المؤلفون: Mareike Rasche, Martin Zimmermann, Emma Steidel, Todd Alonzo, Richard Aplenc, Jean-Pierre Bourquin, Heidrun Boztug, Todd Cooper, Alan Gamis, Robert Gerbing, Iveta Janotova, Jan-Henning Klusmann, Thomas Lehrnbecher, Nora Mühlegger, Nils Neuhoff, Naghmeh Niktoreh, Lucie Sramkova, Jan Stary, Katharina Waack, Christiane Walter, Ursula Creutzig, Michael Dworzak, Gertjan Kaspers, Edward Kolb, Dirk Reinhardt

المصدر: Cancers; Volume 13; Issue 10; Pages: 2336

مصطلحات موضوعية: acute myeloid leukemia, relapse, childhood acute myeloid leukemia, pediatric, salvage therapy

الوصف: Post-relapse therapy remains critical for survival in children with acute myeloid leukemia (AML). We evaluated survival, response and prognostic variables following relapse in independent cooperative group studies conducted by COG and the population-based AML-BFM study group. BFM included 197 patients who relapsed after closure of the last I-BFM relapse trial until 2017, while COG included 852 patients who relapsed on the last Phase 3 trials (AAML0531, AAML1031). Overall survival at 5 years (OS) was 42 ± 4% (BFM) and 35 ± 2% (COG). Initial high-risk features (BFM 32 ± 6%, COG 26 ± 4%) and short time to relapse (BFM 29 ± 4%, COG 25 ± 2%) predicted diminished survival. In the BFM dataset, there was no difference in OS for patients who had a complete remission with full hematopoietic recovery (CR) following post-relapse re-induction compared to those with partial neutrophil and platelet recovery (CRp and CRi) only (52 ± 7% vs. 63 ± 10%, p = 0.39). Among 90 patients alive at last follow-up, 87 had received a post-relapse hematopoietic stem cell transplant (HSCT). OS for patients with post-relapse HSCT was 54 ± 4%. In conclusion, initial high-risk features and early relapse remain prognostic. Response assessment with full hematopoietic recovery following initial relapse therapy does not predict survival. These data indicate the need for post-relapse risk stratification in future studies of relapse therapies.

وصف الملف: application/pdf

العلاقة: Clinical Trials of Cancer; https://dx.doi.org/10.3390/cancers13102336Test

الإتاحة: https://doi.org/10.3390/cancers13102336Test

المؤلفون: Mareike Rasche, Emma Steidel, Martin Zimmermann, Jean-Pierre Bourquin, Heidrun Boztug, Iveta Janotova, E. Anders Kolb, Thomas Lehrnbecher, Nils von Neuhoff, Naghmeh Niktoreh, Nora Mühlegger, Lucie Sramkova, Jan Stary, Christiane Walter, Ursula Creutzig, Michael Dworzak, Dirk Reinhardt

المصدر: Cancers; Volume 13; Issue 4; Pages: 789

مصطلحات موضوعية: acute myeloid leukemia, relapse, childhood acute myeloid leukemia, pediatric, salvage therapy

الوصف: Successful management of relapse is critical to improve outcomes of children with acute myeloid leukemia (AML). We evaluated response, survival and prognostic factors after a second relapse of AML. Among 1222 pediatric patients of the population-based AML-Berlin–Frankfurt–Munster (BFM) study group (2004 until 2017), 73 patients met the quality parameters for inclusion in this study. Central review of source documentation warranted the accuracy of reported data. Treatment approaches included palliation in 17 patients (23%), intensive therapy with curative intent (n = 46, 63%) and other regimens (n = 10). Twenty-five patients (35%) received hematopoietic stem cell transplantation (HSCT), 21 of whom (88%) had a prior HSCT. Survival was poor, with a five-year probability of overall survival (pOS) of 15 ± 4% and 31 ± 9% following HSCT (n = 25). Early second relapse (within one year after first relapse) was associated with dismal outcome (pOS 2 ± 2%, n = 44 vs. 33 ± 9%, n = 29; p < 0.0001). A third complete remission (CR) is required for survival: 31% (n = 14) of patients with intensive treatment achieved a third CR with a pOS of 36 ± 13%, while 28 patients (62%) were non-responders (pOS 7 ± 5%). In conclusion, survival is poor but possible, particularly after a late second relapse and an intensive chemotherapy followed by HSCT. This analysis provides a baseline for future treatment planning.

