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Outcomes in acute myelogenous leukemia (AML), particularly in older individuals, have not changed substantially in the past 30 years, stated Margaret R. O’Donnell, MD, of City of Hope Cancer Center in Duarte, California, and so there is a pressing need for innovative strategies for managing these patients. As the population ages, the incidence of AML appears to be rising, according to the most recent practice guidelines from the National Comprehensive Cancer Network (NCCN).
Currently, the strongest predictors for relapse are cytogenetics and age, reported Dr. O’Donnell. Other prognostic factors for AML include a history of myelodysplasia, FLT3 or nucleophosmin (NPM) mutations, residual disease, and expression of multiple-drug resistance.
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| Dr. O’Donnell |
“The impact of cytogenetics has been very clear,” Dr. O’Donnell said. A study conducted by the Cancer and Leukemia Group B (CALGB 8461; Byrd JC et al. Blood 2002;100:4325–4336) revealed that AML patients with favorable-risk cytogenetics achieved better overall survival than those with intermediate-risk cytogenetics (7.6 years vs 1.3 years). Patients with poor-risk cytogenetics had “abysmal” results (0.5 year). “These data have actually been borne out in several subsequent trials and are fairly consistent across treatment regimens using conventional chemotherapy,” Dr. O’Donnell stated.
Age is another prognostic factor that has a major effect on outcomes. In patients older than age 60, the existence of favorable cytogenetics decreases while that of unfavorable cytogenetics doubles; more than half have expression of multiple-drug resistance and nearly half may have a history of antecedent myelodysplasia, reported Dr. O’Donnell. Based on recent study findings from CALGB stratified by cytogenetic age group, she added, “for patients older than age 60, only those who had favorable karyotypes achieved an appreciable 5-year survival rate (19%). The patients who had more than three karyotypic abnormalities had only a 25% chance of achieving a remission, compared with 40% for patients with a normal karyotype.”
Mutation of FLT3 was reported in the NCCN clinical practice guidelines to confer a worse prognosis in AML. In a study of younger adults (16 to 60 years old) with AML and normal cytogenetics (Frohling S et al. Blood 2002;100:4372–4380), those with a partial tandem duplication of the FLT3 locus had a 5-year survival rate of 20%, compared with 42% of patients with no such FLT3 gene abnormality. Currently, mutational analysis is not commonly available, Dr. O’Donnell admitted, but hematopathologic divisions of referral centers may provide such screening.
The NPM mutation is an abnormality that is receiving
recent attention. “It seems to make cells more sensitive to the cytotoxic
stress of chemotherapy,” according to Dr. O’Donnell, and nearly one third of
patients with this mutation subsequently develop FLT3 gene mutations.
Preliminary study results have shown that disease-free survival may be better
in patients who have only an NPM mutation than in those with isolated FLT3
gene mutations, she stated.
Finally, Dr. O’Donnell emphasized the importance of obtaining sufficient samples of marrow or peripheral blood blasts at diagnosis for cytogenetic analysis. Although these data have not yet had an impact on induction therapy, she added, such information, as well as other prognostic factors, can play a larger part in the selection of appropriate consolidation therapy for AML.
When considering options for consolidation therapy for AML, said Dr. O’Donnell, several factors warrant attention: risk of relapse, risk of treatment-related mortality, an effective salvage option, and quality of life. Since the long-term complications of alternatives such as autologous hematopoietic stem cell transplantation (HSCT) differ from those of high-dose cytarabine (Ara-C) followed by allogeneic HSCT, achieving similar results with less morbidity is always the goal, she reminded the audience. In addition, factors such as patient age, comorbid conditions, and features of the disease at diagnosis (including elevated leukocyte counts or number of cycles of induction needed to achieve remission) should be factored in as well, according to the recent NCCN clinical practice guidelines.
Current choices for consolidation strategies are multiple cycles of high-dose Ara-C, one or more cycles of high-dose Ara-C followed by autologous HSCT, or allogeneic HSCT from sibling or unrelated donors. For patients younger than age 60 who have achieved remission, high-dose Ara-C is a recommended option by the NCCN. “For patients who have good-risk cytogenetics, we’re looking at complete response (CR) rates of about 60% with multiple cycles of high-dose Ara-C,” reported Dr. O’Donnell. For patients younger than age 60 with intermediate-risk cytogenetics, high or intermediate doses of Ara-C and matched sibling or autologous HSCT are recommended by the NCCN guidelines panel.
The NCCN panel considers decisions regarding autologous
versus allogeneic HSCT to be influenced by three major factors: the expected
relapse rate with standard chemotherapy; the additional morbidity and mortality
associated with the transplant procedure; and salvage options. A combined
EORTC/GIMENA trial (Suciu S et al. Blood 2003;102:1232–1240) compared
the two transplant options in younger (< age
46) patients with AML. In the favorable-risk group, the results between the
autologous and allogeneic transplant groups differed little.
However, the NCCN guidelines stipulate that the long-term toxicities associated with allogeneic HSCT are prohibitive for patients with good-risk cytogenetics and that this option is best reserved for patients who have relapsed. For patients with intermediate-risk cytogenetics, the guidelines list transplant-based options using either sibling or autologous stem cell sources to be an appropriate step. For patients with poor-risk cytogenetics or those with therapy-related AML or prior myelodysplasia, the NCCN panel endorsed allogeneic HSCT with sibling or unrelated donors or a clinical trial as consolidation therapy.
For AML patients older than age 60, consolidation therapy is a challenge. The NCCN panel recommends that such patients, regardless of cytogenetics, be enrolled in a clinical trial to assess novel ways to maintain remission. Investigational alternatives being explored in this population include the use of somewhat higher doses of Ara-C, vaccine therapy after one or two cycles of consolidation chemotherapy, hypomethylators or histone deacetylators, and reduced-intensity allogeneic HSCT. “Autologous HSCT may be appropriate for patients up to age 65 with normal cytogenetics,” Dr. O’Donnell said. “Reduced-intensity HSCT may be an option for patients up to age 70, with outcomes based on remission and performance status,” she concluded.
Expanded unrelated donor typing, new immunosuppressive agents, better supportive care, and reduced-intensity conditioning represent the major advances in allogeneic bone marrow transplantation, reported Dr. O’Donnell. “Unrelated donors can be identified within a fairly reasonable time for the majority of patients (70%–80%),” which Dr. O’Donnell considers a major reason for the feasibility of performing transplantations in patients older than age 60.
Growth factors allow for much more rapid engraftment than previously was possible. “With reduced-intensity peripheral blood SCT, neutropenia usually lasts in the range of 10 days, rather than 20 or 22 days with standard conventional marrow transplantation,” Dr. O’Donnell explained.
As previously mentioned, reduced-intensity conditioning regimens may lead to improved patient outcomes in transplantation. Conditioning regimens are being customized for specific diseases and ages, in an attempt to achieve a balance between reduced regimen-related toxicity and disease control, she said. Alternative conditioning regimens include fludarabine/melphalan/alemtuzumab, nonmyeloablative use of fludarabine and total-body irradiation, and targeted radioimmunotherapy.
A large international trial of 112 patients who underwent reduced-intensity HSCT for AML was mentioned by Dr. O’Donnell. Study criteria included age older than 50 at first CR and any age beyond first CR. The conditioning regimen in the majority of patients included 200 cGy of total body irradiation and fludarabine. Most patients received peripheral blood stem cells, nearly evenly divided between sibling and unrelated donor transplants. “Fifty percent of patients in first remission who were older than age 50 remained in CR at 2 years, and surprisingly, a third of patients with poor risk disease were still alive at 2 years,” said Dr. O’Donnell.