Childhood Acute Myelogenous Leukemia Research Articles

Leukemia in Children.

1. Joel A. Kaplan, DO, MPH 1. Department of Pediatrics, Atrium Health Levine Children’s Hospital, Charlotte, NC * Abbreviations: ALL: : acute lymphoblastic leukemia AML: : acute myelogenous leukemia BMT: : bone marrow transplant CBC: : complete blood cell CML: : chronic myelogenous leukemia CNS: : central nervous system DIC: : disseminated intravascular coagulation EFS: : event-free survival HLA: : human leukocyte antigen MRD: : minimal residual disease Ph: : Philadelphia chromosome TKI: : tyrosine kinase inhibitor WBC: : white blood cell Persistent bone pain, limp, back pain, fever, headache, and symptoms of anemia and thrombocytopenia are common ways that pediatric leukemia presents. Many of these symptoms can be seen in common childhood illnesses, so a high index of suspicion in patients with persistent symptoms is required to make the diagnosis. The prognosis for these children is excellent, especially in acute lymphoblastic leukemia, but survivors of childhood leukemia need to be followed closely for long-term toxicities. After completing this article, readers should be able to: 1. Understand the incidence and general epidemiology of childhood leukemia, including syndromes that increase the risk of leukemia in children. 2. Recognize the clinical presentation of childhood leukemia and how this relates to proper interpretation of a complete blood cell count. 3. Understand the potential oncologic emergencies in childhood leukemia. 4. Describe the prognostic factors associated with precursor B-lymphoblastic leukemia, including an understanding of the importance of minimal residual disease. 5. Understand the importance of supportive care in the treatment of childhood acute myelogenous leukemia. 6. Describe the long-term complications of childhood leukemia treatment in the modern era. Leukemia is the most common malignancy of childhood, accounting for 30% of cases of childhood cancer. Although there are some associations between environmental or host factors, most leukemia diagnoses in children are sporadic. There are 3 main subtypes of leukemia: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). ALL is the most common subtype, accounting for approximately 80% of cases. CML is the least common, and this review touches on this subtype only briefly. There are many subgroups within ALL and AML. These subgroups have variable biological features, prognoses, and treatment regimens. Children …

Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse.

The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197-205. ©2016 AACR.

Exchange Transfusion and Leukapheresis in Pediatric AML Patients with High Risk of Early Death for Bleeding and Leukostasis

