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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 414-420 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.2209 Cardiomyopathy in Children With Down Syndrome Treated for Acute Myeloid Leukemia: A Report From the Children's Oncology Group Study POG 9421
From the Division of Pediatric Hematology/Oncology, Lucile Packard Children's Hospital, Stanford, CA; Children's Hospital of Michigan, Detroit, MI; Medical College of Virginia, Richmond, VA; Arkansas Children's Hospital, Little Rock, AR; St Jude Children's Research Hospital, Memphis, TN; and Children's Oncology Group, Arcadia, CA Corresponding author: Gary V. Dahl, MD, Lucile Packard Children's Hospital at Stanford, Division of Pediatric Hematology/Oncology, 1000 Welch Rd, Suite 300, Palo Alto, CA 94304; e-mail: gary.dahl{at}stanford.edu
Purpose To determine the outcomes, with particular attention to toxicity, of children with Down syndrome (DS) and acute myeloid leukemia (AML) treated on Pediatric Oncology Group (POG) protocol 9421. Patients and Methods Children with DS and newly diagnosed AML (n = 57) were prospectively enrolled onto the standard-therapy arm of POG 9421 and were administered five cycles of chemotherapy, which included daunorubicin 135 mg/m2 and mitoxantrone 80 mg/m2. Outcomes and toxicity were evaluated prospectively and were compared with the non-DS–AML cohort (n = 565). A retrospective chart review was performed to identify adverse cardiac events. Results In the DS-AML group, 54 patients (94.7%) entered remission. One experienced induction failure and two died. Of the 54 who entered remission, three relapsed and six died as a result of other causes. The remission induction rate was similar in the non-DS–French-American-British (FAB) M7 (91.7%) and non-DS–non-M7 (89.3%) groups. The 5-year overall survival was significantly better in the DS-AML group (78.6%) than in the non-DS–M7 (36.3%) or the non-DS–non-M7 (51.8%) groups (P < .001). No age-related difference in 5-year, event-free survival was seen between patients younger than 2 years (75.8%) and those aged 2 to 4 years (78.3%). Symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML during or soon after completion of treatment; three died as a result of congestive heart failure. Conclusion The POG 9421 treatment regimen was highly effective in both remission induction and disease-free survival for patients with DS-AML. However, there was a high incidence of cardiomyopathy, which supports current strategies for dose reduction of anthracyclines in this patient population.
Children with Down syndrome (DS) have a marked predisposition to leukemia with a 10- to 20-fold increased risk compared with children without DS.1 Approximately 10% of newborns with DS develop a transient myeloproliferative disorder, which often resolves spontaneously with supportive care but can progress to myelodysplastic syndrome or to acute myeloid leukemia (AML), typically between 1 to 3 years of age.2 Before 5 years of age, there is an excess risk of acute megakaryocytic leukemia; approximately 10% of children enrolled on contemporary trials for AML have DS.2 After the initial report of the Pediatric Oncology Group (POG) protocol 8948, multiple cooperative-group trials confirmed that children with DS and AML (DS-AML) have superior outcomes compared with their non-DS counterparts.3-7 This difference is attributed to increased blast sensitivity to cytarabine and anthracyclines.8-10 Increased cellular sensitivity to chemotherapy also contributes to increased treatment-related morbidity and mortality for patients with DS-AML.4 Although infection has been reported as the major cause of morbidity in children with DS-AML, these children are also at increased risk for anthracycline-related cardiotoxicity.11 In 1994, POG initiated a prospective, randomized study in children with AML to determine whether event-free survival (EFS) improved when induction included high-dose cytarabine and consolidation included cyclosporine A, an MDR1-modulating agent. Patients with DS-AML were enrolled onto POG 9421 and were nonrandomly assigned to the standard arm of therapy. The outcomes of children without DS who were treated on POG 9421 have been previously reported.12 In this article, we describe the primary results of 57 patients with DS-AML who were treated on POG 9421. Overall, the remission induction rate and disease-free survival (DFS) were excellent; however, excessive cardiac toxicity was associated with this regimen in this patient population.
Patient Eligibility Patients were enrolled onto POG 9421 from February 15, 1995, until August 15, 1999. Eligibility criteria included age younger than 21 years and de novo AML with 30% or more nonlymphoid bone marrow blasts. Patients with more than 5% but less than 30% marrow blasts were eligible if they had typical AML karyotypic abnormalities [t(8;21) or inv(16)] or had myelofibrosis with unequivocal megakaryoblasts (French-American British [FAB] M7). Patients with therapy-related AML, prior myelodysplastic syndrome, or acute promyelocytic leukemia (FAB M3) were ineligible. The diagnosis of DS was made on the basis of the report from the treating institution. Written informed consent was obtained before enrollment. The protocol was approved by the institutional review board at each participating center. The study was evaluated at regular intervals by a data-monitoring committee.
