Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. METHODS: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. FINDINGS: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). INTERPRETATION: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. FUNDING: Deutsche Krebshilfe.

A high proportion of germline variants in pediatric chronic myeloid leukemia.

Chronic myeloid leukemia (CML) typically occurs in late adulthood. Pediatric CML is a rare form of leukemia. In all age groups, the characteristic genetic driver of the disease is the BCR::ABL1 fusion gene. However, additional genomic events contribute to leukemic transformation, which is not yet well-characterized in pediatric CML. We investigated the mutational landscape of pediatric CML to determine whether predisposing germline variants may play a role in early-age disease development. Whole exome sequencing and targeted sequencing were performed in pediatric and adult CML samples to identify age-related germline and somatic variants in addition to the BCR::ABL1 translocation. Germline variants were detected in about 60% of pediatric patients with CML, with predominantly hematopoietic genes affected, most frequently ASXL1, NOTCH1, KDM6B, and TET2. The number of germline variants was significantly lower in adult patients with CML. If only confirmed pathogenic variants were regarded as cancer-predisposing variants, the occurrence was ~ 10% of pediatric CML, which is comparable to other hematological malignancies and most childhood cancer entities in general. We hypothesize that the interaction with the strong oncogene BCR::ABL1 may also favor the development of leukemia by weaker variants in the same genes. In pediatric patients, the germline variants of genes associated with clonal hematopoiesis may increase the likelihood that an incidental BCR::ABL1 translocation triggers the early manifestation of CML.

Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I-BFM Study Group.

This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival.

Imatinib treatment and longitudinal growth in pediatric patients with chronic myeloid leukemia: influence of demographic, pharmacological, and genetic factors in the German CML-PAED cohort.

In children and adolescents, impaired growth due to tyrosine kinase inhibitor therapy remains an insufficiently studied adverse effect. This study examines demographic, pharmacological, and genetic factors associated with impaired longitudinal growth in a uniform pediatric cohort treated with imatinib. We analyzed 94 pediatric patients with chronic myeloid leukemia (CML) diagnosed in the chronic phase and treated with imatinib for >12 months who participated in the Germany-wide CML-PAEDII study between February 2006 and February 2021 (clinicaltrials gov. Identifier: NCT00445822). During imatinib treatment, significant height reduction occurred, with medians of -0.35 standard deviation score (SDS) at 12 months and -0.76 SDS at 24 months. Cumulative height SDS change (Δ height SDS) showed a more pronounced effect in prepubertal patients during the first year but were similar between prepubertal and pubertal subgroups by the second year (-0.55 vs. -0.50). From months 12 to 18 on imatinib, only 18% patients achieved individually longitudinal growth adequate to the growth standard (Δ height SDS ≥0). When patients were divided into two subgroups based on median Δ height SDS (classifier Δ height SDS > or ≤-0.37) after 1 year on imatinib therapy, cohort 1 (Δ height SDS ≤-0.37) showed younger age at diagnosis, a higher proportion of prepubertal children, but also better treatment response and higher imatinib serum levels. Exploring the association of growth parameters with pharmacokinetically relevant single nucleotide polymorphisms, known for affecting imatinib response, showed no correlation. This retrospective study provides new insights into imatinib-related growth impairment. We emphasize the importance of optimizing treatment strategies for pediatric patients to realize their maximum growth potential.

CAR-T cells for the treatment of pediatric chronic myeloid leukemia in repeatedly relapsed lymphoid blast phase.

Chronic myeloid leukemia presenting de novo in the blast phase (CML-BP) is a rare diagnosis among pediatric malignancies. We report on a 16-year-old male who presented with CML-BP lymphoid at diagnosis. He was treated with shortened acute lymphoblastic leukemia induction plus the tyrosine kinase inhibitor (TKI) imatinib followed by dasatinib. After achieving molecular remission (MR), hematopoietic stem cell transplantation (HSCT) was performed early after diagnosis. Despite prophylactic dasatinib, he relapsed 3 months later with the kinase domain mutation T315I. Multiple therapeutic approaches including ponatinib, blinatumomab, a 2nd HSCT from a different donor, donor lymphocyte infusions, and high-dose asciminib all resulted in subsequent relapse. Another molecular response was achieved by combining ponatinib plus asciminib with chemotherapy. In this situation, CD19-directed CAR-T cells (Kymriah®) were administered for compassionate use and tolerated without adverse events. Compared to all prior therapies, CAR T-cells maintained remission. After 12 months of follow-up, complete B-cell aplasia and low numbers of CAR-T cells are detectable in the peripheral blood, potentially mediating long-term disease control.

