Originally published as JCO Early Release 10.1200/JCO.2003.08.060 on July 28 2003

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gamis, A. S. Articles by Smith, F. O. Search for Related Content PubMed PubMed Citation Articles by Gamis, A. S. Articles by Smith, F. O. Social Bookmarking                            What's this?

Increased Age at Diagnosis Has a Significantly Negative Effect on Outcome in Children With Down Syndrome and Acute Myeloid Leukemia: A Report From the Children’s Cancer Group Study 2891

From the Children’s Mercy Hospital, Kansas City, MO; Children’s Healthcare of Atlanta at Egleston, Atlanta, GA; Children’s Oncology Group, Arcadia, and University of Southern California Keck School of Medicine, Los Angeles, CA; Children’s Hospital of Philadelphia, Philadelphia, PA; IWK Health Centre, Halifax, Nova Scotia, Canada; University of North Carolina at Chapel Hill, Chapel Hill, NC; and Children’s Hospital Medical Center, Cincinnati, OH.

Address reprint requests to Alan S. Gamis, MD, MPH, Section of Hematology/Oncology/Blood and Marrow Transplantation, Children’s Mercy Hospital and Clinics, 2401 Gillham Rd, Kansas City, MO 64108; e-mail: agamis{at}cmh.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

 
Purpose: To determine the outcome of children with Down syndrome (DS) and acute myeloid leukemia (AML) receiving standard timing chemotherapy without bone marrow transplantation (BMT), with determination of prognostic factors.

Patients and Methods: Children with DS and newly diagnosed AML or myelodysplasia were prospectively enrolled on Children’s Cancer Group study 2891 (N = 161) and treated uniformly with four standard timing induction courses of dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER) followed by intensively timed high-dose cytarabine.

Results: Children with DS were significantly younger at diagnosis than those without (median age, 1.8 v 7.5 years, respectively; P < .001), with more megakaryocytic leukemia (70% v 6%; P < .001). Higher complete remission rates (91%) were achieved in children with DS than among those without DS (75%; P < .001). Equivalent grade 3 to 4 toxicity (29% v 30%; P = .84) was seen, though children with DS had greater pulmonary toxicity (P < .01) during induction and mucositis during intensification (P = .12). Children with DS had significantly better 8-year event-free survival (EFS; 77% v 21% standard and 40% intensive induction; P < .0001). Multivariate analysis in children with DS revealed that only age at diagnosis of 2 years or older was a risk factor for greater relapse risk (odds ratio, 4.9; P = .006) and worse survival. Children between ages 0 to 2 years (n = 94) had a 6-year EFS of 86%; those from 2 to 4 years (n = 58), 70%; and those older than 4 years (n = 9), 28%. Remission failures were the primary reason for worse 6-year EFSs (1% in those 0 to 2 years v 14% if >2 years; P = .002).

Conclusion: Outcome for children with DS and AML is excellent with standard induction therapy, but declines with increasing age.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

 
CHILDREN WITH Down syndrome (DS) are known to develop acute leukemia more frequently (1 in 100 to 200 children), and children younger than 4 years usually develop acute myeloid leukemia (AML; 1 in 300). In the 1960s and 1970s, children with DS and AML were believed to have excessive toxicity with chemotherapy, so few were treated.¹ It was not until the 1980s that many children with DS were enrolled in cooperative group trials. Though study accrual numbers were small, the experience with children with DS on those trials was reported, and, surprisingly, suggested that despite continuing trends toward having more toxicity, this population had similar survival outcomes compared with the children without DS.² In the 1990s, the Children’s Cancer Group (CCG) reported the largest single study in which children with DS and AML were treated.³ Our current report expands on the earlier report with longer follow-up of the original cohort of children,³ more enrolled children who were treated uniformly on the standard timing chemotherapy arm, analysis of prognostic factors, and examination of toxicity and relapse in patients with DS, by focusing on a cohort treated uniformly with standard-timing conventional chemotherapy without bone marrow transplantation (BMT).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

