ABSTRACT
BACKGROUND: In addition to treatment response, cytogenetic and molecular aberrations are the most important prognostic factors in children with de novo acute myeloid leukemia (AML). However, little is known about cytogenetics at the time of relapse. METHODS: This international study analyzed the prognostic value of cytogenetic profiles and karyotypic changes in pediatric relapsed AML in relation to the probability of event-free (pEFS) and overall survival (pOS). For this purpose, cytogenetic reports from all patients registered on the Relapsed AML 2001/01 Study were reviewed and classified. RESULTS: Cytogenetic information at relapse was available for 403 (71%) of 569 registered patients. Frequently detected aberrations at relapse were t(8;21)(q22;q22) (n = 60) and inv(16)(p13.1q22)/t(16;16)(p13.1;q22) (n = 24), both associated with relatively good outcome (4-year pOS 59% and 71%, respectively). Monosomy 7/7q-, t(9;11)(p22;q23), t(10;11)(p12;q23), and complex karyotypes were associated with poor outcomes (4-year pOS 17%, 19%, 22%, and 22%, respectively). Of 261 (65%) patients for whom cytogenetic data were reliable at both diagnosis and relapse, pEFS was inferior for patients with karyotypic instability (n = 128, 49%), but pOS was similar. Unstable karyotypes with both gain and loss of aberrations were associated with inferior outcome. Early treatment response, time to relapse, and cytogenetic profile at time of relapse were the most important prognostic factors, both outweighing karytoypic instability per se. CONCLUSION: The cytogenetic subgroup at relapse is an independent risk factor for (event-free) survival. Cytogenetic assessment at the time of relapse is of high importance and may contribute to improved risk-adapted treatment for children with relapsed AML.
Subject(s)
Chromosome Aberrations , Leukemia, Myeloid, Acute , Child , Cohort Studies , Humans , Leukemia, Myeloid, Acute/genetics , Prognosis , Recurrence , Retrospective StudiesABSTRACT
Children with Down syndrome are at a high risk of developing transient abnormal myelopoiesis (TAM; synonym: TMD) or myeloid leukemia (ML-DS). While most patients with TAM are asymptomatic and go into spontaneous remission without a need for therapy, around 20% of patients die within the first six months due to TAM-related complications. Another 20-30% of patients progress from TAM to ML-DS. ML-DS patients are particularly vulnerable to therapy-associated toxicity, but the prognosis of relapsed ML-DS is extremely poor - thus, ML-DS therapy schemata must strive for a balance between appropriate efficacy (to avoid relapses) and treatment-related toxicity. This guideline presents diagnostic and therapeutic strategies for TAM and ML-DS based on the experience and results of previous clinical studies from the BFM working group, which have helped reduce the risk of early death in symptomatic TAM patients using low-dose cytarabine, and which have achieved excellent cure rates for ML-DS using intensity-reduced treatment protocols.
Subject(s)
Down Syndrome , Leukemia, Myeloid , Leukemoid Reaction , Child , Down Syndrome/diagnosis , Down Syndrome/therapy , GATA1 Transcription Factor/genetics , Humans , Leukemoid Reaction/diagnosis , Leukemoid Reaction/therapyABSTRACT
Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial by Nordic Society for Pediatric Hematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG), and Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) study group. Compared with the historical control arm (reduced-intensity protocol for ML-DS patients from the AML-BFM 98 trial), treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m2) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64), event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%; PGray = .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% ± 16% vs 88% ± 3%; Plog rank = .0008) and gain of chromosome 8 (CIR/NR, 16% ± 7% vs 3% ± 2%, PGray = .02; 5-year EFS, 73% ± 8% vs 91% ± 4%, Plog rank = .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2.
Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Down Syndrome/complications , Leukemia, Myeloid/complications , Leukemia, Myeloid/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Child, Preschool , Chromosomes, Human, Pair 8/genetics , Cytarabine/adverse effects , Cytarabine/therapeutic use , Cytogenetic Analysis , Disease-Free Survival , Down Syndrome/genetics , Etoposide/adverse effects , Etoposide/therapeutic use , Female , Humans , Idarubicin/adverse effects , Idarubicin/therapeutic use , Infant , Leukemia, Myeloid/genetics , Male , Prospective Studies , Treatment Outcome , Trisomy/geneticsABSTRACT
Despite intensified salvage treatments, children with relapsed/refractory acute myeloid leukemia (AML) have poor survival. We evaluated gemtuzumab ozogamicin (CD33-targeted drug) used on a compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia Berlin-Frankfurt-Münster studies, and identified 76 patients (<18 years) with highly-advanced and pre-treated AML [refractory de novo acute myeloid leukemia (n=10), de novo AML refractory to relapse (1st early: n=41; 1st late: n=10; 2nd or more: n=10), and secondary AML (n=5)]. At doses of 2.5-10 mg/m2, 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 immunological reactions (6%), and gastrointestinal symptoms (5%). Three patients experienced veno-occlusive disease (one fatal due to exacerbation of a pre-existing 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.
Subject(s)
Gemtuzumab/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Child , Disease-Free Survival , Female , Gemtuzumab/adverse effects , Humans , Male , Survival Rate , Time FactorsABSTRACT
The incidence of acute myelogenous leukemia (AML) increases progressively with age. Favorable genetic mutations are most prevalent in children, and unfavorable profiles increase proportionately in adolescents and young adults (AYA) and into later adulthood. Survival rates of AYA have improved over recent decades to 50-60%, but their accrual to clinical trials remains poor. In contrast to AYA with acute lymphoblastic leukemia, the prognostic benefit for AYA with AML enrolled in pediatric compared with adult trials is minor and only seen when different protocols are used. The distinctive needs of AYA, including intensive psychological services, call for their treatment within specialized centers that offer complex supportive care.
Subject(s)
Leukemia, Myeloid, Acute/epidemiology , Abnormal Karyotype , Adolescent , Adult , Age of Onset , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Differentiation/drug effects , Child , Child, Preschool , Clinical Trials as Topic , Europe/epidemiology , Female , Hematopoietic Stem Cell Transplantation , Humans , Incidence , Infant , Infertility/epidemiology , Infertility/etiology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Multicenter Studies as Topic , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/etiology , Patient Selection , Prognosis , Survival Analysis , United States/epidemiology , Young AdultABSTRACT
The treatment of acute promyelocytic leukemia (APL) has changed significantly in recent years. Today, APL patients with standard risk (also known as low risk) can be treated chemotherapy-free only with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). For high-risk patients, induction chemotherapy should be added. The curative results are good and comparable to those achieved in the past with chemotherapy plus ATRA. However, toxicities, especially infectious complications, are reduced. The main risk remains early lethal bleeding. Timely diagnosis and early ATRA treatment can reduce this risk. This review presents and discusses current treatment strategies and recommendations for APL in children.
Subject(s)
Antineoplastic Agents/therapeutic use , Arsenic Trioxide/therapeutic use , Leukemia, Promyelocytic, Acute/drug therapy , Tretinoin/therapeutic use , Antineoplastic Combined Chemotherapy Protocols , Child , Humans , Treatment OutcomeABSTRACT
Nowadays, childhood cancer patients survive much more often than they did 40 years ago. Therefore, the cure rates rise over 80%. Approximately 33,000 cured childhood cancer patients are documented by the German Childhood Cancer Registry (GCCR) for long-term follow-up in Germany. But does that mean, they are healthy, too? When compared to the normal population, it can be seen that morbidity and mortality are significantly higher among former childhood cancer patients. In two out of three survivors, the cancer and its treatments can lead to treatment-related late complications 30 years later; in about one-third, these late complications are classified as severe. A structured long-term follow-up is needed to detect and to treat new diseases early. The purpose of this position paper is to update the first position paper from 2007. Current developments are described, how appropriate aftercare structures and aftercare facilities should be planned, taking into account existing structures and increasing needs.