Trajectories of illness perceptions in paediatric cancer patients and their parents and associations with health-related quality of life: Results of a prospective-longitudinal study.

OBJECTIVE: In paediatric oncology, little is known about trajectories of illness perceptions and their longitudinal associations with health-related quality of life (HRQoL). Therefore, the aim of this study was to investigate changes in illness perceptions in children and parents over a one-year-period and to investigate predictive value of child's and parent's illness perceptions during acute treatment for child's HRQoL 1 year later. METHODS: N = 65 child-parent-dyads participated in a longitudinal study (retention rate: 80.2%). Children were 4-18 years of age and underwent acute cancer treatment at baseline. Children and parents reported on their own illness perceptions (Illness-Perception-Questionnaire-Revised), as well as on the child's HRQoL (KINDL-R) at baseline and one-year-follow-up. Paired-samples t-tests were calculated to investigate changes over time. A hierarchical multiple regression analysis was performed to investigate predictive value of child's and parent's illness perceptions for child's HRQoL. RESULTS: Child's HRQoL t(63) = -6.73, p < 0.001, their perceptions of coherence (i.e. understanding; t(54) = -2.36, p = 0.022) and consequences of their illness (t(54) = 2.86, p = 0.006), and parent's perception of cyclical trajectory (t(61) = 2.06, p = 0.044) improved from baseline to 1-year-follow-up. All other illness perceptions remained stable. Exploratory post-hoc analyses showed differences in the pattern of change in age-, gender-, and diagnosis-specific subgroups. After controlling for baseline levels of HRQoL, child's perceptions of symptoms and consequences were independent predictors of their HRQoL 1 year later (R2 = 0.396, F(2,52) = 10.782, p < 0.001), whereas no parent's illness perceptions added predictive value. CONCLUSION: In paediatrics, child's and parent's illness perceptions should be assessed. Our findings highlight the importance of illness perceptions as potential modifiable variables in interventions to improve child's HRQoL.

Challenges in Management of Pediatric Chronic Myeloid Leukemia (pCML) in the Low-Middle Income Countries (LMICs): Insights from an International CML Foundation (iCMLf) Multi-National Survey.

Despite being a rare disease, high-income countries (HICs) have formulated guidelines for management of pediatric CML (pCML). We conducted a survey amongst 24 physicians from 22 Low-Middle Income Countries (LMICs) to gather information regarding their practice and experience in treating children with pCML. Rarity of pCML, lack of adequate expertise, and setting-adapted guidelines along with limitations in diagnostic infrastructure as well as challenges in accessing tyrosine kinase inhibitors (TKIs) were identified as major barriers in optimum management of patients. For the first time in literature, our findings provide valuable insights into the multifaceted challenges faced in managing pCML in LMICs.

A clinical screening tool to detect genetic cancer predisposition in pediatric oncology shows high sensitivity but can miss a substantial percentage of affected children.

PURPOSE: Clinical checklists are the standard of care to determine whether a child with cancer shows indications for genetic testing. Nevertheless, the efficacy of these tests to reliably detect genetic cancer predisposition in children with cancer is still insufficiently investigated. METHODS: We assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding exome sequencing analysis in an unselected single-center cohort of 139 child-parent data sets. RESULTS: In total, one-third of patients had a clinical indication for genetic testing according to current recommendations, and 10.1% (14 of 139) of children harbored a cancer predisposition. Of these, 71.4% (10 of 14) were identified through the clinical checklist. In addition, >2 clinical findings in the checklist increased the likelihood to identifying genetic predisposition from 12.5% to 50%. Furthermore, our data revealed a high rate of genetic predisposition (40%, 4 of 10) in myelodysplastic syndrome cases, while no (likely) pathogenic variants were identified in the sarcoma and lymphoma group. CONCLUSION: In summary, our data show high checklist sensitivity, particularly in identifying childhood cancer predisposition syndromes. Nevertheless, the checklist used here also missed 29% of children with a cancer predisposition, highlighting the drawbacks of sole clinical evaluation and underlining the need for routine germline sequencing in pediatric oncology.