 
CCG-2891, a phase III randomized trial, compared intensively timed induction therapy with standard conventionally timed induction therapy. We compared postremission intensively timed high-dose cytarabine–based chemotherapy with 4HC-purged autologous BMT or matched related allogeneic BMT.⁴ Patients eligible for CCG-2891 were aged 0 to 20 years, with untreated AML or myelodysplastic syndrome. Patients or their legal guardians signed informed consent forms approved by local institutional review boards and in compliance with the Declaration of Helsinki. Between October 12, 1989, and October 15, 1999, 1,202 children were registered onto CCG-2891 (947 patients without DS, 190 with DS, and 65 excluded for various reasons). Accrual for patients without DS ended in 1994. The characteristics and methods of this study were reported previously.^4,5 Acute myeloid leukemia and myelodysplastic syndrome were classified according to the French-American-British (FAB) criteria.^6–9 For this analysis, the definition of myelodysplastic syndrome was limited to 29% or fewer blasts present in the bone marrow (BM) sample. Morphology, histochemistry, and institutional immunophenotype reports were reviewed centrally. When central review was not available, institutional results were used. Methods and concordance have been described elsewhere.¹⁰ Together, central and institutional review allowed the histologic FAB classification of 151 (94%) of 161 total DS patients (M0-M7, RA, RAEB, and RAEB-T). In determining the FAB classification, 21 of 88 patients diagnosed with FAB M7 AML had bone marrow blast percentages less than 30%. When interim analyses as of July 18, 1992, showed excessive toxicity in children with DS, we excluded those children first from allogeneic BMT, and then from autologous BMT and intensively timed induction. Thereafter, children with DS were assigned nonrandomly to standard-timing induction followed by postremission chemotherapy (Fig 1). Because three fourths of the children with DS had treatment assigned, we report "as-treated" analyses rather than "intent-to-treat" analyses. In the patients without DS, the intent-to-treat and as-treated analyses are essentially identical.⁴ The chemotherapy regimen for induction has been described, and includes cytarabine 200 mg/m²/d, daunorubicin 20 mg/m²/d, etoposide 100 mg/m²/d, dexamethasone 6 mg/m²/d, and 6-thioguanine 100 mg/m²/d. Cytarabine, daunorubicin, and etoposide were given by continuous intravenous infusion, and dexamethasone and 6-thioguanine were given orally. All medications were given on days 0 to 4 of each of four induction cycles. The patients who had standard-timing induction received each subsequent induction cycle on blood count recovery from the preceding cycle. Patients were assessed for response on day 7 of induction cycle 1, and for remission at the end of induction cycles 1 and 4, with the end of cycle 4 being defined as the end of induction. The postremission intensification phase of therapy consisted of 3-hour infusions of cytarabine 3,000 mg/m² given every 12 hours on days 0 through 1 and 7 through 8, and L-asparaginase 6,000 U/m² given once intramuscularly on days 1 and 8. Afterwards, patients went on to receive 3 months of relatively low-dose maintenance chemotherapy as described.^3–5

View larger version (16K): [in this window] [in a new window]   Fig 1. Children’s Cancer Group Study 2891 (CCG-2891) schema. Patients with Down syndrome on CCG-2891 were nonrandomly assigned to the standard timing induction therapy; dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER); and the chemotherapy intensification arm (n = 161). Ara-C, cytarabine; BMT, bone marrow transplantation.

We calculated estimates of overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) using the Kaplan-Meier method.¹² EFS is defined as time from study enrollment to induction failure, marrow relapse, or death. We defined RFS as time from induction remission (end of induction cycle 4) to marrow relapse or death caused by progressive disease, censoring deaths from other causes. Patients lost to follow-up were censored at their last known points of study, with a cutoff of February 11, 2000. We calculated confidence intervals with Greenwood’s formula.¹³ Differences in OS and EFS were tested for significance with the log-rank statistic.¹⁴ Incidence of relapse after remission was estimated as cumulative incidence, with death and other competing risks censored.¹⁵

Factors significant in univariate analysis at P < .05 were considered for inclusion in multivariate models. We used Cox regression to construct multivariate survival models.¹⁶ The likelihood ratio test was used to determine whether variables should be added or dropped from the multivariate model. Multivariate analyses included patients with complete covariate data.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

 
Between 1989 and 1999, 190 children with DS were enrolled onto CCG-2891. We excluded patients who were treated on the intensive timing induction arm (n = 20) or who received BMT (n = 9) from this analysis, leaving 161 patients who were treated on the standard timing induction arm followed by chemotherapy intensification, Capizzi II, if induction remission was achieved. These 161 patients did not receive a BMT regardless of the availability of matched siblings.

