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Mortality in Overweight and Underweight Children With Acute Myeloid Leukemia

Mortality in Overweight and Underweight Children With Acute Myeloid Leukemia ContextCurrent treatment for acute myeloid leukemia (AML) in children cures about half the patients. Of the other half, most succumb to leukemia, but 5% to 15% die of treatment-related complications. Overweight children with AML seem to experience excess life-threatening and fatal toxicity. Nothing is known about how weight affects outcomes in pediatric AML.ObjectiveTo compare survival rates in children with AML who at diagnosis are underweight (body mass index [BMI] ≤10th percentile), overweight (BMI ≥95th percentile), or middleweight (BMI = 11th-94th percentiles).Design, Setting, and ParticipantsRetrospective review of BMI and survival in 768 children and young adults aged 1 to 20 years enrolled in Children’s Cancer Group-2961, an international cooperative group phase 3 trial for previously untreated AML conducted August 30, 1996, through December 4, 2002. Data were collected through January 9, 2004, with a median follow-up of 31 months (range, 0-78 months).Main Outcome MeasuresHazard ratios (HRs) for survival and treatment-related mortality.ResultsEighty-four of 768 patients (10.9%) were underweight and 114 (14.8%) were overweight. After adjustment for potentially confounding variables of age, race, leukocyte count, cytogenetics, and bone marrow transplantation, compared with middleweight patients, underweight patients were less likely to survive (HR, 1.85; 95% confidence interval [CI], 1.19-2.87; P = .006) and more likely to experience treatment-related mortality (HR, 2.66; 95% CI, 1.38-5.11; P = .003). Similarly, overweight patients were less likely to survive (HR, 1.88; 95% CI, 1.25-2.83; P = .002) and more likely to have treatment-related mortality (HR, 3.49; 95% CI, 1.99-6.10; P<.001) than middleweight patients. Infections incurred during the first 2 courses of chemotherapy caused most treatment-related deaths.ConclusionTreatment-related complications significantly reduce survival in overweight and underweight children with AML.Each year in the United States, 500 to 600 individuals younger than 21 years develop acute myeloid leukemia (AML).Current treatment for AML typically consists of 3 or 4 courses of intensive, myelosuppressive chemotherapy with or without bone marrow transplantation from a histocompatible family donor. This therapy cures about half the children with AML; of the other half, most succumb to AML-related causes, but 5% to 15% die from toxic effects of treatment.Factors that predict treatment failure and death in AML are relatively older age and higher white blood cell (WBC) count at diagnosis, a slow response to the first course of chemotherapy,and, in the United States, black race and absence of a histocompatible family member to donate marrow for transplantation.Children’s Cancer Group (CCG)-2961 was a phase 3 international cooperative group trial for pediatric patients with untreated AML. It was the impression of investigators (J.F., B.J.L.) on this trial that overweight children and adolescents experienced more toxicity and death than did the other patients. This observation prompted the following retrospective investigation of effects of body mass index (BMI) on survival and treatment-related mortality.METHODSCCG-2961 opened on August 30, 1996, and closed on December 4, 2002. Patients from birth through age 20 years were enrolled after institutional review board approval of each participating institution and written informed consent. Patients with Down syndrome, Fanconi anemia, acute promyelocytic leukemia, acute undifferentiated leukemia, or treatment-related AML were excluded from the study. The trial accrued 902 patients with de novo AML. Thirty patients without outcome data and 104 infants younger than 1 year were excluded from this analysis, leaving 768 patients.AML was classified according to French-American-British criteria.Morphology, histochemistry, and karyotype were centrally reviewed as described.Cytogenetic subsets were classified as normal, favorable [t(8;21); t(9;11) or (inv 16)], unfavorable [del(7) or 7q-], or standard.Figure 1illustrates the treatment plan for CCG-2961. Course 1 consisted of idarubicin, dexamethasone, cytarabine, thioguanine, and etoposide on days 0 to 3 and daunorubicin plus the last 4 drugs on days 10 to 13. Patients in complete or partial remission were randomized to course 2 therapy. Complete remission was defined as less than 5% marrow blasts, with recovery of neutrophils to greater than 1000 × 109/L and platelets to greater than 50 000 × 103/μL, and partial remission was defined as 5% to less than 30% marrow blasts. Course 2 consisted of a repetition of induction therapy (regimen A) or fludarabine, idarubicin, and cytarabine (regimen B).After course 2, patients in complete remission and with a histocompatible relative able to donate marrow were assigned to marrow transplantation; those without donors were assigned high-dose cytarabine/L-asparaginase chemotherapy.Patients in remission after course 3 chemotherapy were randomized to standard follow-up or to interleukin 2.All patients received central nervous system prophylaxis with 8 doses of intrathecal cytarabine. Granulocyte colony-stimulating factor was given on day 14 ± 1 of courses 1 and 2 and continued until the absolute neutrophil count (ANC) was at least 1000 × 109/L.All systemic chemotherapy was given in the hospital.Figure 1.Treatment Plan for CCG-2961Details of therapy are in the ”Methods” section and in Barnard et al10and Lange et al.11GCSF indicates granulocyte colony-stimulating factor.Data entered onto study forms were abstracted from the medical record. They included age, sex, ethnicity, height and weight before each phase of therapy, doses of chemotherapeutic agents, toxicities, infectious complications, duration of hospitalization, and time to neutrophil recovery to 500 × 109/L and 1000 × 109/L. Treating physicians or nurses classified the individual’s race and ethnicity. Drug dosing was based on weight in kilograms up to age 3 years and by surface area thereafter. Dose modifications were provided for hyperbilirubinemia and after May 2001 for reduced glomerular filtration or creatinine clearance. There were no dose modifications for underweight or overweight patients.Body mass index at diagnosis was calculated as weight in kilograms divided by the square of the height in meters.For patients older than 2 years, underweight was defined as BMI less than or equal to the 10th percentile, overweight as BMI greater than or equal to the 95th percentile, and middleweight as BMI greater than the 10th to less than the 95th percentile (11th-94th percentiles). For patients aged 1 to 2 years, greater than or equal to the 95th percentile and less than or equal to the 10th percentile of weight for length were used to define overweight and underweight, respectively.The main outcome measures were remission status after courses 1 and 2 of chemotherapy, overall survival, and treatment-related mortality. Survival was defined as time from registration to death. Treatment-related mortality was defined as time until death from causes other than AML, censoring for progressive disease, relapse, and failure to enter remission after 2 courses of therapy. Patients lost to follow-up were censored at their last known date of contact. Patients in marrow remission (<5% marrow blasts) but without recovery of peripheral counts were censored at the end of course 2. Toxicity grades 3 and 4 were defined by contemporary CCG toxicity grading criteria with protocol-specific modifications to capture details of anticipated gastrointestinal and hematopoietic toxicity.This report analyzes data collected through January 9, 2004, with a median follow-up of 31 months and a range of 0 to 78 months. To compensate for the tendency for bad news (ie, deaths and relapses) to be reported sooner than ongoing follow-up for patients in continuing remission, events such as deaths and relapses were censored on July 9, 2003, 6 months before data cutoff. The Kaplan-Meier method was used to calculate survival estimates. Confidence intervals (CIs) were calculated according to the Greenwood formula. Hazard ratio (HR) of overweight and underweight patients relative to middleweight patients was estimated by Cox proportional hazards models. Hazard ratio was also estimated with multivariate Cox proportional hazards models after adjustment for standard variables that predict outcomes in AML (black vs other race), age (<2 years, 2 to ≤ 10 years, and >10 years), cytogenetics, and WBC count (<50 000 vs ≥50 000 × 109/L), as well as bone marrow transplantation. Multivariate analysis included patients with complete covariate data.Cumulative incidence of neutrophil recovery was estimated by considering death before recovery as a competing event. Cumulative incidence of completing course 1 in remission was estimated by considering disease progression and death before course completion as competing events. Significance of observed differences in proportions was tested using the &khgr;2test and Fisher exact test when data were sparse. For continuous data, the Mann-Whitney test compared medians of distributions. P≤.05 was set as the threshold for significance.RESULTSOf 