Subject(s)
Cancer Survivors/statistics & numerical data , Long-Term Care , Neoplasms/psychology , Population Surveillance/methods , Cancer Survivors/psychology , Child , Child, Preschool , Female , Follow-Up Studies , Germany , Humans , Male , Neoplasms/mortality , Neoplasms/therapy , Outcome Assessment, Health Care , Practice Guidelines as Topic , Quality of Life/psychology , Societies, Medical , Survival AnalysisABSTRACT
Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age ≤18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% ± 2.7% and 49.0% ± 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P = .037) and OS (P = .003) than those diagnosed in 1989 to 1999. Transplantation in first remission did not improve survival. Cytogenetic data were available for 372 (75.9%) patients: hypodiploid (n = 18, 4.8%), normal karyotype (n = 49, 13.2%), pseudodiploid (n = 119, 32.0%), 47 to 50 chromosomes (n = 142, 38.2%), and >50 chromosomes (n = 44, 11.8%). Chromosome gain occurred in 195 of 372 (52.4%) patients: +21 (n = 106, 28.5%), +19 (n = 93, 25.0%), +8 (n = 77, 20.7%). Losses occurred in 65 patients (17.5%): -7 (n = 13, 3.5%). Common structural chromosomal aberrations were t(1;22)(p13;q13) (n = 51, 13.7%) and 11q23 rearrangements (n = 38, 10.2%); t(9;11)(p22;q23) occurred in 21 patients. On the basis of frequency and prognosis, AMKL can be classified to 3 risk groups: good risk-7p abnormalities; poor risk-normal karyotypes, -7, 9p abnormalities including t(9;11)(p22;q23)/MLL-MLLT3, -13/13q-, and -15; and intermediate risk-others including t(1;22)(p13;q13)/OTT-MAL (RBM15-MKL1) and 11q23/MLL except t(9;11). Risk-based innovative therapy is needed to improve patient outcomes.
Subject(s)
Chromosome Aberrations , Leukemia, Megakaryoblastic, Acute/genetics , Leukemia, Megakaryoblastic, Acute/therapy , Adolescent , Antimetabolites, Antineoplastic/therapeutic use , Child , Child, Preschool , Cytarabine/therapeutic use , Disease-Free Survival , Female , Gene Rearrangement , Hematopoietic Stem Cell Transplantation , Humans , Infant , Kaplan-Meier Estimate , Karyotyping , Leukemia, Megakaryoblastic, Acute/diagnosis , Leukemia, Megakaryoblastic, Acute/epidemiology , Male , Prognosis , Retrospective Studies , Treatment OutcomeABSTRACT
Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3-8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all-trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 × 109/L) (P < 0.001) and high PB blast (>30 × 109/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index ≥95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established.
