ABSTRACT
Polymorphisms of DNA repair genes RAD51 and XRCC3 increase susceptibility to acute myeloid leukemia (AML) in adults, an effect enhanced by deletion of the glutathione-S-transferase M1 (GSTM1) gene. In this study, we genotyped 452 children with de novo AML treated on CCG protocols 2941 and 2961 and compared genotype frequencies with those of normal blood donors, and analyzed the impact of genotype on outcome of therapy. XRCC3 Thr241Met, RAD51 G135C and GSTM1 genotypes did not increase susceptibility to AML when assessed singly. In contrast, when XRCC3 and RAD51 genotypes were examined together a significant increase in susceptibility to AML was seen in children with variant alleles. Analysis of outcome of therapy showed that patients heterozygous for the XRCC3 Thr241Met allele had improved post-induction disease-free survival compared to children homozygous for the major or minor allele, each of whom had similar outcomes. Improved survival was due to reduced relapse in the heterozygous children, and this effect was most marked in children randomized to therapy likely to generate DNA double-strand breaks (etoposide, daunomycin), compared with anti-metabolite (fludarabine, cytarabine) based therapy. In contrast, RAD51 G135C and the GSTM1 deletion polymorphism did not influence outcome of AML therapy in our study population.
Subject(s)
Antineoplastic Agents/adverse effects , DNA Repair/genetics , Leukemia, Myeloid, Acute/genetics , Polymorphism, Genetic/genetics , Antineoplastic Agents/therapeutic use , DNA-Binding Proteins/genetics , Disease-Free Survival , Gene Frequency , Genotype , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Prognosis , Rad51 Recombinase/genetics , Recurrence , Treatment OutcomeABSTRACT
In Children's cancer group (CCG) 2891, newly diagnosed patients with AML were randomized between standard and intensive timing induction therapies. Patients in first remission who lacked an HLA matched family donor were randomized between an autologous bone marrow transplantation (ABMT) where marrow was purged with 4 hydroperoxycyclophosphamide and consolidation chemotherapy. One hundred and thirty seven patients received an ABMT. Myeloid and platelet engraftment occurred at a median of 44 and 42 days, respectively. Disease-free survival (DFS), relapse-free survival and overall survival at 8 years post induction were 47% (95% confidence interval (CI): 38-55), 50% (CI: 42-59) and 55% (CI: 46-63), respectively. Multivariate analysis of DFS showed WBC <50 000/microl and having received intensively timed induction therapy were associated with improved DFS. Recipients who received intensive timed induction therapy and whose WBC was less than 50 000/microl had a DFS at 8 years of 62% (CI: 49-73). Conversely, recipients who received intensive timed induction therapy patients whose WBC was > or =50 000/microl had a DFS of 33% (CI: 17-50), P=0.003. The results confirm previous studies that ABMT is effective post remission therapy for pediatric patients with AML in first remission.
Subject(s)
Bone Marrow Transplantation/methods , Leukemia, Myeloid, Acute/therapy , Remission Induction/methods , Adolescent , Adult , Bone Marrow Transplantation/adverse effects , Child , Child, Preschool , Disease-Free Survival , Female , Graft Survival , Humans , Infant , Male , Prospective Studies , Transplantation Conditioning/methods , Transplantation, AutologousABSTRACT
The PTPN11 gene encodes SHP-2, a nonreceptor protein tyrosine phosphatase that relays signals from activated growth factor receptors to p21(ras) (Ras) and other signaling molecules. Somatic PTPN11 mutations are common in patients with juvenile myelomonocytic leukemia (JMML) and have been reported in some other hematologic malignancies. We analyzed specimens from 278 pediatric patients with acute myelogenous leukemia (AML) who were enrolled on Children's Cancer Group trials 2941 and 2961 for PTPN11 mutations. Missense mutations of PTPN11 were detected in 11 (4%) of these samples. None of these patients had mutations in NRAS; however, one patient had evidence of a FLT3 alteration. Four of the patients with PTPN11 mutations (36%) were boys with French-American-British (FAB) morphology M5 AML (P=0.012). Patients with mutations also presented with elevated white blood cell counts. There was no difference in clinical outcome for patients with and without PTPN11 mutations. These characteristics identify a subset of pediatric AML with PTPN11 mutations that share clinical and biologic features with JMML.
