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Individualized Therapy FOr Relapsed Malignancies in Childhood (INFORM)

Program overview

The current treatment of childhood malignancies achieves cure rates of around 75% with modern multi-modal treatment protocols, however relapses from high-risk disease remain a tremendous clinical problem. Only a small proportion (about 10%) of patients with relapses are cured. The INFORM project (INdividualized Therapy FOr Relapsed Malignancies in Childhood), comprising a consortium of leading pediatric oncologists and renowned scientists in the field of high-content genomics research, focuses on addressing this challenge. Since the opening of the registry study in 2015, over 3,000 patients have been enrolled.


The INFORM program biologically characterizes tumor samples from pediatric patients with relapsed or refractory high-risk diseases using state-of-the-art next-generation sequencing (NGS) technologies. This characterization provides a “fingerprint” of each individual tumor, which is then analyzed by an expert panel of pediatric oncologists, bioinformaticians, and biologists. This panel classifies and weighs the aberrations/targets found for each patient according to their clinical relevance. These molecular targets are available within less than 4 weeks after sample receipt, entered into the central database, and discussed in an interdisciplinary molecular tumor board (MTB) with the treating physician and the expert panel. Treating physicians have access to the molecular information/targets of their patients and have full responsibility for deciding whether and in which way to use these data for therapy decision. 


Not only results of the NGS analyses are discussed in the interdisciplinary MTB, but also findings derived from other methods performed at INFORM, which are in their research phase but have proven to be beneficial for several INFORM patients. Among these methods are high-throughput drug sensitivity screening, liquid biopsies and proteomics.


The primary objectives of the INFORM Registry are to continuously develop the logistics for personalized treatments; to establish a sustainable data platform to enable molecular and clinical data sharing and partnership with academic researchers, industry partners, and regulators at an international level; to collect and evaluate data to provide information about clinically relevant targets and their therapy options, and to further develop both the established INFORM NGS analyses and also the developing methods. Other primary objectives of INFORM are the identification of germline variations that may be causally linked to the tumor and diagnostic refinement by molecular analyses.


The secondary objectives of the INFORM Registry include the analysis of responses, progression-free and overall survival rates of registered patients, considering various factors like (targeted) treatments, diagnoses, and actionable target types. Additionally, INFORM aims to establish tumor models (in vivo and in vitro) derived from fresh vital tumor material to validate drug response profiles and correlate them with the clinical response profiles of the patients. These tumor models are accessible to scientific partners worldwide, including companies and healthcare stakeholders, in order to promote and accelerate research in the field of paediatric oncology.

 

Program details 

The INFORM registry includes patients with relapsed/progressive or refractory diagnoses of ALL-HR, ALL post-SCT, ALL post-CAR-T cell therapy, AML, rhabdoid tumor, ependymoma, medulloblastoma, Ewing-sarcoma, high-grade glioma, high-risk neuroblastoma, non-hodgkin lymphoma, osteosarcoma, and soft tissue sarcoma. Additionally, patients with a primary diagnosis of high-risk cancers like high-grade glioma (including DIPG), soft tissue sarcoma, or ETMR, lacking established curative treatments, may also be enrolled.


Enrollment should always be discussed with the relevant GPOH study group or national coordinators before patient registration, or in some cases, with a specific GPOH registry and/or the INFORM Trial Office. The patients are 0 to 40 years old and were treated according to a GPOH protocol or an equivalent protocol as their first-line treatment. Although patients can be included up until the age of 40 years, they must have had their primary diagnosis below the age of 21 years. The collection of tumor and blood samples, as well as cerebrospinal fluid (for brain tumors only), is carried out as part of the routine standard of care for the patients. Patients can be enrolled from the ~60 GPOH centers in Germany and centers in the international partners of the INFORM Consortium (currently: Austria, Belgium, Czech Republic, Finland, Greece, Norway, Poland, Sweden, Switzerland; previously also the Netherlands and Australia, who are now running their own initiatives)


From the beginning of 2015 until the end of October 2023, INFORM has recruited 3,000 registered patients with an analysis rate of >90%. Among these patients, 61% were registered at a GPOH center in Germany, while the remaining 39% were registered at a center in one of the other participating countries. We are typically recruiting around 350 new patients per year.


Benefits and outcomes

Benefits participants can expect from the program. e.g.; improved health outcomes, better quality of life, access to specialized care, or any other positive impacts. Any success stories or testimonials?


Each patient analyzed in INFORM benefits from the comprehensive molecular and biological characterization of the tumor. If this characterization identifies relevant genetic information in the tumor, the treating physician can utilize this information for therapy decisions or inclusion in a specific clinical trial.


Furthermore, molecular and long-term clinical data from over 500 INFORM pediatric patients, collected between January 2015 and September 2019, were evaluated based on target prioritization and the associated clinical outcome (survival time). Progression-free survival (PFS) and overall survival (OS) times showed no significant differences overall between patients receiving targeted vs. conventional therapies. However, patients with very high-priority targets receiving matching therapy doubled PFS (204 days) and increased OS (354 days) compared to all other patients (PFS 117 days, OS 290 days). The analysis shows that comprehensive molecular profiling is feasible, and clinically beneficial for a subset of patients with very high-evidence targets.


