BARCELONA, SPAIN—Does the evidence warrant a reconsideration of the use of autologous stem cell transplantation for adults with acute lymphoblastic leukemia? That was the question proposed here at the European Hematology Association Congress in a session by Anthony Goldstone, MD, Consultant Pathologist at University College in London.
Dr. Goldstone explained that because of improvements in techniques since the 1990s—especially the availability of minimal residual disease (MRD) analysis (which he compared with betting on the match result while the game is in progress—that autologous transplantation could be an option for patients not eligible for allogeneic transplantation or who do not have a donor, in order to avoid lengthy intensive chemotherapy.
The Medical Research Council-Eastern Cooperative Oncology Group (MRC-ECOG) UKALL 12 study, begun in 1993 with approximately 2,000 patients, provided the data underpinning Prof Goldstone's views on this difficult-to-treat malignancy, and he presented evidence for continuing studies among adult patients with ALL in the modern era of monitoring for MRD.
“What's happened in the last five years is that the value of measuring MRD has been learned from pediatricians,” he said in an interview.
It is now known based on that experience that even when the outlook appears positive for such children, that there may be refractory disease in small amounts not eliminated by initial therapy. “You can now factor in MRD analysis—in addition to all the pre-treatment characteristics—to give a whole extra dimension to help decide whether to transplant,” Dr. Goldstone said.
The implication is that the 7% survival inferiority associated with autologous transplantation seen in the UKALL 12 study may have been partly the consequence of autografts being given to patients who still had MRD for whom there was thus little or no chance of success compared with patients who were molecularly free of disease.
Dr. Goldstone suggested that had MRD analysis been available at the time the UKALL study began, that the inclusion criteria for considering autologous transplantation would have been different, but that this omission now opens a window of opportunity for further investigation.
The aim of UKALL 12 had been to give sibling transplants to all eligible patients for whom a donor was available and to randomize the others between extensive, long-lasting chemotherapy (2.5 years) and the much shorter regimen of autografting (6 months in duration). Following confirmation from the study that allografts were superior in all groups and all ages (even though the 40 to 50 percent survival rates at five years in the best prognosis groups did not approach the success rates found in pediatric disease) it was clearly a disappointment that autografts resulted in significantly lower rates of overall survival than those for arduous chemotherapy, Dr. Goldstone said.
Expand Age Range for ‘Pediatric Style’ Regimens
He also discussed the scope for extending “pediatric style” regimens to older patients—i.e., those in their teens and 20s, among whom there may be patients who respond much better than if treated with “adult regimens,” since results have already shown that using pediatric regimens can be better than trying to transplant a patient under the age of 30 with either allo- or auto-grafts.
Defining risk in adults with ALL is paramount, Dr. Goldstone emphasized, noting the different factors defining risk, such as age, and particularly blast cell count—“the higher it is, the worse it is in terms of prognosis.”
Next for testing, he suggested, was to check for any of the chromosome abnormalities in the bone marrow known to produce unsuccessful results with conventional chemotherapy. All of these factors, he stated, should be combined to define high or standard risk before treatment begins.
Today it is possible to “widen the constituency of eligibility for transplantation” because matched unrelated donor transplants can produce results in line with those for sibling donors, he said. In addition, for patients over age 40, results with conventional therapy are so poor that techniques that harness the graft-vs-leukemia effect, such as reduced intensity conditioning—aka “mini-transplants”—and although still risky, might still produce clearly superior outcomes.
Dr. Goldstone said he was impressed by the rationale of these approaches, which reduce the ablative toxicity of transplantation while permitting the graft to “eat away slowly” at the residual disease, and there is good evidence that older patients can survive such transplants and benefit—”unlike a myeloablative transplant, which is very different over the age of 40 or 45.”
Dr. Goldstone acknowledged, though, that problems with engraftment and re-emergence of the disease, as well as with opportunistic infections, remain, and urged the continuation of randomized studies.
Asked whether he thought MRD could be used as the main focus for risk stratification since it incorporates both response to treatment and the biology of the disease, whereas the other main risk factor of age reflects only the biology of the disease, Dr. Goldstone said that that would be too big a leap, to move only to MRD-based analysis, rather than incorporating the other factors still known to be important.
He said it would be difficult to abandon cytogenetics and molecular markers in decision-making, since there was so much emerging about the molecular basis of hematologic malignancies. MRD adds more to decision making, but there is still controversy to be resolved by future studies.