standard and innovation

Die akute lymphoblastische Leukämie im Kindesalter hat mit heutigen Methoden eine Heilungsrate von über 90%. Dagegen überleben nur etwa 50% der Kinder mit Rückfall einer ALL trotz intensiver Chemotherapie und HSZT bei den meisten Patienten. Somit besteht bei Kindern mit ALL-Rezidiv ein dringender Bedarf für die weitere Optimierung der Standardtherapie, der besseren Charakterisierung von biologischen und prognostischen Subgruppen sowie für neue Medikamente mit anderen idealerweise gezielteren Wirkmechanismen, die in der Lage sind, Therapieresistenz der leukämischen Klone zu durchbrechen. Die ALL-REZ BFM Studiengruppe hat seit nunmehr 30 Jahren Therapieoptimierungsstudien durchgeführt und damit die Prognose der Kinder mit ALL-Rezidiv konsequent verbessert. Dabei wurde insbesondere die Dosierung und der Verabreichungsmodus von hoch dosiertem Methotrexat in prospektiven randomisierten Studien untersucht, wobei in der Studie ALL-REZ BFM 90 die Dosis von 1g/m² mit einer Infusionsdauer von 36 und einer reduzierten Leukovorin Rescue als optimales Konzept etabliert werden konnten. Neben den randomisierten Fragen konnte diese Studie eine Reihe weiterer Erkenntnisse über die biologische Charakteristik der Erkrankung, prognostische Faktoren und Therapieverbesserungen im historischen Vergleich erarbeiten. Die intensive Chemotherapie und die allogene hämatopoetische Stammzelltransplantation ist verbunden mit akuten Nebenwirkungen und Spätfolgen zu denen auch das Auftreten von Zweitmalignomen gehört. Im Verlauf der ALL-REZ BFM Studien konnten Patientengruppen definiert werden, die eine besonders schlechte Prognose haben und mit konventioneller Therapie nicht heilbar sind. Zu diesen zählen Patienten mit Rezidiv von lymphoblastischen Lymphomen, sowie Patienten mit Nonresponse auf die konventionelle Rezidiv- Induktionstherapie. Innovative diagnostische Verfahren erlauben darüber hinaus, weitere Patientengruppen zu definieren, die ein hohes Folgerezidivrisiko trotz intensiver konventioneller Therapie haben. Dazu zählt die Quantifizierung minimaler Resterkrankung im Therapieverlauf durch molekularbiologische Methoden. Insbesondere Patienten mit einer hohen minimalen Resterkrankung vor allogener hämatopoetischer Stammzelltransplantation haben ein hohes Risiko für ein erneutes ALL-Rezidiv mit dann infauster Prognose. Die so definierten Patientengruppen haben neben solchen mit Folgerezidiv einer ALL einen dringenden Bedarf für die Einführung von neuen Substanzen mit anderen Wirkmechanismen als die der konventionellen Chemotherapie und idealerweise mit gezielter leukämiespezifischer Aktivität und geringeren akuten und langfristigen Nebenwirkungen. Die ALL-REZ BFM Studiengruppe beteiligt sich an einem Programm zur Entwicklung von neuen Substanzen bei ALL im Kindesalter, das eine enge Interaktion mit den zuständigen Behörden, der pharmazeutischen Industrie und den involvierten akademischen Gruppen erfordert. Die zukünftigen Strategien zur Behandlung von Kindern mit rezidivierter und/oder refraktärer ALL werden in einem durch die EU finanziertes Projekt international harmonisiert und erlauben die Durchführung von prospektiven randomisierten Studien in biologischen Subgruppen, um neue Substanzen nach erfolgreichen Phase I/II Studien in kurative Therapiekonzepte integrieren zu können. Die aus dieser Entwicklung erwachsene Vision ist eine nebenwirkungsarme gezielte und individualisierte Behandlung von Kindern mit ALL mit möglichst vollständiger Vermeidung von Rückfällen der Erkrankung.Today’s cure rates of childhood acute lymphoblastic leukemia (ALL) have exceeded 90%. In contrast, only 50% of children with relapsed ALL survive despite intensive chemotherapy and allogeneic hematopoietic stem-cell Transplantation (HSCT) in most patients. Thus, there is an urgent need for optimization of standard therapy in childhood relapsed ALL, for a better characterization of biologic and prognostic subgroups, and for new drugs with ideally targeted mechanism of action allowing for overcoming treatment resistance of leukemic clones. The ALL-REZ BFM Study Group has conducted clinical trials for optimization of treatment since 30 years and subsequently improved the prognosis of children with relapsed ALL. In particular the dose and mode of application of high dose methotrexate has been investigated in randomized prospective trials. Furthermore, improvement of therapy has been achieved with uncontrolled changes referring to historical controls. Intensive chemotherapy and allogeneic HSCT is associated with acute and late toxicities one of which is secondary malignancy. In the course of the ALL-REZ BFM trials patient subgroups could be defined with a very poor prognosis and without chance of cure with conventional therapies. These include patient with relapse of a lymphoblastic lymphoma and those with nonresponse to conventional salvage induction therapy. The quantification of minimal residual disease (MRD) with molecular biologic techniques allow defining additional patient groups with very high risk for subsequent relapse despite intensive conventional treatment. Those patients with high MRD pre allogeneic HSCT have a high risk of relapse post HSCT with then dismal prognosis. These patient groups have an urgent need for the introduction of new drugs with targeted mechanism of action and less acute and late side effects. The ALL-REZ BFM Study Group joins activities to develop such new agents in close collaboration with industry and competent authorities. Future strategies for treatment of childhood relapsed ALL in Europe are harmonized in an EU funded FP7 project allowing for performing large prospective randomized trials in biologic subgroups to integrate new agents after successfully passing phase I/II trials in curative treatment protocols. The vision for the future is a low-toxic individualized treatment for children with ALL with prevention of relapse of the disease