Background. The risk of early death (ED) due to bleeding and/or leukostasis is high in AML patients with initial hyperleukocytosis (white blood cell count [WBC] > 100 000/µl) and highest in those with hyperleukocytosis and mono- or myelomonocytic leukemia (FAB M4/M5). (Creutzig, et al 1987) Within the AML-BFM studies, emergency strategies for children with AML and high risk for bleeding and leukostasis included exchange transfusion (ET) or leukapheresis (LPh). In order to determine whether these interventions reduced the rate of ED, 1251 AML-BFM patients from the trials AML-BFM 98 and 04 were analyzed. Risk factors for ED and interventions performed were verified focusing on patients with hyperleukocytosis.Patients. 238 of 1251 (19%) AML-patients <18 years of age (FAB M3 excluded) presented with hyperleukocytosis. Twenty-three out of 1251 (1.8%) patients died by bleeding and leukostasis within 15 days from diagnosis, 18 (78%) of these 23 ED patients had hyperleukocytosis. Seventy-two patients received ET and 17 LPh (including 14 patients with WBC counts < 100 000/µl). 149 patients with hyperleukocytosis did not receive ET/LPh. The median age of patients receiving ET was significantly lower compared to those with LPh (3.5 years vs 12.6 years, p = 0.015). WBC counts were similar in both treatment groups (ET median 224 000/µl vs LPh 218 000/µl, p = 0.20).Results. The percentage of ED by bleeding/leukostasis increased with higher WBC counts and was highest in 105 patients with WBC > 200 000/µl (14.3%). The ED rates were even higher in patients with FAB M4/M5 and hyperleukocytosis >200 000/µl compared to others with WBC >200 000/µl (M4/M5 13/65 [20%] vs. others 2/40 [5%], p=0.04). Patients with WBC counts >200 000/µl did slightly better with ET or LPh compared to those without ET/LPh (ED rate 7.5 % vs 21.2 %, p=0.055). Patients with WBC between 100 000/µl and 200 000/µl received ET/LPh less frequently compared to those with WBC >200 000/µl (22/133 [17%] vs. 53/105 [50%]). ET/LPh was mainly given in case of clinical symptoms of bleeding or leukostasis or coagulopathies or insufficient reduction (or increase) of WBC counts despite low dose chemotherapy. 15/80 (19%) patients with FAB M4/5 and WBC 100 000-200 000/µl received ET/LPh and none of these patients died early. ET/LPh was even given in 14 patients with WBC <100 000/µl because of clinical symptoms of bleeding or leukostasis or coagulopathies or rising WBC counts. In multivariate analysis WBC >200 000/µl was the strongest independent risk factor for ED (hazard ratio =15.0, 95% confidence interval 4.9-46.3, p(chi)<0.0001). FAB M4/M5 subtypes, general condition grade 4 and initial bleeding were also significant risk factors. Application of ET/LPh seems to have a non-significant benefit for a reduced ED rate by bleeding/leukostasis (p=0.13). The assessment of the general clinical condition of the patients plays a major role for the decision for ET/LPh. However, this possibly selective cofactor could not be included completely in our calculation because of lack of standardized assessments and documentation of clinical reasons for decision making in particular in patients without ET/LPh. There was no difference in ED rates between ET and LPh. (2/17 vs 5/72, p =0.61). Compared to LPh, ET can be given without time delay. ET is easier to perform especially in young children who need smaller exchange volumes, as well as in adolescents where it can be applied also as partial ET. ET also corrects metabolic disturbances and avoids deterioration of coagulation.Conclusion. Our data confirm the high risk of bleeding/leukostasis in patients with hyperleukocytosis. Although we could only disclose a trend for a clinical benefit of ET/LPh in this retrospective analysis - probably due to some negative selection bias in patients with the intervention - we strongly advocate ET/LPh in AML patients with WBC >200 000/µl, and in particular in those with FAB M4/M5 subtypes or with clinical symptoms of bleeding or leukostasis or coagulopathies even with lower WBC (100 000/µl - 200 000/µl).Creutzig, U. et al. (1987) Early deaths due to hemorrhage and leukostasis in childhood acute myelogenous leukemia: Associations with hyperleukocytosis and acute monocytic leukemia. Cancer,60, 3071-3079. DisclosuresNo relevant conflicts of interest to declare.

Extramedullary Tumor of Cerebral Falx

In childhood acute myelogenous leukemia, extramedullary tumor is an occasional clinical symptom. However, extramedullary acute megakaryocytic leukemia is extremely rare. Here, we report an extremely rare case of acute megakaryocytic leukemia in a patient who presented with extramedullary tumor of cerebral falx as a first manifestation before the diagnosis of systemic bone marrow leukemia.

Prospective validation of a new method of monitoring minimal residual disease in childhood acute myelogenous leukemia.

This study evaluated the prognostic impact of a novel, simple, and standardized assay for monitoring minimal residual disease (MRD) in pediatric acute myelogenous leukemia (AML). The expression of seven leukemia-associated genes (WT1, PRAME, CCL23, GAGED2, MSLN, SPAG6, and ST18) was measured by TaqMan Low Density Arrays in 112 patients and 52 healthy controls. Patients were treated according to the multicenter study AML-BFM 2004. Samples were collected prospectively at standard time points. The laboratory that measured MRD was blinded to patient outcome. Relapse-free survival (RFS) was 95% (N = 19; SE = 5%) if expression of all genes was down to normal on day 15, 63% (N = 41; SE = 8%) if expression was normalized on day 28, and 38% (N = 21; SE = 11%) in patients who still showed elevated expression on day 28. The prognostic impact of MRD remained significant (P = 0.002) when patients were stratified for the AML-BFM 2004 risk group. Multivariate analysis identified the MRD risk group and day 28 cytology as the only independent prognostic factors. Patients with a cytologic nonremission on day 28, which was confirmed by MRD, had a dismal prognosis. Only 1 out of 8 patients survived without relapse. This novel method of monitoring MRD has a strong prognostic impact that is independent from established risk factors in childhood AML.