768 patients at diagnosis, 114 (14.8%) were overweight and 84 (10.9%) underweight. Table 1lists demographic features of overweight, middleweight, and underweight patients, characteristics of their AML, and their treatment assignments. The 3 BMI groups did not differ significantly in distribution by sex, ethnicity or race, or the proportion of patients with incomplete data. Compared with middleweight patients, overweight patients had higher leukocyte counts (P = .001), were marginally more likely to have unfavorable marrow cytogenetics (P = .01), were less likely to have a related marrow donor for marrow transplantation (P = .05), but were equally likely to actually undergo transplantation (9/10 vs 91/106). Underweight patients were younger (P = .04) and more commonly had unfavorable marrow cytogenetics (P = .048).Table 1.Demographics and Disease Characteristics According to Body Mass Index of Patients With De Novo AML*Overweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)PValueOverweight vs MiddleweightUnderweight vs MiddleweightAge, median (range), y11.2 (1.3-19.0)11.0 (1.0-19.8)9.6 (1.1-19.7).44.04Male sex, No. (%)62 (54)299 (53)45 (54).78.94Race, No. (%)White67 (60)378 (68)57 (69).18.93Black16 (14)46 (8)7 (8).06.88Hispanic19 (17)100 (18)13 (16).96.74Asian1 (1)20 (4)3 (4).23>.99Other8 (7)16 (3)3 (4).04.73Unknown3101White blood cell count, median (range), × 109/L27.9 (0.7-860)17.7 (0.5-684)13.9 (1.2-418)<.001.59Morphology, No. (%)FAB M08 (7)31 (6)3 (4).69.61FAB M122 (19)94 (17)17 (21).61.50FAB M237 (33)175 (31)19 (23).89.16FAB M425 (22)118 (21)26 (31).94.05FAB M516 (14)91 (16)14 (17).65.99FAB M6016 (3)2 (2).09>.99FAB M76 (5)27 (5)2 (2).97.57Other08 (1)0.36.61Unknown0101Marrow cytogenetics, No. (%)†Normal14 (22)91 (25)9 (18).74.32Favorable27 (43)127 (35)21 (41).30.49Unfavorable6 (10)8 (2)4 (8).01.048Standard16 (25)136 (38)17 (33).09.67Unknown5120833Treatment, No. (%)‡Phase 2Regimen A44 (46.8)245 (48.2)34 (50.7).89.80Regimen B45 (47.9)249 (49.0)30 (44.8).93.60Phase 3Related donor10 (15.6)106 (28.1)20 (42.6).05.06Received transplant9 (14.1)91 (24.1)16 (34.0).11.20Received cytarabine53 (82.8)268 (71.1)26 (55.3).07.04Phase 4Interleukin 218 (54.5)88 (49.2)8 (47.1).71.93Follow-up15 (45.5)91 (50.8)9 (52.9).71.93Abbreviations: BMI, body mass index; FAB, French-American-British classification.*Numbers and percentages include only those with data.†Cytogenetic results were available for 62% of patients.‡Treatment is shown in Figure 1.Table 2shows the response to therapy for the 3 BMI groups. In course 1, there were no differences in the early response rate as measured by the day 14 marrow blast percentage or in treatment failure rate. There was a trend for a reduced remission rate and an increased death rate among overweight patients, whereas the underweight patients showed a definite reduction in remission rate and increase in death rate. At the end of course 2, compared with middleweight patients, overweight patients were significantly more likely to die (17% vs 5%, P = .001). The actuarial survival after study enrollment of underweight and overweight patients was inferior to that of middleweight patients (Figure 2).Figure 2.Kaplan-Meier Plot of Actuarial Survival According to BMI From Time of Study EntryBMI indicates body mass index.Table 2.Response to Therapy and Events and Outcomes According to BMIOutcomeNo. (%)PValueOverweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)Overweight vs MiddleweightUnderweight vs MiddleweightBlasts in marrow on day 14, %<577 (81)400 (84)60 (85)≥518 (19)79 (16)11 (15).67.97Unknown*199113At end of course 1Remission94 (85)508 (91)67 (82).07.02Treatment failure9 (8)28 (5)6 (7).28.42Death8 (7)23 (4)9 (11).24.02At end of course 2Remission64 (82)377 (89)47 (87).15.89Treatment failure1 (1)25 (6)3 (6).10>.99Death13 (17)23 (5)4 (7).001.53Abbreviation: BMI, body mass index.*Not all patients had day 14 marrow results reported.After course 1, the univariate HR for treatment-related mortality was significantly increased in the overweight patients (HR, 2.12; 95% CI, 1.37-3.28; P = .001) and the underweight patients (HR, 1.80; 95% CI, 1.06-3.06; P = .03) compared with the middleweight patients (Table 3). Survival from study entry was reduced in the overweight patients (HR, 1.47; 95% CI, 1.09-1.98; P = .01) and the underweight patients (HR, 1.42; 95% CI, 1.00-2.03; P = .05). From the end of course 2, there were no differences in survival among the 3 groups or in relapse rates or treatment-related mortality.Table 3.Univariate and Multivariate Hazard Ratios for Survival and Treatment-Related Mortality According to BMI PercentileHazard Ratio (95% CI)PValueOverweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)Overweight vs MiddleweightUnderweight vs MiddleweightUnivariate AnalysisFrom study entrySurvival1.47 (1.09-1.98)1.001.42 (1.00-2.03).01.05Treatment-related mortality2.12 (1.37-3.28)1.001.80 (1.06-3.06).001.03From the end of course 2Survival1.13 (0.71-1.81)1.001.26 (0.72-2.20).61.42Treatment-related mortality1.18 (0.45-3.08)1.001.02 (0.31-3.39).74.97Relapse risk0.97 (0.62-1.53)1.001.35 (0.83-2.19).89.23Multivariate Analysis*From study entryOverall survival1.88 (1.25-2.83)1.001.85 (1.19-2.87).002.006Treatment-related mortality3.49 (1.99-6.10)1.002.66 (1.38-5.11)<.001.003From the end of course 2(n = 35)(n = 245)(n = 26)Overall survival1.39 (0.73-2.66)1.001.22 (0.58-2.54).32.61Treatment-related mortality2.75 (0.96-7.89)1.001.37 (0.31-6.05).06.68Relapse risk0.67 (0.34-1.36)1.000.89 (0.42-1.86).27.75Abbreviations: BMI, body mass index; CI, confidence interval.*Hazard ratios are calculated for the patients who have complete data for all variables of interest. Adjusted for age, white blood cell count, race, cytogenetics, and bone marrow transplantation.Table 3shows the multivariate analysis of HR for survival and treatment-related mortality adjusted for age, race, WBC count, cytogenetics, and allogeneic bone marrow transplantation for the patients with complete data for the 5 variables. After adjustment, overweight and underweight groups were still less likely to survive than middleweight patients, and HR for treatment-related mortality was even higher than in univariate analysis.Table 4lists deaths according to when they occurred and attribution of cause. Compared with middleweight patients, overweight and underweight patients were more likely to die before or during their first remission (P = .002 and P = .047, respectively). In all groups, infection was the most common cause of death before or during remission. After recurrence of AML, the most common cause of death was AML itself in all 3 groups.Table 4.Causes of DeathNo. (%)PValueOverweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)Overweight vs MiddleweightUnderweight vs MiddleweightDeaths before or during remission30 (26)78 (14)19 (23).002.047AML related1 (1)5 (1)2 (2)>.99.22Treatment related29 (25)73 (13)17 (20).001.09Infection20 (18)44 (8)13 (15).002.04Hemorrhage4 (4)3 (1)3 (4).02.03Toxicity2 (2)9 (2)0 (0)>.99.61Graft-vs-host disease0 (0)6 (1)0 (0).60>.99Other3 (3)11 (2)1 (1).71>.99Relapse38 (33)205 (36)33 (39).67.64Deaths after relapse28 (25)135 (24)19 (23).81.89AML related16 (14)72 (13)9 (11).65.72Treatment related12 (11)63 (11)10 (12)>.99.85Infection9 (8)37 (6)2 (2).54.21Hemorrhage2 (2)8 (1)0 (0).68.61Toxicity0 (0)2 (0)3 (4)>.99.02Graft-vs-host disease1 (1)8 (1)1 (1)>.99>.99Other0 (0)8 (1)4 (40).36.06Abbreviations: AML, acute myeloid leukemia; BMI, body mass index.Excessive treatment-related mortality suggests that overweight and underweight patients could be receiving too much chemotherapy. To address this issue, first we examined the doses of protocol therapy actually received. Then we compared toxicity grades 3 and 4, time to neutrophil recovery, and duration of course as indirect measures of drug effect on normal marrow. Of 768 patients, 10 received less than or equal to 90% of dosing of course 1 therapy according to square meters: in 6 (1 underweight, 1 overweight, and 4 middleweight) of these 10 patients, doses were reduced according to protocol guidelines for hyperbilirubinemia. Four overweight patients received reduced doses calculated to fall between their actual weight and their ideal body weight. Overweight patients were significantly more likely to have a dose reduction than middleweight patients: 4.8% vs 0.7% (P = .006).Toxicity grades 3 and 4 were assessed from a menu of 45 clinical and laboratory parameters. Compared with middleweight patients, more overweight patients experienced grade 3 or 4 abdominal pain (P = .05), systolic hypertension (P = .02), pulmonary function abnormalities (P = .03), and coagulopathy (P<.001), whereas more underweight patients experienced grade 3 or 4 elevations of hepatic enzymes (alanine aminotransferase, P = .01; and aspartate aminotransferase, P = .04).Death from infection increases in direct proportion to the magnitude and duration of neutropenia.Hematologic toxicity was probably the most relevant complication for this study. Important landmarks for assessing neutropenia are time to an ANC of 500 × 109/L (the time when empirical antibiotics are typically discontinued) and time to an ANC of 1000 × 109/L (the time when the patient may be able to begin the next chemotherapy course). Within 5 weeks of the start of therapy, 79.5% of middleweight patients who continued to course 2 had an ANC of greater