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Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.

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.

The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, bosutinib, and nilotinib are established for first-line treatment of chronic myeloid leukemia (CML) but may cause side effects such as bleeding and thrombotic complications. We investigated the impact of TKIs on platelet function ex vivo in anticoagulated whole blood (WB) samples from healthy adults by lumiaggregometry and PFA-100 test. Samples (n = 15 per TKI) were incubated for 30 minutes with TKI at therapeutically relevant final concentrations. Aggregation and ATP release were induced by collagen (1 µg/mL), arachidonic acid (0.5 mmol/L), and thrombin (0.5 U/mL). Imatinib, bosutinib, and nilotinib significantly increased collagen-induced aggregation compared with controls. In addition, for bosutinib and nilotinib, a significant increase in aggregation after induction with arachidonic acid was detected. ATP-release and PFA-100 closure times were not influenced significantly by these three TKI. In contrast, dasatinib demonstrated a concentration-dependent inhibition of collagen-induced aggregation and ATP release and a significant prolongation of the PFA-100 closure time with the collagen/epinephrine cartridge. Aggregation and ATP release by other agonists as well as closure time with the collagen/ADP cartridge were not influenced significantly. In conclusion, we clearly show a concentration-dependent inhibition of collagen-induced platelet function in WB by dasatinib confirming prior results obtained in platelet-rich plasma. Bosutinib and nilotinib exerted no impairment of platelet activation. On the contrary, both TKI showed signs of platelet activation. When comparing our results with existing data, imatinib in therapeutic relevant concentrations does not impair platelet function.

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.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.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.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.

Clinical checklists are the current gold standard 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. Here, we assessed the validity of clinically recognizable signs to identify cancer predisposition by correlating a state-of-the-art clinical checklist to the corresponding whole exome sequencing analysis in an unselected single-center cohort of 139 child-parent datasets. We applied a strict testing to only include autosomal dominant or compound heterozygous cancer-related variants.Our study reflects a high consent rate for genetic testing (>90%). In total, 1/3rdof patients had a clinical indication for genetic testing according to current recommendations and 10.8% (n=15/139) of children harbored a proven cancer predisposition based on exome sequencing. Out of these only 73.3% (n=11/15) were identified through the clinical checklist. In addition, >2 clinical findings in the applied checklist increased the likelihood to identifying genetic predisposition from 15% to 50%. While our data revealed a high rate of genetic predisposition (50%, n=5/10) in Myelodysplastic Syndrome (MDS) cases, no cancer predisposition variants were identified in the sarcoma and lymphoma group.In summary, our data showed a low checklist specificity of 68.5%, and missed every 4thchild with genetic predisposition. This highlights the drawbacks of sole clinical evaluation to accurately identify all children at risk and underlines the need for routine germline sequencing of pediatric cancers.

Zusammenfassung Hintergrund Die Chronische Myeloische Leukämie (CML) repräsentiert nur 2–3 % der pädiatrischen Leukämien. Sie wird meist in chronischer Phase (CML-CP) diagnostiziert und schreitet unbehandelt zur akzelerierten (CML-AP) und schließlich akut lebensbedrohlichen Blastenphase (CML-BP) fort. Anders als bei anderen Leukämieformen erfolgt in CML-CP keine intensive Chemotherapie, sondern auf unbestimmte Dauer eine Therapie mit oralen Medikamenten, den Tyrosinkinase-Inhibitoren (TKI). Diese kann mit allgemeinen und entwicklungsspezifischen Nebenwirkungen assoziiert sein. Die Seltenheit der pädiatrischen CML limitiert die Erfahrung bei der Festlegung des Grades der Behinderung (GdB) durch die Behörden. Methoden Es erfolgte eine Fragebogen-Erhebung zu den Abläufen bei Antragsstellung für einen Schwerbehindertenausweis. Resultate 34/70 Patienten (49 %; medianes Alter 11 J, Bereich 3–17 J; CML-CP/-AP/-BP: N = 28/3/3 Patienten) beantworteten die Fragen. Die mediane TKI-Therapiedauer betrug 33 Monate (Bereich 4–163 Mon.), wobei 24/34 Patienten (71 %) Nebenwirkungen berichteten. 5/34 Patienten (15 %) hatten keinen Behindertenausweis beantragt. In CML-BP wurde ein GdB 100 allen und in CML-AP 2 von 3 Patienten bewilligt; dem 3. Patienten wurde GdB 60 zugestanden. Bei den 21 Patienten in CML-CP variierte der bewilligte GdB von 20–100; 9/28 Patienten (32 %) erhielten GdB 50. Das Merkzeichen H (hilflos) wurde bei 5/28 Patienten (18 %) in CML-CP bewilligt. Fazit Verglichen mit anderen pädiatrischen Malignomen lässt die große Spannbreite des GdB bei CML-CP auf eine Unsicherheit bei der Einschätzung der Einschränkungen durch die Erkrankung und Therapie schließen. Vorgaben bei Erwachsenen mit CML bieten nur wenig Orientierung, da sich bei pädiatrischen Patienten auch häufig entwicklungsspezifische Nebenwirkungen ergeben.