Hematopoietic Cell Transplantation in High-Risk Childhood Acute Myelogenous Leukemia

In this issue of Biology of Blood and Marrow Transplantation, Burke et al. present their findings on the efficacy of allogeneic hematopoietic stem cell transplantation (HCT) in patients with high-risk childhood acute myelogenous leukemia (AML). This limited single-institution study demonstrates that patients with high-risk disease (as defined by cytogenetics/molecular markers) who received allogeneic HCT in first compete remission (CR) have a favorable outcome, similar to those with standard-risk disease. The role of HCT as consolidation therapy for childhood AML has evolved significantly since Woods et al. first demonstrated that children who received allogeneic HCT from related donors had an improved outcome compared with chemotherapy recipients [1]. This study further demonstrated that pretransplantation chemotherapy can affect posttransplantation survival; patients who received more intensive induction chemotherapy had a significantly lower rate of relapse and more favorable survival after HCT, suggesting that quality of remission (lower residual disease) was an important determinant of post-HCT survival. In this study, although HCT carried higher treatment-related mortality, lower relapse resulted in more favorable outcomes in HCT recipients. This seminal study led to the change in the standard of care in childhood AML in the United States, where patients with newly diagnosed AML with suitably matched related donors were allocated to receive HCT in first CR. Subsequent studies (Children’s Cancer Group 2961 and Children’s Oncology Group 03P1 pediatric AML trials) allocated all patients with a matched family donor to receive HCT in first CR [2,3]. With the improvements in HLA typing and supportive care, and with broader availability of suitable donors, unrelated HCT has been more broadly used in patients in first CR. Further, reevaluation of the role of stem cell transplantation in AML in the context of emerging prognostic factors has changed the utility of HCT from a biologic allocation based on donor availability to a more risk-appropriate therapeutic allocation aimed at improving outcome while minimizing risk and toxicity. In this risk-based allocation to HCT, patients with

Acute Myelogenous Leukemia (AML)

Acute myelogenous leukemia (AML) is the second most common leukemia in children. The diagnosis of AML requires the presence of blasts (&gt;30%) in the bone marrow in most cases. The intensification of conventional chemotherapy along with improvements in supportive care has improved the prognosis in childhood AML. Instead, advances in the treatment of children with AML will require a greater understanding of the biology of the disease, with particular attention to the genetic abnormalities underlying leukemogenesis and drug resistance. In this review, we summarize recent studies that provide new insight into the genetics and biology of AML, discuss risk stratification and therapy for this disease, and profile some of the therapeutic agents currently under investigation.

Outcome of Transplantation for Acute Myelogenous Leukemia in Children with Down Syndrome

Data on outcomes of allogeneic transplantation in children with Down syndrome and acute myelogenous leukemia (DS-AML) are scarce and conflicting. Early reports stress treatment-related mortality as the main barrier; a recent case series points to posttransplantation relapse. We reviewed outcome data for 28 patients with DS-AML reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2009 and performed a first matched-pair analysis of 21 patients with DS-AML and 80 non-DS AML controls. The median age at transplantation for DS-AML was 3 years, and almost half of the cohort was in second remission. The 3-year probability of overall survival was only 19%. In multivariate analysis, adjusting for interval from diagnosis to transplantation, risks of relapse (hazard ratio [HR], 2.84; P < .001; 62% versus 37%) and transplant-related mortality (HR, 2.52; P = .04; 24% versus 15%) were significantly higher for DS-AML compared to non-DS AML. Overall mortality risk (HR, 2.86; P < .001; 21% versus 52%) was significantly higher for DS-AML. Both transplant-related mortality and relapse contribute to higher mortality. Excess mortality in DS-AML patients can only effectively be addressed through an international multicenter effort to pilot strategies aimed at lowering both transplant-related mortality and relapse risks.