Prevalence of anemia at diagnosis of pediatric chronic myeloid leukemia and prognostic impact on the disease course.

The clinical presentation of chronic myeloid leukemia (CML) at diagnosis differs in children compared to adults. At younger age, anemia appears to be frequent at diagnosis, but its prevalence and its impact on prognosis are not well known. In the International Registry of Childhood CML, we selected children and adolescents in chronic phase at diagnosis of CML and treated upfront with imatinib. We examined their hemoglobin level at diagnosis according to the WHO grades to assess the prevalence of anemia and its impact on response to tyrosine kinase inhibitors (TKIs). Data on 430 patients were included. Anemia at diagnosis was observed in 350 patients (81%), with a mean hemoglobin level of 96.4 g/l (SD 23.6). Among them, 182 patients (52%) presented with moderate anemia and 110 (31%) with severe anemia while 58 (17%) had mild anemia. Compared with mild and no anemia, moderate and severe forms were significantly associated with younger age at diagnosis, asthenia, splenomegaly, and increased leukocyte and basophil counts. Delays in achieving major and deep molecular responses were significantly increased for patients with moderate and severe anemia, and also failure of imatinib treatment was more frequent in these two sub-cohorts. However, hemoglobin level was not significantly associated with survival. Anemia at diagnosis of pediatric CML was frequent and may be considered as a prognostic factor.

Illness perceptions in patients and parents in paediatric oncology during acute treatment and follow-up care.

OBJECTIVE: Recent evidence suggests that illness perceptions in paediatric patients and their parents may differ, with parents holding more negative views compared to their children. Little is known about illness perceptions of very young patients and their parents. This study investigates illness perceptions in paediatric cancer patients aged 4-18 years and their parents in acute treatment or follow-up care, distinguishing patients by age (4-11, 12-18) and stage of medical treatment. METHODS: N = 45 patient-parent dyads in acute treatment and n = 95 dyads in follow-up care were examined. Parents and older children aged 12-18 years completed the Illness Perception Questionnaire-Revised (IPQ-R) and younger children aged 4-11 years were examined using an age-adapted hand puppet interview containing the IPQ-R questions. Difference scores of illness perceptions (symptoms, timeline-acute/chronic, timeline-cyclical, personal control, illness coherence, consequences, emotional representations) between children and parents were tested for significance using Wilcoxon signed-rank tests. RESULTS: Overall, parents perceived more symptoms associated with their child's illness/treatment than the children themselves. In acute treatment, younger children indicated more negative and older children more positive views regarding chronicity than parents. Younger children held less negative views on consequences, and all children reported less negative emotional representations than parents. In follow-up care, all children held less negative views on consequences and emotional representations. Older children reported less negative views on chronicity, cyclicity and illness coherence. CONCLUSION: Differences in illness perceptions of paediatric patients and their parents should be considered during and after treatment/medication and psychosocial care to support illness coping in person- and family-centred interventions.

Recurrent Germline Variant in RAD21 Predisposes Children to Lymphoblastic Leukemia or Lymphoma.