Total body irradiation as part of conditioning regimens in childhood leukemia—long-term outcome, toxicity, and secondary malignancies

Background: Total body irradiation (TBI) is an established part of conditioning regimens prior to stem cell transplantation in childhood leukemia but is associated with long-term toxicity. We retrospectively analyzed survival, long-term toxicity, and secondary malignancies in a pooled cohort of pediatric patients (pts.) treated with the same TBI regimen. Methods: Analyzed were 109 pts. treated between September 1996 and November 2015. Conditioning treatment according to EBMT guidelines and the ALL SCTped 2012 FORUM trial consisted of chemotherapy (CT) and TBI with 2 Gy b.i.d. on 3 consecutive days to a total dose of 12 Gy. Median follow-up was 97.9 months (2-228 months). Results: Overall survival (OS) in our cohort at 2, 5, and 10 years was 86.1, 75.5, and 63.0%, respectively. Median survival was not reached. Long-term toxicity developed in 47 pts. After chronically abnormal liver and kidney parameters in 31 and 7 pts., respectively, growth retardation was the most frequent finding as seen in 13 pts. Secondary malignancies were rare (n = 3). Conclusion: TBI-containing conditioning regimens in pediatric stem cell transplantation (SCT) are highly effective. Efforts to replace TBI- with CT-containing regimens have only been successful in subgroups of pts. Although we could show long-term toxicity in 43% of pts., overall survival was 63% at 10 years. Still, long-term effects such as growth retardation can permanently impact the pts.' quality of life and functioning. Along with new substances, efforts should be undertaken to optimize TBI techniques and accompany the treatment by systematic follow-up programs beyond 5 years to improve detection of rare events

Targeted inhibitors and antibody immunotherapies: Novel therapies for paediatric leukaemia and lymphoma