Stress Hematopoiesis Reveals Abnormal Control of Self-Renewal, Lineage-Bias and Myeloid Differentiation in Mll Partial Tandem Duplication (Mll-PTD) Hematopoietic Stem/Progenitor Cells

AbstractAbstract 3501Rearrangements of the Mixed-Lineage Leukemia (MLL) gene occur in a variety of aggressive human leukemias. The most common ones are balanced translocations in which the genomic sequences encoding the N-terminal portion of MLL are fused to sequences encoding the C-terminus of another translocation partner in acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL). Another mechanism for disrupting the MLL gene in myelodysplastic syndrome (MDS) and AML, but rarely seen in ALL, is partial tandem duplication (MLL-PTD). The MLL–PTD was first identified in de novo AML with a normal karyotype or trisomy 11. Cloning of this region revealed partial duplications within the 5′ region of the MLL gene. These duplications consist of an in-frame repetition of MLL exons in a 5′–3′ direction and produce an elongated protein. The incidence of MLL–PTD was 8% in unselected adult and childhood AML and 5% in MDS. However, the mechanism by which MLL-PTD contributes to MDS and AML development and maintenance is currently unknown. Mll-PTD knock-in mouse model, its expression is regulated by endogenous promoter, has been generated to study the function of Mll-PTD in vitro and in vivo and to identify its downstream targets. This mouse model provides a powerful genetic tool to identify disruptions in normal cellular regulation as a result of this mutation, as well as a model to characterize the contribution of the Mll-PTD in leukemogenesis. Herein, we investigated hematopoietic stem/progenitor cell (HSPC) phenotypes of Mll-PTD knock-in mice. Although HSPCs (Lin−Sca1+Kit+ (LSK)/SLAM+ and LSK) in MllPTD/WT mice are reduced in absolute number in steady state due to increased apoptosis, they have a proliferative advantage in colony replating assays, CFU-spleen assays, and competitive transplantation assays over wild-type HSPCs. The MllPTD/WT–derived phenotypic short-term (ST)-HSCs/multipotent progenitors (MPPs) and granulocyte/macrophage progenitors (GMPs) have self-renewal capability, rescuing hematopoiesis by giving rise to long-term repopulating cells in recipient mice with an unexpected myeloid differentiation blockade and lymphoid-lineage bias. However, MllPTD/WT HSPCs never develop leukemia in primary or recipient mice, suggesting that additional genetic and/or epigenetic defects are necessary for full leukemogenic transformation. In conclusion, the MllPTD/WT mouse model provides unique genetic and biochemical tool to identify new targets and pathways responsible for the altered differentiation/repopulating properties, self-renewal activity, lineage bias and myeloid differentiation blockade relevant to MLL-PTD MDS and AML. This model should also help us to understand the underlying mechanism(s) for each of the phenotypes we found in this study and facilitate improved therapies and patient outcomes in the future. Disclosures:No relevant conflicts of interest to declare.

Analysis of Chromosomal Aberrations and FLT3 gene Mutations in Childhood Acute Myelogenous Leukemia Patients.

Objective: To identify the well-known common translocations and FLT3 mutations in childhood acute myelogenousleukemia (AML) patients in Turkey.Material and Methods: The study included 50 newly diagnosed patients in which t(15;17), t(8;21), and inv(16)chromosomal translocations were identified using real-time PCR and FLT3 gene mutations were identified via direct PCR amplification PCR-RE analysis.Results: In all, t(15;17) chromosomal aberrations were observed in 4 patients (8.0%), t(8;21) chromosomal aberrationswere observed in 12 patients (24.0%), inv(16) chromosomal aberrations were observed in 3 patients (6.0%), and FLT3-ITD mutations were observed in 2 patients (4.0%); FLT3-D835 point mutation heterozygosity was observed in only 1patient (2.0%) patient.Conclusion: Despite of the known literature, a patient with FLT3-ITD and FLT3-D835 double mutation shows a bettersurvival and this might be due to the complementation effect of the t(15;17) translocation. The reportedmutation ratein this article (4%) of FLT3 gene seems to be one of the first results for Turkish population.

