Therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) is a long-term complication of pediatric cancer. We retrospectively studied pediatric t-MDS/AML patients treated at MD Anderson from 1975 to 2007. We also compared those patients to pediatric patients with de novo MDS/AML during this time interval. Among 2589 children with cancer treated at MD Anderson, we identified 22 patients with t-MDS/AML. Patients with t-MDS/AML had a median age of 14 years. There was a male and Hispanic predominance. The most common primary malignancies were osteosarcoma and Hodgkin lymphoma. The median latency period was 4.1 years. Three patients received supportive care only. Group 1 (n=5) underwent stem cell transplantation without induction chemotherapy. Group 2 (n=5) patients received AML-type chemotherapy and a stem cell transplant postremission (n=5). Group 3 (n=4) received a stem cell transplant as salvage therapy. The respective 2-year survival rates for groups 1, 2, and 3 were 20%, 40%, and 25% (P=0.85). Patients with de novo AML were younger (P=0.001) and higher rates of complete remission (P=0.03), and survival (P<0.0001). Independent factors predicting shorter survival were poor/intermediate-risk cytogenetics (P=0.01), lower hemoglobin level (P=0.0001), and t-MDS/AML (vs. de novo) (P=0.003). Childhood t-MDS/AML has a poor prognosis. Although patients benefited from AML-type induction chemotherapy followed by stem cell transplantation as postremission therapy, effective therapies, and prevention are needed.
*Division of Pediatrics
Departments of ‡Investigational Cancer Therapeutics
¶Leukemia, The University of Texas MD Anderson Cancer Center
†Department of Internal Medicine, The University of Texas Medical School at Houston, TX
♯Department of Pediatrics, Division of Hematology/Oncology and Transplantation, Children's Memorial Hospital and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL
Sources of Support: Seth J. Corey is supported by grants RO1-CA108922, AA/MDS Foundation, and JP McCarthy Development Fund.
Financial Disclosures: none.
Dolly G. Aguilera, Christos Vaklavas, and Apostolia M. Tsimberidou contributed equally to this manuscript.
Reprints: Seth J. Corey, MD, MPH, Department of Pediatrics, Division of Hematology/Oncology and Transplantation, Children's Memorial Hospital and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Lurie 5-107, 303 East Superior Street, Chicago, IL 60611 (e-mail: firstname.lastname@example.org).
Received for publication November 12, 2008
accepted July 31, 2009
Therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/AML) is a well-recognized complication of cancer treatment in adults. The major factors contributing to t-MDS/AML are exposure to alkylating agents, epipodophyllotoxin, and radiation therapy. Cases of t-MDS/AML have occurred in children and adolescents diagnosed with Hodgkin lymphoma (HL), non-Hodgkin lymphoma, Ewing sarcoma, osteosarcoma, medulloblastoma, and acute lymphoblastic leukemia (ALL).1–4
Current studies indicate that 1 in 900 adults younger than 45 years of age is a pediatric cancer survivor.5 Continued improvement in therapies is expected to increase the number of survivors at risk for late sequelae. In 1987, the incidence of pediatric t-MDS/AML was estimated at 1%.6 The frequency varies on the basis of the primary cancer and/or treatment regimen. Higher incidences (4% to 6%) have been found in etoposide-treated patients with HL or ALL.7,8 The risk for second cancers in pediatric ALL patients increased during the last 30 years, but the histologic type of these cancers was more often epithelial than hematopoietic.9 In a single-institution study, it was found that most myeloid second malignancies occurred within 5 years of initial diagnosis.9
Previous studies were either multi-institutional and were centered on 1 treatment protocol or single institutional and focused on 1 primary disease. We, therefore, retrospectively analyzed pediatric patients with t-MDS/AML seen at MD Anderson Cancer Center during a 32-year time period. The study objectives were to determine the number of patients diagnosed with t-MDS/AML, describe the clinical characteristics and outcomes of t-MDS/AML, and compare the treatment outcomes of pediatric patients with t-MDS/AML to those of pediatric patients with de novo MDS/AML.