وصف الملف: application/pdf

العلاقة: https://dx.doi.org/10.3390/cancers13040789Test

الإتاحة: https://doi.org/10.3390/cancers13040789Test

المؤلفون: Angela Schumich, Michaela Prchal-Murphy, Margarita Maurer-Granofszky, Andrea Hoelbl-Kovacic, Nora Mühlegger, Ulrike Pötschger, Sabine Fajmann, Oskar A. Haas, Karin Nebral, Nils von Neuhoff, Martin Zimmermann, Heidrun Boztug, Mareike Rasche, Marlies Dolezal, Christiane Walter, Dirk Reinhardt, Veronika Sexl, Michael N. Dworzak

المصدر: HemaSphere, Vol 4, Iss 1, p e312 (2020)

مصطلحات موضوعية: Diseases of the blood and blood-forming organs, RC633-647.5

الوصف: Aberrant activation of key signaling-molecules is a hallmark of acute myeloid leukemia (AML) and may have prognostic and therapeutic implications. AML summarizes several disease entities with a variety of genetic subtypes. A comprehensive model spanning from signal activation patterns in major genetic subtypes of pediatric AML (pedAML) to outcome prediction and pre-clinical response to signaling inhibitors has not yet been provided. We established a high-throughput flow-cytometry based method to assess activation of hallmark phospho-proteins (phospho-flow) in 166 bone-marrow derived pedAML samples under basal and cytokine stimulated conditions. We correlated levels of activated phospho-proteins at diagnosis with relapse incidence in intermediate (IR) and high risk (HR) subtypes. In parallel, we screened a set of signaling inhibitors for their efficacy against primary AML blasts in a flow-cytometry based ex vivo cytotoxicity assay and validated the results in a murine xenograft model. Certain phospho-signal patterns differ between genetic subtypes of pedAML. Some are consistently seen through all AML subtypes such as pSTAT5. In IR/HR subtypes high levels of GM-CSF stimulated pSTAT5 and low levels of unstimulated pJNK correlated with increased relapse risk overall. Combination of GM-CSF/pSTAT5high and basal/pJNKlow separated three risk groups among IR/HR subtypes. Out of 10 tested signaling inhibitors, midostaurin most effectively affected AML blasts and simultaneously blocked phosphorylation of multiple proteins, including STAT5. In a mouse xenograft model of KMT2A-rearranged pedAML, midostaurin significantly prolonged disease latency. Our study demonstrates the applicability of phospho-flow for relapse-risk assessment in pedAML, whereas functional phenotype-driven ex vivo testing of signaling inhibitors may allow individualized therapy.

العلاقة: http://journals.lww.com/10.1097/HS9.0000000000000312Test; https://doaj.org/toc/2572-9241Test; https://doaj.org/article/86d754cbc853436596952dc60b4e601cTest

الإتاحة: https://doi.org/10.1097/HS9.0000000000000312Test
https://doaj.org/article/86d754cbc853436596952dc60b4e601cTest

المؤلفون: Nora Muehlegger, Ursula Creutzig, Emma Steidel, Jan Stary, Dirk Reinhardt, Lucie Sramkova, Christiane Walter, Naghmeh Niktoreh, Nils von Neuhoff, Heidrun Boztug, Thomas Lehrnbecher, Jean-Pierre Bourquin, Michael Dworzak, Iveta Janotova, Mareike Rasche, Martin Zimmermann, Edward A. Kolb