A Phase I Study of Gemtuzumab Ozogamicin (GO) in Combination with Busulfan and Cyclophosphamide (Bu/Cy) and Allogeneic Stem Cell Transplantation in Children with Poor-Risk CD33 + AML: A New Targeted Immunochemotherapy Myeloablative Conditioning (MAC) Regimen

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study.

Cardiac Myeloid Sarcoma

Myeloid sarcomas are rare extramedullary tumors composed of immature myeloid cells. Most cases are seen in childhood acute myelogenous leukemia (AML). They can develop at many sites, but cardiac involvement is a rare finding. We report the case of a 24-year-old woman who, after being in remission from AML for 10 years, developed an isolated cardiac myeloid sarcoma.

Long-Term Outcome of Childhood Acute Myeloid Leukemia Treated in China

Intensive chemotherapy has greatly improved the long-term treatment outcome in children with acute lymphoblastic leukemia (ALL), however, children with de novo acute myelogenous leukemia (AML) remain much less favorable prognosis. Most reports were from western countries while data from Chinese children with AML have been very limited. In this study, we reported the long-term outcome and the prognostic factors of childhood AML treated with modified National Protocol of Childhood Leukemia in China 1997 (NPCLC-AML97) during the past 8 years in our institution. From January1997 to December 2005, 185 children younger than 16 years old with de novo AML were enrolled into our hospital. The NPCLC-AML97 protocol included induction therapy either of DA (daunorubicin + cytarabine), HA (homoharringtonine + cytarabine), DAE (daunorubicin + cytarabine + etoposide) or CAG (Clarithromycin + cytarabine + G-CSF). When CR achieved, the same cycle was repeated as consolidation therapy. Intensification therapy consisted of 3 cycles of intermediate or high dose of cytarabin (I/HDAC) every other month. During the intermission, DA, HA, EA (etoposide + cytarabine) were given. Maintenance therapy was given monthly by sequential HA, EA, AT (cytarabine + 6-mercaptopurine) cycles and I/HDAC was administered every 6 months. The total course was about 2.0~2.5 years from CR. Of the 185 patients, 49 were M3 and 136 were other subtypes. Sixty patients abandoned within the first two weeks after diagnosis, 2 died before chemotherapy, and 123 were eligible for protocol evaluation. The 7-year OS and EFS rates for the whole cohort were 33.1±4.1% and 31.2±3.7%, respectively. For eligible patients, 111 patients (90.2%) achieved CR (95.1% for M3 and 87.8% for non-M3, P = 0.334). With a median follow-up time of 69 months, 70 patients (56.9%) developed significant infection during chemotherapy, 31 patients relapsed and the 5-year cumulative relapse rate was 48.2±5.6% with a median relapse time of 12 (range from 3 to 56) months. No CNS relapse was found. Forty-one patients (33.3%) died in this cohort until data censored. Survival curve showed that the 3-year, 5-year and 7-year estimates of OS were 61.0±4.9%, 55.7±5.1% and 50.2±5.5%, whereas the EFS rates were 50.9±4.9%, 46.9±5.1% and 46.9±5.1%, respectively. M3 was more curable than non-M3 (7-year OS: 66.9±8.8% vs. 38.7±6.8%, P = 0.003; 7-year EFS: 63.5±7.9% vs. 35.9±6.3%, P = 0.005). Univariate analysis showed that superior outcome were favored by initial WBC count less than 100×109/L, M3 subtype, good response to therapy (attaining CR after one cycle of induction for non-M3 or within 30 days for M3), high expression of CD13 and CD33, negative expressions of CD14, CD34 and HLA-DR. And multivariate analysis showed that treatment response, initial WBC count and expression status of CD14 on the surface of leukemic cells were independent prognostic factors for long term survival. We conclude that high incidence of APL, high abandonment rate and low incidence of CNS relapse are the features in this cohort. Abandonment, relapse and infection are the main causes of treatment failure. For patients who adhere to the protocol, a relatively good outcome can be achieved.