than or equal to 500 × 109/L, which was not different from the 87.2% of overweight patients (P = .11) or 77.6% (P = .84) of underweight patients. At 7 weeks, the respective proportions were 97.2%, 98.9%, and 100%. The time to recovery of ANC of 1000 × 109/L after the start of course 1 for the 3 groups was plotted (Figure 3): overweight and middleweight patients had significantly faster neutrophil recovery than underweight patients (P = .004).Figure 3.Kaplan-Meier Plots of the Cumulative Incidence of Recovery to an Absolute Neutrophil Count of at Least 100 000 × 109/L According to BMI and Cumulative Incidence of Entry to Course 2BMI indicates body mass index.The time to complete a course of therapy was another indicator of toxicity. Figure 3shows duration of course 1 in the 3 groups: there was no significant difference in the duration of the course. When patients who had dose reductions were excluded, the relative positions of the 3 groups were unchanged.COMMENTThis study shows that overweight and underweight children and adolescents with AML are less likely to survive than patients with BMI in the 11th through 94th percentiles. Inferior survival in both extreme BMI groups is attributable to early treatment-related mortality, and treatment-related mortality is mostly from infection. Although there is already substantial evidence that underweight children with acute lymphoblastic leukemia and solid tumors experience increased relapses and reduced survival,this is the first study to our knowledge to show excess mortality in overweight pediatric cancer patients.These results contrast with those in most adult cancers in which underweight patients have no excess mortality and overweight patients have excess cancer-related death rather than death from excessive toxicity.One notable exception is marrow transplantation: 3 studies show excess mortality in obese adults from a combination of relapse and treatment-related mortalityor treatment-related mortality alone.Dickson et al28also found that underweight patients experienced higher treatment-related mortality. Marrow transplantation and contemporary AML therapy have in common dose-intensive chemotherapy complicated by a relatively high baseline treatment-related mortality that is exaggerated among underweight and overweight patients.Malnutrition is associated with advanced disease, lower socioeconomic status, immunodeficiency, increased number and spectrum of infections, reduced access to care, and delays in diagnosis.Even after adjustment for socioeconomic status, malnutrition continues to be associated with poor outcome. Malnutrition in children reduces absorption, decreases drug-protein binding, and impedes oxidative and other metabolic reactions. These effects increase half-life, reduce clearance, and impair glomerular filtration of drugs.They also augment toxicity.There is no information about the pharmacology of cancer chemotherapy in underweight patients. Busulfan is the only drug for which there is dosing information according to weight or BMI distribution in children.Malnutrition reduces survival in children with cancer in direct proportion to the extent of their malnutrition.Correction of nutritional status improves outcomes.Thus, it would seem reasonable to determine whether delaying therapy to initiate nutritional supplementation and correction of immunodeficiency is possible, and if correction is possible, to determine whether it improves outcome.There is no obvious solution to the problem of excess treatment-related mortality in overweight patients. The data concerning neutrophil recovery and duration of course do not support the hypothesis that overweight patients in this study received too much chemotherapy. There are few traditional pharmacologic studies of bioavailability of chemotherapeutic agents in obese adults and none in overweight children or adolescents. Several small studies have investigated bioavailability of cyclophosphamide, ifosfamide, doxorubicin, and its metabolite doxorubicinol as single agents.Combination chemotherapy has been investigated in 1 obese patient: compared with normal-weight patients, she showed a substantially increased concentration over time for 4-hydroxy cyclophosphamide, thiotepa, and carboplatinum.Because in general these pharmacologic studies show a trend for reduced clearance and longer half-lives of chemotherapeutic agents, they seem to contradict studies of antibiotics in obese adults in which hyperfiltration increases clearance.Because most recent studies show reduced rather than excessive toxicity among obese individuals, today the consensus is that obese adult cancer patients receive too little rather than too much chemotherapy.In this study, overweight patients experienced more severe abdominal pain, hypertension, pulmonary dysfunction, and coagulopathy. Unfortunately, the information collected does not indicate when these toxicities occured, how long they lasted, or whether they contributed to death or reflected end-stage deterioration. Comorbidities such as these increase risk of death in adult cancer patients with febrile neutropenia, so they may be important in these patients.Overweight patients can also manifest subtle immunologic abnormalities that could contribute to excess infectious death.In 1970, Wiernik and Serpick40described 8 morbidly obese patients among 106 adults with AML. None of the 8 patients survived longer than 1.75 months compared with a median survival of 3.5 months for the whole study. These authors postulate that subclinical diabetes, difficulties in performing thorough physical examinations, or nuances in carrying out routine nursing care could contribute to early demise.This study has the limitations of a retrospective study: CCG-2961 was not designed to investigate BMI as a variable. Some findings, such as the proportion of overweight and underweight patients with donors for marrow transplantation, may be spurious. The study does not illuminate the causes of excess infectious treatment-related mortality. There are no socioeconomic data. All assessments pertain to weight at diagnosis; it was not possible to determine whether weight gain in underweight patients or weight loss in overweight patients improved outcomes after the first course. Finally, it is likely that the observation of excessive treatment-related mortality in overweight patients will be reproducible only in pediatric cancers that involve extremely dose-intensive chemotherapy or marrow transplantation studies as in obese adults.The effect of BMI on outcome in pediatric AML is not a trivial problem: the reduced survival in underweight and overweight patients is roughly equal to the improved survival accomplished by 10 years of progress in pediatric AML. Treatment-related mortality is the worst possible outcome for an individual enrolled in a clinical trial, and if treatment-related mortality is not countered by a net gain in survival, excess treatment-related mortality is also the worst possible outcome for a clinical trial. These results have implications for clinicians and clinical investigators. This is the first example of immediate rather than impending life-shortening effects of excess weight in the young and a confirmation of the risks of undernutrition in other pediatric cancers.Interventions currently available that could reduce the treatment-related mortality in underweight and overweight groups include formal nutritional and immunologic assessment at diagnosis. Underweight patients could benefit from preemptive nutritional intervention or intravenous γ-globulin. In overweight patients, correction of persistent moderate hyperglycemia and hypertension may remediate 2 important comorbidities. Maintaining blood glucose concentration between 80 and 120 mg/dL appears to reduce mortality in patients in intensive care units.However, systematic changes in management should take place as part of controlled studies. Basic pharmacokinetic and pharmacodynamic studies of chemotherapeutic drug disposition in underweight and overweight patients are likely to provide a rational basis for dosing. Until such information is available, it is impossible to know whether doses of chemotherapy should be reduced. Dose reduction is likely to lead to increased relapse, but relapse is the lesser of 2 evils. It is also possible that dose reduction increases relapse and has no effect on toxic mortality. Finally, technologists, nurses, and physicians should examine whether overweight patients are receiving suboptimal care because of difficulties in assessing them, as suggested by Wiernik and Serpick.If that is the case, then it must be determined as to how to change practice to overcome these barriers.Corresponding Author:Beverly J. Lange, MD, Division of Oncology, Children&apos;s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104 (lange@email.chop.edu).Author Contributions: Drs Lange and Alonzo had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Lange, Feusner, Skolnik, Sacks, Smith, Alonzo.Acquisition of data: Lange, Feusner, Sacks, Smith, Alonzo.Analysis and interpretation of data: Lange, Gerbing, Feusner, Skolnik, Smith, Alonzo.Drafting of the manuscript: Lange, Gerbing, Skolnik, Sacks, Smith, Alonzo.Critical revision of the manuscript for important intellectual content: Lange, Feusner, Skolnik, Sacks, Smith, Alonzo.Statistical analysis: Lange, Gerbing, Skolnik, Alonzo.Obtained funding: Lange.Administrative, technical, or material support: Lange, Feusner, Skolnik, Sacks, Smith.Study supervision: Lange, Feusner, Smith.Funding/Support:This study was supported by grants CA098543 and CA098413 from the National Institutes of Health (NIH) from 2000 to 2004 and NIH U-10 grants listed at http://www.childrensoncologygroup.org/admin/grantinfo.htmfrom 1996 to 2000. Dr Lange was supported by the Yetta Dietch Novotny Chair in Clinical Oncology. Chiron provided interleukin 2 to the National Cancer Institute (NCI), which provided interleukin 2 to the institutions.Role of the Sponsors:The Children’s Cancer Group (CCG) was funded by an NIH U-10 grant to perform clinical trials and correlative biology studies and epidemiologic studies in childhood cancer. CCG-2961 was designed by the CCG-2961 Study Committee, which Dr Lange chaired. The Committee reported to the CCG-AML Strategy Group. The design and conduct of the study were reviewed by a data and safety monitoring board composed of CCG and non-CCG cooperative group investigators, an ethicist, a lay member, and representatives of the Clinical Trials Evaluation Program of the NCI, who were nonvoting members. Primary patient data were obtained by nurses and physicians; most were CCG members who were not compensated by CCG for their work. Clinical research associates, supported fully or in part by the CCG institutional grant, abstracted the data and transmitted them to the CCG Operations office, Arcadia, Calif. Dr Lange received copies of all data capture forms. Primary data analyses were performed by Dr Alonzo and Mr Gerbing, CCG statisticians. The interpretation of the data was the primary responsibility of these 2 statisticians and Dr Lange, with all authors participating substantially in the interpretation of the data. All authors except Dr Skolnik, Ms Sacks, and Mr Gerbing were members of the CCG-2961 committee. In 2000, CCG and 3 other groups conducting clinical research in pediatric oncology fused to become the Children’s Oncology Group (COG). The manuscript was sent to COG for final review by the COG editor, Shaun Mason. Submission of the manuscript by Mr Mason to the journal constitutes approval of the manuscript by COG. Chiron had no role in the design, conduct, or analysis of the study.Acknowledgment:We thank Christine Curran for typing the manuscript and Shaun Mason, BA, for editorial support.REFERENCESMSmithLGloecker RiesJGurneyJRossLeukemia SEER Pediatric Monograph.Vol 1999. Bethesda, Md: National Cancer Institute; 1999LCRileyIMHannKWheatleyRFStevensTreatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10): the MCR Childhood Leukaemia Working Party.Br J Haematol199910643644410460604UCreutzigMZimmermannJRitterDefinition of a standard-risk group in children with AML.Br J Haematol199910463063910086807WGWoodsSNeudorfSGoldA comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherpay in children with acute myeloid leukemia in remission.Blood200197566211133742SCRaimondiMNChangYRavindranathChromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative Pediatric Oncology Group Study: POG 8821.Blood1999943707371610572083KWheatleyAKBurnettAHGoldstoneA simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial: United Kingdom Medical Research Council&apos;s Adult and Childhood Leukaemia Working Parties.Br J Haematol1999107697910520026WGWoodsBJLangeFOSmithTAAlonzoResponse: a comparison of allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy in pediatric acute myeloid leukemia.Blood20019736743675MASekeresBPetersonRKDodgeCancer and Leukemia Group B (CALGB)Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia.Blood20041034036404214976037JMBennettDCatovskyMTDanielCriteria for the diagnosis of acute leukemia of megakaryoctye lineage (M7).Ann Intern Med19851034604622411180DRBarnardDKKalousekSRWiersmaMorphologic, immunologic and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Children&apos;s Cancer Group.Leukemia1996105128558938BJLangePDinndorfFOSmithPilot study of idarubicin-based intensive timing induction therapy for children with previously untreated acute myeloid leukemia in Children&apos;s Cancer Group (CCG) Study 2941.J Clin Oncol20042215015614701777PADinndorfVIAvramisSWiersmaPhase I/II study of idarubicin given with continuous infusion fludarabine followed by continuous infusion cytarabine in children with acute leukemia: a report from the Children&apos;s Cancer Group.J Clin Oncol199715278027859256119TAAlonzoNLKobrinskyAAledoImpact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children&apos;s Cancer Group.J Pediatr Hematol Oncol20022462763512439034CLOgdenRJKuczmarksiKMFlegalCenters for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version.Pediatrics2002109458011773541GPBodeyMBuckleyYSSatheEJFreireichQuantitative relationships between circulating leukocytes and infection in patients with acute leukemia.Ann Intern Med1966643283405216294ELobato-MendizabalGJRuiz-ArguellesAMarin-LopezLeukaemia and nutrition, I: malnutrition is an adverse prognostic factor in the outcome of treatment of patients with standard-risk acute lymphoblastic leukaemia.Leuk Res1989138999062586144MBVianaMMuraoGRamosMalnutrition as a prognostic factor in lymphoblastic leukaemia: a multivariate analysis.Arch Dis Child1994713043107979521DGomez-AlmaguerGJRuiz-ArguellesSPonce-de-LeonNutritional status and socio-economic conditions as prognostic factors in the outcome of therapy in childhood acute lymphoblastic leukemia.Int J Cancer Suppl19981152559876479SSDonaldsonMNWesleyWDDeWysRMSuskindNJaffeJvanEysA study of the nutritional status of pediatric cancer patients.Am J Dis Child1981135110711127315806EECalleKCRodriguezKWalker-ThurmondMJThunOverweight, obesity and mortality from cancer in a prospectively studied cohort of U.S. adults.N Engl J Med20033481625163812711737JBastarracheaGNHortobagyiTLSmithSWKauAUBuzdarObesity as an adverse prognostic factor for patients receiving adjuvant chemotherapy for breast cancer.Ann Intern Med199412018258250452MSGeorgiadisSMSteinbergLAHankinsDCIhdeBEJohnsonObesity and therapy-related toxicity in patients treated for small-cell lung cancer.J Natl Cancer Inst1995873613667853417PPoikonenCBlomqvistHJoensuuEffect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area.Acta Oncol200140677111321664JAMeyerhardtPJCatalanoDGHallerInfluence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma.Cancer20039848449512879464GLRosnerJBHargisDRHollisRelationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from Cancer and Leukemia Group B Study 8541.J Clin Oncol199614300030088918498DRFlemingMKRayensJGarrisonImpact of obesity on allogeneic stem cell transplant patients: a matched case-controlled study.Am J Med19971022652689217595GMeloniAProiaSCapriaObesity and autologous stem cell transplantation in acute myeloid leukemia.Bone Marrow Transplant20012836536711571508TMDicksonCRKusnierz-GlazKGBlumeImpact of admission body weight and chemotherapy dose adjustment on the outcome of autologous bone marrow transplantation.Biol Blood Marrow Transplant1999529930510534060ELobato MendizabalGJRuiz-ArguellesLeukemia and malnutrition, III: effect of chemotherapeutic treatment on the nutritional state and its repercussion on the therapeutic response of patients with acute lymphoblastic leukemia with standard risk.Sangre (Barc)1990351891952396166DJMurryLRivaDGPoplackImpact of nutrition of pharmacokinetics of anti-neoplastic agents.Int J Cancer Suppl1998(11)48519876478LLDupuisMNajdovaEFSaundersRetrospective appraisal of busulfan dose adjustment in children.Bone Marrow Transplant2000261143114711149723GPowisPReeceDLAhmannJNIngleEffect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients.Cancer Chemother Pharmacol1987202192223315280MJLindJMMargisonTCernyNThatcherPMWilkinsonProlongation of ifosfamide elimination half-life in obese patients due to altered drug distribution.Cancer Chemother Pharmacol1989251391422557169KARodvoldDARushingDATewksburyDoxorubicin clearance in the obese.J Clin Oncol19886132113273411343MEDe JongeRAMathotSMVan DamJHBeijnenSRodenhuisExtremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin.Cancer Chemother Pharmacol20025025125512203108RABlouinJHKolpekHJMannInfluence of obesity on drug disposition.Clin Pharm198767067143315402JATalcottRFinbergRJMayerLGoldmanThe medical course of cancer patients with fever and neutropenia: clinical identification of a low-risk subgroup at presentation.Arch Intern Med1988148256125683196123DRCottamPASchaeferGWShaftanLDAngusDysfunctional immune-privilege in morbid obesity: implications and effect of gastric bypass surgery.Obes Surg200313495712630613DRCottamPASchaeferDFahmyGWShaftanLDAngusThe effect of obesity on neutrophil Fc receptors and adhesion molecules (CD16, CD11b, CD62L).Obes Surg20021223023511975218PHWiernikAASerpickFactors effecting remission and survival in adult acute nonlymphocytic leukemia (ANLL).Medicine1970495055135286084Gvan den BerghePWoutersFWeekersIntensive insulin therapy in the critically ill patients.N Engl J Med20013451359136711794168 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Mortality in Overweight and Underweight Children With Acute Myeloid Leukemia

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American Medical Association
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Copyright 2005 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.
