To study minimal disseminated disease (MDD) in children with Burkitt's lymphoma (BL) and to determine its impact on prognosis.
We established a simplified long-distance polymerase chain reaction ...(LD-PCR) assay that can amplify up to 15 to 20 Kb of DNA sequence, making it possible to detect the t(8;14) at the genomic level with sensitivity of 10(-4). We prospectively studied diagnostic biopsies and bone marrow aspirates from 134 patients affected by BL.
A specific LD-PCR product was detected in 96 (72%) of 134 BL biopsies. Among 84 patients with t(8;14) positivity on tumor biopsy and bone marrow (BM), 26 (31%) had LD-PCR-positive BM, and 15 (18%) were positive at standard morphologic analysis. Twenty (85%) of 26 MDD-positive patients belonged to the R4 risk group, according to Berlin-Frankfurt-Munster definition. The 3-year progression-free survival was 68% (SE, 10%) in MDD-positive patients in R4 compared with 93% (SE, 5%) in MDD-negative patients in R4 (P = .03). By multivariate analysis (including MDD, sex, lactate dehydrogenase, CNS involvement), only MDD was predictive of higher risk of failure (hazard ratio, 4.7; P = .04).
MDD identifies a poor-prognosis subgroup among children with high-risk BL. To improve disease control in these patients, a more effective risk-adapted therapy, possibly including anti-CD20 monoclonal antibody, should be considered.
NOTCH1/FBXW7 (N/F) mutational status at diagnosis is employed for T-cell lymphoblastic lymphoma (T-LBL) patients’ stratification in the international protocol LBL 2018. Our aim was to validate the ...prognostic role of Minimal Disseminated Disease (MDD) alone and in combination with N/F mutational status in a large retrospective series of LBL pediatric patients. MDD was analyzed in 132 bone marrow and/or peripheral blood samples by flow cytometry. Mutations in N/F genes were analyzed on 58 T-LBL tumor biopsies. Using the previously established cut-off of 3%, the four-year progression-free survival (PFS) was 57% for stage I–III patients with MDD ≥ 3% versus 80% for patients with MDD inferior to cut-off (p = 0.068). We found a significant worsening in the four-year PFS for nonmutated (51 ± 12%) compared to mutated patients (100%, p = 0.0013). Combining MDD and N/F mutational status in a subgroup of available cases, we found a statistically significant difference in the four-year PFS for different risk groups (p = 0.0012). Overall, our results demonstrate that N/F mutational status has a more relevant prognostic value than MDD at diagnosis. However, the combination of N/F mutations with MDD analysis could identify patients with very aggressive disease, which might benefit from a more intensive treatment.
To study the prevalence of t(8;14) at diagnosis and the response kinetics to treatment of minimal residual disease (MRD) in B-cell acute lymphoblastic leukemia (B-ALL) patients and determine its ...impact on prognosis.
A total of 68 children affected by de novo B-ALL enrolled onto the Berlin-Frankfurt-Muenster-based Italian Association of Pediatric Hematology and Oncology LNH-97 clinical protocol were studied. Bone marrow aspirate from each patient was analyzed for the presence of t(8;14)(q24;q32) by long-distance polymerase chain reaction at diagnosis, after the first chemotherapy cycle, and after subsequent cycles until negative for MRD. Morphologic and immunophenotypic analyses were reviewed centrally.
A total of 47 patients (69%) were positive for t(8;14)(q24;q32). MRD response kinetics was determined in 39 patients. All of them reached clinical complete remission and most (31 of 39) became MRD negative after the first chemotherapy cycle. The 3-year relapse-free survival (RFS) was 38% (SE = 17%) in patients MRD positive after the first chemotherapy cycle compared with 84% (SE = 7%) in MRD-negative patients (P = .0005), whereas there was no difference in RFS for children who reached a clinical complete remission after the first chemotherapy cycle versus those who did not (RFS = 72% and SE = 9%; RFS = 79% and SE = 11%, respectively; P = .8). In multivariate analysis, MRD was shown to be predictive of higher risk of failure.
Our study demonstrated that MRD carries a negative prognostic impact in B-ALL patients and suggests that a better risk-adapted therapy, possibly including the use of anti-CD20 monoclonal antibody, should be considered in selected patients.
Summary
Burkitt lymphoma (BL) and Diffuse Large B‐Cell Lymphoma (DLBCL) account for most cases of non‐Hodgkin lymphoma (NHL) in childhood. We report the clinical characteristics, outcome and ...prognostic factors in children with BL or DLBCL treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH‐97 protocol. Patients aged up to 18 years that were newly diagnosed with BL/DLBCL were included in the study. Therapy consisted of pre‐phase followed by 2–6 high‐dose chemotherapy courses tailored according to lactate dehydrogenase (LDH) value and disease stage. A total of 442 patients (379 BL, 63 DLBCL) were enrolled between 1997 and 2014, of whom 18 failed to achieve remission, 6 experienced treatment‐related death, 2 developed second malignancy and 20 relapsed. At a median follow‐up time of 5 years, overall survival was 93% (±1%) and event‐free survival was 90% (±1%). LDH value above the median value had an independently negative prognostic value (P < 0·0001). However, in the subgroup of 128 patients in which minimal disseminated disease (MDD) was analysed, MDD‐positivity became the only unfavourable prognostic factor for progression‐free survival. Tailored chemotherapy could be extremely effective with limited toxicity. Identification of MDD as a hallmark of a higher risk of treatment failure may provide a target population for treatment intensification by anti‐CD20.
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