Health-related quality of life (HR-QOL) and chronic health conditions (CHC) in survivors of childhood acute myelogenous leukemia (AML)

6590 Background: AML therapy has included chemotherapy with or without autologous stem cell transplantation or allogeneic hematopoietic stem cell transplantation (chemo±auto or alloBMT) based on the availability of a matched sibling donor. This allows unbiased comparison of HR-QOL outcomes between these groups. Methods: We surveyed 207 survivors of AML diagnosed before age 21 and treated from 1979 to 1995 on one of 4 COG protocols who survived ≥5 years from diagnosis. Survivors or proxy caregivers completed a CCSS baseline questionnaire and an age-appropriate measure of HR-QOL (SF-36, CHQ-87 or CHQ-PF50). Survivors with Down syndrome were excluded for this analysis. Results: Of the 182 survivors in this analysis, 128 underwent chemo±auto and 54 underwent alloBMT. Median age at diagnosis was 4 years (range, 0 to 20); median age at enrollment was 20 (range 8 to 39). HR-QOL scores were similar among groups and to the normative population (Physical component score: chemo±auto mean 50.8 vs. alloBMT 49.7, p=0.43; mental component score: chemo±auto 49.8 vs. alloBMT 52.0, p=0.20; normative score 50, SD 10). Differences remained insignificant in adjusted analyses. For children ages 12–13 years and children ages 11 and younger, scores were also similar among groups. With regard to chronic health conditions (CHC), in the chemo±auto group, 47% had at least one CHC compared with 76% in the alloBMT group (OR: 3.5, 95% CI: 1.6- 7.6). Twenty-one percent had a severe or life-threatening CHC (chemo±auto16% vs. 33% alloBMT; OR 2.6, 95% CI: 1.2–5.7). One-fourth had ≥3 CHC (chemo±auto17% vs. 40% alloBMT: OR: 3.2, 95% CI: 1.5–7.0). Nearly all (95%) reported that their health was excellent, very good or good. Less than 10% in each group reported activity limitations, functional impairment and/or cancer-related pain. Conclusions: Scores on the HR-QOL measures were similar between treatment groups; however, alloBMT survivors reported more frequent and severe chronic health conditions. No significant financial relationships to disclose.

Expression of components of the IGF axis in childhood acute myelogenous leukemia

Insulin-like growth factor (IGF) system as regulator for cellular proliferation is of particular interest in search for new prognostic approaches in cancer treatment. We analyzed the mRNA expression profile of IGF-I, -II, and IGFBP-2, -3 in 50 children with previously untreated AML (mean age 10.8 +/- 4.8 years; patients in CCR n = 20, patients with relapse during later course of disease n = 15). MNC samples from peripheral blood as well as bone marrow of healthy donors were used as controls. IGFBP-2 expression was significantly higher in AML cells than in healthy cells of peripheral MNC (P < 0.001) and of bone marrow cells (P < 0.01). Conversely, AML cells showed significantly lower IGFBP-3 and IGF-I gene expression compared to controls (P = 0.02; P < 0.001). Patients with relapse (median +/- range: 0.0929 +/- 0.049) during later course of disease demonstrated higher IGFBP-2 expression compared to patients in CCR (0.0121 +/- 0.047; P = 0.06) at time of diagnosis. A multivariate analysis identified the IGFBP-2 mRNA expression as an independent factor for the prediction of relapse. Furthermore, the probability of relapse-free survival (RFS) in patients with IGFBP-2 mRNA level >0.1000 was 28%; whereas, the probability of RFS in patients with IGFBP-2 mRNA level <0.1000 was 62% (P = 0.04, log-rank test). No prognostic influence could be found for the other investigated genes. Results identified different expressions of IGF components between normal and AML cells. Patients with IGFBP-2 mRNA levels up to 0.1000 (relative to KG1 cell line) more likely developed a relapse. Identification of these patients at diagnosis may allow more individualized treatment.