Moreover, this study identified underlying hereditary cancer predisposition syndromes in 7.5% of the analyzed patients, allowing for treatment adjustments in some cases. Additionally, clinically relevant discrepancies between local diagnosis and brain/sarcoma DNA methylation-based classification systems were discovered in 6.6% of the patients, which is very important for further therapy decisions, regardless of specific targets [1]. 


As a result of these analyses, we have been successful in signing a specialist services contract with the German health insurance companies, who now support the provision of INFORM profiling as a diagnostic standard of care for eligible patients.


Even if this data is relevant and demonstrates some benefits for a small group of patients, the most significant health advantages resulting from the work of the INFORM registry are expected to manifest in the coming years, primarily benefiting future generations.

Expert team 

Prof. Dr. med. Olaf Witt
(Coordinator INFORM registry study and INFORM2)
Director Translational Program
Hopp Children’s Cancer Center Heidelberg (KiTZ)
Head, Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ)
Head, KiTZ Clinical Trial Unit (ZIPO) and Brain Tumors
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital

Prof. Dr. med. Stefan Pfister
(Coordinator INFORM program)
Director Preclinical Program
Hopp Children’s Cancer Center Heidelberg (KiTZ)
Head, Division of Pediatric Neurooncology, DKFZ
Deputy Head, KiTZ Clinical Trial Unit and Brain Tumors
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital

David T. W. Jones, Ph.D.
(Coordinator molecular diagnostics)
Group Leader, Pediatric Glioma Research Group, DKFZ
Hopp Children’s Cancer Center Heidelberg (KiTZ)

Prof. Dr. med. Uta Dirksen
(Coordinator participating GPOH groups)
Vice Director Pediatrics III, Oncology, Hematology, Immunology, Cardiology, Pulmonology,
West German Cancer Centre, Essen

Robert (RJ) Autry, Ph.D.
(Coordinator bioinformatics)
Group Leader Translational Genomics, DKFZ
Hopp Children’s Cancer Center Heidelberg (KiTZ)

Technology and Innovation

Next-Generation Sequencing (NGS)
The NGS platform used in INFORM is Illumina NovaSeq 6000, NovaSeq X, or equivalent, with a 2-3 day runtime. Samples from multiple patients on one lane typically achieve the following coverages:

  • WES tumor – 120x
  • WES germline – 100x
  • lcWGS tumor – 2x
  • lcWGS germline – 2x
  • RNA sequencing - ~100 million paired-end reads

High-depth exome sequencing detects somatic single-nucleotide variants and InDels with good sensitivity. Whole-genome sequencing provides a genome-wide copy number profile for assessing structural alterations occurring in the tumor. Matched germline sequencing distinguishes somatic from germline alterations and detects damaging germline variants. Future plans may involve switching to full coverage (~50x) whole-genome sequencing of tumor and matched germline samples for additional benefits.


Furthermore, INFORM analyzes and quantifies circulating tumor DNA for solid tumors to address the question whether tumor-derived circulating genetic information is suitable for molecular diagnostics and/or target identification. Finally, the RNA sequencing component of the molecular analysis pipeline provides detailed gene expression, fusion events, mRNA splice variants, and supports DNA mutation evidence by checking their presence in RNA.


Methylation Array Analysis
The Illumina Infinium HumanMethylationEPICv2 array is employed to assess DNA methylation, covering over 99% of RefSeq-annotated genes with 850,000 probes. Each chip accommodates up to 8 samples, facilitating efficient and high-throughput analysis. Our in-house pipelines address issues like ambiguous probe mapping and overlap with polymorphic sites. Additionally, we utilize probe intensity values for DNA copy number inference, providing valuable complementary data. In the INFORM registry, these arrays serve as a valuable tool for identifying epigenetic prognostic or predictive markers. They also contribute copy-number data, independently verifying alterations found in whole genome sequencing profiles.


Drug Sensitivity Profiling
After a successful pilot phase, Drug Sensitivity Profiling (DSP) is now an integral part of the INFORM MTB, contributing to enhance molecular tumor characterization. DSP is a personalized platform where the responses of individual tumor samples to 80 anticancer drugs are analyzed ex vivo. These anticancer drugs are approved or in clinical trials [2] .


Other Information

  • Coordinating Investigator Registry: Prof. Dr. med. Olaf Witt
  • Registry Code: NCT-2013-0220
  • German Clinical Trial Register ID: DRKS00007623

References

  1. van Tilburg, C.M., et al., The Pediatric Precision Oncology INFORM Registry: Clinical Outcome and Benefit for Patients with Very High-Evidence Targets. Cancer Discovery, 2021. 11(11): p. 2764-2779.
  2. Peterziel, H., et al., Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM. NPJ Precis Oncol, 2022. 6(1): p. 94.