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3.
Blood Adv ; 3(22): 3688-3699, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31765480

RESUMO

We conducted a clinical trial and report the long-term outcome of 773 children with acute lymphoblastic leukemia upon risk-adapted therapy accrued in trial CoALL 07-03 (from the Cooperative Study Group for Childhood Acute Lymphoblastic Leukemia). In a 2-step stratification, patients were allocated to receive either low- or high-risk treatment, based on initial white blood cell count, age, and immunophenotype. A second stratification was performed according to the results of in vitro pharmacosensitivity toward prednisolone, vincristine, and asparaginase (PVA score) and in vivo response after induction therapy (minimal residual disease [MRD]). Therapy was reduced for both risk groups in patients with a low PVA score or negative MRD result, and intensified in patients with a high PVA score. Overall outcome improved significantly compared with the predecessor CoALL 06-97 trial, with identical therapy backbone despite treatment reduction in 15.8% of patients (10-year probability of event-free survival, 83.5% vs 73.9%; overall survival, 90.7% vs 83.8%). Outcome for patients in the reduced treatment arms was superior to that of patients in the standard arms, associated with a profound reduction in frequency and severity of infectious complications. Importantly, we observed a lack of correlation between in vitro and in vivo drug response, as well as a lower predictive value of in vitro drug testing, reflecting an intrinsic limitation of this methodology that prevents its use for treatment stratification in future trials. In conclusion, it might be possible to reduce chemotherapy in children with acute lymphoblastic leukemia selected by stringent in vivo measurement of MRD without jeopardizing overall outcome.

4.
Eur J Cancer ; 122: 61-71, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31629941

RESUMO

BACKGROUND: Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years. METHODS: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10-17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10-14 and 15-17 years. FINDINGS: Compared with younger children (aged 1-9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10-14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15-17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm. INTERPRETATION: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15-17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.

5.
Leukemia ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578451

RESUMO

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).

7.
Haematologica ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601692

RESUMO

ABL-class fusions other than BCR-ABL1 characterize about 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of >5x10-4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality 20.8+6.8%. One out of 13 cases with tyrosine kinase inhibitor added to chemotherapy relapsed while eight of 33 cases without tyrosine kinase inhibitor treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high treatment-related mortality (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of tyrosine kinase inhibitors, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (ClinicalTrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).

8.
Haematologica ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649129

RESUMO

Detection of minimal disseminated disease is a validated prognostic factor in ALK-positive anaplastic large cell lymphoma. We previously reported that quantification of minimal disease by quantitative real-time PCR in bone marrow applying a cut-off of 10 copies NPM-ALK/104 copies of the reference transcript ABL1 identifies a very high-risk group of patients. In the present study, we aimed to confirm the prognostic value of quantitative minimal disseminated disease evaluation by real-time PCR and to validate digital PCR as alternative method. Among 91 patients analyzed by real-time PCR in bone marrow, the cumulative incidence of relapses of 18 patients with more than 10 normalized copy-numbers of NPM-ALK was 61+/-12% compared to 21+/-5% for the remaining 76 patients (p=.0002). Results in blood correlated with bone marrow (r=0.74) in 70 patients with both materials. Copy numbers tended to be higher in blood compared to bone marrow. Transcripts were quantified in addition by digital PCR in 75 bone marrow and 57 blood samples. Copy number estimation by using digital PCR and real-time PCR correlated in 132 samples (r=.85). Applying a cut-off of 30 copies NPM-ALK/104 copies ABL1 for quantification by digital PCR, almost identical patient groups were separated compared to real-time PCR. In summary, the prognostic impact of quantification of minimal disseminated disease in bone marrow could be confirmed for patients with anaplastic large cell lymphoma. Quantification of minimal disease by digital PCR provides a promising tool to facilitate harmonization of minimal disease measurement between laboratories and for clinical studies.

