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Simple Summary: Detection of minimal disease in blood or bone marrow is associated with high relapse risk in children with anaplastic large cell lymphoma (ALCL). The persistence of minimal residual disease after one course of chemotherapy indicates a relapse risk of 80%. While quantification of minimal disease might further improve the identification of high-risk patients, the assays used for quantification currently are not transferable between multiple laboratories. We aimed to test a digital PCR method (dPCR) for comparison of minimal disease quantification between two laboratories and the usefulness of quantification for risk stratification of children with ALCL. Quantification of minimal disease by dPCR was concordant between laboratories and allowed identification of patients at very high risk for relapse. Qualitative detection of minimal residual disease after one course of chemotherapy sufficed to identify children at the highest risk of treatment failure. International dissemination of this assay will allow patient selection for new targeted treatment approaches. Minimal disseminated and residual disease (MDD/MRD) analyzed by qualitative PCR for NPM-ALK fusion transcripts are validated prognostic factors in pediatric ALK-positive anaplastic large cell lymphoma (ALCL). Although potentially promising, MDD quantification by quantitative real-time PCR in international trials is technically challenging. Quantification of early MRD might further improve risk stratification. We aimed to assess droplet digital PCR for quantification of minimal disease in an inter-laboratory setting in a large cohort of 208 uniformly treated ALCL patients. Inter-laboratory quality control showed high concordance. Using a previously described cut-off of 30 copies NPM-ALK/104 copies ABL1 (NCN) in bone marrow and peripheral blood, MDD quantification allowed identification of very high-risk patients (5-year PFS% 34 ± 5 for patients with ≥30 NCN compared to 74 ± 6 and 76 ± 5 for patients with negative or <30 NCN, respectively, p < 0.0001). While MRD positivity was confirmed as a prognostic marker for the detection of very high-risk patients in this large study, quantification of MRD fusion transcripts did not improve stratification. PFS% was 80 ± 5 and 73 ± 6 for MDD- and MRD-negative patients, respectively, versus 35 ± 10 and 16 ± 8 for MRD-positive patients with <30 and ≥30 NCN, p < 0.0001. Our results suggest that MDD quantification by dPCR enables improved patient stratification in international clinical studies and patient selection for early clinical trials already at diagnosis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite success of targeted therapy, cancer cells very often find a way to survive treatment; this eventually causes a tumor to relapse. In a particular type of lymphoma carrying a specific chromosomal rearrangement named anaplastic large-cell lymphoma (ALCL), selective drugs targeting the cause of the disease can induce spectacular remission of chemotherapy-resistant cancer. However, the lymphoma relapses again in about half of the cases, leaving no therapeutic options. We studied the possibility to combine two simultaneous treatments in order to prevent the relapse, starting from the hypothesis that acquiring resistance to two drugs at the same time is statistically very unlikely. We demonstrate that treating lymphoma cells with drug combinations has superior efficacy in comparison with single drug treatments, both in cell cultures and in mice. Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30–40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population. We here investigated the efficacy of upfront rational drug combinations to prevent the rise of resistant ALCL, in vitro and in vivo. Different combinations of crizotinib with CHOP chemotherapy, decitabine and trametinib, or with second-generation ALK inhibitors, were investigated. We found that in most cases combined treatments completely suppressed the emergence of resistant cells and were more effective than single drugs in the long-term control of lymphoma cells expansion, by inducing deeper inhibition of oncogenic signaling and higher rates of apoptosis. Combinations showed strong synergism in different ALK-dependent cell lines and better tumor growth inhibition in mice. We propose that drug combinations that include an ALK inhibitor should be considered for first-line treatments in ALK+ ALCL. [ABSTRACT FROM AUTHOR]