Somatic loss of function mutations in cohesin genes are frequently associated with various cancer types, while cohesin disruption in the germline causes cohesinopathies such as Cornelia-de-Lange syndrome (CdLS). Here, we present the discovery of a recurrent heterozygous RAD21 germline aberration at amino acid position 298 (p.P298S/A) identified in three children with lymphoblastic leukemia or lymphoma in a total dataset of 482 pediatric cancer patients. While RAD21 p.P298S/A did not disrupt the formation of the cohesin complex, it altered RAD21 gene expression, DNA damage response and primary patient fibroblasts showed increased G2/M arrest after irradiation and Mitomycin-C treatment. Subsequent single-cell RNA-sequencing analysis of healthy human bone marrow confirmed the upregulation of distinct cohesin gene patterns during hematopoiesis, highlighting the importance of RAD21 expression within proliferating B- and T-cells. Our clinical and functional data therefore suggest that RAD21 germline variants can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a CdLS phenotype.

Paediatric chronic myeloid leukaemia presenting in de novo or secondary blast phase - a comparison of clinical and genetic characteristics.

Additional data on blast phase (BP) chronic myeloid leukaemia (CML) in children and adolescents is essential for improving diagnostic and therapeutic approaches of this rare but serious condition. Here, we describe distinct clinical and genetic characteristics of 18 paediatric patients with de novo (n = 10) and secondary (n = 8) BP CML enrolled in the CML-PAED-II trial and registry. Our findings suggest that paediatric patients exhibit a diverse cytogenetic profile compared to adults with BP CML. In addition, patients with de novo BP CML in this cohort presented at a younger age, whereas patients with secondary BP CML more often harboured complex karyotypes.

How I treat chronic myeloid leukemia in children and adolescents.

Evidence-based recommendations have been established for treatment of chronic myeloid leukemia (CML) in adults treated with tyrosine kinase inhibitors (TKIs), but the rarity of this leukemia in children and adolescents makes it challenging to develop similar recommendations in pediatrics. In addition to imatinib, which was approved for pediatric CML in 2003, the second-generation TKIs dasatinib and nilotinib were recently approved for use in children, expanding the therapeutic options and pushing allogeneic stem cell transplantation to a third-line treatment of most pediatric cases. Yet, without sufficient data on efficacy and safety specific to pediatric patients, the selection of a TKI continues to rely on clinical experience in adults. Here, we present 4 case scenarios highlighting common yet challenging issues encountered in the treatment of pediatric CML (suboptimal response, poor treatment adherence, growth retardation, and presentation in advanced phases). Limited experience with very young children, the transition of teenagers to adult medicine, and the goal of achieving treatment-free remission for this rare leukemia are additional significant obstacles that require further clinical investigation through international collaboration.

Features and outcome of chronic myeloid leukemia at very young age: Data from the International Pediatric Chronic Myeloid Leukemia Registry.

INTRODUCTION: Chronic myeloid leukemia (CML) is rare in the first two decades of life comprising only 3% of newly diagnosed pediatric and adolescent leukemias. We studied the epidemiologic and clinical features of patients with CML diagnosed at younger than 3 years of age and evaluated treatment and long-term outcome. METHOD: Data from the International Pediatric I-BFM/CML Registry were retrospectively analyzed using the European LeukemiaNet criteria of the year 2006. Characteristics and treatment outcome of patients <3 years old at diagnosis were evaluated from standardized forms. RESULTS: Twenty-two patients (n = 22/479; 4.6%, male/female:14/8) were enrolled with a median age of 22 months (range, 10-34 m). Major symptoms comprised asthenia (30%), fever (30%), abdominal pain (20%), extramedullary signs (14%), hemorrhage (5%), and weight loss (5%). The extramedullary signs were specified in eight children: blueberry muffin (n = 1), sudden swollen abdomen (n = 1), sustained vomiting (n = 1), and cervical and inguinal lymph nodes (n = 5). Two of five children with cervical and inguinal lymph nodes were categorized as accelerated phase. Overall, 19 of 22 (86%) children were diagnosed in chronic phase, while the remaining three patients were in advanced phase. Median follow-up was 78 months (range, 7-196 m). Twenty-one out of 22 patients initially received imatinib, while one child received IFN + ARA-C. Imatinib was changed to second-line tyrosine kinase inhibitors (TKIs) in 29% of cases. During follow-up, 41% patients underwent stem cell transplantation (SCT). While on TKI, major molecular response (MMR) was achieved in 48% of children. Among the remaining patients, 21% are alive on TKI without MMR and 22% achieved complete molecular response following SCT. Twenty-one of 22 (95%) children are alive, while one patient died of posttransplant complications. CONCLUSION: This report demonstrates for the first time the efficacy and long-term effects of upfront imatinib in the so far largest cohort of children with CML diagnosed at very young age.

