Refined Risk Stratification Guides Leukemia Transplant Decisions



SAN FRANCISCO – Risk stratification is becoming progressively more refined in adults with acute leukemia, helping to identify patients most likely to benefit from transplantation, according to Dr. Robert S. Negrin.

"What has become clear is that there is important prognostic information that one can gain from the patient at the time of diagnosis that can really help guide therapy," Dr. Negrin, a professor of medicine and chief of the division of blood and marrow transplantation at Stanford (Calif.) University, said at the annual Oncology Congress.

"Clearly, one can identify patients who are at higher risk for [poor outcome]. They can be split, cytogenetics being the first pass and then molecular markers being the second pass," he told attendees.

AML Status Predicts Outcome

Typically, three groups of adults with acute myeloid leukemia (AML) are offered transplantation, he said: those having a failure of induction chemotherapy, those in a first complete remission but having an intermediate or high risk for relapse, and those beyond first complete remission.

Dr. Robert S. Negrin

"The No. 1 predictor of outcome is the status of the disease at the time of transplant consideration, by far and away," noted Dr. Negrin. With transplantation, the 10-year overall survival rate is only 17% for the patients with induction failure or relapsed disease, in the Stanford experience. But patients in first complete remission fare better, at 57%.

Outcomes among patients in first complete remission are varied, however, with cytogenetics identifying distinct subgroups: better risk (10%-15% of these patients), poor risk (20%-30%), and intermediate risk (all the rest).

The better-risk subgroup does fairly well with chemotherapy alone, according to Dr. Negrin. "Those are patients that we generally would recommend not to consider transplant in first complete remission. One would only consider transplant at time of relapse or second remission." At the other extreme, the poor-risk subgroup "should clearly be considered for transplant up front."

Then there is the large subgroup having intermediate risk, many of whom have normal cytogenetics. Molecular markers have shown these cytogenetically normal AMLs to be highly heterogeneous (Blood 2010;115:453-74) – information that is now being used to guide transplant decisions.

For example, patients with mutation of the nucleophosmin (NPM1) gene have a favorable prognosis and are generally managed with chemotherapy alone. In contrast, their counterparts with a mutation of the FMS-like tyrosine kinase 3 (FLT3) gene have an unfavorable prognosis with chemotherapy and may fare better with transplantation.

"So this [molecular analysis] is very helpful because it helps split those patients with cytogenetically normal AML into favorable and unfavorable groups of patients," he commented. And he predicted that such molecular risk stratification will likely be even further refined in the future.

Research is also showing that molecular prognostic information may modify cytogenetic prognostic information. For instance, in the better-risk subgroup in first remission, among patients having the favorable inversion 16 cytogenetic profile, those with a KIT mutation have poorer survival with chemotherapy than do their counterparts with wild-type KIT (J. Clin. Oncol. 2006;24:3904-11).

"By and large, unfortunately, negative markers overcome the positive ones. That’s obviously a gross generalization, but unfortunately, it is reasonably accurate," Dr. Negrin commented. "So just finding a favorable cytogenetic abnormality does not tell the whole story. One needs to do the molecular studies as well."

And doing them early is key.

"Cytogenetic and molecular studies should be done on all leukemic patients," he stressed. "When we see patients in referral, a lot of patients still are not having these molecular studies done on a routine basis, and that’s unfortunate because it’s very important that we do the best we can to try to [evaluate] patients with the most advanced technologies we have. ... It’s very important that we identify these patients up front to treat them as appropriately as we can."

Know bcr-abl Status in ALL

Risk stratification is also improving among adults with acute lymphoblastic leukemia (ALL). In these cases as well, three groups are typically offered transplantation: those having a failure of induction chemotherapy, those in first complete remission having high-risk disease, and those in either a second complete remission or first relapse.

"Clearly, one can identify patients who are at higher risk for [poor outcome]. They can be split."

Disease status at the time of transplantation is also the best predictor of outcome in ALL. In the Stanford experience, the 10-year rate of overall survival is 62% for patients who undergo transplantation in first complete remission, compared with 43% for patients having relapsed or refractory disease at transplantation.

In terms of cytogenetics, the bcr-abl translocation (Philadelphia chromosome) is "a very ominous" finding among patients with B cell–lineage ALL, according to Dr. Negrin. These patients are not cured by intensive chemotherapy and derive only short-term benefit from tyrosine kinase inhibitors. Transplantation can achieve cure, however, although less often than in other ALL subtypes.


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