المساهمون: University of Zurich, Rasche, Mareike

المصدر: Cancers, Vol 13, Iss 789, p 789 (2021)
Cancers
Volume 13
Issue 4

مصطلحات موضوعية: Acute promyelocytic leukemia, Pediatrics, medicine.medical_specialty, Down syndrome, Immunology, Population, Medizin, childhood acute myeloid leukemia, 610 Medicine & health, acute myeloid leukemia, Biochemistry, lcsh:RC254-282, Article, acute myeloid leukemia -- relapse -- childhood acute myeloid leukemia -- pediatric -- salvage therapy, Refractory, hemic and lymphatic diseases, medicine, Cumulative incidence, 1306 Cancer Research, ddc:610, salvage therapy, education, relapse, education.field_of_study, business.industry, Medizinische Fakultät » Universitätsklinikum Essen » Zentrum für Kinder- und Jugendmedizin » Klinik für Kinderheilkunde III, Myeloid leukemia, Cell Biology, Hematology, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Clinical trial, Regimen, pediatric, 10036 Medical Clinic, 2730 Oncology, business

الوصف: Successful management of relapse is critical to improve outcomes of children with acute myeloid leukemia (AML). We evaluated response, survival and prognostic factors after a second relapse of AML. Among 1222 pediatric patients of the population-based AML-Berlin–Frankfurt–Munster (BFM) study group (2004 until 2017), 73 patients met the quality parameters for inclusion in this study. Central review of source documentation warranted the accuracy of reported data. Treatment approaches included palliation in 17 patients (23%), intensive therapy with curative intent (n = 46, 63%) and other regimens (n = 10). Twenty-five patients (35%) received hematopoietic stem cell transplantation (HSCT), 21 of whom (88%) had a prior HSCT. Survival was poor, with a five-year probability of overall survival (pOS) of 15 ± 4% and 31 ± 9% following HSCT (n = 25). Early second relapse (within one year after first relapse) was associated with dismal outcome (pOS 2 ± 2%, n = 44 vs. 33 ± 9%, n = 29
p <
0.0001). A third complete remission (CR) is required for survival: 31% (n = 14) of patients with intensive treatment achieved a third CR with a pOS of 36 ± 13%, while 28 patients (62%) were non-responders (pOS 7 ± 5%). In conclusion, survival is poor but possible, particularly after a late second relapse and an intensive chemotherapy followed by HSCT. This analysis provides a baseline for future treatment planning.

وصف الملف: cancers-13-00789-v2.pdf - application/pdf; application/octet-stream; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::90173760db6dc24a9f98249fddf7de1eTest
https://pubmed.ncbi.nlm.nih.gov/33672815Test

المؤلفون: Jean-Pierre Bourquin, Dirk Reinhardt, Nora Muehlegger, Iveta Janotova, Ursula Creutzig, Alan S. Gamis, Jan Stary, Edward A. Kolb, Robert B. Gerbing, Martin Zimmermann, Emma Steidel, Mareike Rasche, Richard Aplenc, Naghmeh Niktoreh, Thomas Lehrnbecher, Todd A. Alonzo, Lucie Sramkova, Michael Dworzak, Nils von Neuhoff, Christiane Walter, Heidrun Boztug

المصدر: Blood. 136:6-7

مصطلحات موضوعية: medicine.medical_specialty, Down syndrome, Multivariate analysis, business.industry, Proportional hazards model, Immunology, Myeloid leukemia, Subgroup analysis, Cell Biology, Hematology, medicine.disease, Biochemistry, First relapse, Cog, Internal medicine, Cohort, medicine, business