Is Age an Independent Risk Factor for Chemically Induced Acute Myelogenous Leukemia in Children?

Secondary or therapy-related acute myelogenous leukemia (t-AML) is a rare but unfortunate consequence of treatment with certain classes of cytotoxic chemotherapeutic agents or chronic exposure to high concentrations of benzene. Drugs known to produce AML following chemotherapy of primary malignancy are usually alkylating agents or topoisomerase II inhibitors. Both children and adults develop AML following treatment with these classes of antineoplastic drugs. In this review, the effect of age at treatment on a child's susceptibility to developing therapy related AML was investigated. The clinical literature describing pediatric cancer patients treated with cytotoxic chemotherapeutic agents was used to characterize risk factors associated with chemical leukemogenesis in children. As demonstrated in the published literature, the risk of developing AML following chemotherapy is not reliably correlated with the age of the pediatric patient. There is no consistent evidence that indicates that younger children will be at increased risk; in fact, some studies suggest that younger children might actually display a decreased susceptibility. The age dependency of treatment-related malignancies (all types) in children appears to vary considerably with the type of secondary neoplasm in question. For example, secondary solid tumors such as breast, central nervous system (CNS), bone, and thyroid cancer are highly dependent on the age of the patient at time of diagnosis and treatment; in contrast, an age dependency for t-AML risk was not observed in these same patient populations. Predictably, the induction of t-AML in children follows a rational dose-response relationship, with increasing doses of chemotherapy resulting in greater risk. Recent U.S. Environmental Protection Agency (EPA) cancer risk assessment guidance recommends a default assumption that children are inherently up to 10-fold more sensitive than adults to carcinogen exposures. Available scientific and medical literature does not support the hypothesis that children necessarily possess an increased risk of developing AML following leukemogenic chemical exposure.

Extramedullary infiltration at diagnosis and prognosis in children with acute myelogenous leukemia

Extramedullary infiltration (EMI) is an occasional clinical symptom in childhood acute myelogenous leukemia (AML), but there is considerable controversy regarding the prognostic significance of EMI in AML. We evaluated the frequency and prognostic significance of EMI at diagnosis of AML in children. Of 240 cases of de novo AML excluding children with Down syndrome and acute promyelocytic leukemia, 56 (23.3%) showed EMI at diagnosis. Patients with EMI had a higher initial WBC count and a higher proportion of M4/M5 morphological variants. The complete remission rate following induction chemotherapy was lower in patients with EMI. However, the overall survival and event-free survival did not differ between patients with and without EMI. A detailed analysis showed that patients with EMI with a WBC count at diagnosis of over 100 x 10(9)/L or infiltration into the central nervous system are likely to have a poor prognosis. CNS leukemia and EMI together with a WBC count of >100 x 10(9)/L at diagnosis of AML are high risk factors for relapse, and alternative treatment approaches for patients with these characteristics should be explored.

Risk factors for acute leukemia in children: a review.

Although overall incidence is rare, leukemia is the most common type of childhood cancer. It accounts for 30% of all cancers diagnosed in children younger than 15 years. Within this population, acute lymphocytic leukemia (ALL) occurs approximately five times more frequently than acute myelogenous leukemia (AML) and accounts for approximately 78% of all childhood leukemia diagnoses. Epidemiologic studies of acute leukemias in children have examined possible risk factors, including genetic, infectious, and environmental, in an attempt to determine etiology. Only one environmental risk factor (ionizing radiation) has been significantly linked to ALL or AML. Most environmental risk factors have been found to be weakly and inconsistently associated with either form of acute childhood leukemia. Our review focuses on the demographics of childhood leukemia and the risk factors that have been associated with the development of childhood ALL or AML. The environmental risk factors discussed include ionizing radiation, non-ionizing radiation, hydrocarbons, pesticides, alcohol use, cigarette smoking, and illicit drug use. Knowledge of these particular risk factors can be used to support measures to reduce potentially harmful exposures and decrease the risk of disease. We also review genetic and infectious risk factors and other variables, including maternal reproductive history and birth characteristics.