Subject(s)
Leukemia, Myeloid/genetics , Mutation, Missense/genetics , Protein Tyrosine Phosphatases/genetics , Acute Disease , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Intracellular Signaling Peptides and Proteins , Leukemia, Myeloid/classification , Leukocyte Count , Male , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , SH2 Domain-Containing Protein Tyrosine Phosphatases , src Homology DomainsABSTRACT
Monosomy 7 or deletions of 7q are associated with many myeloid disorders; however, the significance of such abnormalities in childhood acute lymphoblastic leukemia (ALL) is unknown. Among 1880 children with ALL, 75 (4%) had losses involving chromosome 7, 16 (21%) with monosomy 7, 41 (55%) with losses of 7p (del(7p)), 16 (21%) with losses of 7q (del(7q)), and two (3%) with losses involving both arms. Patients with losses involving chromosome 7 were more likely to be > or =10 years old, National Cancer Institute (NCI) poor risk, and hypodiploid than patients lacking this abnormality. Patients with or without these abnormalities had similar early response to induction therapy. Event-free survival (EFS) and survival for patients with monosomy 7 (P<0.0001 and P=0.0007, respectively) or del(7p) (P<0.0001 and P=0.0001, respectively), but not of patients with del(7q), were significantly worse than those of patients lacking these abnormalities. The poorer EFS was maintained after adjustment for a Philadelphia (Ph) chromosome, NCI risk status, ploidy, or an abnormal 9p. However, the impact on survival was not maintained for monosomy 7 after adjustment for a Ph. These results indicate that the critical region of loss of chromosome 7 in pediatric ALL may be on the p-arm.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 7 , Monosomy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Humans , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , PrognosisABSTRACT
Acute myeloid leukaemia (AML) is characterized by a block in differentiation and an unregulated proliferation of myeloid progenitor cells. While the cause of AML in children is unknown, risk factors that have been identified include exposure to toxins such as ethanol, pesticides and dietary topoisomerase II inhibitors, prior chemotherapy with alkylating agents or topoisomerase II inhibitors, constitutional disorders such as Down's syndrome and type I neurofibromatosis, and haematopoietic failure syndromes such as Fanconi anaemia and severe congenital neutropenia. With intensified chemotherapy including high-dose Ara-C, followed in many cases by bone marrow transplantation, and with improvements in supportive care, current survival rates approach 50%. Future advances in paediatric AML will include better risk stratification to determine optimal treatment and targeted cytotoxic therapy.
Subject(s)
Leukemia, Myeloid , Acute Disease , Adolescent , Child , Child, Preschool , Clinical Trials as Topic , Humans , Leukemia, Myeloid/diagnosis , Leukemia, Myeloid/etiology , Leukemia, Myeloid/therapy , Risk Factors , Treatment OutcomeABSTRACT
PURPOSE: We used duration of hospitalization as a surrogate for cost and event-free survival as a measure of effectiveness to estimate the cost-effectiveness ratios of various treatment regimens on Children's Cancer Group trials for acute lymphoblastic leukemia. PATIENTS AND METHODS: The analyses included 4,986 children (2 to 21 years of age) with newly diagnosed acute lymphoblastic leukemia enrolled onto risk-adjusted protocols between 1988 and 1995. Analyses were based on a model of 100 patients. The marginal cost-effectiveness ratio (hospital days per additional patient surviving event-free) was the difference in total duration of hospitalization divided by the difference in number of event-free survivors at 5 years for two regimens. Relapse-adjusted marginal cost of frontline therapy was the difference in total duration of hospitalization for frontline therapy plus relapse therapy divided by the difference in number of event-free survivors at 5 years on the frontline therapy for two regimens. RESULTS: One or two delayed intensification (DI) phases, augmented therapy, and dexamethasone all improved outcome. Marginal cost-effectiveness of these regimens compared with the control regimens was 133 days per patient for DI, 117 days per patient for double DI, and 41 days per patient for augmented therapy. Dexamethasone resulted in 17 fewer days per patient. Relapse-adjusted marginal costs were 68 days per patient for DI and 52 days for double DI. Augmented therapy and dexamethasone-based therapy resulted in 16 and 82 fewer hospital days, respectively. The estimated cost-effectiveness for treating any first relapse was 250 days per patient. CONCLUSION: DI, double DI, augmented therapy, and dexamethasone-based therapy are cost-effective strategies compared with current treatment of first relapse.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/economics , Health Care Costs , Length of Stay/economics , Outcome Assessment, Health Care/methods , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/economics , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Child , Child, Preschool , Clinical Trials as Topic/statistics & numerical data , Cost-Benefit Analysis , Disease-Free Survival , Drug Administration Schedule , Humans , Outcome Assessment, Health Care/economics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , RecurrenceABSTRACT
