50 Years Ago in The Journal of Pediatrics:

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Steffey JM. J Pediatr 1962;60:183-90

The history of childhood acute lymphoblastic leukemia (ALL) therapy is a Cinderella story. Fifty years ago, a child with ALL had a dismal prognosis. In The Journal in 1962, Steffey bemoaned the rate of children experiencing leukemia relapse in the central nervous system (CNS), particularly the meninges. Indeed, as a child, I remember vividly praying in church every Sunday that a boy 2 years older than me would overcome his ALL. He died after approximately 2 years, much like the children Steffey described.

Steffey reported 6 cases of meningeal involvement complicating leukemia. By the 1960s, because of combination and systemic chemotherapy, the likelihood of remission was high, but survival only averaged a few years. Three-quarters of children later presented with CNS leukemia, manifested by headache, vomiting, and nuchal rigidity. Lumbar cerebrospinal fluid analysis showed elevated opening pressure, pleocytosis with lymphocytosis and leukemic blasts, elevated protein, and often hypoglycoracchia.

Five of Steffey’s patients received intrathecal methotrexate and experienced relief of clinical manifestations. Steffey presaged, “Whether prophylactic intrathecal injections of methotrexate at monthly intervals would yield better results than treatment when the complication has developed merits further investigation.” This is the standard 50 years later; however, 20 years would pass after Steffey’s article before prophylactic intrathecal chemotherapy was shown to be effective.¹

Why the delay? Craniospinal irradiation was initially found to protect the CNS from becoming a sanctuary for ALL, but the resulting myelosuppression was excessive. This led to the use of cranial irradiation plus intrathecal chemotherapy, until altered intellectual function became apparent in survivors. Triple intrathecal chemotherapy emerged, and was later replaced by intrathecal methotrexate alone.

A theme emerges: Effective therapies are discovered, children are overtreated or toxicity ensues, and therapy is then refined to mitigate damage. We would do well to heed the lesson here. When a brief report such as Steffey’s comes along, sometimes we should take notice sooner than later. We do not have to cure every last child of a disease and witness severe toxicity before changing course. Even Cinderella in her pumpkin coach knew the admonition of philosopher George Santayana: “Those who cannot remember the past are condemned to fulfill it.”

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Reference 

1. Sullivan MP, Chen T, Dyment P, Hvizdala E, Steuber CP. Equivalence of intrathecal chemotherapy and radiotherapy as central nervous system prophylaxis in children with acute lymphatic leukemia: a Pediatric Oncology Group study. Blood. 1982;60:948–958
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