Patients With DS Versus Those Without DS
Table 1 provides the presenting characteristics of the children with DS and the characteristics of those without DS. Children with DS were significantly younger at AML/MDS diagnosis than those without DS. At AML/MDS diagnosis, only 2% of children with DS were older than 5 years, whereas 61% of children without DS were older than 5 years. Patients with DS presented with AML/MDS significantly earlier than those without DS. Among DS children alone, no significant difference in age incidence between those diagnosed with AML (1.86 years) or MDS (1.81 years) was identified (P = .222). A larger percentage of children with DS were nonwhite, but this was not statistically significant. Hepatomegaly (P = .02) and splenomegaly (P = .06) were seen in a significantly greater percentage of patients with DS, whereas adenopathy (P < .001) was seen significantly less often in DS children. Evidence of CNS disease (CSF or cranial nerve involvement) was relatively rare in those with DS compared with those without DS. Hyperleukocytosis (WBC count > 100,000/mm³) was very rare among the patients with DS, and median WBC count at diagnosis was significantly lower than in patients without DS. Patients with DS also had significantly lower platelet levels at diagnosis.

Histochemical staining characteristics of leukemic blasts from patients with DS were significantly different from those without it, and reflected the differences in FAB types between the two populations. Auer rods were seen in only 3% of children with DS, compared with 38% in those without DS (data not shown; P < .001). Cytogenetic abnormalities also reflected differences in FAB distribution; t(8;21) was not diagnosed in any patient with DS. Flow cytometry results showed a significant proportion of patients with DS who had the T-cell cell surface marker CD7 (81%), which was much less common in patients without DS (29%; P < .001). Antiplatelet glycoprotein positivity also was found in a higher percentage of patients with DS, corresponding with the higher percentage of patients with FAB M7. CD15 blast positivity was found significantly less often in the patients with DS.

To study tolerance of treatment regimens, we collected information on the incidence of grade 3 or 4 toxicity in patients with and without DS who received standard induction and chemotherapy intensification (Table 2). Comparing tolerance of standard timing induction regimens in children with and without DS revealed no significant differences in overall toxicity (P = .84). One significant difference during standard timing induction was a significantly higher rate of pulmonary toxicity among children with DS (P = .004). This difference was primarily during the first course of induction (9.3% v 2.8%). When limiting this to only functional pulmonary toxicity (oxygen or assisted ventilation required), the difference between children with and without DS remained significant (P = .005). Examination of the intensification phase, in which intensively timed high-dose cytarabine was used, revealed that the phase was tolerated equally well in both populations, with no difference in cumulative incidence of grade 3 or 4 toxicities (P = .31), although there were some significant differences in certain organ toxicities during this phase of therapy (Table 2).

View larger version (16K): [in this window] [in a new window]   Fig 2. Relapse probability in children with and without Down syndrome.

Survival among the children with DS was better (6-year OS, 79%; 6-year EFS, 77%) than in children without DS (6-year OS, 43%; 6-year EFS, 33%; P < .0001). Survival rates for children with DS were better than for children without it, regardless of induction timing (Fig 3). Children with DS who had CR had better RFS from the end of induction (86%) than children without DS who were in CR at the end of induction, and who had intensive (57%) or standard (38%) induction (P < .001). These rates were better, though they included children with DS who received the chemotherapy intensification only, compared with children without DS who received either chemotherapy or transplantation for their intensification therapy.

View larger version (17K): [in this window] [in a new window]   Fig 3. Overall survival (OS) for children with and without Down syndrome.

DS-Restricted Analysis: Prognostic Factors
Because of the large number of patients with DS enrolled in this study, we could examine factors that predict EFS. All items presented in Table 1 were reviewed. In univariate analysis, only age at the time of diagnosis (P = .002) and rapidity of response (day-7 BM result; P = .03) were predictive of EFS. In multivariate models (Table 3), only age was predictive of EFS. Children with DS who were older than 2 years at diagnosis had a five-fold greater chance of adverse outcome than those who were age 2 years or younger when fit with the day-7 BM examination (P = .006). Children with DS who were age 2 years or younger had a 6-year EFS of 86% compared with those older than 2 years who had a 6-year EFS of 64% (P = .002). While less statistically significant, slower response (odds ratio, 2.6; P = .07) independently trended toward a greater risk of adverse outcome. As in the early analysis of CCG-2891, the 6-year EFS of children with DS and myelodysplastic syndrome was as good (78%) as that for children with DS with AML (76%; P was not significant).

