CCRI: Pediatric high-risk tumors: gene defect shortens survival and needs targeted treatment

Neuroblastomas, the most common solid tumors outside the brain in children, are associated with poorer survival if they have genetic alterations in the ALK gene and belong to the high-risk group. This was shown by scientists from St. Anna Children's Cancer Research institute together with colleagues in an international collaboration. If such alterations are detected, it is conceivable that treatment with ALK inhibitors could be used as upfront therapy in future trials. The study was published in the renowned Journal of Clinical Oncology.

Genetic alterations in the so-called ALK gene and the associated protein can fuel the growth of malignant nerve tumors in children. These tumors, namely neuroblastomas, are neoplasms outside the brain that arise from nervous tissue during embryonic development. In a very aggressive form of neuroblastoma (high-risk neuroblastoma), certain genetic alterations in ALK have now been identified for the first time as independent predictive markers of decreased survival. Affected children should therefore receive targeted treatment with an ALK inhibitor in future studies. This is the conclusion of a team from St. Anna Children's Cancer Research Institute (St. Anna CCRI) in collaboration with St. Anna Children's Hospital and research groups throughout Europe and Israel.

Better chances for survival thanks to targeted ALK inhibition?

ALK stands for "anaplastic lymphoma kinase", a protein that promotes tumor growth when activated. "Our results convincingly argue for the use of an ALK inhibitor together with chemotherapy and immunotherapy as initial treatment for high-risk neuroblastoma harboring an ALK mutation or amplification (i.e., massive replication of the affected DNA sequence). The presence of an ALK mutation or amplification worsens survival outcome of affected patients. These patients should therefore receive an ALK inhibitor as tailored therapy in future clinical studies", explains Univ.-Prof. Ruth Ladenstein, MD, MBA, cPM, co-senior author of the study and head of the "Studies & Statistics for Integrated Research and Projects (S2IRP)" group at St. Anna CCRI.

Co-first author Ulrike Pötschger, PhD, senior statistician of the S2IRP group, adds, "ALK alterations are also a risk factor for survival in a later phase of treatment, when patients receive immunotherapy to maintain previous treatment success." Prof. Ladenstein concludes, "This result strongly suggests that integration of ALK inhibitors throughout all phases of modern era high-risk neuroblastoma therapy is warranted." 

ALK alterations are a relevant risk factor

This international, randomized phase III trial included 3,334 participants aged 12 months to 20 years with high-risk neuroblastoma. Of these, 762 were screened for an ALK mutation and 901 for an ALK amplification. ALK mutations were detected in 14 percent (106/762) and ALK amplifications in 4.5 percent (41/901) of these patients.

Overall, ALK alterations were a significant predictor for poorer survival in high-risk neuroblastoma (5-year overall survival: 48 vs. 67% with ALK alteration vs. no ALK alteration, p=0.03). This was also evident in the subgroup already treated with current standard high-dose chemotherapy (busulfan/melphalan) including anti-GD2 immunotherapy.

Furthermore, evaluation of ALK amplification alone was also associated with poorer long-term survival (5-year overall survival: 28 vs. 51% with ALK amplification vs. no ALK amplification, p<0.001), particularly in cases with metastatic MYCN amplified disease.

A subset of ALK mutations, namely those with a high "mutation dose" (i.e., clonal mutations; mutant allele fraction >20%) also proved to be a risk factor for poorer long-term survival (5-year overall survival: 34 vs. 59 vs. 49% for clonal ALK mutation vs. subclonal vs. no ALK mutation, p=0.018). ALK mutations with high "mutation dose" comprise approximately 10% of all high-risk neuroblastomas.

Strong European collaboration

This study was made possible thanks to a strong European collaboration, with a close cooperation between the Biological Reference Laboratories of the International Society of Pediatric Oncology Europe Neuroblastoma Group (SIOPEN), the contribution of the clinical centers of SIOPEN, and the close coordination between the principal investigators at St. Anna CCRI, Vienna, Austria, Newcastle University, UK and Institut Curie, Paris, France.