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.

Zusammenfassung Hintergrund Die Chronische Myeloische Leukämie (CML) repräsentiert nur 2–3% der pädiatrischen Leukämien. Sie wird meist in chronischer Phase (CML-CP) diagnostiziert und schreitet unbehandelt zur akzelerierten (CML-AP) und schließlich akut lebensbedrohlichen Blastenphase (CML-BP) fort. Anders als bei anderen Leukämieformen erfolgt in CML-CP keine intensive Chemotherapie, sondern auf unbestimmte Dauer eine Therapie mit oralen Medikamenten, den Tyrosinkinase-Inhibitoren (TKI). Diese kann mit allgemeinen und entwicklungsspezifischen Nebenwirkungen assoziiert sein. Die Seltenheit der pädiatrischen CML limitiert die Erfahrung bei der Festlegung des Grades der Behinderung (GdB) durch die Behörden. Methoden Es erfolgte eine Fragebogen-Erhebung zu den Abläufen bei Antragsstellung für einen Schwerbehindertenausweis. Resultate 34/70 Patienten (49%; medianes Alter 11 J, Bereich 3–17 J; CML-CP/-AP/-BP: N= 28/3/3 Patienten) beantworteten die Fragen. Die mediane TKI-Therapiedauer betrug 33 Monate (Bereich 4–163 Mon.), wobei 24/34 Patienten (71%) Nebenwirkungen berichteten. 5/34 Patienten (15%) hatten keinen Behindertenausweis beantragt. In CML-BP wurde ein GdB 100 allen und in CML-AP 2 von 3 Patienten bewilligt; dem 3. Patienten wurde GdB 60 zugestanden. Bei den 21 Patienten in CML-CP variierte der bewilligte GdB von 20–100; 9/28 Patienten (32%) erhielten GdB 50. Das Merkzeichen H (hilflos) wurde bei 5/28 Patienten (18%) in CML-CP bewilligt. Fazit Verglichen mit anderen pädiatrischen Malignomen lässt die große Spannbreite des GdB bei CML-CP auf eine Unsicherheit bei der Einschätzung der Einschränkungen durch die Erkrankung und Therapie schließen. Vorgaben bei Erwachsenen mit CML bieten nur wenig Orientierung, da sich bei pädiatrischen Patienten auch häufig entwicklungsspezifische Nebenwirkungen ergeben.

