Allogeneic (Donor) Stem-Cell Transplant Boosts Survival in Ph-Negative, Standard-Risk ALL
In the largest-ever clinical trial of treatment for adults with acute lymphoblastic leukemia (ALL), patients with standard-risk, Philadelphia-chromosome-negative ALL lived significantly longer after chemotherapy-induced first remission when they received allogeneic (donor) stem-cell transplantation instead of continued chemotherapy. Surprisingly, high-risk Ph-negative patients benefited less from having a stem-cell donor than the standard-risk patients. Autologous (self) stem-cell transplantation was less effective than continued chemotherapy for those patients without a stem-cell donor.
Blood, released online Nov. 29, 2007 (see the journal abstract)
(Blood. 2007 Nov 29 [Epub ahead of print])
Allogeneic (donor) bone-marrow stem-cell transplantation has become a treatment option for adults with acute lymphoblastic leukemia (ALL), a cancer of the white blood cells. White blood cells are produced in the bone marrow.
In allogeneic transplantation, doctors first destroy the patient’s bone marrow with high-dose chemotherapy or radiation therapy. Then healthy bone-marrow stem cells from a compatible sibling donor are infused into the patient, to produce new bone marrow.
Allogeneic transplantation causes what scientists call the “graft versus leukemia” effect: the immune cells produced by the new bone marrow recognize leukemia cells as cancer and attack them, unlike the patient’s original immune cells, which saw the leukemia cells as “self” - a normal part of the body.
Patients with ALL who do not have a matched donor sometimes undergo autologous (self) stem-cell transplantation. In this procedure bone-marrow stem cells are taken from the patient while in remission and preserved. Doctors then use high-dose chemotherapy or radiation therapy to kill cancer cells and the remaining bone marrow. Finally, doctors transfuse the preserved stem cells back into the patient where they produce new and ideally healthy bone marrow.
Autologous transplantation allows patients to receive higher doses of chemotherapy than would otherwise be possible, but does not produce a beneficial graft versus leukemia effect. Therefore, autologous transplantation is not thought to be as effective as allogeneic transplantation.
Because stem-cell transplantation can have severe side effects, it has mostly been used for patients who relapse after standard chemotherapy treatment or who are thought to be at high risk for relapse. Researchers designed the largest-ever clinical trial of treatment for adults with ALL to answer two questions about stem-cell transplantation:
- Could allogeneic transplantation, when done as a first treatment instead of chemotherapy, improve survival for patients both at standard risk and at high risk of relapse?
- Is autologous transplantation as effective as continued standard chemotherapy for patients who do not have a matched donor for allogeneic transplantation?
From 1993 to 2006 adult ALL patients with or without a genetic mutation called the Philadelphia (Ph) chromosome were enrolled in the International ALL Trial (MRC UKALL XII/ ECOG E2993). Patients with the mutation (called Ph-positive) are at the highest risk of relapse (see the protocol summary).
All patients enrolled in the trial first received high-dose chemotherapy, called induction chemotherapy. Patients who went into remission following induction chemotherapy could proceed to the main part of the trial. All patients in first remission who were under an established age limit and who had a matched sibling donor received allogeneic bone-marrow transplantation.
Researchers randomly assigned patients without a donor to receive either autologous transplantation or continued chemotherapy for two and a half years. Patients in both of these groups received an intensified dose of chemotherapy before their randomly assigned treatment.
The researchers classified patients as standard or high risk depending on their age, the number of white blood cells present at diagnosis, and the presence or absence of the Philadelphia chromosome. They compared overall survival, time to relapse or death, relapse rate, and non-relapse-related deaths between standard-risk and high-risk patients in each treatment group, and between the groups.
Investigators from the United Kingdom Medical Research Council and the Eastern Cooperative Oncology Group of the United States jointly planned and performed the International ALL trial. The study’s lead author was Anthony H. Goldstone, M.D., from the North London Cancer Network.
The results described here include only the trial’s Ph-negative patients, who can be at standard or high risk of relapse depending on other factors. Researchers will release data concerning the trial’s Ph-positive patients (those at highest risk of relapse) at a later date.
Out of 1,913 eligible patients in the trial, 1,646 were Ph-negative. Of these, 1,351 achieved first remission and went on to the main part of the trial. Overall, 53 percent of Ph-negative patients with a matched donor were alive five years after treatment compared to 45 percent of patients without a donor, regardless of treatment.
When analyzed separately, high-risk patients with a donor did not live significantly longer than those without a donor (41 percent versus 35 percent). This was because the transplant-related death rate was higher in the high-risk patients, mostly due to graft-versus-host disease and infection. Overall survival was significantly improved for standard-risk patients with a donor versus those without (62 percent versus 52 percent).
Among the 456 patients who did not have a donor, those randomly assigned to the chemotherapy group had both significantly improved time to relapse or death as well as better overall survival than those receiving autologous transplant. Non-relapse deaths, including those from transplant or treatment effects, did not differ between groups, for either standard-risk or high-risk Ph-negative patients.
The researchers then performed an analysis to compare patients who received chemotherapy (no donor) to those who underwent allogeneic transplant (donor available). Patients at standard risk but not high risk had better five-year and overall survival with allogeneic transplant.
One limitation of the study, explained Steven Gore, M.D., associate professor of oncology at the Johns Hopkins University in Baltimore, Md., was the toxicity of the regimen used to prepare the patient as part of allogeneic transplantation. “The particular transplant protocol used was more toxic than what would be considered standard…it’s possible that the transplant outcomes were negatively offset by the choice of transplant regimen,” he said.
In addition, said Alan Wayne, M.D., clinical director of the National Cancer Institute’s Pediatric Oncology Branch, the survival advantage was only demonstrated in patients under the age of 55, due to the design of the study. The benefits and risks of transplantation for patients older than 55 were not measured in this trial.
“Surprising though it might appear, the high-risk patients benefit less from having a donor than the standard-risk patients in terms of overall survival,” stated the authors. “This is an important finding since there is often a view that high-risk patients should go immediately to allogeneic transplant.”
“Sibling donor allogeneic transplant is the treatment of choice for adults with standard-risk ALL in remission, providing the greatest chance for a long-term survival. Autologous transplant has a less favorable outcome than consolidation/maintenance chemotherapy for those without a donor,” they concluded.
“This study should serve to further deter the use of autologous transplant as a treatment for ALL,” agreed Wayne. As for allogeneic transplantation, he said, “as stem-cell transplant technologies improve and render alternative donor transplants safer - such as transplants from an unrelated donor - this approach is expected to assume a greater role in the treatment of adult ALL.”