Intensive, myelosuppressive therapy is necessary to maximize outcomes for patients with acute myeloid leukemia (AML). A comparison was made of 3 aggressive postremission approaches for children and adolescents with AML in a randomized trial, CCG-2891. A total of 652 children and adolescents with AML who achieved remission on 2 induction regimens using identical drugs and doses (standard and intensive timing) were eligible for allocation to allogeneic bone marrow transplantation (BMT) based on matched related donor status (n = 181) or randomization to autologous BMT (n = 177) or to aggressive high-dose cytarabine-based chemotherapy (n = 179). Only 115 patients (18%) refused to participate in the postremission phase of this study. Overall compliance with the 3 allocated regimens was 90%. At 8 years actuarial, 54% +/- 4% (95% confidence interval) of all remission patients remain alive. Survival by assigned regimen ("intent to treat") is as follows: allogeneic BMT, 60% +/- 9%; autologous BMT, 48% +/- 8%; and chemotherapy, 53% +/- 8%. Survival in the allogeneic BMT group is significantly superior to autologous BMT (P =.002) and chemotherapy (P =.05); differences between chemotherapy and autologous BMT are not significant (P =.21). No potential confounding factors affected results. Patients receiving intensive-timing induction therapy had superior long-term survival irrespective of postremission regimen received (allogeneic BMT, 70% +/- 9%; autologous BMT, 54% +/- 9%; chemotherapy, 57% +/- 10%). Allogeneic BMT remains the treatment of choice for children and adolescents with AML in remission, when a matched related donor is available. For all others, there is no advantage to autologous BMT; hence, aggressive nonablative chemotherapy should be used.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation/standards , Leukemia, Myeloid/therapy , Actuarial Analysis , Acute Disease , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/toxicity , Child , Child, Preschool , Disease-Free Survival , Follow-Up Studies , Humans , Infant , Infant, Newborn , Leukemia, Myeloid/complications , Remission Induction , Risk Factors , Survival Rate , Transplantation, Autologous/standards , Transplantation, Homologous/standards , Treatment OutcomeABSTRACT
The partner gene of MLL was identified in a patient with treatment-related acute myeloid leukemia in which the karyotype suggested t(3;11)(q25;q23). Prior therapy included the DNA topoisomerase II inhibitors, teniposide and doxorubicin. Southern blot analysis indicated that the MLL gene was involved in the translocation. cDNA panhandle polymerase chain reaction (PCR) was used, which does not require partner gene-specific primers, to identify the chimeric transcript. Reverse-transcription of first-strand cDNAs with oligonucleotides containing known MLL sequence at the 5' ends and random hexamers at the 3' ends generated templates with an intra-strand loop for PCR. In-frame fusions of either MLL exon 7 or exon 8 with the GMPS (GUANOSINE 5'-MONOPHOSPHATE SYNTHETASE) gene from chromosome band 3q24 were detected. The fusion transcript was alternatively spliced. Guanosine monophosphate synthetase is essential for de novo purine synthesis. GMPS is the first partner gene of MLL on chromosome 3q and the first gene of this type in leukemia-associated translocations. (Blood. 2000;96:4360-4362)
Subject(s)
Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 3/genetics , Leukemia, Myelomonocytic, Acute/genetics , Neoplasms, Second Primary/genetics , Oncogene Proteins, Fusion/genetics , Translocation, Genetic/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Child, Preschool , Chromosomes, Human, Pair 11/ultrastructure , Chromosomes, Human, Pair 3/ultrastructure , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , DNA, Complementary/genetics , DNA, Neoplasm/genetics , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Fatal Outcome , Humans , Leukemia, Myelomonocytic, Acute/etiology , Leukemia, Radiation-Induced/etiology , Leukemia, Radiation-Induced/genetics , Male , Molecular Sequence Data , Myeloid-Lymphoid Leukemia Protein , Neoplasm Recurrence, Local , Neoplasms, Second Primary/etiology , Neuroblastoma/drug therapy , Neuroblastoma/radiotherapy , Neuroblastoma/therapy , Polymerase Chain Reaction , Teniposide/administration & dosage , Teniposide/adverse effects , Transplantation Conditioning/adverse effects , Transplantation, Autologous , Vincristine/administration & dosage , Vincristine/adverse effects , Whole-Body Irradiation/adverse effectsABSTRACT