10.
Haematologica ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31371414

RESUMO

Children with Down syndrome and acute lymphoblastic leukemia often suffer from severe toxicities during treatment, especially with high-dose methotrexate. Systematic data on methotrexate toxicity in these patients are rare. We analyzed seven methotrexate-associated toxicities during consolidation therapy in 103 Down-syndrome- and 1,109 Non-Down-syndrome-patients with acute lymphoblastic leukemia enrolled in ALL-BFM trials between 1995-2016 and 1995-2007, respectively. Patients received four courses methotrexate (5 g/m2 each) plus intrathecal methotrexate and 6-mercaptopurine. From 2004 on, a dose of 0.5 g/m2 in the 1st methotrexate course was recommended for Down-syndrome-patients. Down-syndrome-patients showed higher rates of 3/4 toxicities after the 1st course with 5 g/m2 methotrexate compared to Non-Down-syndrome-patients (62 3/4 toxicities in 45 Down-syndrome- vs. 516 in 1,089 Non-Down-syndrome-patients, p<0.001). Dose reduction (0.5 g/m2) in Down-syndrome-patients reduced toxicity (39 in 51 patients, p<0.001) without increasing the relapse risk (reduced dose, 5 year cumulative relapse incidence = 0.09+/-0.04 vs. high dose, 0.10+/-0.05, p=0.51). Methotrexate dose escalation to 1.0 g/m2 for Down-syndrome-patients who tolerated 0.5 g/m2 (n= 28/51 patients) did not result in an increased rate of 3/4 toxicities after the 2nd course (p=0.285). Differences in methotrexate plasma levels at 42 h and 48 h after start of the 1st methotrexate infusion did not explain higher toxicity rates in Down-syndrome-patients treated with 0.5 g/m2 as compared to Non-Down-syndrome-patients treated with 5 g/m2. Within the Down-syndrome cohort a higher methotrexate plasma level was associated with increased toxicity. In conclusion, dose reduction in the 1st methotrexate course reduced severe toxicities without increasing the risk of relapse.

12.
Bone Marrow Transplant ; 54(11): 1847-1858, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31089287

RESUMO

Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.

13.
Pediatr Blood Cancer ; 66(7): e27752, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30977593

RESUMO

BACKGROUND: Epstein-Barr virus (EBV) is linked to a variety of malignancies; most endemic Burkitt lymphoma (BL) harbor EBV, whereas only a subset of the cases of sporadic BL is EBV positive. PROCEDURE: We retrospectively determined the herpesvirus seroprevalence at the time of diagnosis in pediatric non-Hodgkin lymphoma (NHL) patients enrolled in NHL-BFM (Berlin-Frankfurt-Muenster) studies. We accessed the seroepidemiological data from 1147 patients that became available during 1990-2007. We included the records from patients 6 months to 18 years of age with BL, T-cell lymphoblastic lymphoma (T-LBL), lymphoblastic precursor B-cell lymphoma (pB-LBL), diffuse large B-cell lymphoma (DLBCL), or anaplastic large cell lymphoma (ALCL). RESULTS: EBV seropositivity was significantly more frequent in patients with BL than in those with T-LBL. EBV was more prevalent in patients younger than 6 years of age and in patients with BL than in those with non-BL or T-LBL. Event-free survival was significantly lower in varicella-zoster-seronegative patients, but there was no indication of an association to complications due to varicella zoster infection. We found no associations between herpes simplex virus, varicella zoster virus, or human cytomegalovirus seroprevalence and the pediatric Central European NHL cases. CONCLUSION: Early EBV exposure may increase the risk of BL in Central Europe. A higher involvement of EBV in European BL than originally reported appears at least probable. Our data support the thesis that the distinction between endemic and sporadic BL is artificial and should be replaced by the differentiation between EBV-positive and EBV-negative BL.

14.
Haematologica ; 104(9): 1812-1821, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30705097

RESUMO

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 levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT.