View larger version (14K): [in this window] [in a new window]   Fig 4. Event-free survival of patients with Down syndrome by age at diagnosis. Age comparisons: 0–2 years versus 2–4 years, P = .021; 0–4 years versus >4 years, P = .0001. (*), 5 years.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

This study confirms the findings in prior series of children with DS and myeloid leukemias that identified unique characteristics not found in children without DS who have AML, including megakaryoblastic predominance,^17–19 increased CD7 expression,^18,19 high percentage of patients with myelodysplasia,¹⁹ and younger age at diagnosis.^17–22

This study additionally found that CNS involvement was relatively rare in the DS population (5% v 20% without DS; P < .001), a finding similar to prior observations that did not have enough patients to draw statistical conclusions.^18,19 This finding may reflect the generally lower total WBC counts at diagnosis, an association previously recognized.²³

Examination of this large population confirmed several smaller series^{18,19,22,24,25} that found patients with DS had improved outcomes compared with patients without DS treated with similar or more intensive therapy. This improved outcome was a result of significantly greater remission rates, equivalent or lower toxicity, and less subsequent relapse when they were treated with the standard timing induction chemotherapy regimen (Tables 1 and 2; Fig 2).

The size of this cohort of DS patients has permitted analysis of prognostic factors. Several poor prognostic factors found in children with AML without DS had either no effect on our DS patients’ outcomes or were not seen in this cohort. Monosomy 7, slightly more prevalent in this cohort of DS children than the children without DS (10.3% v 6.1%; P = .217), did not have a significant effect on CR (Table 1) or EFS (EFS: monosomy 7 present, 63% v absent, 82%; P = .173). Only one patient with DS had a WBC count more than 100,000, and thus no effect of high WBC count could be analyzed. WBC count greater or less than 20,000 had no effect on prognosis (78% v 72%; P = .31).

We found that among the characteristics identified to be unique to the DS population of myeloid leukemia patients, only age at diagnosis had independent prognostic significance (odds ratio, 4.9), primarily a result of poor remission induction in older patients (Table 3). It is known that children with DS have a greater risk of developing leukemia,²⁴ and myeloid leukemia in particular.²² As with other congenital cancer predispositions, the unique age distribution of myeloid leukemias in children with DS is skewed towards earlier age at diagnosis. Children with DS in this study were significantly younger than those without DS (median age, 1.8 v 7.5 years; P < .001), so much so that only 2% of the cohort were older than 5 years at diagnosis.

As age was the only significant prognostic indicator, examination of the differences between the younger and older DS patients was undertaken (Table 4). Examination into characteristics of the leukemia present in the two age groups found few differences. The leukemia found in the older children tended to be associated with more bulk disease and less expression of the typically T-cell markers, CD2 and CD7. Whether this represents some fundamental difference between the types of leukemia not discernable by histologic or cytogenetic differences is unknown and requires further study. As the one factor other than age that approached an independent prognostic level in overall DS population was reduction of BM blasts to less than 5% by day 7 of induction, a difference in leukemia cell chemosensitivity or a difference in chemotherapy metabolism might be considered. While there was no difference between the age groups in rapidity of BM blast clearance measured on day 7 (data not shown), there was a significantly worse induction of remission for older DS patients. The possible causes for the poorer remission rate in older DS children were either an increase in toxic mortality or more patients with persistent leukemia at the end of induction. Data indicate the latter.

Increased toxic complications among patients with DS have been reported by several investigators,^2,19,24,26 and were presumed to be caused by increased chemosensitivity. This current trial found that when dose-intensity was decreased instead of absolute dose, toxicity in the entire cohort of patients with DS was no worse than in patients without DS. In the younger DS cohort this reduction of toxicity was achieved without worsening remission rates at the end of induction and without worsening subsequent RFS (Fig 4). In the older DS patients there appeared to be less chemosensitivity illustrated by the combination of a greater risk of persistent leukemia at the end of induction, combined with the absence of increased toxicity.