PURPOSE: Little is known about nonrandom deletions of chromosome bands 13q12 to 13q14 (13q12-14) in acute lymphoblastic leukemia (ALL). We determined the prognostic significance of cytogenetically identified breakpoints in 13q12-14 in children with newly diagnosed ALL treated on Children's Cancer Group protocols from 1988 to 1995. PATIENTS AND METHODS: Breakpoints in 13q12-14 were identified in 36 (2%) of the 1,946 cases with accepted cytogenetic data. Outcome analysis used standard life-table methods. RESULTS: Seventeen patients (47%) with an abnormal 13q12-14 were classified, according to the National Cancer Institute (NCI), as poor risk, and 15 patients (42%) were standard risk; four (11%) were infants less than 12 months of age. Eight cases had balanced rearrangements of 13q12-14, 27 patients had a partial loss of 13q, and one had both a partial gain and a partial loss. The most frequent additional abnormalities among these patients were an abnormal 12p, a del(6q), a del(9p), a 14q11 breakpoint, and an 11q23 breakpoint. Nineteen patients were pseudodiploid, 10 were hyperdiploid, and seven were hypodiploid. Patients with an abnormal 13q12-14 had significantly worse event-free survival than patients lacking such an abnormality, with estimates at 6 years of 61% (SD = 14%) and 74% (SD = 1%), respectively (P =.04; relative risk = 1.74). Overall survival, however, was similar for the two groups (P =.25). The prognostic effect of an abnormal 13q was attenuated in a multivariate analysis adjusted for NCI risk status and ploidy (P =.72). CONCLUSION: Aberrations of 13q12-14 may contribute to leukemogenesis of childhood ALL and confer increased risk of treatment failure but are associated with other poor-risk features.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 13 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Chromosome Breakage , Chromosome Deletion , Clinical Trials as Topic , Cohort Studies , Disease-Free Survival , Humans , Infant , Karyotyping , Ploidies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Treatment OutcomeABSTRACT
BACKGROUND: Despite improvements in the treatment of pediatric acute lymphoblastic leukemia, approximately one in five patients will develop recurrent disease. The majority of these patients do not survive. This limited institution study sought to improve event-free survival (EFS) by intensification of chemotherapy. PROCEDURE: Twenty-one patients with either an isolated marrow (n = 16) or a combined marrow and central nervous system relapse (n = 5) received treatment according to Children's Hospital of Philadelphia protocol CHP-540. Six patients had an initial remission of <36 months, and five patients had relapsed within 1 year of completion of phase III therapy. Induction and reinduction therapy consisted of idarubicin, vincristine, dexamethasone, asparaginase, and triple intrathecal chemotherapy. Consolidation and reconsolidation therapy employed high-dose cytarabine, etoposide, and asparaginase given in a sequential manner. Maintenance therapy included courses of high- or low-dose cytarabine followed by sequential etoposide and asparaginase pulse, moderate-dose methotrexate with delayed leukovorin rescue, and vincristine/dexamethasone pulses. Therapy continued for 2 years from the start of interim maintenance in the 16 patients who did not receive a bone marrow transplant (BMT). Two patients underwent an HLA-identical sibling BMT specified by protocol. Four received a nonprotocol-prescribed alternative donor BMT. RESULTS: The complete remission induction rate was 95%. With a median follow-up from date of relapse of 49 months in survivors, the actuarial EFS based on intent to treat is 75%. There were three toxic deaths in patients in CR and two deaths from relapse. CONCLUSIONS: This regimen is toxic but effective and deserves study in a larger setting.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/drug effects , Neoplasm Recurrence, Local/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antibiotics, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Asparaginase/administration & dosage , Bone Marrow Transplantation , Central Nervous System Neoplasms/drug therapy , Child , Child, Preschool , Cytarabine/administration & dosage , Dexamethasone/administration & dosage , Disease-Free Survival , Etoposide/administration & dosage , Female , Follow-Up Studies , Humans , Idarubicin/administration & dosage , Infant , Injections, Spinal , Male , Remission Induction , Vincristine/administration & dosageABSTRACT