Treatment Plan
Induction 1 Therapy Bone marrow evaluation was performed on day 15. For patients with hypoplastic bone marrow (< 20% cellularity by biopsy) and less than 10% blasts, induction 2 was delayed until peripheral-blood cell counts recovered (absolute neutrophil count > 0.5 x 109/L; platelet count > 75 x 109/L). If recovery was delayed, bone marrow aspiration was repeated on day 28 and then weekly until recovery of peripheral-blood counts or until evidence of residual leukemia was observed. Patients with residual leukemia at day 15 began induction 2 immediately.
Induction 2 Therapy
Consolidation Therapy
Required Observations
Cardiomyopathy
Statistical Analyses
Patient Characteristics A total of 654 patients with AML were registered onto POG 9421; 622 were eligible, and 57 (9.2%) of these had DS-AML. Table 1 lists the characteristics of patients with DS-AML compared with those patients without DS (with and without FAB M7 morphology). Children with either DS-AML or non-DS–M7 AML were younger at diagnosis than those in the non-DS–non-M7 cohort. Two thirds of the patients in the DS-AML group were younger than 2 years (median age, 20 months). The majority (79%) of patients with DS-AML had disease that was morphologically M7, whereas only 9% of patients with non-DS–AML had that FAB subtype (P < .0001). Sixteen patients (28%) with DS-AML had a history of a transient myeloproliferative disorder. No patient with DS-AML had CNS involvement. Three patients (5%) had granulocytic sarcoma that involved the facial or skull bones. Cytogenetic analysis of leukemic blasts was available for 47 patients. Favorable cytogenetics, such as inv(16) and t(8;21), were not observed. Nine patients had normal karyotypes with constitutional trisomy 21 only; three had constitutional mosaicism. The remainder had complex karyotypes with aneuploidy and translocations.
Induction Response and Toxicity All 57 patients with DS-AML were assessable for induction response (Table 2). Remission induction rates were similar for the DS-AML, non-DS–non-M7, and non-DS–M7 groups. Three patients in the DS-AML group did not enter remission. One 30-month-old girl with FAB M1 morphology experienced induction failure and died as a result of refractory leukemia. Two patients experienced early death during induction. One child with unrepaired tetralogy of Fallot (TOF) had a fatal cyanotic spell, and the other presented with fulminant meningococcemia at the time of AML diagnosis and died as a result of sepsis-related multiorgan failure 21 days after completing induction 1.
Consolidation Therapy and Outcomes Fifty-three of the 54 patients who experienced morphologic remission proceeded to consolidation chemotherapy. One patient with underlying congenital heart disease (CHD) developed florid CHF and pulmonary hemorrhage during induction 1. Remission was demonstrated by bone marrow aspiration after induction 1, and the family chose to discontinue AML treatment. The patient underwent mitral valve replacement and remained in first remission 4 years later without additional chemotherapy. Three patients experienced AML relapse, one on therapy and two within 9 months of therapy completion; all had the M7 morphology. Two died as a result of disease, and one died as a result of complications after an off-protocol allogeneic bone marrow transplantation, which was performed during second remission. One patient developed B-progenitor acute lymphoblastic leukemia (ALL) 8 months after completion of AML therapy. At last follow-up, both leukemias remained in first remission more than 3 years after completion of ALL therapy. The estimated 5-year DFS probability for the DS-AML cohort was 81.8% ± 4.5%.