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0098-7484
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1538-3598
DOI
10.1001/jama.293.2.203
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15644547
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Abstract

ContextCurrent treatment for acute myeloid leukemia (AML) in children cures about half the patients. Of the other half, most succumb to leukemia, but 5% to 15% die of treatment-related complications. Overweight children with AML seem to experience excess life-threatening and fatal toxicity. Nothing is known about how weight affects outcomes in pediatric AML.ObjectiveTo compare survival rates in children with AML who at diagnosis are underweight (body mass index [BMI] ≤10th percentile), overweight (BMI ≥95th percentile), or middleweight (BMI = 11th-94th percentiles).Design, Setting, and ParticipantsRetrospective review of BMI and survival in 768 children and young adults aged 1 to 20 years enrolled in Children’s Cancer Group-2961, an international cooperative group phase 3 trial for previously untreated AML conducted August 30, 1996, through December 4, 2002. Data were collected through January 9, 2004, with a median follow-up of 31 months (range, 0-78 months).Main Outcome MeasuresHazard ratios (HRs) for survival and treatment-related mortality.ResultsEighty-four of 768 patients (10.9%) were underweight and 114 (14.8%) were overweight. After adjustment for potentially confounding variables of age, race, leukocyte count, cytogenetics, and bone marrow transplantation, compared with middleweight patients, underweight patients were less likely to survive (HR, 1.85; 95% confidence interval [CI], 1.19-2.87; P = .006) and more likely to experience treatment-related mortality (HR, 2.66; 95% CI, 1.38-5.11; P = .003). Similarly, overweight patients were less likely to survive (HR, 1.88; 95% CI, 1.25-2.83; P = .002) and more likely to have treatment-related mortality (HR, 3.49; 95% CI, 1.99-6.10; P<.001) than middleweight patients. Infections incurred during the first 2 courses of chemotherapy caused most treatment-related deaths.ConclusionTreatment-related complications significantly reduce survival in overweight and underweight children with AML.Each year in the United States, 500 to 600 individuals younger than 21 years develop acute myeloid leukemia (AML).Current treatment for AML typically consists of 3 or 4 courses of intensive, myelosuppressive chemotherapy with or without bone marrow transplantation from a histocompatible family donor. This therapy cures about half the children with AML; of the other half, most succumb to AML-related causes, but 5% to 15% die from toxic effects of treatment.Factors that predict treatment failure and death in AML are relatively older age and higher white blood cell (WBC) count at diagnosis, a slow response to the first course of chemotherapy,and, in the United States, black race and absence of a histocompatible family member to donate marrow for transplantation.Children’s Cancer Group (CCG)-2961 was a phase 3 international cooperative group trial for pediatric patients with untreated AML. It was the impression of investigators (J.F., B.J.L.) on this trial that overweight children and adolescents experienced more toxicity and death than did the other patients. This observation prompted the following retrospective investigation of effects of body mass index (BMI) on survival and treatment-related mortality.METHODSCCG-2961 opened on August 30, 1996, and closed on December 4, 2002. Patients from birth through age 20 years were enrolled after institutional review board approval of each participating institution and written informed consent. Patients with Down syndrome, Fanconi anemia, acute promyelocytic leukemia, acute undifferentiated leukemia, or treatment-related AML were excluded from the study. The trial accrued 902 patients with de novo AML. Thirty patients without outcome data and 104 infants younger than 1 year were excluded from this analysis, leaving 768 patients.AML was classified according to French-American-British criteria.Morphology, histochemistry, and karyotype were centrally reviewed as described.Cytogenetic subsets were classified as normal, favorable [t(8;21); t(9;11) or (inv 16)], unfavorable [del(7) or 7q-], or standard.Figure 1illustrates the treatment plan for CCG-2961. Course 1 consisted of idarubicin, dexamethasone, cytarabine, thioguanine, and etoposide on days 0 to 3 and daunorubicin plus the last 4 drugs on days 10 to 13. Patients in complete or partial remission were randomized to course 2 therapy. Complete remission was defined as less than 5% marrow blasts, with recovery of neutrophils to greater than 1000 × 109/L and platelets to greater than 50 000 × 103/μL, and partial remission was defined as 5% to less than 30% marrow blasts. Course 2 consisted of a repetition of induction therapy (regimen A) or fludarabine, idarubicin, and cytarabine (regimen B).After course 2, patients in complete remission and with a histocompatible relative able to donate marrow were assigned to marrow transplantation; those without donors were assigned high-dose cytarabine/L-asparaginase chemotherapy.Patients in remission after course 3 chemotherapy were randomized to standard follow-up or to interleukin 2.All patients received central nervous system prophylaxis with 8 doses of intrathecal cytarabine. Granulocyte colony-stimulating factor was given on day 14 ± 1 of courses 1 and 2 and continued until the absolute neutrophil count (ANC) was at least 1000 × 109/L.All systemic chemotherapy was given in the hospital.Figure 1.Treatment Plan for CCG-2961Details of therapy are in the ”Methods” section and in Barnard et al10and Lange et al.11GCSF indicates granulocyte colony-stimulating factor.Data entered onto study forms were abstracted from the medical record. They included age, sex, ethnicity, height and weight before each phase of therapy, doses of chemotherapeutic agents, toxicities, infectious complications, duration of hospitalization, and time to neutrophil recovery to 500 × 109/L and 1000 × 109/L. Treating physicians or nurses classified the individual’s race and ethnicity. Drug dosing was based on weight in kilograms up to age 3 years and by surface area thereafter. Dose modifications were provided for hyperbilirubinemia and after May 2001 for reduced glomerular filtration or creatinine clearance. There were no dose modifications for underweight or overweight patients.Body mass index at diagnosis was calculated as weight in kilograms divided by the square of the height in meters.For patients older than 2 years, underweight was defined as BMI less than or equal to the 10th percentile, overweight as BMI greater than or equal to the 95th percentile, and middleweight as BMI greater than the 10th to less than the 95th percentile (11th-94th percentiles). For patients aged 1 to 2 years, greater than or equal to the 95th percentile and less than or equal to the 10th percentile of weight for length were used to define overweight and underweight, respectively.The main outcome measures were remission status after courses 1 and 2 of chemotherapy, overall survival, and treatment-related mortality. Survival was defined as time from registration to death. Treatment-related mortality was defined as time until death from causes other than AML, censoring for progressive disease, relapse, and failure to enter remission after 2 courses of therapy. Patients lost to follow-up were censored at their last known date of contact. Patients in marrow remission (<5% marrow blasts) but without recovery of peripheral counts were censored at the end of course 2. Toxicity grades 3 and 4 were defined by contemporary CCG toxicity grading criteria with protocol-specific modifications to capture details of anticipated gastrointestinal and hematopoietic toxicity.This report analyzes data collected through January 9, 2004, with a median follow-up of 31 months and a range of 0 to 78 months. To compensate for the tendency for bad news (ie, deaths and relapses) to be reported sooner than ongoing follow-up for patients in continuing remission, events such as deaths and relapses were censored on July 9, 2003, 6 months before data cutoff. The Kaplan-Meier method was used to calculate survival estimates. Confidence intervals (CIs) were calculated according to the Greenwood formula. Hazard ratio (HR) of overweight and underweight patients relative to middleweight patients was estimated by Cox proportional hazards models. Hazard ratio was also estimated with multivariate Cox proportional hazards models after adjustment for standard variables that predict outcomes in AML (black vs other race), age (<2 years, 2 to ≤ 10 years, and >10 years), cytogenetics, and WBC count (<50 000 vs ≥50 000 × 109/L), as well as bone marrow transplantation. Multivariate analysis included patients with complete covariate data.Cumulative incidence of neutrophil recovery was estimated by considering death before recovery as a competing event. Cumulative incidence of completing course 1 in remission was estimated by considering disease progression and death before course completion as competing events. Significance of observed differences in proportions was tested using the &khgr;2test and Fisher exact test when data were sparse. For continuous data, the Mann-Whitney test compared medians of