We have compared outcome for 167 (9.0%) children with a del(6q) and 1713 (91%) children without a del(6q) treated on Children's Cancer Group (CCG) risk-adjusted treatment protocols for acute lymphoblastic leukemia (ALL). Thirty-three patients had a del(6q) as the sole aberration; 22 patients had a del(6q) only as a secondary abnormality. Thirty-six cases had a del(6q) and high hyperdiploidy (>50 chromosomes). Six patients with a del(6q) also had +16 and 8 patients had loss of a sex chromosome. Frequent recurring breakpoints were q13, q15, q21, q23, and q25. Patients with a del(6q) were more likely to have T-lineage ALL (p < 0.001), a mediastinal mass (p = 0.01), and higher WBC counts (p = 0.04), although only half of these patients were classified as poor risk. Event-free survival at 6 years was similar for patients with or without a del(6q), with estimates of 77% (SD = 5%) and 74% (SD = 2%), respectively (p = 0.44). This finding was also observed within NCI poor and standard risk groups. Thus, cytogenetically detectable del(6q) is not associated with adverse risk in pediatric ALL.
Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 6 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Antineoplastic Agents/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , PrognosisABSTRACT
BACKGROUND: The authors have determined the prognostic significance of cytogenetically detectable 12p abnormalities, which are frequent in children with acute lymphoblastic leukemia (ALL), in a large cohort of patients treated on risk-adjusted protocols of the Children's Cancer Group (CCG). METHODS: The presence of an abnormal 12p was identified among 1880 children with newly diagnosed ALL; outcome was assessed by standard life table methods. RESULTS: A total of 174 cases (9%) had cytogenetically detectable 12p abnormalities; the majority of cases had a balanced translocation, a del(12p), or an add(12p). In the overall cohort, event free survival (EFS) at 6 years was similar for patients with or without a 12p abnormality (76%, SD = 6%, vs. 75%, SD = 2%, respectively; P = 0.60). Among patients with pseudodiploidy, an abnormal 12p conferred improved outcome (P = 0.008; relative risk = 0.51; 95% confidence interval [CI], 0.31-0.85). There was a trend for improved EFS for those with abnormalities in both chromosome 12 homologues (P = 0.16; relative risk = 0.39; 95% CI, 0.10-1.55) and those with low hyperdiploidy (P = 0.07; relative risk = 0.44; 95% CI, 0.18-1.09). Among T-lineage ALL patients, there was a trend for worse outcome for abnormal versus normal 12p (P = 0.14; relative risk = 1.97; 95% CI, 0.78-4.93). There was no difference in EFS for the 12 patients with a dic(9;12) compared with patients lacking an abnormal 12p. CONCLUSIONS: These data suggest that although a cytogenetically detectable 12p aberration is a favorable risk factor for children with ALL and pseudodiploidy, it is not prognostic for the overall group of pediatric ALL patients treated with contemporary therapies of the CCG.
Subject(s)
Chromosome Aberrations , Chromosome Disorders , Chromosomes, Human, Pair 12/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Infant , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Retrospective Studies , Risk AssessmentABSTRACT
PURPOSE: Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (> 50 chromosomes) have improved outcome compared with other ALL patients. We sought to identify cytogenetic features that would predict differences in outcome within this low-risk subset of ALL patients. MATERIALS AND METHODS: High-hyperdiploid ALL patients (N = 480) were enrolled between 1988 and 1995 on Children's Cancer Group (CCG) trials. Karyotypes were determined by conventional banding. Treatment outcome was analyzed by life-table methods. RESULTS: Patients with 54 to 58 chromosomes had better outcome than patients with 51 to 53 or 59 to 68 chromosomes (P = .0002). Patients with a trisomy of chromosome 10 (P<.0001), chromosome 17 (P = .0002), or chromosome 18 (P = .004) had significantly improved outcome compared with their counterparts who lacked the given trisomy. Patients with a trisomy of chromosome 5 had worse outcome than patients lacking this trisomy (P = .02). Patients with trisomies of both chromosomes 10 and 17 had better outcome than those with a trisomy of chromosome 10 (P = .09), a trisomy of chromosome 17 (P =.01), or neither trisomy (P<.0001). Multivariate analysis indicated that trisomy of chromosome 10 (P = .001) was the most significant prognostic factor for high-hyperdiploid patients, yet trisomy of chromosome 17 (P =.02) or chromosome 5 (P = .01) and modal chromosome number (P = .02) also had significant multivariate effects. CONCLUSION: Trisomy of chromosomes 10 and 17 as well as modal chromosome number 54 to 58 identify subgroups of patients with high-hyperdiploid ALL who have a better outcome than high-hyperdiploid patients who lack these cytogenetic features. Trisomy of chromosome 5 confers poorer outcome among high-hyperdiploid patients.