Subject(s)
Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 17/genetics , Disseminated Intravascular Coagulation , Translocation, Genetic , Tretinoin , Adolescent , Adult , Child , Child, Preschool , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/chemically induced , Disseminated Intravascular Coagulation/genetics , Disseminated Intravascular Coagulation/mortality , Female , Humans , Infant , Infant, Newborn , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/mortality , Leukocyte Count , Male , Obesity/blood , Obesity/drug therapy , Obesity/genetics , Obesity/mortality , Risk Factors , Tretinoin/administration & dosage , Tretinoin/adverse effectsABSTRACT
BACKGROUND: There is no consensus on the treatment for pediatric patients with acute myeloid leukemia and initial central nervous system (CNS) involvement. METHODS: To evaluate different CNS-directed treatment options (intrathecal [IT] therapy, CNS irradiation, hematopoietic stem cell transplantation [HSCT]), 261 patients (excluding acute promyelocytic leukemia) with initial CNS involvement treated in trials with similar intensive chemotherapy by four cooperative European study groups (1998-2013) were studied and compared with CNS-negative patients from the Berlin-Frankfurt-Münster group. RESULTS: Patient characteristics in the different study groups were comparable. Young age, high white blood cell count, extramedullary involvement other than the CNS, monoblastic morphology, and inv(16) were associated with CNS involvement (each P < 0.0001). There were no major differences in outcome between the study groups. The cumulative incidence of relapse (CIR) regarding the CNS was higher in initially CNS-positive versus initially CNS-negative patients (all: 8 ± 2% vs. 3 ± 1%, P(Gray) = 0.001; isolated: 4 ± 1% vs. 1 ± 0%, P(Gray) = 0.03). However, global outcome of the CNS-positive cohort (overall survival, 64 ± 3%; event-free survival 48 ± 3%; and CIR 33% ± 3%) did not differ significantly from CNS-negative patients. Risk groups defined by cytogenetics were of likewise prognostic significance in CNS-positive and -negative patients. CNS treatment with cranial irradiation was not superior compared to IT therapy and systemic chemotherapy (± HSCT). CONCLUSION: Although CNS relapses occurred more frequently in initially CNS-positive patients, their global outcome was similar as in CNS-negative patients. Intensified IT therapy was heterogeneous; however, at least eight applications, preferably with triple IT chemotherapy, seem to be appropriate to accompany dose-intensive systemic chemotherapy.
Subject(s)
Central Nervous System Neoplasms/therapy , Leukemia, Myeloid, Acute/therapy , Adolescent , Central Nervous System Neoplasms/mortality , Child , Child, Preschool , Cranial Irradiation , Hematopoietic Stem Cell Transplantation , Humans , Infant , Infant, Newborn , Leukemia, Myeloid, Acute/mortality , Neoplasms, Second Primary/epidemiology , Proportional Hazards Models , Recurrence , Treatment OutcomeABSTRACT
Recently, studies in adults with acute promyelocytic leukemia (APL) showed high cure rates in low-risk patients treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO), while toxicities were significantly reduced compared to the standard treatment with ATRA and chemotherapy. Here we report about first experience with 11 pediatric patients with low-risk APL treated with ATRA and ATO. All patients stayed in molecular remission. All suffered from hyperleukocytosis. Two patients experienced reversible severe side effects. One suffered from osteonecroses at both femurs, seizures, as well as posterior reversible encephalopathy syndrome, the other patient had an abducens paresis.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenicals/administration & dosage , Leukemia, Promyelocytic, Acute/drug therapy , Oxides/administration & dosage , Tretinoin/administration & dosage , Adolescent , Arsenic Trioxide , Arsenicals/adverse effects , Child , Child, Preschool , Female , Humans , Infant , Male , Oxides/adverse effects , Retrospective Studies , Treatment Outcome , Tretinoin/adverse effectsABSTRACT
BACKGROUND: To obtain better insight into the biology of acute myeloid leukemia (AML) in various age groups, this study focused on the genetic changes occurring during a lifetime. METHODS: This study analyzed the relation between age and genetics from birth to 100 years in 5564 patients with de novo AML diagnosed from 1998 to 2012 (1192 patients from nationwide pediatric studies [AML Berlin-Frankfurt-Münster studies 98 and 2004] and 4372 adults registered with the Munich Leukemia Laboratory). RESULTS: The frequencies of cytogenetic subgroups were age-dependent. Favorable subtypes (t(8;21), inv(16)/t(16;16), and t(15;17)) decreased in general from the pediatric age group (2 to < 18 years; 33%) to the oldest groups (<5% for > 70 years; P < .0001). Unfavorable cytogenetics (-7/del(7), -5/del(5q) or 