Background: Chronic myeloid leukaemia (CML) is a rare disease in children. The frequency and outcome of children evolving to accelerated phase (AP) or blastic phase (BP) under treatment with imatinib is unknown. The aim of the current study is to assess the inci-dence of progression from CML in chronic phase with imatinib frontline in a paediatric setting and describe the management and outcome of these patients.Patients and methods: In the I-CML-Ped Study database (www.clinicaltrials.gov, #NCT01281735), 19 of 339 paediatric patients in chronic phase treated with imatinib in the frontline evolved to CML-AP or CML-BP.Results: With a median follow-up of 38 months (range: 2-190 months), the cumulative inci-dence of progression at 1 and 3 years was 3% (confidence interval [CI] 95%: 1-5%) and 7% (CI 95%: 4-11%), respectively. We observed a large predominance of lymphoid-BP (70%) over myeloid-BP (30%) with imatinib in frontline therapy. Sixteen patients underwent haemato-poietic stem cell transplantation, and eight were treated with a tyrosine kinase inhibitor after transplant. Only the transplanted patients are alive. The 5-year overall survival rate of children with CML-AP/BP is 44%, with no statistical difference between the lymphoid-BP and myeloid-BP outcome.Conclusion: Children evolving to AP or BP under treatment with imatinib have a very poor prognosis with an overall survival under 50%, much worse than children with advanced phase at diagnosis. (c) 2020 Elsevier Ltd. All rights reserved.

Chronic myeloid leukemia (CML) in minors is a rare disease which can be effectively treated by tyrosine kinase inhibitors (TKIs) since the year 2000. A majority of pediatricians will encounter one or two CML patients in the course of their careers and will typically have to rely on written information along with their own intuition to provide care. Knowledge of response to TKIs and of age-specific side effects has an impact on the design of pediatric CML trials in many ways aiming to contribute toward greater predictability of clinical improvements. Information from a registry on a rare disease like CML offers the enormous benefit of enabling treating physicians to interact and share their collective experience. The International Registry on Pediatric CML (IR-PCML) was founded at Poitiers/France almost 10 years ago. Since then, the number of collaboration centers and in parallel of registered patients continuously increased (> 550 patients as of December 2019). Ideally, from a given treatment center in a country data are transferred to a national coordinator who interacts with the IR-PCML. In the sense of quality assurance, the registry can offer dissemination of knowledge on state-of-the-art diagnostics (including reference appraisal), optimal treatment approaches, and follow-up procedures within a network that is exerting its strength via participation. With continuous growth during the recent years, very rare subgroups of patients could be identified (e.g., CML diagnosed at age < 3 years, children presenting with specific problems at diagnosis or during course of treatment) which had not been described before. Publications coming from the IR-PCML disseminated this useful information derived from patients who robustly participate and share information about their disease, among themselves and with their caregivers and clinicians. Patient input driving the collection of data on this rare leukemia is the basis for the considerable success of bringing new therapeutics into clinical use.

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.

Background Isolated myelosarcoma of infancy is a rare presentation of acute myelogenous leukaemia (AML). Because of its rarity and early onset in infancy underlying genetic predisposition is potentially relevant in disease initiation. Methods and Results We report an oncologic emergency in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma causing acute myelon compression and lower leg palsy. Whole‐exome sequencing of the patient's germline DNA identified a rare PALB2 (OMIM 610355) variant (p.A1079S), which is located in a domain critical for the gene's proper function within the homology‐directed repair pathway. In line with potential DNA damage repair defects mediated by the PALB2 deregulation, the patient's fibroblasts showed increased sensitivity towards radiation and DNA intercalating agents. Conclusion Therefore, we suggest PALB2 p.A1079S as a pathogenic variant potentially contributing to the here observed patient phenotype., We present the finding of an infant with thoracic and intraspinal aleukemic myeloid sarcoma with a rare germline PALB2 variant (p.A1079S). The identified variant is located in a domain critical for the gene's proper function within the homology‐directed repair pathway. A functional role of the variant is further supported by increased sensitivity towards irradiation and DNA intercalating agents observed in primary cells from the patient carrying PALB2 p.A1079S.