Subject(s)
Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 5/genetics , Diploidy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Trisomy/genetics , Child , Child, Preschool , Female , Humans , Infant , Karyotyping , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Predictive Value of Tests , Prognosis , Treatment OutcomeABSTRACT
Leukemias with MLL gene translocations are a complication of primary cancer treatment with DNA topoisomerase II inhibitors. How early translocations appear during primary cancer treatment has not been investigated. We tracked the leukemic clone with an MLL gene translocation during neuroblastoma therapy in a child who developed acute myeloid leukemia. The karyotype of the leukemic clone showed del(11)(q23). We used panhandle PCR-based methods to isolate the breakpoint junction involving MLL and an unknown partner gene. Marrow DNA from neuroblastoma diagnosis and DNA and RNA from serial preleukemic marrows were examined for the translocation. The karyotypic del(11)(q23) was a cryptic t(11;17). GAS7, a growth arrest-specific gene at chromosome band 17p13, was the partner gene of MLL. Two different MLL-GAS7 fusion transcripts were expressed. The translocation was already detectable by 1.5 months after the start of neuroblastoma treatment. The translocation was not detectable in the marrow at neuroblastoma diagnosis or in peripheral blood lymphocyte DNAs of six normal subjects. GAS7 is a new partner gene of MLL in treatment-related acute myeloid leukemia. MLL gene translocations can be present early during anticancer treatment at low cumulative doses of DNA topoisomerase II inhibitors. Although MLL has many partner genes and most have not been characterized, panhandle PCR strategies afford new means for detecting MLL gene translocations early during therapy when the partner gene is unknown.
Subject(s)
DNA-Binding Proteins/genetics , Nerve Tissue Proteins/genetics , Neuroblastoma/drug therapy , Neuroblastoma/genetics , Proto-Oncogenes , Topoisomerase II Inhibitors , Transcription Factors , Translocation, Genetic , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Base Sequence , Blotting, Southern , Chromosomes, Human, Pair 11 , Cisplatin/adverse effects , Cyclophosphamide/adverse effects , Doxorubicin/adverse effects , Etoposide/adverse effects , Exons , Fatal Outcome , Histone-Lysine N-Methyltransferase , Humans , Leukemia, Myeloid/chemically induced , Leukemia, Myeloid/genetics , Male , Molecular Sequence Data , Myeloid-Lymphoid Leukemia Protein , Polymerase Chain Reaction , Time Factors , Vincristine/adverse effectsABSTRACT
PURPOSE: Up to 80% of children with acute myelogenous leukemia treated with intensive chemotherapy achieve remission; however, a large proportion of patients develops recurrent disease. Because interleukin (IL)-2 can induce remission in patients with overt evidence of acute myelogenous leukemia, we hypothesized that it might prevent relapse when administered to patients in first remission after intensive consolidation chemotherapy. A pilot Children's Cancer Group (CCG) trial (CCG-0941) demonstrated the feasibility of this approach, and we initiated a prospective randomized trial (CCG-2961) to further evaluate the safety and potential efficacy of IL-2 therapy in preventing relapse of acute myelogenous leukemia. PATIENTS AND METHODS: In trial CCG-0941, 21 pediatric patients in complete remission following induction and consolidation chemotherapy on protocol CCG-2941 received IL-2 therapy. In CCG-2961, 79 patients in complete remission were randomized as of February 1999 to receive either IL-2 (n = 39) or no further therapy. In both trials, recombinant IL-2 was given at a dose of 9 million IU/m2/d by continuous intravenous infusion for 4 days. After 4 days of rest, IL-2 was resumed at a dose of 1.6 million IU/m2/d for 10 days by continuous infusion. We monitored patients for toxicity and relapse. RESULTS: The majority of patients treated with IL-2 in these two trials experienced some degree of fever. Seven of 60 patients (12%) had clinically significant rashes, and grade 3 vascular leak syndrome and hypotension have each been observed in five patients (8%). Hypotension resolved promptly after treatment with intravenous fluids. No patients have experienced renal toxicity or required cardiac vasopressors or transfer to an intensive care unit; there have been no treatment-related deaths. Overall, the incidence and severity of adverse events remain similar in the two trials. Total projected accrual to the IL-2 randomization is anticipated to be 326 patients, and relapse and survival data remain blinded. CONCLUSION: The dose and schedule of IL-2 used in these two trials continue to be reasonably well tolerated by children with acute myelogenous leukemia in first remission. Any conclusions with regard to efficacy must await completion of the randomized trial.