5p, inv(3)/t(3;3), t(6;9), complex karyotype, 12p, 17p, and 11q23/mixed-lineage leukemia aberrations, excluding t(9;11)) were frequent (42%) in infants (<2 years), had a low frequency in children and young adults (<22%), and increased in frequency up to 36% in patients older than 85 years (P = .01). This was even more significant for complex karyotypes (P ≤ .0001), which also showed a strong increase in the absolute age-specific incidence with age. Interestingly, the frequency of 11q23 abnormalities decreased from infants to older patients. The proportion of clinically relevant molecular aberrations of CCAAT/enhancer binding protein α, nucleophosmin (NPM1), and NPM1/fms-related tyrosine kinase 3-internal tandem duplication increased with age. CONCLUSIONS: Altogether, with the exclusion of infants, a significant decrease in the proportion of favorable cytogenetic subtypes and an increase in unfavorable cytogenetics were observed with increasing age. These findings indicate different mechanisms for the pathogenesis of AML; these different mechanisms also suggest directions for etiological research and contribute to the more unfavorable prognosis with increasing age. Cancer 2016;122:3821-3830. © 2016 American Cancer Society.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Chromosome Aberrations , Cytogenetic Analysis/methods , Cytogenetics/methods , Female , Humans , Infant , Infant, Newborn , Karyotyping , Male , Middle Aged , Molecular Biology/methods , Nucleophosmin , Prognosis , Young AdultABSTRACT
Children with Down syndrome are at high risk to develop myeloid leukemia (ML-DS). Despite their excellent prognosis, children with ML-DS particularly suffer from severe therapy-related toxicities and for relapsed ML-DS the cure rates are very poor. Here we report the clinical course of one child with ML-DS treated with the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid) after second relapse. The child had previously received conventional chemotherapy and stem cell transplantation, yet showed a remarkable clinical and hematologic response. Thus, HDAC inhibitor may represent an effective class of drugs for the treatment of ML-DS.
Subject(s)
Down Syndrome/complications , Histone Deacetylase Inhibitors/therapeutic use , Hydroxamic Acids/therapeutic use , Leukemia, Myeloid/drug therapy , Child, Preschool , Cross-Sectional Studies , Humans , Leukemia, Myeloid/blood , Male , VorinostatABSTRACT
We evaluated the in vitro glucocorticoid (GC) responsiveness of 117 pediatric acute myeloid leukemia cells by considering GC resistance, GC-induced proliferation, and GC-induced differentiation. None of the samples was highly GC sensitive, and only 15% were intermediately sensitive. GC-induced differentiation was not observed, while GC-induced proliferation was observed in 27% of the samples. Samples with French-American-British classification (FAB) type M5 or activating Fms-like tyrosine kinase 3 (FLT3) mutations were significantly more prone to this phenomenon. Although we could not confirm this in our study, if induced proliferation in vitro is paralleled in vivo, GCs during consolidation may have adverse effects on minimal residual leukemic cells, which might increase relapse risk.
Subject(s)
Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Dexamethasone/therapeutic use , Glucocorticoids/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Prednisolone/therapeutic use , Treatment Outcome , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
BACKGROUND: To analyze whether expression of ABC-transporters is associated with remission rate and long-term outcome in a prospective clinical trial of childhood acute myeloid leukemia (AML). PROCEDURE: The expression of four ABC-transporter genes (ABCA3 encoding drug transporter ABCA3, ABCB1 encoding multidrug resistance protein 1, ABCC3 encoding multidrug resistance-associated protein 3, and ABCG2 encoding breast cancer resistance protein) was measured by TaqMan real time polymerase chain reaction in pretreatment samples from 112 children with AML. Patients were treated according to multicenter study AML-Berlin, Frankfurt, Munich (BFM) 2004. RESULTS: ABCC3 (P = 0.009) and ABCG2 (P = 0.03) were associated with a lower chance to achieve remission after the first course of chemotherapy. ABCC3 was associated with lower relapse free survival (RFS) (P = 0.02). ABCG2 was expressed at higher levels in subtypes of AML with favorable outcome but within standard- and high-risk patients, it was associated with poor outcome (P = 0.02). A strong association was observed between the number of overexpressed ABC-transporters and the chance to achieve remission (P = 0.01) or the chance of RFS (P < 0.001). CONCLUSIONS: The intensive treatment regimen of AML-BFM 2004 did not readily overcome drug resistance caused by ABC-transporters. Inhibition of ABC-transporters might be particularly useful in patients who express multiple of these genes.