Bleeding signs due to acquired von Willebrand syndrome at diagnosis of chronic myeloid leukaemia in children.

A considerable proportion of patients with chronic myeloid leukaemia (CML) may present at diagnosis with high platelet counts. This may result in thrombosis or bleeding complications due to binding of von Willebrand factor (VWF) multimers to platelets. Paediatric CML is very rare and no systematic investigation on clinical complications of elevated platelets has been reported. Data on platelet count and associated haemostaseological complications were retrospectively analysed in a cohort of 156 children with CML. Fifty-one percent (81/156) patients presented with thrombocytosis (platelet count> 500 × 109 /l), and were extreme (>1 000 × 109 /l) in 23/156 (16%). There were no cases of thrombosis but mild bleeding signs were present in 12% (n = 9) children with thrombocytosis. Bleeding occurred without correlation to elevated platelet counts and was associated with reduced large VWF multimers, indicating a diagnosis of acquired von Willebrand syndrome (AVWS), which resolved after initiation of CML treatment. Patients with paediatric CML frequently exhibit high platelet counts not resulting in thrombosis. In patients with thrombocytosis mild bleeding signs due to a low percentage of large VWF multimers can be demonstrated. AVWS may be underdiagnosed in paediatric CML (Clinical-Trials.gov NCT00445822, 9 March 2007).

Experience with ponatinib in paediatric patients with leukaemia.

Ponatinib has proven to be effective in adults with Philadelphia chromosome-positive leukaemias, but data in paediatrics are scarce. Among paediatric patients with chronic myeloid leukaemia (n = 9) or acute lymphoblastic leukaemia (n = 12) treated with varying doses of ponatinib in 13 centres, 71% showed a decrease in disease burden after a median of three months. Ponatinib was well tolerated, with grade 3 toxicities occurring in 29% of patients. Toxicities were similar to those reported in adults, with the exception of arterial thrombotic events, which were not observed. Ponatinib has a favourable safety profile in this paediatric cohort, but dose-finding studies are needed.

[Disability Rating in Children and Adolescents with Chronic Myeloid Leukemia]. / Einstufung des Grades der Schwerbehinderung bei Kindern und Jugendlichen mit Chronischer Myeloischer Leukämie.

BACKGROUND: CML comprises only 2-3% of all diagnosed pediatric leukemias. Mostly diagnosed in chronic phase (CML-CP), the disease progresses without treatment to accelerated phase (CML-AP) and finally to life-limiting blastic phase (CML-BP). Contrasting the therapy of other leukemia types, CML-CP is not treated by intense chemotherapy but with oral drugs -termed tyrosine kinase inhibitors (TKI)- for an unlimited duration. This therapy may be associated with general and developmental-specific side effects. The rarity of pediatric-CML is limiting the experience in assessment of the disability rating (DR) as an administrative health authority procedure. METHODS: A questionnaire was sent out evaluating the procedures and results associated with the application of a disabled person's pass. RESULTS: 34 out of 70 patients (49%; median age 11 yrs., range 3-17 yrs.; CML-CP/-AP/-BP: N= 28/3/3) replied to the questionnaire. Median duration of TKI therapy was 33 months (range 4-163) and associated in 71% (24/34) of the patients with side effects. 5/34 (15%) patients did not apply for a pass. DR 100 was assigned to all patients with CML-BP and to 2/3 patients with CML-AP; the 3rd patient was assigned DR 60. In the 21 patients with CML-CP the assigned DR varied from 20-100; 9/28 patients (32%) were assigned to DR 50. Special identifier label H (helpless) was assigned to 5/28 patients (18%) with CML-CP. CONCLUSION: Compared to other pediatric malignancies, the broad range of DR in CML-CP points to unsureness when assessing the limitations exerted by the disease and its therapy. Guidelines for adults with CML offer little orientation only as pediatric patients frequently suffer from developmental-specific side effects.