Subject(s)
Interleukin-2/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Leukemia, Myeloid, Acute/prevention & control , Male , Recombinant Proteins/therapeutic use , RecurrenceABSTRACT
We have determined the prognostic significance of hypodiploidy (<46 chromosomes) in a large cohort of children with acute lymphoblastic leukemia (ALL) treated by the Children's Cancer Group. Among 1,880 patients, 110 (5.8%) had hypodiploid karyotypes: 87 had 45 chromosomes, 15 had 33 to 44 chromosomes, none had 29 to 32 chromosomes, and 8 had 24 to 28 chromosomes (near-haploidy). Six-year event-free survival (EFS) estimates for patients with 45 chromosomes, 33 to 44 chromosomes, or 24 to 28 chromosomes were 65% (standard deviation [SD], 8%), 40% (SD, 18%), and 25% (SD, 22%), respectively (log rank, P =.002; test for trend, P =.0009). The combined hypodiploid group had worse outcome than nonhypodiploid patients, with 6-year EFS of 58% (SD, 7%) and 76% (SD, 2%), respectively (P <.0001). EFS for the subgroup with 45 chromosomes was similar to that of patients with pseudodiploidy (P =.43) or 47 to 50 chromosomes (P =.76). None of the patients with 24 to 28 chromosomes had a t(4;11), a t(9;22), or a t(1;19), and most received highly intensive therapy. The adverse risk associated with 33 to 44 and 24 to 28 chromosomes remained significant in multivariate analyses adjusted for important risk factors including age, white blood cell count, and Philadelphia chromosome status. Thus, hypodiploidy with less than 45 chromosomes, particularly 24 to 28 chromosomes, is a significant adverse risk factor despite treatment with contemporary intensive therapies.
Subject(s)
Ploidies , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Female , Humans , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Predictive Value of Tests , Prognosis , Survival AnalysisABSTRACT
Cytogenetic abnormalities of chromosome arm 9p occur frequently in children with acute lymphoblastic leukemia (ALL). We analyzed 201 such cases (11%) in 1,839 children with newly diagnosed ALL treated between 1989 and 1995 on risk-adjusted protocols of the Children's Cancer Group (CCG). The majority of patients (131; 65%) with a 9p abnormality were classified as higher risk. Nearly all patients had complex karyotypes; most cases had deletions of 9p, add/der(9p), a dicentric involving chromosome arm 9p, and/or balanced translocations and inversions involving 9p. Event-free survival (EFS) estimates at 6 years for patients with and without a 9p aberration were 61% (standard deviation [SD] = 5%) and 76% (SD = 2%; P <.0001). In addition, patients with a 9p abnormality had an increased cumulative incidence of both marrow (P =.04) and central nervous system (P =.0001) relapses. Overall survival also was significantly worse for patients with an abnormal 9p (P <.0001). These effects were most pronounced in standard-risk patients (age 1 to 9 years with white blood cell count <50,000/microL): 6-year EFS of 61% (SD = 9%) versus 80% (SD = 2%; P <.0001). Also, a 9p aberration was an adverse risk factor for B-lineage, but not T-lineage patients. The effect of 9p status on EFS was attenuated, but maintained in a multivariate analysis of EFS after adjustment for Philadelphia chromosome status, age, white blood cell (WBC) count, sex, race, and ploidy group (P =.01). Thus, abnormalities of chromosome arm 9p identify a subgroup of standard-risk patients with increased risk of treatment failure.
