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

Case report: HLA-haploidentical HSCT rescued with donor lymphocytes infusions in a patient with X-linked chronic granulomatous disease

Chronic granulomatous disease is an inborn error of immunity due to disrupted function of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. This results in impaired respiratory burst of phagocytes and insufficient killing of bacteria and fungi. Patients with chronic granulomatous disease are at increased risk for infections, autoinflammation and autoimmunity. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only widely available curative therapy. While HSCT from human leukocyte antigen (HLA) matched siblings or unrelated donors are standard of care, transplantation from HLA-haploidentical donors or gene therapy are considered alternative options. We describe a 14-month-old male with X-linked chronic granulomatous disease who underwent a paternal HLA-haploidentical HSCT using T-cell receptor (TCR) alpha/beta(+)/CD19(+) depleted peripheral blood stem cells followed by mycophenolate graft versus host disease prophylaxis. Decreasing donor fraction of CD3(+) T cells was overcome by repeated infusions of donor lymphocytes from the paternal HLA-haploidentical donor. The patient achieved normalized respiratory burst and full donor chimerism. He remained disease-free off any antibiotic prophylaxis for more than three years after HLA-haploidentical HSCT. In patients with x-linked chronic granulomatous disease without a matched donor paternal HLA-haploidentical HSCT is a treatment option worth to consider. Administration of donor lymphocytes can prevent imminent graft failure

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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Real-world data suggest effectiveness of the allogeneic mesenchymal stromal cells preparation MSC-FFM in ruxolitinib-refractory acute graft-versus-host disease

Background Patients with steroid-refractory acute graft-versus-host disease (aGvHD) not tolerating/responding to ruxolitinib (RR-aGvHD) have a dismal prognosis. Methods We retrospectively assessed real-world outcomes of RR-aGvHD treated with the random-donor allogeneic MSC preparation MSC-FFM, available via Hospital Exemption in Germany. MSC-FFM is provided as frozen cell dispersion for administration as i.v. infusion immediately after thawing, at a recommended dose of 1–2 million MSCs/kg body weight in 4 once-weekly doses. 156 patients, 33 thereof children, received MSC-FFM; 5% had Grade II, 40% had Grade III, and 54% had Grade IV aGvHD. Median (range) number of prior therapies was 4 (1–10) in adults and 7 (2–11) in children. Results The safety profile of MSC-FFM was consistent with previous reports for MSC therapies in general and MSC-FFM specifically. The overall response rate at Day 28 was 46% (95% confidence interval [CI] 36–55%) in adults and 64% (45–80%) in children; most responses were durable. Probability of overall survival at 6, 12 and 24 months was 47% (38–56%), 35% (27–44%) and 30% (22–39%) for adults, and 59% (40–74%), 42% (24–58%) and 35% (19–53%) for children, respectively (whole cohort: median OS 5.8 months). Conclusion A recent real-world analysis of outcomes for 64 adult RR-aGvHD patients not treated with MSCs reports survival of 20%, 16% and 10% beyond 6, 12 and 24 months, respectively (median 28 days). Our data thus suggest effectiveness of MSC-FFM in RR-aGvHD

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study

Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity level