Childhood leukemia: tackling the challenge of CNS relapse

Clinicians have achieved a gratifyingly high success rate in treating childhood leukemias—with up to 90 percent five-year survival for acute lymphoblastic leukemia and 60 percent for acute myeloid leukemia.

Now, a major challenge is to improve treatment of central nervous system (CNS) leukemia in these patients, said Ching-Hon Pui, MD, Oncology chair. Two to 3 percent of patients present with overt CNS leukemia at diagnosis, and 3 to 8 percent develop relapse in the CNS during or after treatment.

“Because the control of cancer in the bone marrow has improved so much, CNS relapse has become proportionally more important,” Pui said. “If we are to further increase the cure rate and improve the quality of life of our patients, we need to concentrate on preventing CNS relapse.”

A key goal is to improve chemotherapy for preventing such relapse and avoid the use of cranial irradiation, Pui said. He and Scott Howard, MD, Oncology, reviewed the current state and directions for such treatment in an article in the March 2008 issue of The Lancet Oncology.

While cranial irradiation for prevention and treatment of CNS relapse has proven effective, that effectiveness is offset by often severe side effects, wrote Pui and Howard. These side effects include stunted growth, neuro-cognitive problems, multiple endocrinopathies and secondary cancers.

“Most clinicians still feel strongly that high-risk patients need radiation treatment, because they think that without radiation such patients have a very high risk of relapse,” Pui said. “But I disagree. I think that we should avoid using radiation in all patients, even those at high risk of relapse. With optimal chemotherapy we can reduce the relapse rate to a very low level. We should reserve radiation for the treatment of relapse. What’s more, the salvage rate for CNS relapse in patients who did not receive prior radiation is very high, and if patients who are treated with radiation develop bone marrow or CNS relapse later on, it is more difficult to treat them successfully.”

Pui and Howard have found optimal “triple treatment” with three anticancer drugs—methotrexate, cytarabine and hydrocortisone—to be effective in preventing and treating CNS relapse. They cite studies showing that such treatment avoids the side effects of irradiation, while achieving comparable success. The intrathecal treatment they use involves administering the drugs directly into cerebrospinal fluid by lumbar puncture so that the drugs circulate in the cerebrospinal fluid that bathes the brain and spinal cord.

“Optimisation of intrathecal therapy to allow adequate distribution of intrathecal therapy in the CNS and to avoid traumatic lumbar puncture which leads to an increase in CNS relapse are essential for the success of CNS-directed treatment,” Howard noted.

Even with such success, Pui said, studies are still ongoing to explore the best strategies for intrathecal and systemic chemotherapy treatments and to determine whether triple treatment affects bone marrow relapse of the leukemia.

One approach to treating CNS relapse has been to use bone marrow transplantation. In this treatment, the patient is given massive chemotherapy and radiation to eradicate bone marrow cells, including the leukemic cells. Then the bone marrow is restored by transplanting stem cells.

“However, there are no conclusive trials that show this approach to be superior to intensive chemotherapy,” Pui said. “So, whether transplantation has any role in the treatment of isolated CNS relapse is uncertain.”

“CNS relapse and bone marrow relapse are competing events,” Pui said. “CNS relapse may just be the tip of the iceberg—meaning that while we may see CNS relapse, there may be hidden leukemia in the bone marrow. If you have good CNS control, you’d better have good bone marrow control, because if you do not, the patient may relapse in the bone marrow later on and be worse off.

“At St. Jude, our treatment protocols involve detecting subclinical CNS leukemia early and treating it aggressively,” Pui continued. “Such treatment has allowed both good CNS and bone marrow control. Therefore, we have achieved excellent outcomes for our patients.”

Pui added that the bottom line is that radiation of the brain should not be used for preventive purposes. It should be used only for the treatment of CNS relapse in patients who really need it to survive.

Also, in The Lancet Oncology article, Pui and Howard emphasise the importance of continuing research, concluding that “despite impressive gains in the management of CNS disease in children with leukaemia, effective chemotherapy is clearly needed for patients who have had a CNS relapse or have a very high risk of developing this condition.”

(Source: The Lancet Oncology: St. Jude Children's Research Hospital: April 2008)