Further, the dose-intensity of the intensively timed intensification that followed induction caused no significantly greater toxicity in patients with DS than in those without it nor was there greater toxicity during this phase in the older than in the younger DS cohort. Several reports have also suggested that high-dose cytarabine affects survival in patients with DS and is relatively well tolerated.^18,19,26 All patients on our trial received high-dose cytarabine, which prevented randomized evaluation of its benefit, but the excellent outcomes appear to confirm that it did not reduce efficacy or cause excessive toxicity despite its intensive timing. CCG-2891 examined the effect of increasing dose-intensity through the administration of identical doses in either rapid sequence before blood count recovery (on the intensive timing arm) or in standard monthly pulses after blood count recovery (standard timing arm). It is difficult to determine whether therapeutic regimens administered with prior trials would result in a better outcome for older DS patients than that seen with the standard timing chemotherapy — dexamethasone, cytarabine arabinoside, 6-thioguanine, etoposide, daunorubicin (DCTER). A review of these trials finds that few of those enrolled were in this older, apparently high-risk age group identified in this study.^18,19,21

This study, in combination with this trial’s earlier analysis of the intensive timing arm patients,³ suggests that older children with DS and AML or MDS require a more intensive induction than found in standard timing 4 day DCTER but less than that found in the intensively timed DCTER. Future studies should include examination of the impact of age on remission induction and RFS to confirm these findings. In addition, further analysis of the leukemia in the two age cohorts (eg, prevalence of Flt3 ligand and minimal residual disease as measured by new techniques) may more accurately identify risk factors that cosegregate with age.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

 
The authors indicated no potential conflicts of interest.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS’ DISCLOSURES OF... REFERENCES

 
1. Lange B: The management of neoplastic disorders of haematopoiesis in children with Down’s syndrome. Br J Haematol 110:512–524, 2000[CrossRef][Medline]

2. Robison LL, Nesbit ME Jr, Sather HN, et al: Down syndrome and acute leukemia in children: A 10-year retrospective survey from Children’s Cancer Study Group. J Pediatr 105:235–242, 1984[CrossRef][Medline]

3. Lange BJ, Kobrinsky N, Barnard DR, et al: Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: Children’s Cancer Group studies 2861 and 2891. Blood 91:608–615, 1998[Abstract/Free Full Text]

4. Woods WG, Kobrinsky N, Buckley JD, et al: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: A report from the Children’s Cancer Group. Blood 87:4979–4989, 1996[Abstract/Free Full Text]

5. Woods WG, Kobrinsky N, Buckley J, et al: Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: A Children’s Cancer Group pilot study. J Clin Oncol 11:1448–1457, 1993[Abstract/Free Full Text]

6. Bennett JM, Catovsky D, Daniel MT, et al: Criteria for the diagnosis of acute leukemia of megakaryocytic lineage (M7): A report of the French-American-British Cooperative Group. Ann Intern Med 103:460–462, 1985[Abstract/Free Full Text]

7. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Ann Intern Med 103:620–625, 1985[Abstract/Free Full Text]

8. Bennett JM, Catovsky D, Daniel MT, et al: Proposal for the recognition of minimally differentiated acute myeloid leukemia (AML-M0). Br J Haematol 78:325–329, 1991[Medline]

9. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199, 1982[Medline]

10. Barnard DR, Kalousek DK, Wiersma SR, et al: Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: A report from the Children’s Cancer Group. Leukemia 10:5–12, 1996[Medline]

11. Mann HB, Whitney DR: On a test of whether one of two random variables is stochastically larger than the other. Ann Math Stat 18:50–60, 1947[CrossRef]

12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

13. Greenwood M: The Natural Duration of Cancer: Reports on Public Health and Medical Subjects, 33126. London, United Kingdom, Her Majesty’s Stationery Office, 1926

14. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc A 135:185–207, 1972[CrossRef]

15. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley, 1980

16. Cox DR: Regression models and life tables. J R Stat Soc B, 34:187–220, 1972

17. Zipursky A, Peeters M, Poon A: Megakaryoblastic leukemia and Down’s syndrome: A review. Pediatr Hematol Oncol 4:211–230, 1987[Medline]

18. Ravindranath Y, Abella E, Krischer JP, et al: Acute myeloid leukemia (AML) in Down’s syndrome is highly responsive to chemotherapy: Experience on Pediatric Oncology Group AML study 8498. Blood 80:2210–2214, 1992[Abstract/Free Full Text]

19. Creutzig U, Ritter J, Vormoor J, et al: Myelodysplasia and acute myelogenous leukemia in Down’s syndrome: A report of 40 children of the AML-BFM Study Group. Leukemia 10:1677–1686, 1996[Medline]

20. Zipursky A, Poon A, Doyle J: Leukemia in Down syndrome: A review. Pediatr Hematol Oncol 9:139–149, 1992[Medline]

21. Kojima S, Sako M, Kato K, et al: An effective chemotherapeutic regimen for acute myeloid leukemia and myelodysplastic syndrome in children with Down’s syndrome. Leukemia 14:786–791, 2000[CrossRef][Medline]