Acquired polyneuropathies (PN) are rare in childhood and adolescent. We report on a 15-year-old male patient who presented with progressive gait instability, ataxia, neuropathic pain, distal muscle weakness and progressive loss of ambulation. Nerve conduction studies (NCS) revealed a progressive demyelinating sensorimotor polyneuropathy predominantly of the lower limbs. Cerebrospinal fluid (CSF) analyses revealed a cytoalbuminologic dissociation. Extensive diagnostic workup for autoantibodies and inflammatory markers was inconclusive. Corticosteroids and intravenous immunoglobulins did not affect. Cranial MRI revealed leptomeningeal enhancement of the cerebellum and the brainstem. Brain biopsy of the cerebellar lesions revealed an unclassifiable sarcoma. The patient was treated according to the CWS guidance study resulting in a decrease in enhanced lesion size. After two years NCS still revealed a demyelinating sensorimotor PN. This case report describes for the first time the clinical course of a chronic PN, putative paraneoplastic, associated with isolated unclassifiable CNS-sarcoma in an adolescent patient. Paraneoplastic pathogenesis should be considered in an unusual sequence of subacute progressive neurological symptoms even in children and adolescents.

Simple Summary The low incidence (1:1,000,000) of chronic myeloid leukemia (CML) in the first two decades of life presents an obstacle to accumulation of pediatric experience and knowledge on this leukemia. Biological features of CML are shared but also differing between adult and pediatric patients. This review aims; (i) to define the disease based on an unified terminology, (ii) to list the diseases to be considered as a differential diagnosis in children, (iii) to outlines the morphological, histopathological and immuno-phenotypical findings of pediatric CML, (iv) to illustrate rare but classical complications resulting from high white cell and platelet counts at diagnosis, and (v) to recommend a uniform approach for the diagnostic procedures to be applied. Evidently, only a clear detailed picture of all relevant features can lay the basis for standardized treatment approaches. Abstract Depending on the analytical tool applied, the hallmarks of chronic myeloid leukemia (CML) are the Philadelphia Chromosome and the resulting mRNA fusion transcript BCR-ABL1. With an incidence of 1 per 1 million of children this malignancy is very rare in the first 20 years of life. This article aims to; (i) define the disease based on the WHO nomenclature, the appropriate ICD 11 code and to unify the terminology, (ii) delineate features of epidemiology, etiology, and pathophysiology that are shared, but also differing between adult and pediatric patients with CML, (iii) give a short summary on the diseases to be considered as a differential diagnosis of pediatric CML, (iv) to describe the morphological, histopathological and immunophenotypical findings of CML in pediatric patients, (v) illustrate rare but classical complications resulting from rheological problems observed at diagnosis, (vi) list essential and desirable diagnostic criteria, which hopefully in the future will help to unify the attempts when approaching this rare pediatric malignancy.

Targeted therapy by tyrosine kinase inhibitors (TKIs) has dramatically improved survival rates in CML. Today stem cell transplantation is no longer the first-line treatment also in children. However, in the majority of patients, TKIs probably have to be administered over decades to control instead of eradicating completely the malignant cell clone. Thus, CML nowadays has to be regarded in sensu stricto as “chronic” which is in sharp contrast to the other pediatric malignancies dealt with in the context of this book. Lifelong TKI administration requires assessment of any side or “late” effect as a possible “untargeted consequence of a targeted treatment,” which represents a novelty in pediatric oncology. Systematic investigations on TKI late effects in adults are missing, and the cumulative toxicity of ongoing exposure in a growing organism with regard to young and old adulthood is presently hard to be judged on.