distributions. P≤.05 was set as the threshold for significance.RESULTSOf 768 patients at diagnosis, 114 (14.8%) were overweight and 84 (10.9%) underweight. Table 1lists demographic features of overweight, middleweight, and underweight patients, characteristics of their AML, and their treatment assignments. The 3 BMI groups did not differ significantly in distribution by sex, ethnicity or race, or the proportion of patients with incomplete data. Compared with middleweight patients, overweight patients had higher leukocyte counts (P = .001), were marginally more likely to have unfavorable marrow cytogenetics (P = .01), were less likely to have a related marrow donor for marrow transplantation (P = .05), but were equally likely to actually undergo transplantation (9/10 vs 91/106). Underweight patients were younger (P = .04) and more commonly had unfavorable marrow cytogenetics (P = .048).Table 1.Demographics and Disease Characteristics According to Body Mass Index of Patients With De Novo AML*Overweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)PValueOverweight vs MiddleweightUnderweight vs MiddleweightAge, median (range), y11.2 (1.3-19.0)11.0 (1.0-19.8)9.6 (1.1-19.7).44.04Male sex, No. (%)62 (54)299 (53)45 (54).78.94Race, No. (%)White67 (60)378 (68)57 (69).18.93Black16 (14)46 (8)7 (8).06.88Hispanic19 (17)100 (18)13 (16).96.74Asian1 (1)20 (4)3 (4).23>.99Other8 (7)16 (3)3 (4).04.73Unknown3101White blood cell count, median (range), × 109/L27.9 (0.7-860)17.7 (0.5-684)13.9 (1.2-418)<.001.59Morphology, No. (%)FAB M08 (7)31 (6)3 (4).69.61FAB M122 (19)94 (17)17 (21).61.50FAB M237 (33)175 (31)19 (23).89.16FAB M425 (22)118 (21)26 (31).94.05FAB M516 (14)91 (16)14 (17).65.99FAB M6016 (3)2 (2).09>.99FAB M76 (5)27 (5)2 (2).97.57Other08 (1)0.36.61Unknown0101Marrow cytogenetics, No. (%)†Normal14 (22)91 (25)9 (18).74.32Favorable27 (43)127 (35)21 (41).30.49Unfavorable6 (10)8 (2)4 (8).01.048Standard16 (25)136 (38)17 (33).09.67Unknown5120833Treatment, No. (%)‡Phase 2Regimen A44 (46.8)245 (48.2)34 (50.7).89.80Regimen B45 (47.9)249 (49.0)30 (44.8).93.60Phase 3Related donor10 (15.6)106 (28.1)20 (42.6).05.06Received transplant9 (14.1)91 (24.1)16 (34.0).11.20Received cytarabine53 (82.8)268 (71.1)26 (55.3).07.04Phase 4Interleukin 218 (54.5)88 (49.2)8 (47.1).71.93Follow-up15 (45.5)91 (50.8)9 (52.9).71.93Abbreviations: BMI, body mass index; FAB, French-American-British classification.*Numbers and percentages include only those with data.†Cytogenetic results were available for 62% of patients.‡Treatment is shown in Figure 1.Table 2shows the response to therapy for the 3 BMI groups. In course 1, there were no differences in the early response rate as measured by the day 14 marrow blast percentage or in treatment failure rate. There was a trend for a reduced remission rate and an increased death rate among overweight patients, whereas the underweight patients showed a definite reduction in remission rate and increase in death rate. At the end of course 2, compared with middleweight patients, overweight patients were significantly more likely to die (17% vs 5%, P = .001). The actuarial survival after study enrollment of underweight and overweight patients was inferior to that of middleweight patients (Figure 2).Figure 2.Kaplan-Meier Plot of Actuarial Survival According to BMI From Time of Study EntryBMI indicates body mass index.Table 2.Response to Therapy and Events and Outcomes According to BMIOutcomeNo. (%)PValueOverweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)Overweight vs MiddleweightUnderweight vs MiddleweightBlasts in marrow on day 14, %<577 (81)400 (84)60 (85)≥518 (19)79 (16)11 (15).67.97Unknown*199113At end of course 1Remission94 (85)508 (91)67 (82).07.02Treatment failure9 (8)28 (5)6 (7).28.42Death8 (7)23 (4)9 (11).24.02At end of course 2Remission64 (82)377 (89)47 (87).15.89Treatment failure1 (1)25 (6)3 (6).10>.99Death13 (17)23 (5)4 (7).001.53Abbreviation: BMI, body mass index.*Not all patients had day 14 marrow results reported.After course 1, the univariate HR for treatment-related mortality was significantly increased in the overweight patients (HR, 2.12; 95% CI, 1.37-3.28; P = .001) and the underweight patients (HR, 1.80; 95% CI, 1.06-3.06; P = .03) compared with the middleweight patients (Table 3). Survival from study entry was reduced in the overweight patients (HR, 1.47; 95% CI, 1.09-1.98; P = .01) and the underweight patients (HR, 1.42; 95% CI, 1.00-2.03; P = .05). From the end of course 2, there were no differences in survival among the 3 groups or in relapse rates or treatment-related mortality.Table 3.Univariate and Multivariate Hazard Ratios for Survival and Treatment-Related Mortality According to BMI PercentileHazard Ratio (95% CI)PValueOverweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)Overweight vs MiddleweightUnderweight vs MiddleweightUnivariate AnalysisFrom study entrySurvival1.47 (1.09-1.98)1.001.42 (1.00-2.03).01.05Treatment-related mortality2.12 (1.37-3.28)1.001.80 (1.06-3.06).001.03From the end of course 2Survival1.13 (0.71-1.81)1.001.26 (0.72-2.20).61.42Treatment-related mortality1.18 (0.45-3.08)1.001.02 (0.31-3.39).74.97Relapse risk0.97 (0.62-1.53)1.001.35 (0.83-2.19).89.23Multivariate Analysis*From study entryOverall survival1.88 (1.25-2.83)1.001.85 (1.19-2.87).002.006Treatment-related mortality3.49 (1.99-6.10)1.002.66 (1.38-5.11)<.001.003From the end of course 2(n = 35)(n = 245)(n = 26)Overall survival1.39 (0.73-2.66)1.001.22 (0.58-2.54).32.61Treatment-related mortality2.75 (0.96-7.89)1.001.37 (0.31-6.05).06.68Relapse risk0.67 (0.34-1.36)1.000.89 (0.42-1.86).27.75Abbreviations: BMI, body mass index; CI, confidence interval.*Hazard ratios are calculated for the patients who have complete data for all variables of interest. Adjusted for age, white blood cell count, race, cytogenetics, and bone marrow transplantation.Table 3shows the multivariate analysis of HR for survival and treatment-related mortality adjusted for age, race, WBC count, cytogenetics, and allogeneic bone marrow transplantation for the patients with complete data for the 5 variables. After adjustment, overweight and underweight groups were still less likely to survive than middleweight patients, and HR for treatment-related mortality was even higher than in univariate analysis.Table 4lists deaths according to when they occurred and attribution of cause. Compared with middleweight patients, overweight and underweight patients were more likely to die before or during their first remission (P = .002 and P = .047, respectively). In all groups, infection was the most common cause of death before or during remission. After recurrence of AML, the most common cause of death was AML itself in all 3 groups.Table 4.Causes of DeathNo. (%)PValueOverweight (BMI ≥95%) (n = 114)Middleweight (BMI 11%-94%) (n = 570)Underweight (BMI ≤10%) (n = 84)Overweight vs MiddleweightUnderweight vs MiddleweightDeaths before or during remission30 (26)78 (14)19 (23).002.047AML related1 (1)5 (1)2 (2)>.99.22Treatment related29 (25)73 (13)17 (20).001.09Infection20 (18)44 (8)13 (15).002.04Hemorrhage4 (4)3 (1)3 (4).02.03Toxicity2 (2)9 (2)0 (0)>.99.61Graft-vs-host disease0 (0)6 (1)0 (0).60>.99Other3 (3)11 (2)1 (1).71>.99Relapse38 (33)205 (36)33 (39).67.64Deaths after relapse28 (25)135 (24)19 (23).81.89AML related16 (14)72 (13)9 (11).65.72Treatment related12 (11)63 (11)10 (12)>.99.85Infection9 (8)37 (6)2 (2).54.21Hemorrhage2 (2)8 (1)0 (0).68.61Toxicity0 (0)2 (0)3 (4)>.99.02Graft-vs-host disease1 (1)8 (1)1 (1)>.99>.99Other0 (0)8 (1)4 (40).36.06Abbreviations: AML, acute myeloid leukemia; BMI, body mass index.Excessive treatment-related mortality suggests that overweight and underweight patients could be receiving too much chemotherapy. To address this issue, first we examined the doses of protocol therapy actually received. Then we compared toxicity grades 3 and 4, time to neutrophil recovery, and duration of course as indirect measures of drug effect on normal marrow. Of 768 patients, 10 received less than or equal to 90% of dosing of course 1 therapy according to square meters: in 6 (1 underweight, 1 overweight, and 4 middleweight) of these 10 patients, doses were reduced according to protocol guidelines for hyperbilirubinemia. Four overweight patients received reduced doses calculated to fall between their actual weight and their ideal body weight. Overweight patients were significantly more likely to have a dose reduction than middleweight patients: 4.8% vs 0.7% (P = .006).Toxicity grades 3 and 4 were assessed from a menu of 45 clinical and laboratory parameters. Compared with middleweight patients, more overweight patients experienced grade 3 or 4 abdominal pain (P = .05), systolic hypertension (P = .02), pulmonary function abnormalities (P = .03), and coagulopathy (P<.001), whereas more underweight patients experienced grade 3 or 4 elevations of hepatic enzymes (alanine aminotransferase, P = .01; and aspartate aminotransferase, P = .04).Death from infection increases in direct proportion to the magnitude and duration of neutropenia.Hematologic toxicity was probably the most relevant complication for this study. Important landmarks for assessing neutropenia are time to an ANC of 500 × 109/L (the time when empirical antibiotics are typically discontinued) and time to an ANC of 1000 × 109/L (the time when the patient may be able to begin the next chemotherapy course). Within 5 weeks of the