MATERIALS AND METHODS
We searched databases of the Department of Pediatrics [leukemia, solid tumors, and stem cell transplantation (SCT)] at The University of Texas MD Anderson Cancer Center for patients registered from January 1975 to December 2007. Search criteria were age <21 years at the time of the first cancer, with a history of solid tumor, leukemia, or lymphoma and subsequent development of t-MDS/AML. We reviewed all available patient medical records to identify clinical and pathologic characteristics such as initial cancer diagnosis, age at time of initial tumor occurrence, sex, ethnicity, treatment for primary cancer, latency period, age at time of diagnosis of t-MDS/AML, complete blood counts at diagnosis of t-MDS/AML, percentage of bone marrow blasts, bone marrow cytogenetics findings, Zubrod performance status,10 t-MDS/AML treatment, and clinical outcomes. A waiver of informed consent and authorization were granted by the institutional review board.
L. Jeffrey Medeiros (hematopathologist) confirmed the diagnosis of t-MDS/AML after reviewing the relevant slides of bone marrow aspirate smears and biopsy sections (if performed), immunophenotypic data, and/or pathology reports. t-MDS/AML was classified according to a pediatric modification of the World Health Organization classification system.11 Conventional cytogenetic studies were performed on bone marrow aspirate material using standard G-banding techniques. Twenty metaphases were analyzed.
Endpoints and Statistical Methods
Response to treatment for patients with therapy-related and de novo AML was assessed using the International Working Group criteria.12 Complete remission (CR) was defined using standard criteria: no morphologic evidence of AML, including evidence of normal erythropoiesis, granulopoiesis, and megakaryocytopoiesis, and ≤5% blasts in bone marrow aspirate smears, an absolute neutrophil count >1×109/L, and platelets ≥100×109/L. Response to the treatment for t-MDS and de novo MDS was determined by following the International Working Group guidelines.13
The latency period was defined as the time from the diagnosis of primary cancer to the diagnosis of t-MDS/AML. Differences in the latency period among patients treated with different treatment modalities were calculated using a Wilcoxon's rank-sum test. Overall survival was measured from diagnosis of t-MDS/AML to death from any cause or last follow-up. Characteristics and outcomes of patients with t-MDS/AML were compared with those of patients with de novo MDS/AML registered during the same time period. A Cox regression model was fitted for survival, in which cytogenetics, age, performance status, leukocyte counts, platelet counts, hemoglobin level, and diagnosis (t-MDS/AML vs. de novo MDS/AML) were included. Statistical analyses were carried out using S Plus 2000 (Insightful Corp, Seattle, WA). P values were derived from 2-sided tests and were significant if <0.05.
Incidence of t-MDS/AML at MD Anderson Cancer Center
Overall, 2717 patients were recorded in the 3 databases in the Division of Pediatrics including primary and referred patients. Owing to database overlap, the number was adjusted after 128 patients were counted only once to a final number of 2589 unique patients. Among 2589 patients, we identified 22 (0.85%) patients with t-MDS/AML. During a 32-year period (1975 to 2007), there was a statistically significant increase in the frequency of children diagnosed with t-MDS/AML (P=0.001 in Cochran-Armitage trend test, Fig. 1). However, over the past decade, there has been no increase, suggesting that the frequency of t-MDS/AML has stabilized.
The clinical and laboratory characteristics of the 22 patients with t-MDS/AML are summarized in Table 1. The median age at diagnosis was 14 years (range: 3 to 20). There were 15 males (68%) and 7 females (32%). Distribution by ethnicity was Hispanic (59%), White (23%), African American (13%), and Asian (5%). Distribution by ethnicity of primary diagnosis patients included Whites (57%), Hispanics (31%), and African Americans (9%).
The primary cancer diagnoses were osteosarcoma in 5 patients (23%), HL in 4 (18%), precursor B-cell lymphoblastic leukemia/lymphoma in 4 (18%), brain tumors in 3 (14%), precursor T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) in 2 (9%), Ewing sarcoma in 2 (9%), neuroblastoma in 1 (5%), and rhabdomyosarcoma in 1 (5%). One of the 4 patients with a history of B-ALL also had neurofibromatosis, type-1. There were 10 cases of with t-MDS and 12 cases of t-AML. During the same time period, the number of patients seen at the institution with the above diagnoses, and the proportion of patients who developed t-MDS/AML was as follows: osteosarcoma, n=580, proportion t-MDS/t-AML 0.8%; HL n=268, 1.4%; ALL n=780, 0.7%; Ewing sarcoma n=230, 0.8%; MB n=125, 0.8%; GBM n=57, 1.7%; neuroblastoma n=158, 0.6%; and rhabdomyosarcoma n=210, 0.4%.
Therapy for Primary Cancers
The primary cancers were treated with several modalities that consisted of alkylating agents, epipodophyllotoxin, or anthracyclines with or without radiation therapy. Of 22 patients, 20 (93%) had received prior therapy for their primary cancer with alkylating agents, 18 (81%) with etoposide and anthracyclines, and 9 (41%) with radiation therapy. Seven (31%) of 22 patients received all the 3 treatment modalities. The mean radiation dose was 2297 cGy. Treatment regimens for the primary diagnosis are shown in Table 2.
Conventional cytogenetic analysis performed on bone marrow aspirates demonstrated deletion (del) of chromosome 7 in 10 patients (45%), t(9;11) in 4 patients (18%), and the following abnormalities in 1 patient each: t(8;21), del(6), del(9), del(11q23), inv(11), inv(9), and t(7;11). None of the available specimens had normal cytogenetics. The 10 patients with del(7) had all received prior therapy with alkylating agents; and 2 of 4 patients who had t(9;11) had received etoposide. For 1 patient, no cytogenetic studies were available.
The median latency period was 4.1 years (range: 1 to 9.9). Latency period by diagnosis is shown in Table 1. The median latency period for the 4 patients whose first cancer was B-cell lymphoblastic leukemia/lymphoma was 3.6 years, compared with a median of 4 years for the remaining 18 patients (P=0.89). In addition, when all 22 patients were considered, the latency periods from time of treatment with alkylating agents, etoposide, or radiation therapy were 4.2, 3.4, and 4.3 years, respectively.
Induction Therapy for t-MDS/AML
Nineteen (86%) patients received chemotherapy for t-MDS/AML: AML-type induction chemotherapy (n=14) or allogeneic SCT (n=5). Among the patients who received induction chemotherapy, 11 (57%) were treated with cytarabine and an anthracycline, with or without etoposide. One patient each received cytarabine and fludarabine, cytarabine and interferon, and azacytidine and bevacizumab. Each of the 5 patients (3 MDS and 2 AML) who underwent allogeneic SCT received a different conditioning regimen: cyclophosphamide and busulfan; fludarabine and busulfan; busulfan and thiotepa; cyclophosphamide, 5-azacytidine and total body irradiation (TBI); fludarabine, cyclophosphamide, anti-thymyocyte globulin, and clorafabine. Three (13%) patients, seen between 1980 and 1996, received only supportive care. The overall CR rate with either induction chemotherapy or SCT was 36% (n=7). Of the patients who achieved CR with induction therapy, 6 received AML-type induction chemotherapy and 1 received a conditioning regimen with cyclophosphamide and busulfan before SCT.
One patient who underwent SCT as induction therapy has remained with a CR for 6.3 years. Of the 6 patients who achieved CR with induction chemotherapy, 1 patient, treated with chemotherapy alone, achieved remission and completed 5 additional cycles of chemotherapy with daunomycin, cytarabine, etoposide, 6-thioguanine, and dexamethasone. This patient is disease-free and alive for >9.6 years after the t-MDS/AML diagnosis. The remaining 5 patients underwent consolidation therapy with SCT. One patient each received: TBI, cyclophosphamide, thiotepa, and ATG; fludarabine, melphalan, TBI; thiotepa, fludarabine, melphalan, ATG; thiotepa, cyclophosphamide, and busulfan. One treatment regimen was unknown.
A total of 14 (63%) patients had SCT. Five patients underwent SCT as induction therapy. Five patients underwent SCT as postremission therapy, and 4 patients underwent allogeneic SCT as salvage therapy. Details of patients who underwent SCT after AML-type chemotherapy are listed in Table 3. Response and survival for patients who underwent SCT are included in Table 4. All SCTs were myeloablative and allogeneic (1 haploidentical from father, 3 allogeneic-matched from siblings, 10 matched unrelated donors). Sources of stem cells were as follows: peripheral blood 4, umbilical cord blood 4, and bone marrow 7. One patient underwent a double allogeneic transplant (bone marrow and peripheral blood).
Time from diagnosis of t-MDS/AML to SCT ranged from 2 to 17 months (median, 4). After transplant, 6 (43%) patients with t-MDS/AML were in remission, 2 (14%) were lost to follow-up and 6 (43%) patients had relapsed. Of the 6 patients who achieved CR after transplant, 4 received SCT as consolidation therapy, 1 achieved CR after receiving SCT for salvage therapy, and 1 received SCT as an induction regimen.