الوصف: BACKGROUND: Children with high risk acute myeloid leukemia (AML) still experience consistently high rates of relapse. Survival after first relapse increased from 21% between 1987 and 1997 up to 39% in recent studies. However, since 2009, there have been no publications on subsequent large pediatric AML relapse trials. As the indications for HSCT during first-line treatment have been extended since then, the current survival of these patients at relapse remains unclear. Herein, we report outcome results from the BFM and COG study group, which represents the largest available dataset analyzed for post-relapse survival. PATIENTS AND METHODS: Pediatric patients with first relapse of AML (no Down syndrome, secondary leukemia or FAB M3) have been analyzed from two large study groups with patients from the United States, Canada, Australia, New Zealand, Germany, Austria, Czech Republic and Switzerland. Out of 1222 patients in the BFM cohort (AML-BFM study 2004, registry 2012 and study 2012), 350 experienced at least one relapse and 197 of those had a first relapse after closure of the last I-BFM relapse trial (04/2009 through 2017). Within the Children's Oncology Group (COG) Phase 3 trials (AAML0531 and AAML1031, n=2119) 852 pediatric patients suffered a relapse. Five-year probability of overall survival (pOS) and event-free survival (pEFS) were calculated according to Kaplan-Meier. EFS was calculated for the BFM cohort as time from relapse to the next event (second relapse, death, failure to achieve a second remission or secondary malignancy) or until last follow-up, while OS reflects the time from relapse until death or last follow-up. The Cox proportional hazards model was used for multivariate analysis of outcomes. Living patients were censored at last follow-up with a median follow-up after relapse of 4·2 years (BFM) and 4·8 years (COG). Data have been frozen at 03/27/2020 (BFM) and 03/31/2020 (COG). RESULTS: In the 197 patients with relapse after closure of the last BFM relapse trial (04/2009 through 2017) the pOS at 5 years was 42±4% (BFM). The 5-year pOS in patients relapsing after COG trials 2006-2018 was 35±2% (n=852). Patients experiencing a relapse between 2014 to 2017 had a pOS of 49±6% (BFM, n=78) and 40±3% (COG, n=333). Risk classification at initial diagnosis and a short time from diagnosis to relapse predicted a diminished survival probability in both cohorts (see Table 1). However, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival: Within the BFM dataset, a subgroup analysis in all patients receiving DNX-FLA (n=156) have been performed. Initial characteristics are comparable to the total cohort. Among these patients 147 were evaluable for response (7 excluded due to early death before evaluation, 2 for insufficient data). Eighty-nine (57%) achieved a CR (n=69) or CRp (n=20) and 52 (33%) no response. Overall survival was superior for patients with a CR/CRp (54±6% (CR/CRp) vs. 32±7% (No CR/CRp); p=0·0064), but long-term survival was still possible even with a poor re-induction response. Patients with a CRp had a comparable survival to those with a CR after a second re-induction (pOS 60±11% (CRp) vs. pOS 52±7% (CR); p=0·57). Patients with >5% leukemic blasts (n=32) had the lowest survival (pOS 27±9%). The 5-year pEFS for this cohort was 29±4% (pEFS 50±6% (CR) vs. pEFS 50±11% (CRp)). The analysis of post-relapse treatment showed that the vast majority of patients who survive had a HSCT following relapse. By landmark analysis, survival was significantly higher in patients with subsequent HSCT compared to that of non-transplanted patients (BFM: pOS 53±4%, n=154 vs. pOS 5±5%, n=21; p(Mantel-Byar)=0·0002). CONCLUSION: This is the largest report to date on post relapse survival in children with AML. Our analysis confirmed previously described risk factors for poor survival while also highlighting new findings contrary to established standards. Strikingly, the absence of full hematopoietic regeneration of the bone marrow after re-induction did not predict survival at first relapse, thereby questioning the current value of the established International Working Group Criteria published by Cheson et al for response-evaluation in pediatric AML. As the international pediatric AML community embarks on collaborative efforts to evaluate new therapies in children with relapsed AML, a comprehensive review of post relapse survival is critical. Disclosures Bourquin: Servier: Other: Travel Support. Reinhardt:Novartis: Membership on an entity's Board of Directors or advisory committees; CLS Behring: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::559424b70a219897dabf3bb1b1e253aeTest
https://doi.org/10.1182/blood-2020-141774Test