BOURNEMOUTH, UK—For patients with chronic myelogenous leukemia (CML), even though the complete response rate for imatinib is similar to that with stem cell transplant, the drug is the first choice for many adults because they are ineligible for transplant due to age or lack of donor.
But the case is different for children, and the choice of treatment is far more difficult.
Children may have several more good years with imatinib, but they have better outcomes with transplant and more opportunities for it, notes Irene Roberts, MD, Professor of Pediatric Hematology at Hammersmith Hospital in London, speaking here at the annual British Cancer Research Meeting. “Current strategies for management require a choice between two radically different approaches.”
Dr. Roberts explained that the value of stem cell transplants in childhood CML was established last year by the European Blood and Bone Marrow Transplant Group registry, and through a national UK registry by the Children's Leukemia Working Party of the National Cancer Research Institute.
Childhood CML is a rare disease, and so is experience treating it. These registries help by comparing the natural history of childhood CML with that in adults, she continued.
“The UK Children's Leukemia Working Party reached the conclusion that for all children who have HLA-identical donors, whether sibling or unrelated donor, transplant is the first treatment option.”
Bite the Bullet
For the group of children who do not have an HLA-identical match, imatinib is a reasonable option, but the children must be monitored closely for signs of progression, Dr. Roberts said. Imatinib resistance usually heralds rapidly transforming disease.
Upon drug resistance, or if the child fails to respond to the drug at all, it is better to accept the risk of a transplant from any available donor, even though morbidity and mortality risks are high when mismatched donors are used, she said.
“At that point you've got to ‘bite the bullet’ and accept the rigors of transplantation and the reduced chance of a successful transplant.”
Dr. Roberts said there is quite often the option of a haplo-identical donor in children, because at least one parent or sibling is alive, and because children will tolerate a mismatch transplant better than adults.
Management of childhood CML is directed by its triphasic nature—treatment response is optimal in the chronic phase, with a median duration of four years; less successful in the accelerated phase, during which the median response is six to 12 months; and poor in blast crisis, with response durations of three to six months.
The first option, stem cell transplantation, offers a high rate of long-term cure but at the expense of significant mortality and morbidity.
The second option, molecular therapy with the tyrosine kinase inhibitor imatinib, induces a high cytogenetic response rate with minimal morbidity but with an unknown—and very low if any—chance of long-term cure.
Dr. Roberts said recent data indicate a predicted cure of greater than 70% for sibling-donor transplants and 60% with volunteer unrelated donors.
During accelerated phase or blast crisis, a stem cell transplant should be done as soon as possible using the best available donor (mismatched or haplo-identical donors if necessary) since the risk of treatment resistance is high.
But imatinib may also be used in the accelerated phase or myeloid blast crisis to achieve temporary control, with stem cell transplant carried out as soon as evidence of imatinib resistance is detected, she said.
Childhood Data Scarce
Childhood CML is rare, with the number of cases diagnosed each year only 10 to 20 in the UK and about 50 in the US. About 600 adults are diagnosed annually in the UK, she said.
Untreated CML is inevitably fatal, with median survival for adults of about five years.
“Transplant is the only known curative therapy for adults or children, but the difficulty is in knowing when to transplant,” Dr. Roberts said. “Adults who transform early from chronic phase to accelerated phase have a low one-year survival rate, but adults who transform later can live for 10 years or longer.”
There are so few children with CML that there are no rigorous survival data, but a recent epidemiologic study showed a five-year survival rate of about 14%, she said. That is a median figure, a mixture of the natural history of the disease plus effects of interventions.
“In adults there are data on the natural history of CML from patients treated with hydroxyurea,” Dr. Roberts said. Hydroxyurea reduces the white count quickly in chronic phase, but does not affect the natural history of CML or survival. “But data are hard to collect for children because there is always an intervention.”
In the UK, imatinib has been approved as primary therapy for CML in adults, as in the US, but Dr. Roberts said she is happy to see American scientists coming out on the side of stem cell therapy for children.
“A recent published commentary [Medical Pediatric Oncology, June 2003] questioned whether one should subject children to a procedure that has a definite morbidity and mortality,” she said. “Those authors came to independent findings that you have to go for a cure despite toxicities.”
A US oncologist asked about treatment in this country for pediatric and young CML patients considered bone marrow transplantation to still be the standard, although there are those who would try imatinib first.
“The standard is BMT, but some people don't want to take the chance,” said Thomas G. Gross, MD, Associate Professor and Chair for Pediatric Cancer at Ohio State University.
The decision doesn't come up often, he said. Ohio State sees only about one child with CML a year.
But the decision is even more difficult because children with CML, unlike those with acute leukemias, are not very sick at diagnosis, he said.
“When [parents and children] are told that with imatinib they might maintain that quality of life for five years or more, compared with the short-term morbidity and mortality of [a potentially curative] transplant, that's a tough decision to have to make.”
Blunderbuss vs. Rifle
If imatinib's targeted therapy is the “rifle” approach, then stem cell transplant is the “blunderbuss” treatment, Dr. Roberts said.
“Until we have combination treatments with imatinib that are curative, in children we need to be aiming for cure. Although transplant is a ‘blunderbuss’ approach, we need to employ strategies to reduce the mortality of the only curative regimen—transplant—while at the same time following the data from adult studies with great interest because they probably apply to children.”
Dr. Roberts said it would be ideal if researchers could manage to identify curative drug regimens, which would clearly be preferable, “but I think that's quite some years away.”