15.
Oncogene ; 38(19): 3616-3635, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30651597

RESUMO

The melanocytic lineage, which is prominently exposed to ultraviolet radiation (UVR) and radiation-independent oxidative damage, requires specific DNA-damage response mechanisms to maintain genomic and transcriptional homeostasis. The coordinate lineage-specific regulation of intricately intertwined DNA repair and transcription is incompletely understood. Here we demonstrate that the Microphthalmia-associated transcription factor (MITF) directly controls general transcription and UVR-induced nucleotide excision repair by transactivation of GTF2H1 as a core element of TFIIH. Thus, MITF ensures the rapid resumption of transcription after completion of strand repair and maintains transcriptional output, which is indispensable for survival of the melanocytic lineage including melanoma in vitro and in vivo. Moreover, MITF controls c-MYC implicated in general transcription by transactivation of far upstream binding protein 2 (FUBP2/KSHRP), which induces c-MYC pulse regulation through TFIIH, and experimental depletion of MITF results in consecutive loss of CDK7 in the TFIIH-CAK subcomplex. Targeted for proteasomal degradation, CDK7 is dependent on transactivation by MITF or c-MYC to maintain a steady state. The dependence of TFIIH-CAK on sequence-specific MITF and c-MYC constitutes a previously unrecognized mechanism feeding into super-enhancer-driven or other oncogenic transcriptional circuitries, which supports the concept of a transcription-directed therapeutic intervention in melanoma.


Assuntos
Reparo do DNA/fisiologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Fosfoproteínas/metabolismo , Fator de Transcrição TFIIH/metabolismo , Fatores de Transcrição TFII/metabolismo , Animais , Células Cultivadas , Reparo do DNA/efeitos da radiação , Receptor com Domínio Discoidina 1/genética , Receptor com Domínio Discoidina 1/metabolismo , Feminino , Genes myc , Humanos , Melanócitos/fisiologia , Melanócitos/efeitos da radiação , Melanoma/metabolismo , Melanoma/patologia , Camundongos SCID , Fator de Transcrição Associado à Microftalmia/genética , Fosfoproteínas/genética , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Fator de Transcrição TFIIH/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição TFII/genética , Transcrição Genética , Raios Ultravioleta
16.
Genes Chromosomes Cancer ; 58(6): 365-372, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30578714

RESUMO

Rare cases of hematological precursor neoplasms fulfill the diagnostic criteria of mixed phenotype acute leukemia (MPAL), characterized by expression patterns of at least two hematopoietic lineages, for which a highly aggressive behavior was reported. We present a series of 11 pediatric non-leukemic MPAL identified among 146 precursor lymphoblastic lymphomas included in the prospective trial Euro-LBL 02. Paraffin-embedded biopsies of 10 cases were suitable for molecular analyses using OncoScan assay (n = 7), fluorescence in situ hybridization (FISH; n = 7) or both (n = 5). Except for one case with biallelic KMT2A (MLL) breaks, all cases analyzed by FISH lacked the most common translocations defining molecular subsets of lymphoblastic leukemia/lymphomas. Two non-leukemic B-myeloid MPALs showed the typical genomic profile of hyperdiploid precursor B-cell lymphoblastic leukemia with gains of chromosomes 4, 6, 10, 14, 18, and 21. One B-T MPAL showed typical aberrations of T-cell lymphoblastic lymphoma, such as copy number neutral loss of heterozygosity (CNN-LOH) at 9p targeting a 9p21.3 deletion of CDKN2A and 11q12.2-qter affecting the ATM gene. ATM was also mutated in a T-myeloid MPAL case with additional loss at 7q21.2-q36.3 and mutation of NRAS, two alterations common in myeloid disorders. No recurrent regions of CNN-LOH were observed. The outcome under treatment was good with all patients being alive in first complete remission after treatment according to a protocol for precursor lymphoblastic lymphoma (follow-up 3-10 years, median: 4.9 years). In summary, the present series of non-leukemic MPALs widely lacked recurrently reported translocations in lymphoid/myeloid neoplasias and showed heterogeneous spectrum of chromosomal imbalances.


Assuntos
Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Adolescente , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , GTP Fosfo-Hidrolases/genética , Instabilidade Genômica/efeitos dos fármacos , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Proteínas de Membrana/genética , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
17.
EMBO Mol Med ; 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389682