Subject(s)
ATP-Binding Cassette Transporters/biosynthesis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , ATP-Binding Cassette Transporters/genetics , Child , Disease-Free Survival , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Prospective Studies , Real-Time Polymerase Chain Reaction , Treatment OutcomeABSTRACT
BACKGROUND: The risk of early death (ED) by bleeding/leukostasis is high in patients with AML with hyperleukocytosis (>100,000/µl). Within the pediatric AML-BFM (Berlin-Frankfurt-Münster) 98/04 studies, emergency strategies for these children included exchange transfusion (ET) or leukapheresis (LPh). Risk factors for ED and interventions performed were analyzed. PATIENTS: Two hundred thirty-eight of 1,251 (19%) patients with AML presented with hyperleukocytosis; 23 of 1,251 (1.8%) patients died of bleeding/leukostasis. RESULTS: ED due to bleeding/leukostasis was highest at white blood cell (WBC) count >200,000/µl (14.3%). ED rates were even higher (20%) in patients with FAB (French-American-British) M4/M5 and hyperleukocytosis >200,000/µl. Patients with WBC >200,000/µl did slightly better with ET/LPh compared to those without ET/LPh (ED rate 7.5% vs. 21.2%, P = 0.055). Multivariate WBC >200,000/µl was of strongest prognostic significance for ED (P(χ(2) ) <0.0001). CONCLUSION: Our data confirm the high risk of bleeding/leukostasis in patients with hyperleukocytosis. ET/LPh shows a trend toward reduced ED rate due to bleeding/leukostasis and is recommended at WBC >200,000/µl, and in FAB M4/M5 even at lower WBC.
Subject(s)
Blood Transfusion , Leukapheresis , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/therapy , Child , Child, Preschool , Female , Hemorrhage/etiology , Hemorrhage/mortality , Hemorrhage/prevention & control , Humans , Infant , Leukemia, Myeloid, Acute/mortality , Leukostasis/etiology , Leukostasis/mortality , Leukostasis/prevention & control , Male , Proportional Hazards Models , Risk FactorsABSTRACT
BACKGROUND: Children with acute myeloid leukemia (AML) and Down syndrome have high survival rates with intensity-reduced chemotherapeutic regimens, although the optimal balance between dose intensity and treatment toxicity has not been determined. We, therefore, characterized infectious complications in children with AML and Down syndrome treated according to AML-BFM 2004 study (ClinicalTrials.gov NCT00111345; amended 2006 for Down syndrome with reduced intensity). PROCEDURE: Data on infectious complications were gathered from the medical records in the hospital where the patient was treated. Infectious complications were categorized as fever without identifiable source (FUO), or as microbiologically or clinically documented infections. RESULTS: A total of 157 infections occurred in 61 patients (60.5% FUO, 9.6% and 29.9% clinically and microbiologically documented infections, respectively). Almost 90% of the pathogens isolated from the bloodstream were Gram-positive bacteria, and approximately half of them were viridans group streptococci. All seven microbiologically documented episodes of pneumonia were caused by viruses. Infection-related mortality was 4.9%, and all three patients died due to viral infection. CONCLUSIONS: Our data demonstrate that a reduced-intensity chemotherapeutic regimen in children with AML and Down syndrome is still associated with high morbidity. Although no patient died due to bacteria or fungi, viruses were responsible for all lethal events. Future studies, therefore, have to focus on the impact of viruses on morbidity and mortality of patients with AML and Down syndrome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Down Syndrome/complications , Infections/epidemiology , Leukemia, Myeloid, Acute/complications , Leukemia, Myeloid, Acute/drug therapy , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Child , Child, Preschool , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin/administration & dosage , Daunorubicin/adverse effects , Etoposide/administration & dosage , Etoposide/adverse effects , Female , Humans , Idarubicin/administration & dosage , Idarubicin/adverse effects , Infant , Male , Mitoxantrone/administration & dosage , Mitoxantrone/adverse effectsABSTRACT
Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensification of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m(2) per day for 3 days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% ± 3% [L-DNR] vs 75% ± 3% [idarubicin], Plogrank = .65; event-free survival [EFS] 59% ± 3% vs 53% ± 3%, Plogrank = .25; cumulative incidence of relapse 29% ± 3% vs 31% ± 3%, P(Gray) = .75), as were EFS results for standard (72% ± 5% vs 68% ± 5%, Plogrank = .47) and high-risk (51% ± 4% vs 46% ± 4%, Plogrank = .45) patients. L-DNR resulted in significantly better probability of EFS in patients with t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P = .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Daunorubicin/administration & dosage , Idarubicin/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Liposomes/administration & dosage , Adolescent , Antibiotics, Antineoplastic/adverse effects , Antibiotics, Antineoplastic/pharmacokinetics , Bone Marrow/drug effects , Bone Marrow/pathology , Child , Child, Preschool , Daunorubicin/adverse effects , Daunorubicin/pharmacokinetics , Dose-Response Relationship, Drug , Female , Heart Diseases/chemically induced , Heart Diseases/mortality , Humans , Idarubicin/adverse effects , Idarubicin/pharmacokinetics , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Liposomes/pharmacokinetics , Male , Multivariate Analysis , Neoplasms, Second Primary/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Proportional Hazards Models , Risk Factors , Treatment OutcomeABSTRACT
Despite recent advances in the treatment of children with acute megakaryoblastic leukemia (AMKL) using intensified treatment protocols, clear prognostic indicators, and treatment recommendations for this acute myeloid leukemia (AML) subgroup are yet to be defined. Here, we report the outcome of 97 pediatric patients with de novo AMKL (excluding Down syndrome [DS]) enrolled in the prospective multicenter studies AML-BFM 98 and AML-BFM 04 (1998-2014). AMKL occurred in 7.4 % of pediatric AML cases, at younger age (median 1.44 years) and with lower white blood cell count (mean 16.5 × 10(9)/L) as compared to other AML subgroups. With 60 ± 5 %, children with AMKL had a lower 5-year overall survival (5-year OS; vs. 68 ± 1 %, P log rank = 0.038). Yet, we achieved an improved 5-year OS in AML-BFM 04 compared to AML-BFM 98 (70 ± 6 % vs. 45 ± 8 %, P log rank = 0.041). Allogeneic hematopoietic stem cell transplantation in first remission did not provide a significant survival benefit (5-year OS 70 ± 11 % vs. 63 ± 6 %; P Mantel-Byar = 0.85). Cytogenetic data were available for n = 78 patients. AMKL patients with gain of chromosome 21 had a superior 5-year OS (80 ± 9 %, P log rank = 0.034), whereas translocation t(1;22)(p13;q13) was associated with an inferior 5-year event-free survival (38 ± 17 %, P log rank = 0.04). However, multivariate analysis showed that treatment response (bone marrow morphology on day 15 and 28) was the only independent prognostic marker (RR = 4.39; 95 % CI, 1.97-9.78). Interestingly, GATA1-mutations were detected in six patients (11 %) without previously known trisomy 21. Thus, AMKL (excluding DS) remains an AML subgroup with inferior outcome. Nevertheless, with intensive therapy regimens, a steep increase in the survival rates was achieved.
Subject(s)
Leukemia, Megakaryoblastic, Acute/diagnosis , Leukemia, Megakaryoblastic, Acute/therapy , Adolescent , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Infant, Newborn , Leukemia, Megakaryoblastic, Acute/epidemiology , Male , Prospective Studies , Treatment OutcomeABSTRACT
Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment.