Since the early 1970s, the Dana-Farber Cancer Institute (DFCI) Acute Lymphoblastic Leukaemia (ALL) Consortium has undertaken many successful clinical trials in childhood acute lymphoblastic ...leukaemia, which are mainly characterised by an early and prolonged intensification therapy with high-dose asparaginase, a drug that is regarded as a mainstay of treatment for this disease.1 In The Lancet Oncology, Andrew Place and colleagues report the results of the DFCI ALL Consortium protocol 05-001,2 a phase 3 randomised open-label trial that compared, after induction therapy, the use of 15 biweekly doses of intravenous PEG-asparaginase with 30 weekly doses of intramuscular native Escherichia coli (E coli) l-asparaginase.
Between September 1991 and May 1997, within the International Berlin-Frankfurt-Muenster Study Group (I-BFM-SG), a randomized study was performed aimed at assessing the efficacy of prolonged use of ...high-dose l-asparaginase (HD-l-ASP) during continuation therapy in children with standard risk (SR) acute lymphoblastic leukemia (ALL), treated with a reduced BFM-type chemotherapy.
The Italian, Dutch, and Hungarian groups participated in this study denominated IDH-ALL-91, and 494 children were enrolled. Treatment consisted of a BFM-type modified backbone with omission of the IB part in induction and elimination of two doses of anthracyclines during reinduction in both arms at the beginning of continuation therapy. Patients were randomly assigned to receive (YES-ASP) or not (NO-ASP) 20 weekly HD-l-ASP (25,000 IU/m2).
The event-free-survival and overall survival probabilities at 10 years for the entire group were 82.5% (1.8) and 90.3% (1.3), respectively. Of the 490 patients eligible for random assignment, 355 (72.4%) were randomly assigned (178 YES-ASP and 177 NO-ASP). After a median follow-up of 9 years, the probability of disease-free survival at 10 years was 87.5% (SE, 2.5) for YES-ASP arm versus 78.7% (SE, 3.3) for NO-ASP arm (P = .03). In multivariate analysis, NO-ASP arm (P = .03), male sex (P = .004), and age older than 10 years (P = .0003) had a significantly adverse impact on outcome.
In this subset of patients, selected with criteria not including monitoring of minimal residual disease, application of extended HD-l-ASP may improve prognosis, compensating reduced leukemia control that results from adoption of a reduced-intensity BFM-backbone for treatment of children with SR ALL.
Despite intensive risk-based treatment protocols, 15% of paediatric patients with B-Cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL) experience relapse. There is urgent need of novel strategies ...to target poor prognosis subgroups, like PAX5 translocated.
We considered 289 childhood BCP-ALL cases consecutively enrolled in Italy in the AIEOP-BFM ALL2000/R2006 protocols and we performed extensive molecular profiling, integrating gene expression, copy number analyses and fusion genes discovery by target-capture NGS. We developed preclinical strategies to target PAX5 fusion genes.
We identified 135 cases without recurrent genetic rearrangements. Among them, 59 patients (43·7%) had a Ph-like signature; the remaining cases were identified as ERG-related (26%), High-Hyperdiploid-like (17%), ETV6::RUNX1-like (8·9%), MEF2D-rearranged (2·2%) or KMT2A-like (1·5%). A poor prognosis was associated with the Ph-like signature, independently from other high-risk features.
Interestingly, PAX5 was altered in 54·4% of Ph-like compared to 16·2% of non-Ph-like cases, with 7 patients carrying PAX5 fusions (PAX5t), involving either novel (ALDH18A1, IKZF1, CDH13) or known (FBRSL1, AUTS2, DACH2) partner genes. PAX5t cases have a specific driver activity signature, extending to multiple pathways including LCK hyperactivation. Among FDA-approved drugs and inhibitors, we selected Dasatinib, Bosutinib and Foretinib, in addition to Nintedanib, known to be LCK ligands. We demonstrated the efficacy of the LCK-inhibitor BIBF1120/Nintedanib, as single agent or in combination with conventional chemotherapy, both ex vivo and in patient-derived xenograft model, showing a synergistic effect with dexamethasone.
This study provides new insights in high-risk Ph-like leukaemia and identifies a potential therapy for targeting PAX5-fusion poor risk group.
Ricerca Finalizzata-Giovani Ricercatori (Italian Ministry of Health), AIRC, Transcall, Fondazione Cariparo.
Next-generation sequencing (NGS) and liquid biopsy (LB) showed positive results in the fight against different cancer types. This paper aims to assess the uptake of advanced molecular diagnostics/NGS ...for quick and efficient genetic profiles of tumour cells. For that purpose, the European Alliance for Personalised Medicine conducted a series of expert interviews to ascertain the current status across member states. One stakeholder meeting was additionally conducted to prioritize relevant factors by stakeholders. Seven common pillars were identified, and twenty-five measures were defined based on these pillars. Results showed that a multi-faceted approach is necessary for successful NGS implementation and that regional differences may be influenced by healthcare policies, resources, and infrastructure. It is important to consider different correlations when interpreting the results and to use them as a starting point for further discussion.
The incidence of hypersensitivity reactions (HSRs) to PEG‐asparaginase (PEG‐ASNase) was evaluated in 6136 children with ALL enrolled in the AIEOP‐BFM ALL 2009 study. Patients with B‐cell ...precursor‐acute lymphoblastic leukemia (BCP‐ALL) were stratified as standard‐risk/medium‐risk (MR)/high‐risk (HR) and those with T‐ALL as non‐High/HR. PEG‐ASNase was administered intravenously at 2500 IU/sqm/dose. All patients received 2 PEG‐ASNase doses in induction; thereafter non‐HR versus HR patients received 1 versus 6 PEG‐ASNase doses, respectively. After the single regular dose of PEG‐ASNase at the beginning of delayed intensification, BCP‐ALL‐MR patients were randomized to receive 9 additional PEG‐ASNase doses every 2 weeks (experimental arm EA) versus none (standard arm SA); HR patients were randomized to receive, in consolidation, 4 weekly PEG‐ASNase doses (EA) versus none (SA). The HSR cumulative incidence (CI) was estimated adjusting for competing risks. An HSR occurred in 472 of 6136 (7.7%) patients. T‐non‐ HR/BCP‐Standard‐Risk, BCP‐MR‐SA, BCP‐MR‐EA, HR‐SA and HR‐EA patients had 1‐year‐CI‐HSR (±SE) rates of 5.2% (0.5), 5.2% (0.5), 4.0% (0.8), 20.2% (1.2), and 6.4% (1.3), respectively. The randomized intensification of PEG‐ASNase did not significantly impact on HSR incidence in BCP‐MR patients (1‐y‐CI‐HSR 3.8% 0.8 versus 3.2% 0.6 in MR‐EA versus MR‐SA; P = 0.55), while impacted significantly in HR patients (1‐y‐CI‐HSR 6.4% 1.3 versus 17.9% 1.8 in HR‐EA and HR‐SA, respectively; P < 0.001). The CI‐HSR was comparable among non‐HR groups and was not increased by a substantial intensification of PEG‐ASNase in the BCP‐MR‐EA group whilst it was markedly higher in HR‐SA than in HR‐EA patients, suggesting that, in such a chemotherapy context, a continuous exposure to PEG‐ASNase reduces the risk of developing an HSR.
Effective cancer diagnosis, treatment and control depend on interactions among numerous distinct factors, from technology to data to skills to sociology. But a crucial influence is the extent to ...which the health system takes account of the distinct perspectives of the many different groups of interdependent stakeholders concerned with cancer, including patients, practitioners and planners. This paper provides some elucidation as to how far and how efficiently these interactions currently take place in Europe. It also makes some tentative suggestions as to how conscious systematic interventions could improve cancer outcomes. It is based on a series of expert panels and surveys conducted by the European Alliance for Personalised Medicine (EAPM) that provided information at the national level on three selected parameters: implementation of next-generation sequencing (NGS) and liquid biopsy (LB), attitudes of patients to prevention and practices of sharing genomic data among healthcare professionals (HCPs). The varying data infrastructure highlights the urgent need for substantial improvements to accommodate the increasing importance of genomics data in cancer diagnosis and care. Additionally, we identify disparities in age-specific approaches to cancer prevention, emphasising the necessity for tailored strategies to address unique age group perspectives. Moreover, distinct regional prioritizations in cancer treatment underscore the importance of considering regional variations when shaping future cancer care strategies. This study advocates for collaborative data sharing supported by technological innovation to overcome these challenges, ultimately fostering a holistic and equitable provision of cancer care in Europe.
More than 35,000 children are diagnosed with cancer and treated in Europe each year. With the 1st SIOP Europe Course in Paediatric Oncology, the European Society for Paediatric Oncology (SIOP Europe) ...aimed to equip aspiring physicians to become leaders within a pan-European network and ensure state-of-the-art treatment for children across Europe. Fifty participants from 24 countries and 37 centres were enrolled on the course. With a virtual and a face-to-face meeting complete, we herewith report on the course concept, application process and first meetings of this 3-year educational program.
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