RESUMO

We compared 24 primary pediatric T-cell acute lymphoblastic leukemias (T-ALL) collected at the time of initial diagnosis and relapse from 12 patients and 24 matched patient-derived xenografts (PDXs). DNA methylation profile was preserved in PDX mice in 97.5% of the promoters (ρ = 0.99). Similarly, the genome-wide chromatin accessibility (ATAC-Seq) was preserved remarkably well (ρ = 0.96). Interestingly, both the ATAC regions, which showed a significant decrease in accessibility in PDXs and the regions hypermethylated in PDXs, were associated with immune response, which might reflect the immune deficiency of the mice and potentially the incomplete interaction between murine cytokines and human receptors. The longitudinal approach of this study allowed an observation that samples collected from patients who developed a type 1 relapse (clonal mutations maintained at relapse) preserved their genomic composition; whereas in patients who developed a type 2 relapse (subset of clonal mutations lost at relapse), the preservation of the leukemia's composition was more variable. In sum, this study underlines the remarkable genomic stability, and for the first time documents the preservation of the epigenomic landscape in T-ALL-derived PDX models.

18.
Haematologica ; 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30262570

RESUMO

Thromboembolism is a serious complication of induction therapy for childhood acute lymphoblastic leukemia. We prospectively compared efficacy and safety of antithrombotic interventions in the consecutive leukemia trials ALL-BFM 2000 and AIEOP-BFM ALL 2009. Patients with newly diagnosed acute lymphoblastic leukemia (n=949, age 1 to 18 years) were randomized to receive low-dose unfractionated heparin, prophylactic low-molecular-weight heparin (enoxaparin) or activity-adapted antithrombin throughout induction therapy. Primary objective was to test whether enoxaparin or antithrombin reduce the incidence of thromboembolism as compared to unfractionated heparin. Principal safety outcome was hemorrhage; leukemia outcome was a secondary endpoint. Thromboembolism occurred in 42 patients (4.4%). Patients assigned to unfractionated heparin had a higher risk of thromboembolism (8.0%) compared with those randomized to enoxaparin (3.5%; P=0.011) or antithrombin (1.9%; P<0.001). The proportion of patients who refused antithrombotic treatment as allocated was 3% in the unfractionated heparin or antithrombin, and 33% in the enoxaparin arm. Major hemorrhage occurred in eight patients (no differences between the groups). 5-year-event free survival was 80.9±2.2% if assigned to antithrombin compared to 85.9±2.0% in the unfractionated heparin (P=0.06), and 86.2±2.0% in the enoxaparin group (P=0.10). In conclusion, prophylactic use of antithrombin or enoxaparin significantly reduced thromboembolism. Despite the considerable number of patients rejecting the assigned treatment with subcutaneous injections, the result remains nonambiguous. Thromboprophylaxis - for the present time primarily with enoxaparin - can be recommended for children and adolescents with acute lymphoblastic leukemia during induction therapy. Whether and how antithrombin may affect leukemia outcome remains to be determined.

19.
Blood ; 132(15): 1584-1592, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30150206

RESUMO

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 × 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.

20.
Haematologica ; 2018 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-30093401

RESUMO

Despite intensified salvage treatments, children with relapsed/refractory acute myeloid leukemia have poor survival. We evaluated Gemtuzumab Ozogamicin (CD33-targeted drug) used on compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia-Berlin-Frankfurt-Munster studies and identified 76 patients (<18 years) with highly-advanced and pretreated acute myeloid leukemia [refractory de novo acute myeloid leukemia (n=10), de novo acute myeloid leukemia refractory to relapse (1st early: n=41; 1st late: n=10; 2nd or more: n=10), and secondary acute myeloid leukemia (n=5)]. At doses of 2.5-10 mg/m,2, Gemtuzumab Ozogamicin was administered in 1-4 cycles as single agent (47%), combined with cytarabine (47%), or others (6%). Most common grade 3/4 adverse events were infections or febrile neutropenia (78% of severe adverse events), infusion-related immunologic reactions (6%), and gastrointestinal symptoms (5%). Three patients experienced veno-occlusive disease (one fatal due to exacerbation of a preexisting cardiomyopathy). Sixty-four percent received subsequent hematopoietic stem cell transplantation. Probability of 4-year overall survival was 18±5% in all, 27±7% in patients with and 0% in patients without hematopoietic stem cell transplantation (p<0.0001). Administration of Gemtuzumab Ozogamicin on a patient-specific, compassionate use basis was frequently considered in our study group and proved to be effective for bridging children with very advanced AML to hematopoietic stem cell transplantation. Uniform prospective studies for these patients are urgently needed.

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