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Assessing 'Cure' in AML
Abstract & Commentary
By William B. Ershler, MD, Editor
Synopsis: Two recent reports provide information regarding durability of complete remission for those treated for acute myeloid leukemia. The rapidity with which blasts are cleared from the peripheral blood turns out to be an excellent predictor of relapse free survival. For those who remain in complete remission at 3 years, cytogenetic features and patient age remain predictors of relapse.
Sources: Yanada M, et al. Potential cure of acute myeloid leukemia: Analysis of 1069 consecutive patients in first complete remission. Cancer. 2007;110:2756-2760.; Elliott MA, et al. Blood. 2007;110:4172-4174.
Although the majority of patients with acute myeloid leukemia (AML) achieve complete remission following standard induction chemotherapy with agents such as daunorubicin and cytosine arabinoside, most will relapse and relatively few are cured. Clinicians are well aware that cytogenetic abnormalities and advancing age are predictive factors, as well as the number of cycles it takes to induce remission, but two recent reports indicate additional useful prognostic information.
Rate of Blast Clearance Elliott and colleagues from the Mayo Clinic in Rochester, Minnesota examined the outcomes of 86 adult AML (excluding acute promyelocytic leukemia) patients achieving complete remission (CR) during the years 1994 to 2006. All patients received standard induction chemotherapy (idarubicin at 12 mg/m2 per day [n=70] or daunorubicin at 45 mg/m2 per day [n=16] on days 1-3 in conjunction with continuous infusion cytarabine at 100 mg/m2 per day on days 1 to 7) followed by consolidation therapy which was most typically one repeat of the induction regimen followed by three cycles of high-dose cytarabine (3g/m2 q12 hours on days 1, 3 and 5). Patients over the age of 60 years received the same schedule but the dose of cytarabine during consolidation was 1.5 g/m2. The majority of patients (83%) completed at least 3 cycles of consolidation. At the time of analysis, 37 (43%) had died, primarily of relapsed leukemia (97%). Of the remainder, the median survival of surviving patients was 42.5 months (range 8-133). The median overall survival (OS) and relapse free survival (RFS) were 30.2 months (range 5.5-133) and 14 months (range 2-131.5), respectively.
Of the 86 patients, 73 had circulating peripheral blood blasts (PBB). PBB clearance was defined as the interval in days from the first day of induction chemotherapy until the day that PBB were not detected in the peripheral blood. The median time to PBB clearance was 5 days (range 2-10). The rate of relapse for those who cleared PBB on or before day 5 (n=45) was less than that for those who took greater than 5 days for blast clearance (33% vs 79%, respectively; P<0.001). Furthermore, RFS and OS were better for those who cleared PBB by or on day 5. The prognosis for those who cleared blasts by day 3 was even better, with a relapse rate of 12.5%, compared with 47% for those who cleared on days 4 or 5, or 78% for those who cleared on days 6 or beyond. In univariate analysis, clearance of PBB gave the strongest prediction of RFS and OS. Other factors which significantly influenced these parameters was the necessity for two induction cycles to achieve CR and unfavorable cytogenetics. A number of other factors were tested, but did not reach significance. These included age, gender, FAB group, de novo vs secondary AML, leukocyte count, platelet count, marrow blast %, and LDH. By multivariate analysis, clearance of PBB was the only independent factor that retained prognostic value with regard to RFS (P=0.001).
Cures Yanada and colleagues report the experience from M.D. Anderson Cancer Center regarding late relapse of AML was also recently published. This analysis included data from 1069 consecutive AML patients in CR (between 1991 and 2003) for whom factors associated with late relapse were examined. For the group as a whole, the failure rate (recurrence or nonrecurrence mortality per 100 years of patient follow-up) was 69.1, 37.7, 17.0, 7.6, and 6.6 for years 1, 2, 3, 4, 5 respectively. Age at diagnosis and cytogenetics both influenced long-term survival. However, the effect of cytogenetics on RFS was constant throughout the first 3 years whereas the effect of age increased with time. The probability of RFS for patients alive at 3 years was 84% that they would remain alive through 6 years. For those with "favorable" cytogenetics (22%, including t(8:21), inv(16), and t(15:17)) the serial 5 year survival rates were 30.9, 30.9, 5.8, 2.5, and 2.5. For those with "intermediate" cytogenetics (including normal, -Y, 11q23, or others), or "adverse" cytogenetics (including monosomy or deletion of long arm of chromosome 5 and/or 7) long-term RFS was less certain. For those with intermediate cytogenetics alive at 3 years, those <60 years old had excellent outcomes but for those 60 years and older there remained a substantial risk for relapse, even after 3 years of CR (failure rate by 6 years of 43.5%). Thus, this analysis demonstrates that the risk of treatment failure differs over time, according to both cytogenetic profile and age.
These are two reports that should prove useful to those immersed in clinical practice. Although there are a number of new laboratory findings, such as the identification of the molecular mutation NUCLEOPHOSMIN-1 which show promise as useful prognostic tools, these tests are not readily available.1 Yet, the findings from these reports provide confidence for those relying on clinical intuition. We learned from the Mayo Clinic series that those who achieve rapid blast clearance have the most durable CRs with significantly improved RFS and OS. Although a relatively small series, the patients were all treated similarly and carefully followed. It was remarkable that of all the factors, including age and cytogenetics, the rate of blast clearance provided the most useful information.
From the larger but less well described M.D. Anderson series (with regard to treatments received), additional useful information was presented. The take-home message was that the relapse rate after 3 years of CR was very low for those with "favorable" cytogenetics (any age) and for those younger than 60 years with "intermediate" cytogenetics.
With the increasing availability and utilization of allogeneic stem cell transplant for patients with AML in CR, including those beyond age 60 at some Centers, these reports might prove useful in guiding decision making.
1. Mrozek K, et al. Curr Opin Hematol. 2007;14(2):106-114.