Despite improved outcomes achieved in the last decades for children with newly diagnosed leukaemia and lymphoma, treatment of patients with refractory/relapsed disease remains a challenge. The cure rate is still unsatisfactory and often achieved at the cost of significant morbidity. Exploring treatment with novel agents should offer less toxic therapeutic options, without compromising efficacy. Bispecific and antibody-drug conjugates targeting CD19 and CD22 (blinatumomab and inotuzumab ozogamicin) play an important role in the treatment of relapsed and refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL); antibodies targeting CD123 and CD38 are also under investigation for acute myeloid leukaemia (AML) and T-ALL, respectively. Targeted therapy with small molecules is of primary importance for specific genetic subtypes, such as BCR-ABL-positive ALL, FLT3-ITD AML and anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma. KMT2A-directed targeted therapy with menin inhibitors holds promise to be of relevance in KMT2A-rearranged leukaemias, known to have dismal prognosis. Target inhibition in cellular pathways such as BCL-2, RAS, MEK, Bruton's tyrosine kinase, JAK-STAT or CDK4/CDK6 inhibition may be suitable for different diseases with common mutated pathways. Nevertheless, development and approval of new agents for paediatric cancers lags behind adult therapeutic options. New regulations were implemented to accelerate drug development for children. Considering the number of oncology medicinal products available for adults and the rarity of paediatric cancers, prioritisation based on scientific evidence and medical need, as well as international collaboration, is critical. Herein, we review the current status of drug development for children with leukaemia and lymphoma, excluding cellular therapy despite its well-known significance

Allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT) Following Blinatumomab-Induced Remission in Pediatric Patients with Relapsed/Refractory (r/r) B-Precursor Acute Lymphoblastic Leukemia (ALL): Preliminary Results from a Phase I/II Stud

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Blinatumomab versus historical standard therapy in pediatric patients with relapsed/refractory Ph-negative B-cell precursor acute lymphoblastic leukemia

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Frequent and sex-biased deletion of SLX4IP by illegitimate V(D)J-mediated recombination in childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) accounts for ∼25% of pediatric malignancies. Of interest, the incidence of ALL is observed ∼20% higher in males relative to females. The mechanism behind the phenomenon of sex-specific differences is presently not understood. Employing genome-wide genetic aberration screening in 19 ALL samples, one of the most recurrent lesions identified was monoallelic deletion of the 5′ region of SLX4IP. We characterized this deletion by conventional molecular genetic techniques and analyzed its interrelationships with biological and clinical characteristics using specimens and data from 993 pediatric patients enrolled into trial AIEOP-BFM ALL 2000. Deletion of SLX4IP was detected in ∼30% of patients. Breakpoints within SLX4IP were defined to recurrent positions and revealed junctions with typical characteristics of illegitimate V(D)J-mediated recombination. In initial and validation analyses, SLX4IP deletions were significantly associated with male gender and ETV6/RUNX1-rearranged ALL (both overall P < 0.0001). For mechanistic validation, a second recurrent deletion affecting TAL1 and caused by the same molecular mechanism was analyzed in 1149 T-cell ALL patients. Validating a differential role by sex of illegitimate V(D)J-mediated recombination at the TAL1 locus, 128 out of 1149 T-cell ALL samples bore a deletion and males were significantly more often affected (P = 0.002). The repeatedly detected association of SLX4IP deletion with male sex and the extension of the sex bias to deletion of the TAL1 locus suggest that differential illegitimate V(D)J-mediated recombination events at specific loci may contribute to the consistent observation of higher incidence rates of childhood ALL in boys compared with girl

Clinical relevance of molecular characteristics in Burkitt lymphoma differs according to age

While survival has improved for Burkitt lymphoma patients, potential differences in outcome between pediatric and adult patients remain unclear. In both age groups, survival remains poor at relapse. Therefore, we conducted a comparative study in a large pediatric cohort, including 191 cases and 97 samples from adults. While TP53 and CCND3 mutation frequencies are not age related, samples from pediatric patients showed a higher frequency of mutations in ID3, DDX3X, ARID1A and SMARCA4, while several genes such as BCL2 and YY1AP1 are almost exclusively mutated in adult patients. An unbiased analysis reveals a transition of the mutational profile between 25 and 40 years of age. Survival analysis in the pediatric cohort confirms that TP53 mutations are significantly associated with higher incidence of relapse (25 ± 4% versus 6 ± 2%, p-value 0.0002). This identifies a promising molecular marker for relapse incidence in pediatric BL which will be used in future clinical trials

Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.Peer reviewe