Outcomes Stratified by Age
Treatment-Related Mortality Eight deaths occurred that were not related to leukemia. Two deaths during induction (meningococcemia, TOF spell) were described above. Two patients died after becoming neutropenic after consolidation 2. One died as a result of respiratory syncytial virus pneumonia. The second developed pulmonary edema with diminished fractional shortening by echocardiogram during admission for febrile neutropenia; 10 days after admission, she suffered a cardiopulmonary arrest. No infectious agent was identified, and autopsy revealed global, severe, dilated cardiomyopathy. Four deaths occurred after the completion of therapy, two were a result of CHF. One child had a partially repaired atrioventricular canal defect with residual mitral regurgitation and was taking furosemide and enalapril at baseline with adequate prechemotherapy cardiac function (FS 39%). Three months after completion of AML therapy, the patient presented in shock after a viral upper respiratory infection. All cultures were negative, and echocardiogram revealed FS 14% before her death. The second child had a moderate ventricular septal defect (VSD) with normal function and required no cardiac medications during therapy for AML. One day after completing therapy, she developed head and neck swelling. Echocardiogram demonstrated brachiocephalic venous thrombosis and dilated cardiomyopathy. She was treated aggressively with diuretics, cardiac inotropes, and afterload reduction but ultimately died 4 years later of recalcitrant cardiomyopathy. Two other off-therapy deaths were not related definitively to cardiac factors. One child presented in cardiopulmonary arrest 2 months after completion of therapy for AML and was pronounced dead on arrival. The second child died as a result of a respiratory illness 6 months after the completion of therapy. Postmortem examinations were not performed in either case. Prospectively gathered toxicity data revealed few differences between the DS-AML group and either the non-DS–AML group overall or the subgroup of patients without DS who were treated with identical therapy to that given to the DS-AML cohort (standard arm). Patients in the DS-AML group were twice as likely to have grade 3 or higher stomatitis. However, grade 3 or higher bacterial infections were experienced by 35% to 40% of patients in all groups. The rate of death as a result of toxicity during induction therapy was not significantly higher for patients with DS-AML (two of 57; 3.5%) compared with those without DS (14 of 560; 2.5%; P = 1).
Cardiomyopathy Clinically symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML (Table 4). All received full-dose therapy (daunorubicine 135 mg/m2 and mitoxantrone 80 mg/m2) or infant dose adjustment as prescribed. Five of these 10 patients had CHD, though only one required cardiac medications at baseline. Nine presented with symptoms either while on therapy or within 6 months of therapy completion. Three children died as a result of cardiomyopathy; all of these had CHD, although one had only a functionally insignificant ASD.
Ravindranath et al3 first reported the excellent outcome for patients with DS-AML in a group of 12 children on POG 8498 who were treated with high-dose cytarabine. Results from POG 9421 are comparable to those of other contemporary cooperative group trials (Table 5). Data from Children's Cancer Group (CCG) 2891 suggested that outcomes are worse with increasing age at diagnosis of DS-AML, particularly for children older than 4 years.20 Other cooperative group studies have not found a difference in outcome among patients younger than 4 years at diagnosis.5,6 In CCG/Children's Oncology Group (COG) 2971, a protocol with therapy similar to CCG 2891, there was a negative impact of increasing age for those patients older than 4 years, with fewer adverse events in the 2- to 4-year-old group than was seen on CCG 2891.21 On POG 9421, no patient was older than 40 months, and the analysis that compared outcomes for children 2 years of age or younger with those who were 2 to 4 years old did not reveal any significant differences.
Although patients with DS-AML have significantly better DFS than those with non-DS–AML, they also have increased treatment-related toxicity with intensive regimens.4,6,7 On POG 9421, prospectively gathered toxicity data did not reveal excess toxicity, including infection, in the DS-AML group. However, retrospective chart review identified a substantial incidence of early-onset cardiomyopathy. Anthracycline-associated cardiomyopathy results from oxygen free-radical damage and cardiac myocyte loss through apoptosis.22 Patients who develop early-onset symptoms (within 1 year of treatment) are at the greatest risk for chronic cardiac dysfunction.22 Risk factors for anthracycline-associated cardiomyopathy include higher cumulative dose (> 300 mg/m2), female sex, age younger than 4 years, and radiotherapy.23-25 In addition, Krischer et al11 found that trisomy 21 itself imparted a 3.4-fold relative risk for clinical cardiotoxicity. An increased risk of anthracycline-related cardiomyopathy in patients with DS may, in part, be caused by gene dosage effects of genes located on chromosome 21, including carbonyl reductase, which reduces anthracyclines to metabolites implicated in cardiotoxicity, and superoxide dismutase, which increases lipid peroxidation and hypersensitivity to oxidative stress.26 CHD occurs