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.A questionnaire was sent out evaluating the procedures and results associated with the application of a disabled person's pass.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 3Compared 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.Die Chronische Myeloische Leukämie (CML) repräsentiert nur 2–3% der pädiatrischen Leukämien. Sie wird meist in chronischer Phase (CML-CP) diagnostiziert und schreitet unbehandelt zur akzelerierten (CML-AP) und schließlich akut lebensbedrohlichen Blastenphase (CML-BP) fort. Anders als bei anderen Leukämieformen erfolgt in CML-CP keine intensive Chemotherapie, sondern auf unbestimmte Dauer eine Therapie mit oralen Medikamenten, den Tyrosinkinase-Inhibitoren (TKI). Diese kann mit allgemeinen und entwicklungsspezifischen Nebenwirkungen assoziiert sein. Die Seltenheit der pädiatrischen CML limitiert die Erfahrung bei der Festlegung des Grades der Behinderung (GdB) durch die Behörden.Es erfolgte eine Fragebogen-Erhebung zu den Abläufen bei Antragsstellung für einen Schwerbehindertenausweis.34/70 Patienten (49%; medianes Alter 11 J, Bereich 3–17 J; CML-CP/-AP/-BP: N= 28/3/3 Patienten) beantworteten die Fragen. Die mediane TKI-Therapiedauer betrug 33 Monate (Bereich 4–163 Mon.), wobei 24/34 Patienten (71%) Nebenwirkungen berichteten. 5/34 Patienten (15%) hatten keinen Behindertenausweis beantragt. In CML-BP wurde ein GdB 100 allen und in CML-AP 2 von 3 Patienten bewilligt; dem 3. Patienten wurde GdB 60 zugestanden. Bei den 21 Patienten in CML-CP variierte der bewilligte GdB von 20–100; 9/28 Patienten (32%) erhielten GdB 50. Das Merkzeichen H (hilflos) wurde bei 5/28 Patienten (18%) in CML-CP bewilligt.Verglichen mit anderen pädiatrischen Malignomen lässt die große Spannbreite des GdB bei CML-CP auf eine Unsicherheit bei der Einschätzung der Einschränkungen durch die Erkrankung und Therapie schließen. Vorgaben bei Erwachsenen mit CML bieten nur wenig Orientierung, da sich bei pädiatrischen Patienten auch häufig entwicklungsspezifische Nebenwirkungen ergeben.

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.Krebserkrankungen bei Kindern und Jugendlichen unter 18 Jahren sind selten; im Jahr 2017 wurden ca. 2220 Neuerkrankungen in Deutschland an das Deutsche Kinderkrebsregister gemeldet. Ziel der GPOH war es immer, möglichst alle betroffenen Patienten standardisiert, am besten in prospektiven, kontrollierten Studien, zu behandeln. Diese Vorgabe hat auch der Gemeinsame Bundesausschuss in der Kinderonkologierichtlinie festgeschrieben. In einer Umfrage unter den Studienleitern der GPOH wurde ermittelt, wie sich nach der geänderten Arzneimittelgesetzgebung, die Zahl der klinischen Studien verändert hat. Im Jahr 2002 waren 33 Therapieoptimierungs-studien (TOS) der GPOH geöffnet. Insgesamt ist ein Rückgang der TOS von 33 im Jahre 2002 auf 2 im Jahre 2017 zu verzeichnen. Die Zahl der Arzneimittelstudien hat sich bis zum Jahr 2017 auf 16 erhöht (knapp 1100 erfasste Patienten). Zeitgleich hat sich die Zahl der klinischen Register auf 28 erhöht mit insgesamt mehr als 1800 dort erfassten Patienten. Diese Beobachtung zeigt, dass die klinischen Register eine neue Bedeutung in der pädiatrischen Onkologie bekommen haben. An 3 Beispielen wird dargelegt, welche Beiträge Register im Verhältnis zu Studien zur Behandlung der Patienten und zum wissenschaftlichen Fortschritt leisten können. Zusammengefasst verdeutlichen die bisherigen Erfahrungen aus den diskutierten Beispielen, dass Studien und Register wechselseitig eine sinnvolle und notwendige Ergänzung der Studiengruppenstruktur in der Kinderonkologie darstellen.