The median follow-up (from diagnosis of t-MDS/AML to last follow-up) of surviving patients was 9.5 years (range: 6.3 to 10.8). Nineteen (86%) patients have died, and 3 patients remain alive at 6.3+, 9.6+, and 10.8+ years after the diagnosis of t-MDS/AML. The characteristics of the 3 long-term survivors were as follows: 1 survivor with an initial diagnosis of T-LBL/ALL developed t-MDS and received allogeneic SCT as induction therapy. He is alive and disease-free for >6.3 years after the diagnosis of t-MDS. The second survivor had HL, followed by t-MDS. He received induction therapy with AML-type chemotherapy, failed to achieve CR, and underwent SCT as salvage therapy. The conditioning regimen was thiotepa, busulfan, and cyclophosphamide. He is alive and disease-free for >10.8 years after the onset of t-MDS. The third survivor initially had T-LBL/ALL followed by a diagnosis of t-AML. Her treatment consisted of chemotherapy alone and achieved a CR. She received 5 additional cycles of chemotherapy. The patient has survived >9.6 years since her diagnosis of AML.
There was 1 induction therapy-related death because of sepsis and multiorgan failure. The most common causes of death were progressive disease (n=7), respiratory failure (n=3), and multiorgan failure/sepsis (n=4).
The primary cancer was in remission at the time of death or last follow-up in 20 patients, and had relapsed in 2 patients (metastatic osteosarcoma and medulloblastoma). The status of t-MDS/AML at the time of death or last follow-up was as follows: relapse in 13 (59%) patients, remission in 7 (32%), and data not available for 2 other patients.
The overall survival (OS) of the 22 patients by type of treatment for their t-MDS/AML is shown in Figure 2A. OS by disease (t-MDS or t-AML) is shown in Figure 2B. The median OS for patients who underwent induction with AML-type chemotherapy, SCT, or supportive care was 1 year, 0.5 years, and 0.2 years, respectively (Fig. 2C, log-rank test, P=0.03). At 1-year, the estimated cumulative survival rates were 50% for AML-type induction chemotherapy, 40% for induction with SCT, and 0% for supportive care.
Survival by disease status at the time of SCT is illustrated in Figure 2D. Overall, 14 patients underwent SCT as induction (n=5), postremission (in CR) (n=5), or salvage therapy (n=4). At 2 years, the estimated cumulative survival rates were 20%, 40%, and 25%, respectively, but the survival curves of the postremission and salvage treatment groups crossed over (log-rank test, P=0.85).
Comparison With De Novo MDS/AML
During this period of time, 141 patients with de novo MDS/AML were identified. Comparison of presenting characteristics and outcomes between patients with t-MDS/AML and those with de novo AML or MDS is shown in Table 5. Patients with t-MDS/AML were older than patients with newly diagnosed MDS/AML (P=0.001), and they had lower rates of CR (P=0.028) and survival (P<0.0001) (Table 5 and Fig. 3). When a Cox regression model was fitted for survival, in which diagnosis (t-MDS/AML vs. de novo MDS/AML) was included in the model, independent factors predicting shorter survival were poor or intermediate-risk cytogenetics [relative risk (RR), 4.72, P=0.01], lower hemoglobin levels (RR=1.24, continuous variable; P=0.0001), t-MDS/AML (RR 2.58, P=0.003), and older age (RR=1.05, continuous variable; P=0.056) (Table 6).
In this retrospective analysis, the proportion of children and adolescents diagnosed with t-MDS/AML among those treated for cancer was 0.85%. Several findings of this study are of particular interest. Firstly, the most common primary cancers were osteosarcoma, followed by HL and ALL/LBL. Secondly, there was a male and Hispanic predominance. Thirdly, a trend toward an increased number of patients with t-MDS/AML was noted during the past 32 years but its frequency has stabilized in the past decade. Fourthly, patients with de novo MDS/AML were younger (P=0.001) and had higher rates of CR (P=0.03) and survival (P<0.0001). More importantly, a Cox regression analysis showed that the adverse impact of t-MDS/AML on survival was independent of cytogenetic abnormalities or hemoglobin levels. Lastly, there was no survival difference between t-MDS and t-AML (P=0.37), with a median survival of fewer than 11 months. Patients benefited from AML-type induction chemotherapy followed by allogeneic SCT.
