Post-Remission Therapy that Includes All-Trans Retinoic Acid is Effective for Acute Promyelocytic Leukemia
Giving a reduced dose of the chemotherapy drug mitoxantrone together with all-trans retinoic acid (ATRA) during consolidation (post-remission) therapy in APL patients with low- or intermediate-risk disease appeared to result in fewer toxic effects but maintained the relatively high disease-free survival rates achieved in an earlier phase II study. For high-risk patients, adding cytarabine to the combination of ATRA plus idarubicin used in consolidation therapy appeared to reduce the relapse rate compared with what had been seen in the earlier study.
Blood, published online April 14, 2010 (see the journal abstract).
Acute promyelocytic leukemia (APL) is an uncommon but aggressive subtype of acute myeloid leukemia (AML) in which there are too many immature blood-forming cells in the blood and bone marrow. Initial, or induction, treatment with an anthracycline chemotherapy drug plus all-trans retinoic acid (ATRA), which is a relative of vitamin A, or with arsenic trioxide induces remission in most patients. After the leukemia is in remission, patients undergo a second phase of treatment known as post-remission, or consolidation, therapy to kill any cancer cells that remain in the body and could cause a relapse. In APL, consolidation therapy is usually followed by a year or more of maintenance therapy.
In an earlier study of APL treatment, the LPA99 trial, researchers from the Spanish cooperative PETHEMA group showed that APL patients who received ATRA and anthracycline-based chemotherapy for consolidation therapy had a much lower rate of disease relapse than patients in a previous study who received anthracycline chemotherapy alone for consolidation therapy. In LPA99, consolidation therapy was given in three monthly courses. The first and third courses included ATRA plus idarubicin, an anthracycline chemotherapy drug. The second course included ATRA plus mitoxantrone, an anthracycline-related drug.
The researchers designed a new study, the LPA2005 trial, with the goals of further improving outcome and reducing toxic side effects through modifications in the consolidation phase of treatment.
A total of 404 children and adults with newly diagnosed APL from Europe and South America participated in the LPA2005 study. The patients ranged from 2 to 83 years in age, with the majority (79 percent) between the ages of 18 and 60. At the time of diagnosis, patients were classified as having a low, intermediate, or high risk of relapse on the basis of their white blood cell and platelet counts.
All patients received induction therapy with oral ATRA plus intravenous idarubicin, an anthracycline chemotherapy drug. After their disease entered complete remission, patients were treated with three monthly courses of consolidation therapy modified from the regimens used in the earlier LPA99 trial. In the new trial, patients in the low- and intermediate-risk groups received different drugs and doses than those in the high-risk group. As in the earlier trial, all patients who remained alive after consolidation therapy were given maintenance therapy with ATRA plus low-dose chemotherapy.
The primary goal of this study was to decrease the relapse rate in high-risk patients younger than 60 years. Therefore, these patients received the chemotherapy drug cytarabine along with ATRA and idarubicin in the first and third courses of consolidation therapy. A secondary objective was to reduce toxic side effects in patients with low- and intermediate-risk disease without sacrificing the effectiveness of treatment. To this end, the researchers reduced the duration of mitoxantrone treatment in the second consolidation course compared with that used in the LPA99 trial. The researchers compared outcomes in patients treated in LPA2005 with those in patients treated in the earlier LPA99 trial.
The study was sponsored by the Spanish PETHEMA Foundation and included patients from 81 institutions in Spain, Poland, the Netherlands, Argentina, Uruguay, and the Czech Republic. The study was conducted by investigators with the PETHEMA and HOVON (Hemato-Oncology Foundation for Adults in the Netherlands) Groups, and the lead author was Miguel A. Sanz, M.D., of the Hospital Universitario La Fe, Valencia, Spain.
Induction therapy led to complete remission in 372 of the 402 patients in the study who could be evaluated (92.5 percent). The other 30 patients died during induction therapy, mainly from hemorrhage or infection. Of the 372 patients in remission, 361 (97 percent) completed the three courses of consolidation therapy and went on to receive maintenance therapy.
Out of the 372 evaluable patients, 92 percent were alive and had not had a relapse of disease in the first 3 years after complete remission. This 3-year disease-free survival rate was not statistically significantly different from that in the earlier LPA99 trial.
The 3-year cumulative incidence of relapse for all patients, which was calculated from the date of complete remission, was 7 percent. Among high-risk patients, 11 percent had a relapse within 3 years after complete remission, compared with 26 percent of high-risk patients treated in the LPA99 trial.
Three years after they started induction therapy, 89 percent of patients in the LPA2005 study and 85 percent of those in the LPA99 study were still alive; this difference in overall survival was not statistically significant.
High-risk patients treated with the combination of ATRA, idarubicin, and cytarabine during consolidation had more hematologic (blood-related) complications and required longer hospital stays than high-risk patients in the LPA99 trial, who were not given cytarabine. However, these patients did not have a higher death rate than those in the LPA99 trial and did not drop out of the study at a greater rate.
Low- and intermediate-risk patients and high-risk patients older than 60 years of age, all of whom were treated with a reduced dose of mitoxantrone during the second consolidation course, had fewer hematologic events and shorter hospital stays than low- and intermediate-risk patients in the LPA99 trial. Moreover, the toxic effects were reduced without affecting the relapse rate, disease-free survival rate, or overall survival rate. The overall survival rate at 3 years was 96 percent in low-risk patients and 93 percent in intermediate-risk patients.
“This study reminds us that patients with APL are at risk for treatment complications, including life-threatening hemorrhagic [bleeding] events and infections,” said Richard Little, M.D., from NCI’s Clinical Investigations Branch. Although the study had some limitations (see below), Dr. Little said, “I think it is fair to say that favorable outcomes with reasonable toxicity are achieved, and appear to compare favorably to prior studies.”
“Overall survival is in many ways the most important endpoint,” added Dr. Little. “However, if many patients have recurrent leukemia and then are successfully treated for that relapse with prolonged subsequent survival, the overall survival rates may not provide information about the original treatment. Information from disease-free survival—that is, survival without relapse of those patients whose leukemia completely responded to the therapy—and cumulative incidence of relapse are important measures for understanding the anti-leukemia benefit of the regimen.”
This study was a single-arm phase II study and not a randomized clinical trial, in which participants are assigned by chance to separate groups that compare different treatments. Instead, all patients in each risk group in the study received the same treatment, and the comparison was to similar groups who participated in a separate, earlier trial. Therefore, it cannot be concluded that the reduction in toxic effects is due solely to the modification of the consolidation regimen rather than to some other factors such as changes in supportive care management or patient selection. “In my view,” Dr. Little said, “one should be quite circumspect in saying that one treatment is better than another unless there has been a randomized study. It appears the favorable results [of the earlier study] can be maintained with the modifications of the current study, but I’m reluctant to place too much emphasis on comparing specific toxicity profiles between two studies.”