start of therapy, 79.5% of middleweight patients who continued to course 2 had an ANC of greater than or equal to 500 × 109/L, which was not different from the 87.2% of overweight patients (P = .11) or 77.6% (P = .84) of underweight patients. At 7 weeks, the respective proportions were 97.2%, 98.9%, and 100%. The time to recovery of ANC of 1000 × 109/L after the start of course 1 for the 3 groups was plotted (Figure 3): overweight and middleweight patients had significantly faster neutrophil recovery than underweight patients (P = .004).Figure 3.Kaplan-Meier Plots of the Cumulative Incidence of Recovery to an Absolute Neutrophil Count of at Least 100 000 × 109/L According to BMI and Cumulative Incidence of Entry to Course 2BMI indicates body mass index.The time to complete a course of therapy was another indicator of toxicity. Figure 3shows duration of course 1 in the 3 groups: there was no significant difference in the duration of the course. When patients who had dose reductions were excluded, the relative positions of the 3 groups were unchanged.COMMENTThis study shows that overweight and underweight children and adolescents with AML are less likely to survive than patients with BMI in the 11th through 94th percentiles. Inferior survival in both extreme BMI groups is attributable to early treatment-related mortality, and treatment-related mortality is mostly from infection. Although there is already substantial evidence that underweight children with acute lymphoblastic leukemia and solid tumors experience increased relapses and reduced survival,this is the first study to our knowledge to show excess mortality in overweight pediatric cancer patients.These results contrast with those in most adult cancers in which underweight patients have no excess mortality and overweight patients have excess cancer-related death rather than death from excessive toxicity.One notable exception is marrow transplantation: 3 studies show excess mortality in obese adults from a combination of relapse and treatment-related mortalityor treatment-related mortality alone.Dickson et al28also found that underweight patients experienced higher treatment-related mortality. Marrow transplantation and contemporary AML therapy have in common dose-intensive chemotherapy complicated by a relatively high baseline treatment-related mortality that is exaggerated among underweight and overweight patients.Malnutrition is associated with advanced disease, lower socioeconomic status, immunodeficiency, increased number and spectrum of infections, reduced access to care, and delays in diagnosis.Even after adjustment for socioeconomic status, malnutrition continues to be associated with poor outcome. Malnutrition in children reduces absorption, decreases drug-protein binding, and impedes oxidative and other metabolic reactions. These effects increase half-life, reduce clearance, and impair glomerular filtration of drugs.They also augment toxicity.There is no information about the pharmacology of cancer chemotherapy in underweight patients. Busulfan is the only drug for which there is dosing information according to weight or BMI distribution in children.Malnutrition reduces survival in children with cancer in direct proportion to the extent of their malnutrition.Correction of nutritional status improves outcomes.Thus, it would seem reasonable to determine whether delaying therapy to initiate nutritional supplementation and correction of immunodeficiency is possible, and if correction is possible, to determine whether it improves outcome.There is no obvious solution to the problem of excess treatment-related mortality in overweight patients. The data concerning neutrophil recovery and duration of course do not support the hypothesis that overweight patients in this study received too much chemotherapy. There are few traditional pharmacologic studies of bioavailability of chemotherapeutic agents in obese adults and none in overweight children or adolescents. Several small studies have investigated bioavailability of cyclophosphamide, ifosfamide, doxorubicin, and its metabolite doxorubicinol as single agents.Combination chemotherapy has been investigated in 1 obese patient: compared with normal-weight patients, she showed a substantially increased concentration over time for 4-hydroxy cyclophosphamide, thiotepa, and carboplatinum.Because in general these pharmacologic studies show a trend for reduced clearance and longer half-lives of chemotherapeutic agents, they seem to contradict studies of antibiotics in obese adults in which hyperfiltration increases clearance.Because most recent studies show reduced rather than excessive toxicity among obese individuals, today the consensus is that obese adult cancer patients receive too little rather than too much chemotherapy.In this study, overweight patients experienced more severe abdominal pain, hypertension, pulmonary dysfunction, and coagulopathy. Unfortunately, the information collected does not indicate when these toxicities occured, how long they lasted, or whether they contributed to death or reflected end-stage deterioration. Comorbidities such as these increase risk of death in adult cancer patients with febrile neutropenia, so they may be important in these patients.Overweight patients can also manifest subtle immunologic abnormalities that could contribute to excess infectious death.In 1970, Wiernik and Serpick40described 8 morbidly obese patients among 106 adults with AML. None of the 8 patients survived longer than 1.75 months compared with a median survival of 3.5 months for the whole study. These authors postulate that subclinical diabetes, difficulties in performing thorough physical examinations, or nuances in carrying out routine nursing care could contribute to early demise.This study has the limitations of a retrospective study: CCG-2961 was not designed to investigate BMI as a variable. Some findings, such as the proportion of overweight and underweight patients with donors for marrow transplantation, may be spurious. The study does not illuminate the causes of excess infectious treatment-related mortality. There are no socioeconomic data. All assessments pertain to weight at diagnosis; it was not possible to determine whether weight gain in underweight patients or weight loss in overweight patients improved outcomes after the first course. Finally, it is likely that the observation of excessive treatment-related mortality in overweight patients will be reproducible only in pediatric cancers that involve extremely dose-intensive chemotherapy or marrow transplantation studies as in obese adults.The effect of BMI on outcome in pediatric AML is not a trivial problem: the reduced survival in underweight and overweight patients is roughly equal to the improved survival accomplished by 10 years of progress in pediatric AML. Treatment-related mortality is the worst possible outcome for an individual enrolled in a clinical trial, and if treatment-related mortality is not countered by a net gain in survival, excess treatment-related mortality is also the worst possible outcome for a clinical trial. These results have implications for clinicians and clinical investigators. This is the first example of immediate rather than impending life-shortening effects of excess weight in the young and a confirmation of the risks of undernutrition in other pediatric cancers.Interventions currently available that could reduce the treatment-related mortality in underweight and overweight groups include formal nutritional and immunologic assessment at diagnosis. Underweight patients could benefit from preemptive nutritional intervention or intravenous γ-globulin. In overweight patients, correction of persistent moderate hyperglycemia and hypertension may remediate 2 important comorbidities. Maintaining blood glucose concentration between 80 and 120 mg/dL appears to reduce mortality in patients in intensive care units.However, systematic changes in management should take place as part of controlled studies. Basic pharmacokinetic and pharmacodynamic studies of chemotherapeutic drug disposition in underweight and overweight patients are likely to provide a rational basis for dosing. Until such information is available, it is impossible to know whether doses of chemotherapy should be reduced. Dose reduction is likely to lead to increased relapse, but relapse is the lesser of 2 evils. It is also possible that dose reduction increases relapse and has no effect on toxic mortality. Finally, technologists, nurses, and physicians should examine whether overweight patients are receiving suboptimal care because of difficulties in assessing them, as suggested by Wiernik and Serpick.If that is the case, then it must be determined as to how to change practice to overcome these barriers.Corresponding Author:Beverly J. Lange, MD, Division of Oncology, Children&apos;s Hospital of Philadelphia, 34th and Civic Center Boulevard, Philadelphia, PA 19104 (lange@email.chop.edu).Author Contributions: Drs Lange and Alonzo had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.Study concept and design: Lange, Feusner, Skolnik, Sacks, Smith, Alonzo.Acquisition of data: Lange, Feusner, Sacks, Smith, Alonzo.Analysis and interpretation of data: Lange, Gerbing, Feusner, Skolnik, Smith, Alonzo.Drafting of the manuscript: Lange, Gerbing, Skolnik, Sacks, Smith, Alonzo.Critical