Comment on Whitlock et al, page 4043

In this issue of Blood, Whitlock and colleagues from the Children's Cancer Group (CCG) present the largest series to date confirming prior observations that children with Down syndrome (DS) and standard-risk acute lymphoblastic leukemia (ALL) have an inferior outcome when compared with children with standard-risk ALL but without Down syndrome.

Down syndrome (DS) is the most common factor predisposing children to the development of leukemia. Three distinct patterns of leukemia have been well described in children with DS: transient myeloproliferative disorder (TMD), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). However, only recently have children with DS and leukemia been systematically enrolled on prospective clinical trials. In fact, for many years there was hesitation on the part of parents and physicians to aggressively treat many children with DS and leukemia.1,2  The recent enrollment of these children on large cooperative group clinical trials has subsequently revealed numerous unique features about the epidemiology and biology of leukemia in these children, furthering our understanding of the mechanisms underlying leukemogenesis.1 

Treatment strategies for children with DS and leukemia are now becoming apparent. It is now understood that most children with TMD will respond to close observation and supportive care, and most research efforts are now directed toward the early identification of children with high-risk TMD that would benefit from therapy. For AML, Gamis et al3  from the CCG recently demonstrated excellent outcomes for children with DS using therapy that was less intensive than that currently used for the treatment of AML in children without DS.

Whitlock and colleagues now present clinical and laboratory characteristics and outcomes for 179 children with DS and ALL who were treated on CCG protocols between 1983 and 1995, comparing these children to 8268 children without DS, also enrolled on the same prospective clinical trials. This retrospective analysis clearly demonstrates the inferior outcome of children with DS and standard-risk ALL when compared with children with standard-risk ALL but without DS. The reasons for a worse outcome in these DS patients is not clear, although possible explanations include a decreased prevalence of hyper-diploidy in DS patients, a favorable prognostic factor in childhood ALL.

Of interest, children with DS and high-risk ALL had outcomes comparable with children without DS but with high-risk ALL, perhaps suggesting the ability of DS patients to tolerate more aggressive treatment regimens, despite a known propensity for increased toxicities due to the altered metabolism of chemotherapy agents used to treat ALL (eg, methotrexate). Given the inferior outcome in DS children with standard-risk ALL, clinicians should use caution when considering dose reductions for chemotherapy agents due to toxicity concerns in these children. Less intensive treatment could have an adverse effect on the outcome of these children.

As Lange so eloquently stated, “The current management strategy for these disorders, with few exceptions and considerable caution, is simple: in TMD, `do nothing'; in AML, `do less'; and in ALL, `do more.'”1p512 This study argues for “doing more” for standard-risk children with DS, with treatment on more intensive regimens or with therapy that is tailored to the unique biology of the DS host and leukemic blasts. ▪

Lange B. The management of neoplastic disorders of haematopoiesis in children with Down's syndrome.
Br J Haematol
Churchill LR. Bone marrow transplantation, physician bias, and Down syndrome: ethical reflections.
J Pediat
Gamis AS, Woods WG, Alonzo TA, et al. 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.
J Clin Oncol