[Registries and studies in the Society for Pediatric Oncology and Hematology (GPOH) - What contribution do they make to progress?] / Register und Studien in der Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) ­ Welchen Beitrag leisten sie zum Fortschritt?

Cancer in children and adolescents under the age of 18 is rare; in 2017, approximately 2220 new cases in Germany were reported to the German Childhood Cancer Registry. The aim of the GPOH has always been to treat as many affected patients as possible in a standardized way, preferably in prospective, controlled studies. The Joint Federal Committee has also laid down this requirement in the paediatric oncology guideline. In a survey among the study chairs of the GPOH, it was determined how the number of clinical trials has changed following the amended drug legislation. In 2002, 33 therapy optimization studies (TOS) of the GPOH were open. Overall, TOS decreased from 33 in 2002 to 2 in 2017. The number of drug trials has increased to 16 by 2017 (almost 1100 patients registered). At the time, the number of clinical registries has increased to 28 with a total of more than 1800 registered patents. This observation shows that the clinical registers have taken on a new significance in paediatric oncology. Three examples are used to examine what contributions registries can make in relation to studies on the treatment of patients and to scientific progress. In summary, the experience gained so far from the examples discussed illustrates that studies and registries mutually represent a meaningful and necessary addition to the study group structure in paediatric oncology.

Integration of mathematical model predictions into routine workflows to support clinical decision making in haematology.

BACKGROUND: Individualization and patient-specific optimization of treatment is a major goal of modern health care. One way to achieve this goal is the application of high-resolution diagnostics together with the application of targeted therapies. However, the rising number of different treatment modalities also induces new challenges: Whereas randomized clinical trials focus on proving average treatment effects in specific groups of patients, direct conclusions at the individual patient level are problematic. Thus, the identification of the best patient-specific treatment options remains an open question. Systems medicine, specifically mechanistic mathematical models, can substantially support individual treatment optimization. In addition to providing a better general understanding of disease mechanisms and treatment effects, these models allow for an identification of patient-specific parameterizations and, therefore, provide individualized predictions for the effect of different treatment modalities. RESULTS: In the following we describe a software framework that facilitates the integration of mathematical models and computer simulations into routine clinical processes to support decision-making. This is achieved by combining standard data management and data exploration tools, with the generation and visualization of mathematical model predictions for treatment options at an individual patient level. CONCLUSIONS: By integrating model results in an audit trail compatible manner into established clinical workflows, our framework has the potential to foster the use of systems-medical approaches in clinical practice. We illustrate the framework application by two use cases from the field of haematological oncology.

Large amplicon droplet digital PCR for DNA-based monitoring of pediatric chronic myeloid leukaemia.

Quantification of tumour-specific molecular markers at the RNA and DNA level for treatment response monitoring is crucial for risk-adapted stratification and guidance of individualized therapy in leukaemia and other malignancies. Most pediatric leukaemias and solid tumours of mesenchymal origin are characterized by a relatively low mutation burden at the single nucleotide level and the presence of recurrent chromosomal translocations. The genomic fusion sites resulting from translocations are stable molecular tumour markers; however, repeat-rich DNA sequences flanking intronic breakpoints limit the design of high sensitivity PCR assays for minimal residual disease (MRD) monitoring. Here, we quantitatively evaluated the impact of repeat elements on assay selection and the feasibility of using extended amplicons (≤1330 bp) amplified by droplet digital PCR to monitor pediatric chronic myeloid leukaemia (CML). Molecular characterization of 178 genomic BCR-ABL1 fusion sites showed that 64% were located within sequence repeat elements, impeding optimal primer/probe design. Comparative quantification of DNA and RNA BCR-ABL1 copy numbers in 687 specimens from 55 pediatric patients revealed that their levels were highly correlated. The combination of droplet digital PCR, double quenched probes and extended amplicons represents a valuable tool for sensitive MRD assessment in CML and may be adapted to other translocation-positive tumours.