in 45% of children with DS.27 In this cohort, we did not find a significant relationship between age or presence of underlying CHD and the risk of cardiomyopathy. Although five of the 10 patients with symptomatic cardiomyopathy had CHD, 16 patients with CHD who survived long-term (ie, without AML relapse or death as a result of infection) did not develop cardiomyopathy, and five of the 10 patients with symptomatic cardiomyopathy did not have CHD. It is notable, however, that the three cardiomyopathy-related deaths occurred in children with CHD, which suggests that they had an impaired ability to tolerate a substantial decrement in cardiac function. Cardiomyopathy has been reported infrequently in prior DS-AML studies. None was reported in the 12 patients with DS-AML treated on POG 8948 (daunorubicine 135 mg/m2), though five (15%) of 34 patients with DS-AML who were treated on POG 8821 (daunorubicin 350 mg/m2) developed cardiomyopathy (Y. Ravindranath, personal communication, June 2007).28 In contrast, no difference on CCG-2891 was reported in cardiomyopathy rates between children with or without DS (1% v 2%) who received standard-timing induction therapy (daunorubicin 350 mg/m2).4 Among patients with DS-AML treated on the Berlin-Frankfurt-Munster (BFM)-93 and BFM-98 protocols with anthracycline doses of 220 to 240 mg/m2, 2.7% developed early-onset cardiomyopathy. Late cardiomyopathy occurred in 2 (4%) of 69 patients, which suggests that this anthracycline dose generally is tolerable in patients with DS-AML.29 On POG 9421, cumulative anthracycline exposure was substantial (535 mg/m2 using a 5:1 conversion for mitoxantrone).30 This dose, coupled with increased host sensitivity to oxidative stress, likely accounts for the striking incidence of cardiomyopathy. Interestingly, cardiomyopathy was only rarely reported in the POG 9421 prospectively gathered toxicity data (ie, two patient cases [1%] with grade 3 or greater cardiac function toxicity), and the true incidence became evident only on focused retrospective chart review. This reporting bias raises the question of whether the anthracycline doses on other DS-AML protocols are actually safe or if this toxicity has not been adequately captured previously. One might also expect the incidence of cardiomyopathy to be high for the POG 9421 non-DS cohort at this anthracycline dose. Prospective toxicity data identified only six (1.1%) of 560 patients with non-DS–AML who suffered cardiac function toxicity; however, this may also be an underestimate. Given the superior DFS for patients with DS-AML, there has been a trend toward developing protocols with lower-intensity regimens to minimize toxicity without sacrificing leukemia control, including treatment strategies without anthracyclines and with low-dose cytarabine. On POG 9421, one patient received only induction 1 therapy and experienced long-term remission, which suggests that a subset of patients may require minimal therapy. In a Canadian cohort of 18 patients with DS-AML, the EFS probability was 67% for patients treated only with low-dose cytarabine, which suggests that a large proportion of patients have exquisitely sensitive disease and can be cured with lower-intensity therapy, whereas a subgroup of as yet clinically indistinguishable patients require more intensive therapy.18 The high rate of cardiomyopathy on POG 9421 and the excellent EFS of patients with AML who were administered a BFM-98 protocol that provided only a 220 mg/m2 cumulative dose of anthracycline clearly support attempts to decrease anthracycline exposure for patients with DS-AML.5 The recently opened COG AAML0431 protocol includes daunorubicin 240 mg/m2 with no mitoxantrone for children with DS-AML who are younger than 4 years at diagnosis. Ultimately, the safe anthracycline dose for patients with DS-AML remains unknown. Given the increased sensitivity and incidence of CHD in these patients, attention to cardiac function and long-term follow-up are crucial components of DS-AML management. Patients with DS-AML may be an ideal population for prospective studies of anthracycline toxicity, including the roles of cardiac monitoring, wall stress studies, and serum troponin measurements, as well as early initiation of afterload reduction for patients with asymptomatic decrease in cardiac function. Moreover, research into the biology of DS-AML and identification of adverse features is essential to the prospective identification of those patients at risk for treatment failure and therefore in need of aggressive therapy.
The author(s) indicated no potential conflicts of interest.
Conception and design: Gary V. Dahl Administrative support: David Becton, Gary V. Dahl Provision of study materials or patients: Jeffrey W. Taub, Gita V. Massey, Kimo C. Stine, Susana C. Raimondi, David Becton, Yaddanapudi Ravindranath, Gary V. Dahl Collection and assembly of data: Maureen M. O'Brien, Myron N. Chang, Gita V. Massey, Susana C. Raimondi, David Becton, Gary V. Dahl Data analysis and interpretation: Maureen M. O'Brien, Myron N. Chang, Gary V. Dahl Manuscript writing: Maureen M. O'Brien, Jeffrey W. Taub, Myron N. Chang, Yaddanapudi Ravindranath, Gary V. Dahl Final approval of manuscript: Maureen M. O'Brien, Jeffrey W. Taub, Myron N. Chang, Gita V. Massey, Susana C. Raimondi, David Becton, Gary V. Dahl
We thank Angela McArthur, PhD, ELS, at St Jude Children's Research Hospital for her review and editing of this manuscript.