Background Ponatinib is effective in adults with Philadelphia chromosome–positive (Ph+) leukaemias, but scant data are available regarding the use of this tyrosine kinase inhibitor in children. Aims The aim of this study isto describe the tolerance and efficacy of compassionate use of ponatinib in a paediatric cohort of patients with Ph+ leukaemias. Methods Data from 11 children with chronic myeloid leukaemia (CML) registered to the international registry of childhood chronic myeloid leukaemia and from 3 children with Ph+ acute lymphoblastic leukaemia (Ph+ ALL) treated with ponatinib were collected retrospectively. Results In 11 girls and 3 boys (median age 14 years), ponatinib was used as a second- to eighth-line treatment. Ponatinib was administered as single therapy (9 patients) or in combination with chemotherapy (8 patients). The status of the disease when ponatinib was started was as follows: CML in advanced phases (n = 8), CML in chronic phase without achievement of molecular response (n = 2) or presence of T315I mutation (n = 1) and Ph + ALL in molecular (n = 1) or marrow (n = 2) relapses. The median dose administered was 21.4 mg/m2 and median duration of ponatinib was 2.5 months. Ponatinib alone or in combination with chemotherapy administered on 16 occasions led to achievement of major molecular response in 50% of cases. Ponatinib was used as a bridge to transplant in 4 cases. Among the 9 patients treated with ponatinib alone, toxicity grade III–IV (2 patients) was exclusively haematologic. No vascular events related to ponatinib were observed. Conclusion Ponatinib may be a reasonable additional treatment option for children with Ph+ leukaemias who have failed several lines of therapy.

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

ZusammenfassungKrebserkrankungen bei Kindern und Jugendlichen unter 18 Jahren sind selten; im Jahr 2017 wurden ca. 2220 Neuerkrankungen in Deutschland an das Deutsche Kinderkrebsregister gemeldet. Ziel der GPOH war es immer, möglichst alle betroffenen Patienten standardisiert, am besten in prospektiven, kontrollierten Studien, zu behandeln. Diese Vorgabe hat auch der Gemeinsame Bundesausschuss in der Kinderonkologierichtlinie festgeschrieben. In einer Umfrage unter den Studienleitern der GPOH wurde ermittelt, wie sich nach der geänderten Arzneimittelgesetzgebung, die Zahl der klinischen Studien verändert hat. Im Jahr 2002 waren 33 Therapieoptimierungs-studien (TOS) der GPOH geöffnet. Insgesamt ist ein Rückgang der TOS von 33 im Jahre 2002 auf 2 im Jahre 2017 zu verzeichnen. Die Zahl der Arzneimittelstudien hat sich bis zum Jahr 2017 auf 16 erhöht (knapp 1100 erfasste Patienten). Zeitgleich hat sich die Zahl der klinischen Register auf 28 erhöht mit insgesamt mehr als 1800 dort erfassten Patienten. Diese Beobachtung zeigt, dass die klinischen Register eine neue Bedeutung in der pädiatrischen Onkologie bekommen haben. An 3 Beispielen wird dargelegt, welche Beiträge Register im Verhältnis zu Studien zur Behandlung der Patienten und zum wissenschaftlichen Fortschritt leisten können. Zusammengefasst verdeutlichen die bisherigen Erfahrungen aus den diskutierten Beispielen, dass Studien und Register wechselseitig eine sinnvolle und notwendige Ergänzung der Studiengruppenstruktur in der Kinderonkologie darstellen.

We used hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA) of pediatric Hodgkin lymphoma (PHL) patients to determine pathogenic mechanisms and assess the clinical utility of this method. Hodgkin-Reed/Sternberg (HRS) cell-derived single nucleotide variants, insertions/deletions, translocations and VH-DH-JH rearrangements were detected in pretherapy ccfDNA of 72 of 96 patients. Number of variants per patient ranged from 1 to 21 with allele frequencies from 0.6 to 42%. Nine translocation breakpoints were detected. Genes involved in JAK/STAT, NFkB and PI3K signaling and antigen presentation were most frequently affected. SOCS1 variants, mainly deletions, were found in most circulating tumor (ct) DNAs, and seven of the nine translocation breakpoints involved SOCS1. Analysis of VH-DH-JH rearrangements revealed an origin of PHL HRS cells from partially selected germinal center B cells. Amounts of pretherapy ctDNA were correlated with metabolic tumor volumes. Furthermore, in all ccfDNA samples of 43 patients with early response assessment quantitative qPET 3, indicative of a favorable clinical course, ctDNA was not detectable. In contrast, in five of six patients with qPET 3, indicative of an unfavorable clinical course, ctDNA remained detectable. ccfDNA analysis of PHL is thus a suitable approach to determine pathogenic mechanisms and monitor therapy response.