revision of the manuscript for important intellectual content: Lange, Feusner, Skolnik, Sacks, Smith, Alonzo.Statistical analysis: Lange, Gerbing, Skolnik, Alonzo.Obtained funding: Lange.Administrative, technical, or material support: Lange, Feusner, Skolnik, Sacks, Smith.Study supervision: Lange, Feusner, Smith.Funding/Support:This study was supported by grants CA098543 and CA098413 from the National Institutes of Health (NIH) from 2000 to 2004 and NIH U-10 grants listed at http://www.childrensoncologygroup.org/admin/grantinfo.htmfrom 1996 to 2000. Dr Lange was supported by the Yetta Dietch Novotny Chair in Clinical Oncology. Chiron provided interleukin 2 to the National Cancer Institute (NCI), which provided interleukin 2 to the institutions.Role of the Sponsors:The Children’s Cancer Group (CCG) was funded by an NIH U-10 grant to perform clinical trials and correlative biology studies and epidemiologic studies in childhood cancer. CCG-2961 was designed by the CCG-2961 Study Committee, which Dr Lange chaired. The Committee reported to the CCG-AML Strategy Group. The design and conduct of the study were reviewed by a data and safety monitoring board composed of CCG and non-CCG cooperative group investigators, an ethicist, a lay member, and representatives of the Clinical Trials Evaluation Program of the NCI, who were nonvoting members. Primary patient data were obtained by nurses and physicians; most were CCG members who were not compensated by CCG for their work. Clinical research associates, supported fully or in part by the CCG institutional grant, abstracted the data and transmitted them to the CCG Operations office, Arcadia, Calif. Dr Lange received copies of all data capture forms. Primary data analyses were performed by Dr Alonzo and Mr Gerbing, CCG statisticians. The interpretation of the data was the primary responsibility of these 2 statisticians and Dr Lange, with all authors participating substantially in the interpretation of the data. All authors except Dr Skolnik, Ms Sacks, and Mr Gerbing were members of the CCG-2961 committee. In 2000, CCG and 3 other groups conducting clinical research in pediatric oncology fused to become the Children’s Oncology Group (COG). The manuscript was sent to COG for final review by the COG editor, Shaun Mason. Submission of the manuscript by Mr Mason to the journal constitutes approval of the manuscript by COG. Chiron had no role in the design, conduct, or analysis of the study.Acknowledgment:We thank Christine Curran for typing the manuscript and Shaun Mason, BA, for editorial support.REFERENCESMSmithLGloecker RiesJGurneyJRossLeukemia SEER Pediatric Monograph.Vol 1999. Bethesda, Md: National Cancer Institute; 1999LCRileyIMHannKWheatleyRFStevensTreatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10): the MCR Childhood Leukaemia Working Party.Br J Haematol199910643644410460604UCreutzigMZimmermannJRitterDefinition of a standard-risk group in children with AML.Br J Haematol199910463063910086807WGWoodsSNeudorfSGoldA comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherpay in children with acute myeloid leukemia in remission.Blood200197566211133742SCRaimondiMNChangYRavindranathChromosomal abnormalities in 478 children with acute myeloid leukemia: clinical characteristics and treatment outcome in a cooperative Pediatric Oncology Group Study: POG 8821.Blood1999943707371610572083KWheatleyAKBurnettAHGoldstoneA simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial: United Kingdom Medical Research Council&apos;s Adult and Childhood Leukaemia Working Parties.Br J Haematol1999107697910520026WGWoodsBJLangeFOSmithTAAlonzoResponse: a comparison of allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy in pediatric acute myeloid leukemia.Blood20019736743675MASekeresBPetersonRKDodgeCancer and Leukemia Group B (CALGB)Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia.Blood20041034036404214976037JMBennettDCatovskyMTDanielCriteria for the diagnosis of acute leukemia of megakaryoctye lineage (M7).Ann Intern Med19851034604622411180DRBarnardDKKalousekSRWiersmaMorphologic, immunologic and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Children&apos;s Cancer Group.Leukemia1996105128558938BJLangePDinndorfFOSmithPilot study of idarubicin-based intensive timing induction therapy for children with previously untreated acute myeloid leukemia in Children&apos;s Cancer Group (CCG) Study 2941.J Clin Oncol20042215015614701777PADinndorfVIAvramisSWiersmaPhase I/II study of idarubicin given with continuous infusion fludarabine followed by continuous infusion cytarabine in children with acute leukemia: a report from the Children&apos;s Cancer Group.J Clin Oncol199715278027859256119TAAlonzoNLKobrinskyAAledoImpact of granulocyte colony-stimulating factor use during induction for acute myelogenous leukemia in children: a report from the Children&apos;s Cancer Group.J Pediatr Hematol Oncol20022462763512439034CLOgdenRJKuczmarksiKMFlegalCenters for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version.Pediatrics2002109458011773541GPBodeyMBuckleyYSSatheEJFreireichQuantitative relationships between circulating leukocytes and infection in patients with acute leukemia.Ann Intern Med1966643283405216294ELobato-MendizabalGJRuiz-ArguellesAMarin-LopezLeukaemia and nutrition, I: malnutrition is an adverse prognostic factor in the outcome of treatment of patients with standard-risk acute lymphoblastic leukaemia.Leuk Res1989138999062586144MBVianaMMuraoGRamosMalnutrition as a prognostic factor in lymphoblastic leukaemia: a multivariate analysis.Arch Dis Child1994713043107979521DGomez-AlmaguerGJRuiz-ArguellesSPonce-de-LeonNutritional status and socio-economic conditions as prognostic factors in the outcome of therapy in childhood acute lymphoblastic leukemia.Int J Cancer Suppl19981152559876479SSDonaldsonMNWesleyWDDeWysRMSuskindNJaffeJvanEysA study of the nutritional status of pediatric cancer patients.Am J Dis Child1981135110711127315806EECalleKCRodriguezKWalker-ThurmondMJThunOverweight, obesity and mortality from cancer in a prospectively studied cohort of U.S. adults.N Engl J Med20033481625163812711737JBastarracheaGNHortobagyiTLSmithSWKauAUBuzdarObesity as an adverse prognostic factor for patients receiving adjuvant chemotherapy for breast cancer.Ann Intern Med199412018258250452MSGeorgiadisSMSteinbergLAHankinsDCIhdeBEJohnsonObesity and therapy-related toxicity in patients treated for small-cell lung cancer.J Natl Cancer Inst1995873613667853417PPoikonenCBlomqvistHJoensuuEffect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area.Acta Oncol200140677111321664JAMeyerhardtPJCatalanoDGHallerInfluence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma.Cancer20039848449512879464GLRosnerJBHargisDRHollisRelationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: results from Cancer and Leukemia Group B Study 8541.J Clin Oncol199614300030088918498DRFlemingMKRayensJGarrisonImpact of obesity on allogeneic stem cell transplant patients: a matched case-controlled study.Am J Med19971022652689217595GMeloniAProiaSCapriaObesity and autologous stem cell transplantation in acute myeloid leukemia.Bone Marrow Transplant20012836536711571508TMDicksonCRKusnierz-GlazKGBlumeImpact of admission body weight and chemotherapy dose adjustment on the outcome of autologous bone marrow transplantation.Biol Blood Marrow Transplant1999529930510534060ELobato MendizabalGJRuiz-ArguellesLeukemia and malnutrition, III: effect of chemotherapeutic treatment on the nutritional state and its repercussion on the therapeutic response of patients with acute lymphoblastic leukemia with standard risk.Sangre (Barc)1990351891952396166DJMurryLRivaDGPoplackImpact of nutrition of pharmacokinetics of anti-neoplastic agents.Int J Cancer Suppl1998(11)48519876478LLDupuisMNajdovaEFSaundersRetrospective appraisal of busulfan dose adjustment in children.Bone Marrow Transplant2000261143114711149723GPowisPReeceDLAhmannJNIngleEffect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients.Cancer Chemother Pharmacol1987202192223315280MJLindJMMargisonTCernyNThatcherPMWilkinsonProlongation of ifosfamide elimination half-life in obese patients due to altered drug distribution.Cancer Chemother Pharmacol1989251391422557169KARodvoldDARushingDATewksburyDoxorubicin clearance in the obese.J Clin Oncol19886132113273411343MEDe JongeRAMathotSMVan DamJHBeijnenSRodenhuisExtremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin.Cancer Chemother Pharmacol20025025125512203108RABlouinJHKolpekHJMannInfluence of obesity on drug disposition.Clin Pharm198767067143315402JATalcottRFinbergRJMayerLGoldmanThe medical course of cancer patients with fever and neutropenia: clinical identification of a low-risk subgroup at presentation.Arch Intern Med1988148256125683196123DRCottamPASchaeferGWShaftanLDAngusDysfunctional immune-privilege in morbid obesity: implications and effect of gastric bypass surgery.Obes Surg200313495712630613DRCottamPASchaeferDFahmyGWShaftanLDAngusThe effect of obesity on neutrophil Fc receptors and adhesion molecules (CD16, CD11b, CD62L).Obes Surg20021223023511975218PHWiernikAASerpickFactors effecting remission and survival in adult acute nonlymphocytic leukemia (ANLL).Medicine1970495055135286084Gvan den BerghePWoutersFWeekersIntensive insulin therapy in the critically ill patients.N Engl J Med20013451359136711794168

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