Subject(s)
Chromosome Aberrations , Chromosomes, Human, Pair 9 , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Child , Child, Preschool , Female , Humans , Infant , Male , Multivariate Analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Risk FactorsABSTRACT
PURPOSE: To study the pharmacokinetics of single daily dose (SDD) gentamicin in children with cancer. METHODS: Serum concentrations of gentamicin were prospectively measured at 0.5, 8, 16, and 24 hours after a single daily dose of gentamicin 6 mg/kg, given as a 30-minute infusion in 18 febrile children with cancer and a central venous catheter. Then the peak (0.5-hour) and 12-hour serum concentrations of gentamicin were prospectively measured after a SDD of 7 mg/kg during 73 febrile episodes in 54 pediatric cancer patients with suspected infections. The aim was to achieve a peak serum concentration of 15 to 20 microg/mL 10 times the minimum inhibitory concentration (MIC) for sensitive Pseudomonas strains, resulting in good bactericidal activity and a long post-antibiotic effect (PAE) after a SDD of gentamicin. RESULTS: The mean serum peak gentamicin concentration 30 minutes after the end of the infusion of 6 mg/kg was 13.3 +/- 4.0 microg/mL. The mean serum concentration 16 hours after the infusion was 0.3 +/- 0.2 microg/mL. The mean peak and 12-hour serum concentration after SDD of 7 mg/kg was 17.2 +/- 3.9 microg/mL and 0.9 +/- 0.7 microg/mL, respectively. The mean peak serum concentration after SDD of 7 mg/kg in children younger than 5 years of age (16.1 +/- 3.5 microg/mL ) was significantly lower than that of children over 5 years of age (18.2 +/- 3.9 microg/mL; P = 0.02). The desired peak serum concentration was achieved in 67% of children younger and 84% of those older than 5 years of age. CONCLUSION: Adequate peak serum concentrations of gentamicin in children may be obtained with a SDD of 7 mg/kg. Children younger than 5 years of age achieve lower peak serum gentamicin concentration after SDD of 7 mg/kg than those older than 5 years.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacokinetics , Gentamicins/administration & dosage , Gentamicins/pharmacokinetics , Antibiotics, Antineoplastic/blood , Catheterization, Central Venous , Child , Child, Preschool , Drug Administration Schedule , Female , Gentamicins/blood , Humans , Infusions, Intravenous , Male , Prospective StudiesABSTRACT
PURPOSE: To describe patterns of central venous catheter (CVC) use and determine the risk of infection associated with a catheter in children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Children with ALL (n = 1934), participating in Children's Cancer Group studies for good-prognosis ALL (CCG-1881) and intermediate-risk ALL (CCG-1891) were evaluated in a retrospective case-control study. The presence of a catheter and the occurrence of infectious complications were recorded after each treatment phase. RESULTS: Young age and enrollment in the intermediate-risk study were associated with higher rates of catheter use. During each of the first four phases of therapy, the adjusted risk of infection was two- to fourfold higher when a catheter was in place. The proportion of patients with infection during the first four phases of therapy was 2.6 times higher with a CVC (14.4% versus 5.7%). Catheter use was associated with significantly increased hospitalization rates during induction, consolidation, and interim maintenance, but not during delayed intensification. A catheter did not significantly increase the risk of fever during neutropenia. CONCLUSION: The presence of a CVC increases the risk of infection during the early phases of low-intensity therapy for ALL.
Subject(s)
Antineoplastic Agents/administration & dosage , Catheterization, Central Venous/adverse effects , Infections/etiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Case-Control Studies , Child , Child, Preschool , Female , Humans , Incidence , Male , Retrospective Studies , Risk , United StatesABSTRACT
Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in infants have in common a high incidence of translocations of the MLL gene at chromosome band 11q23. Similar translocations occur in leukemias associated with chemotherapies that target DNA topoisomerase II. MLL has numerous different partner genes. The role of the many MLL fusion proteins in leukemogenesis is not yet understood. The t(4;11) translocation, the most common translocation in infant ALL, adversely affects the outcome. Additional genetic changes, especially Ikaros alterations, are found in infant ALL. Other forms of myeloid leukemia in infants present as myelodysplastic and myeloproliferative syndromes, which may be associated with constitutional disorders. This review will consider all leukemia in infants, but will focus on leukemias with MLL gene translocations.