Supported in part by the National Institutes of Health Grant No. RO1 CA90916 (G.V.D.). A complete listing of grant support for research conducted by the Children's Cancer Group (CCG) and by the Pediatric Oncology Group (POG) before initiation of the Children's Oncology Group (COG) grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm. Presented in part at the 48th Annual Meeting and Exposition of the American Society of Hematology, December 9-12, 2006, Orlando, FL. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Leukemia 19:1355-1360, 2005[CrossRef][Medline] 6. Rao A, Hills RK, Stiller C, et al: Treatment for myeloid leukaemia of Down syndrome: Population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. Br J Haematol 132:576-583, 2005[CrossRef] 7. Craze JL, Harrison G, Wheatley K, et al: Improved outcome of acute myeloid leukemia in Down's syndrome. Arch Dis Child 81:32-37, 1999 8. Taub JW, Huang X, Matherly LH, et al: Expression of chromosome 21-localized genes in acute myeloid leukemia: Difference between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood 94:1393-1400, 1999 9. Frost BM, Gustaffson G, Larsson R, et al: Cellular cytotoxic drug sensitivity in children with acute leukemia and Down's syndrome: An explanation to difference in clinical outcome? Leukemia 14:943-944, 2000[CrossRef][Medline] 10. Zwaan CM, Kaspers GJ, Pieters R, et al: Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 99:245-251, 2002 11. Krischer JP, Epstein S, Cuthbertson DD, et al: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The Pediatric Oncology Group experience. J Clin Oncol 15:1544-1552, 1997[Abstract] 12. Becton D, Dahl G, Ravindranath Y, et al: Randomized use of cyclosporin A (CsA) to modulate P-glycoprotein in children with AML in remission: Pediatric Oncology Group Study 9421. Blood 107:1315-1324, 2006 13. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:475-481, 1958 14. Peto RPJ: Asymptotically efficient rank invariant test procedures. J R Stat Soc 135:185-206, 1972 15. Ravindranath Y, Yeager AM, Chang MN, et al: Acute myeloid leukemia in children: A randomized comparative study of purged autologous bone marrow transplantation versus intensive multiagent consolidation chemotherapy in first remission (Pediatric Oncology Group Study –POG 8821). N Engl J Med 334:1428-1434, 1996 16. Abildgaard L, Ellebaek E, Gustafsson G, et al: Optimal treatment intensity in children with Down syndrome and myeloid leukaemia: Data from 56 children treated on NOPHO-AML protocols and a review of the literature. Ann Hematol 85:275-280, 2006[CrossRef][Medline] 17. Gibson BES, Wheatley K, Hann IM, et al: Treatment strategy and long-term results in paediatric patients treated in consecutive UK AML trials. Leukemia 19:2130-2138, 2005[CrossRef][Medline] 18. Al-Ahmari A, Shah N, Sung L, et al: Long-term results of an ultra low-dose cytarabine-based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome. 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Lipshultz SE: Exposure to anthracyclines during childhood causes cardiac injury. Semin Oncol 33:S8-S14, 2006 (3 suppl 8)[Medline] 24. Nysom K, Holm K, Lipsitz SR, et al: Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 16:545-550, 1998[Abstract] 25. Lipshultz SE, Colan SD, Gelber RD, et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324:808-815, 1991[Abstract] 26. Kowald A, Klipp E: Alternative pathways might mediate toxicity of high concentrations of superoxide dismutase. Ann N Y Acad Sci 1019:370-374, 2004[CrossRef][Medline] 27. Roizen NJ, Patterson D: Down's syndrome. Lancet 361:1281-1289, 2003[CrossRef][Medline] 28. Ravindranath Y, Chang M, Steuber C, et al: Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): A review of four consecutive childhood AML trials conducted between 1981 and 2000. Leukemia 19:2101-2116, 2005[CrossRef][Medline] 29. Creutzig U, Diekamp S, Zimmerman M, et al: Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML. Pediatr Blood Cancer 48:651-662, 2007[CrossRef][Medline] 30. Reamon GH, Altman AJ, eds: Supportive Care of Children with Cancer: Current Guidelines from the Children's Oncology Group (ed 3). Baltimore, MD, Johns Hopkins University Press, 2004, pp 122-125 Submitted July 19, 2007; accepted October 12, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. All reported P values are two-sided. 