We found a disproportionate number of male and Hispanic patients in our series. Almost all case reports of pediatric t-MDS/AML fail to discuss sex or ethnicity (unpublished data, Christos Vaklavas and Seth Corey). Before our review, 1 letter suggested a high incidence of secondary AML in Hispanic children.14 Patients with t-MDS/AML treated on Children's Cancer Group protocol 2891 (1989 to 1999) showed a similar male proportion (71% vs. 68% in our series).15 That report also noted that a higher proportion of patients were Hispanic, but the association did not achieve statistical significance. The United States census estimated that Hispanics comprised 9% of the total population in 1990 and 12.5% in 2000.16 Although most of our patients come from Texas, Hispanics (58% in our series) represented 25.5% and 32% of the Texas population in the 1990 census and 2000 census.17 Bias in referral population cannot completely explain the male and Hispanic predominance. Host factors, that is, obesity or genetic polymorphisms affecting drug clearance found among the Hispanic population18–21 may predispose these pediatric patients to t-MDS/AML. A retrospective review of body mass index and survival in Children's Cancer Group-2961 showed poorer outcome owing to increased treatment-related mortality among the obese, although the underlying mechanism is unknown.22
In contrast to previous studies, we found that the most common primary cancer was osteosarcoma, followed by HL and ALL/LBL. Our observed proportion of osteosarcoma-associated t-MDS/AML was 23%. Interestingly, patients with osteosarcoma had primary lower-extremity disease without macroscopic metastasis at the time of t-MDS/AML. Patients with metastatic disease may not survive long enough to develop t-MDS/AML. It is unknown whether patients with metastatic osteosarcoma are at higher risk for t-MDS/AML than patients with non-metastatic disease because of the intensity and number of chemotherapy treatments they undergo. Surveillance and Endpoint Epidemiology Research data show that the excess absolute risk of second cancers among osteosarcoma patients was reported to be 15, lower than that observed for Ewing sarcoma patients, which was 44.23 In our study, the latency period for patients with osteosarcoma was 2.6 years (range: 2.3 to 8.9), similar to that previously reported by other investigators.24 Those investigators observed that leukemia was the most common secondary malignancy in osteosarcoma survivors.
In our study, patients with Ewing sarcoma had a median latency period of 15.5 months, as reported by other investigators who also attributed the increased risk of t-MDS/AML in Ewing sarcoma to exposure to higher doses of alkylating agents and doxorubicin.2
The t-MDS/AML has been previously reported to be resistant to conventional chemotherapy regimens.25 We too found a poorer prognosis where 63% of the t-MDS/AML patients failed to achieve CR in induction versus 33% of the de novo MDS/AML group (P=0.028). The survival rates in this study are comparable with 2 previously reported studies in pediatric and adult patients.21–23 In one of these studies, prolonged survival was noted in 1 of 17 patients with chemotherapy and in 3 of 16 with SC.26 Respective figures for the second study were 1 of 4 and 2 of 10 patients.22 Additionally, a remission-induction rate of 92% has been reported in pediatric patients with epipodophyllotoxins-associated t-MDS/AML who had a favorable cytogenetic profile.21
In this study, there was no difference in survival between t-MDS and t-AML. These data also support the combined diagnosis of t-MDS and t-AML in the World Health Organization classification. Other investigators reported that a higher percentage of blasts at the time of SCT correlated with the risk of relapse.24 However, our study did not demonstrate a statistically significant difference regarding survival from the time of SCT either as induction, postremission or as a salvage therapy, but the number of patients was small, precluding robust analyses. In addition, some patients may develop t-MDS/AML after age 21 years. The databases include consecutive patients with pediatric cancer seen at MD Anderson, so it is possible that some patients developed t-MDS/AML at a later age and did not return to MD Anderson or they were lost to follow-up and the incidence of t-MDS/AML could be higher.
In conclusion, our results suggest that patients with t-MDS/AML benefit from AML-type induction chemotherapy followed by SCT as postremission therapy. Until more effective antileukemic therapies are developed, more effort should be directed toward identifying host risk factors that predispose children to t-MDS/AML.
The authors express their gratitude to Dr Lynne V. Abruzzo for her assistance in retrieving cytogenetic reports, Dr Norman Jaffe for his comments, Dr Hillary Mowbray and Maha Boktour for their assistance, and Drs Joann Ater and Laura Worth for access to the patient databases.
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
therapy-related MDS; AML; late effects