IDENTIFICATION OF NOVEL GENES WITH PROGNOSTIC VALUE IN CHILDHOOD LEUKEMIA USING cDNA MICROARRAY AND QUANTITATIVE RT-PCR

The aim of this study was to identify genes distinctively expressed or suppressed in childhood leukemia with different prognoses, using cDNA microarray and quantitative reverse transcription–polymerase chain reaction (RT-PCR). The expression levels of the selected genes by cDNA microarray were quantified in primary leukemic blasts from 44 patients (acute lymphoblastic leukemia, 28; acute myelogenous leukemia (AML), 13; transient myeloproliferative disorder, 3). The expression levels of CDKN2C, CRADD, and IGFBP-2 genes were significantly associated with the event-free survival of the patients in AML. The present results suggest that a combination of cDNA microarray and quantitative RT-PCR may be useful to identify novel genes with prognostic value in childhood AML.

Quality of Life in Survivors of Childhood and Adolescent Acute Myelogenous Leukemia (AML) Does Not Differ by Treatment (Bone Marrow Transplant (BMT) vs. Chemotherapy). A Report from the Children's Oncology Group (COG).

Childhood and adolescent AML requires intensive therapy. Beginning in 1979, the Childrens Cancer Group (CCG) randomized patients with newly-diagnosed AML to allogeneic bone marrow transplantation (alloBMT) based solely on the availability of an HLA-identical sibling donor. Two decades of successive CCG trials using a similar design have shown a significant survival advantage for alloBMT. To determine whether BMT was associated with a diminished quality of life (QOL) in long-term survivors compared to those who had been treated with chemotherapy alone (chemo), we conducted a cross-sectional telephone survey study of AML survivors. To be eligible, survivors must have been enrolled on a CCG AML study (beginning in 1979), have survived at least five years, and reside in the US or Canada. QOL was measured using the Medical Outcomes Study Short Form 36 (SF-36) and the Child Health Questionnaire (CHQ). 206 survivors completed the study, including 124 treated with chemo, 54 treated with alloBMT and 28 treated with autologous BMT (autoBMT). Median age at diagnosis was 3 years (range, 0–20), median age at survey was 19 years (range 8–39) and median time from diagnosis was 13.4 years. 48% were male, and 87% were white. QOL summary scores for the 82 survivors treated with BMT did not differ from those of the 124 treated with chemo (see table). Also, the adjusted summary scores did not differ by treatment after adjustment for other factors, such as age at diagnosis, race, gender, relapse, etc. None of the physical or mental SF-36 or CHQ subscale domains significantly differed by treatment, although physical subscale domains trended to be better in the chemo group. Multivariate analyses found that females had significantly lower physical and mental scores, that relapse significantly diminished the physical summary score, and that age at diagnosis was positively and significantly associated with higher mental summary score. Our data suggest that survivors of childhood and adolescent AML have similar overall QOL scores, regardless of whether they were treated with BMT or chemo. In addition, the QOL scores in most physical and mental health domains were high, suggesting that AML survivors as a group enjoyed good QOL. These data suggest that QOL in long-term survivors is not diminished by BMT and that the primary concern in assigning treatment remains survival.QOL Summary ScoresTreatmentPhysical ScoreMental ScoreMean95% CIp-valueMean95% CIp-valueAll49.3(48.0,50,7)49.9(48.4,51.3)BMT (n=82)49.0(46.8,51.1)0.6851.3(49.0,53.6)0.11Chemo (n=124)49.6(47.8,51.3)48.9(47.0,50.8)