The biological analyses in this study were based on the expertise of the reference laboratories of the Biology Committee of SIOPEN, chaired by Gudrun Schleiermacher, MD, PhD, physician scientist and delegate director for translational research of the Integrated Pediatric Oncology Center SIREDO at Institut Curie, Paris, France. This team contributed to the discovery, in 2008, of the role of ALK alterations in neuroblastoma. It is now the strong collaboration between the SIOPEN biology reference laboratories that has enabled to demonstrate that ALK alterations are predictors of poor survival in children with high-risk neuroblastoma.

About high-risk neuroblastoma

Neuroblastomas are the most common pediatric solid tumors derived from nerve tissue outside the brain. High-risk neuroblastomas are tumors harboring a MYCN amplification, independent of age, or metastatic tumors in children aged twelve months or older. Unfortunately, the prognosis is still unsatisfactory, with only about half of the children with high-risk neuroblastoma surviving the disease in the long-term. Current standard treatment includes chemotherapy, surgery, autologous stem cell rescue, and isotretionin in combination with immunotherapy.

About the study

The international, randomized Phase III High-Risk Neuroblastoma trial (HR-NBL1), conducted by SIOPEN, enrolled a total of 3,334 patients between 2002 and 2019. Of these, 1,092 patients were included in the ALK analysis group, which did not differ in overall survival from the general study population. 132 institutions/hospitals in 19 different countries participated in the trial. Inclusion criteria included stage 2 to stage 4S neuroblastoma according to the International Neuroblastoma Staging System and MYCN amplification or stage 4 without MYCN amplification in patients aged over 12 months at diagnosis up to 20 years. Within the study, multiple randomized treatment arms consisting of chemotherapy, radiation, and immunotherapy were defined over different time periods.

A large proportion of children were older than 18 months at diagnosis (81%) and had reached an advanced stage of disease (88%, stage 4). MYCN amplification, a significant independent risk factor, was present in 47%.


Frequency and prognostic impact of ALK amplifications and mutations in the European Neuroblastoma Study Group (SIOPEN) high-risk neuroblastoma trial (HR-NBL1)

Angela Bellini*, Ulrike Pötschger*, Virginie Bernard, Eve Lapouble, Sylvain Baulande, Peter F. Ambros, Nathalie Auger, Klaus Beiske, Marie Bernkopf, David R. Betts, Jaydutt Bhalshankar, Nick Bown,  Katleen de Preter, Nathalie Clément,  Valérie Combaret, Jaime Font de Mora, Sally L. George, Irene Jiménez Marta Jeison, Barbara Marques, Tommy Martinsson, Katia Mazzocco, Martina Morini, Annick Mühlethaler-Mottet, Rosa Noguera, Gaelle Pierron6, Caroline Maria Rossing, Sabine Taschner-Mandl, Nadine Van Roy, Ales Vicha, Louis Chesler, Walentyna Balwierz, Victoria Castel, Martin Elliott, Per Kogner,  Geneviève Laureys, Roberto Luksch, Josef Malis, Maja Popovic-Beck,  Shifra Ash, Olivier Delattre, Dominique Valteau-Couanet, Deborah A. Tweddle**, Ruth Ladenstein**, Gudrun Schleiermacher**

* Both authors contributed equally to this work and are to be considered as joint first authors
** All 3 authors contributed equally to this work and are to be considered joint senior authors
Journal of Clinical Oncology, June XX 2021. DOI:  10.1200/JCO.21.00086.


This study received funding from the European Union. The companies Pierre Fabre Médicament, as well as APEIRON provided drugs. St. Anna Children's Cancer Research Institute was the academic sponsor of the study. Additional funding was provided by SIOPEN and by national funding agencies and institutes in the participating countries.

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