22. Kojima S, Matsuyama T, Sato T, et al: Down’s syndrome and acute leukemia in children: an analysis of phenotype by use of monoclonal antibodies and electron microscopic platelet peroxidase reaction. Blood 76:2348–2353, 1990[Abstract/Free Full Text]

23. Cassileth PA, Sylvester LS, Bennett JM, et al: High peripheral blast count in adult acute myelogenous leukemia is a primary risk factor for CNS leukemia. J Clin Oncol 6:495–498, 1988[Abstract]

24. Levitt GA, Stiller CA, Chessells JM: Prognosis of Down’s syndrome with acute leukaemia. Arch Dis Child 65:212–216, 1990[Abstract/Free Full Text]

25. Lie SO, Jonmundsson G, Mellander L, et al: A population-based study of 272 children with acute myeloid leukaemia treated on two consecutive protocols with different intensity: Best outcome in girls, infants, and children with Down’s syndrome. Nordic Society of Paediatric Haematology and Oncology (NOPHO). Br J Hematol 94:82–88, 1996[CrossRef][Medline]

26. Zubizarreta P, Felice M, Alfaro E, et al: High toxicity of AML-BFM treatment strategy in Down’s syndrome: Report of a single pediatric institution. Blood 88:178b, 1996

Submitted August 8, 2002; accepted June 9, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				S. Malinge, S. Izraeli, and J. D. Crispino Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome Blood, March 19, 2009; 113(12): 2619 - 2628. [Abstract] [Full Text] [PDF]

				K. R. Rabin and J. A. Whitlock Malignancy in Children with Trisomy 21 Oncologist, February 1, 2009; 14(2): 164 - 173. [Abstract] [Full Text] [PDF]

				M. M. O'Brien, J. W. Taub, M. N. Chang, G. V. Massey, K. C. Stine, S. C. Raimondi, D. Becton, Y. Ravindranath, and G. V. Dahl Cardiomyopathy in Children With Down Syndrome Treated for Acute Myeloid Leukemia: A Report From the Children's Oncology Group Study POG 9421 J. Clin. Oncol., January 20, 2008; 26(3): 414 - 420. [Abstract] [Full Text] [PDF]

				K. Kudo, S. Kojima, K. Tabuchi, H. Yabe, A. Tawa, M. Imaizumi, R. Hanada, K. Hamamoto, R. Kobayashi, A. Morimoto, et al. Prospective Study of a Pirarubicin, Intermediate-Dose Cytarabine, and Etoposide Regimen in Children With Down Syndrome and Acute Myeloid Leukemia: The Japanese Childhood AML Cooperative Study Group J. Clin. Oncol., December 1, 2007; 25(34): 5442 - 5447. [Abstract] [Full Text] [PDF]

				D. Barbaric, T. A. Alonzo, R. B. Gerbing, S. Meshinchi, N. A. Heerema, D. R. Barnard, B. J. Lange, W. G. Woods, R. J. Arceci, and F. O. Smith Minimally differentiated acute myeloid leukemia (FAB AML-M0) is associated with an adverse outcome in children: a report from the Children's Oncology Group, studies CCG-2891 and CCG-2961 Blood, March 15, 2007; 109(6): 2314 - 2321. [Abstract] [Full Text] [PDF]

				Y. Ge, A. A. Dombkowski, K. M. LaFiura, D. Tatman, R. S. Yedidi, M. L. Stout, S. A. Buck, G. Massey, D. L. Becton, H. J. Weinstein, et al. Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia Blood, February 15, 2006; 107(4): 1570 - 1581. [Abstract] [Full Text] [PDF]

				F. O. Smith ALL in children with Down syndrome Blood, December 15, 2005; 106(13): 4018 - 4018. [Full Text] [PDF]

				D. G. Gilliland, C. T. Jordan, and C. A. Felix The Molecular Basis of Leukemia Hematology, January 1, 2004; 2004(1): 80 - 97. [Abstract] [Full Text] [PDF]

				Y. Ravindranath Down Syndrome and Acute Myeloid Leukemia: The Paradox of Increased Risk for Leukemia and Heightened Sensitivity to Chemotherapy J. Clin. Oncol., September 15, 2003; 21(18): 3385 - 3387. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gamis, A. S. Articles by Smith, F. O. Search for Related Content PubMed PubMed Citation Articles by Gamis, A. S. Articles by Smith, F. O. Social Bookmarking                            What's this?