guidelines in a population‐based national childhood cancer registry

“…found that 8030 (86%) had CNS1 disease. 17 Thus, the Australian population-based proportion of CNS1 disease, although somewhat higher, is not substantially more so than the COG experience. We do, however, acknowledge that the proportion of CNS1 in these particular COG trials is higher than that reported by other cooperative groups.…”