June 16, 2011 (London, United Kingdom) — Patients being treated for the most common form of leukemia receive up to 10 times more of one chemotherapy drug than necessary, Bob Löwenberg, MD, professor of hematology at Erasmus University in Rotterdam, the Netherlands, told delegates here at the 16th Congress of the European Hematology Association (EHA).
The standard remission induction phase of treatment for acute myeloid leukemia (AML) consists of an anthracycline combined with doses of cytarabine up to 3000 mg/m2 twice daily. Dr. Löwenberg's Dutch team found that doses above 1000 mg/m2 confer excess toxicity with no gain in remissions.
The group recently published these findings in the New England Journal of Medicine (2011;364:1027-1036), as reported at the time by Medscape Medical News.
Over the years, doses of cytarabine have ranged from 100 to 3000 mg/m2; doses of 1000 mg/m2 are considered intermediate and doses above that are considered high, Dr. Löwenberg explained. The differences in dosing go back to early studies in the United States, he said. "If patients presented with relapsed leukemia, physicians tried to rescue these patients" with dosages as high as 3000 mg/m2. These studies, from the early 1980s, all showed responses in patients with relapses. "This moved these high dose levels to front-line treatment," he said.
A landmark study, published by the Cancer and Leukemia Group B in the New England Journal of Medicine (1994;331:896-903), set high dose levels as the standard. The study compared 100 mg/m2, 400 mg/m2, and 3000 mg/m2 for consolidation therapy, and showed the best overall survival with the highest dose. "Since then, the 3000 mg/m2 dose level has [been used in] clinical practice in the front-line treatment of newly diagnosed patients," Dr. Löwenberg explained. Two other studies — 1 from Australia and 1 from the United States — showed prevention of relapse with high dosages.
The high dose levels were accepted, but presented big problems. "It's a very toxic treatment, and in patients over 60 years of age, it was not possible to administer these dose levels because it was just too toxic," Dr. Löwenberg said. "Patients would die from it."
Two Doses of Cytarabine Compared
The Dutch study randomly assigned newly diagnosed AML patients (n = 860), between the ages of 18 and 60 years, to 1 of 2 induction regimens — containing the same doses of anthracycline but different doses of cytarabine — to test the efficacy and safety of lower doses. A lower-dose group (n = 431) received 200 mg/m2 by continuous intravenous infusion (CIV) for 24 hours on days 1 to 7 during cycle 1 of induction therapy, and 1000 mg/m2 CIV for 3 hours twice daily on days 1 to 6 during cycle 2. An escalated-dose group (n = 429) received 1000 mg/m2 every 12 hours on days 1 to 5 in cycle 1, followed by 2000 mg/m2 twice daily on days 1,2, 4, and 6 during cycle 2. Patients achieving a complete response received a third cycle of chemotherapy, consisting of only mitoxantrone and etoposide, or underwent an autologous or allogeneic stem cell transplant.
The 2 groups were well matched for age (median, 49 years; range, 17 to 60 years) and karyotype classification.
No Difference in Survival
The complete remission rate was 80% in the lower-dose group and 82% in the escalated-dose group after 2 cycles of induction therapy. Most of the remissions occurred during the first cycle (60% vs 66%). "The survival is also exactly the same; no difference," Dr. Löwenberg reported. At 5 years, event-free survival was 34% vs 35%, and overall survival was 40% vs 42%, respectively (P = .79 and P = .87 by log-rank test, respectively).
However, those in the lower-dose group experienced significantly less toxicity. "The [escalated] dose prolongs neutropenia (32 vs 27 days) and prolongs thrombocytopenia; . . . even after cycle 3, this disadvantage of retarded hematological recovery is maintained," Dr. Löwenberg reported. In addition, the escalated-dose group had longer hospitalizations.
Dr. Löwenberg concluded that a dose level above 1,000 mg/m2 confers excess toxicity with no gain in benefit. "In fact, if you go higher, it is overdosing. It is above the plateau of the dose–response relationships, and we think this will have an impact on the standard of care of patients with acute myeloid leukemia," he said.
The results also have a financial impact, which will differ in each country. Dr. Löwenberg calculated that in Holland, use of lower doses would result in a savings of "at least €7000 per treatment."
He noted that the study involved interim analyses of the data by an independent committee to be sure that lower doses were effective and that patients were not being undertreated. It is possible that even lower doses could be effective, but such a large study would be difficult to repeat. The investigators now suggest a dose of 1000 mg/m2. "One thousand is at the plateau" of the dose–response curve, Dr. Löwenberg emphasized.
Same Results With Half the Dose
Robin Foà, MD, head of the division of hematology at Sapienza University in Rome, Italy, and past president of the EHA, said: "By halving the doses, you can get more or less the same results. . . . What is unfortunate is that AML in adults is still having a poor prognosis." In the Dutch study, overall survival was only about 40% in each group.
Dr. Foà told Medscape Medical News that in a larger context, the management of hematologic disorders has changed over time, and doses need to be retested. Some may need to go up, and others could possibly go down. Furthermore, regimens need to be individualized on the basis of age, performance status, and risk. Although the majority of patients in clinical trials tend to be younger and fitter, typical patients are often older and more debilitated.
After a suggestion that treatment registries would allow clinicians to follow more patients and more forms of therapy, Dr. Foà said the gold standard for judging the efficacy, safety, and even the quality of life associated with a particular treatment is still the randomized clinical trial, but overly stringent regulations can get in the way of carrying them out. He said the EHA is working with European Commission authorities in Brussels, Belgium, to simplify procedures, allowing more randomized trials to be done.
The study did not receive any commercial funding. Dr. Löwenberg and Dr. Foà have disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA).Presented June 10, 2011.
The standard remission induction phase of treatment for acute myeloid leukemia (AML) consists of an anthracycline combined with doses of cytarabine up to 3000 mg/m2 twice daily. Dr. Löwenberg's Dutch team found that doses above 1000 mg/m2 confer excess toxicity with no gain in remissions.
The group recently published these findings in the New England Journal of Medicine (2011;364:1027-1036), as reported at the time by Medscape Medical News.
Over the years, doses of cytarabine have ranged from 100 to 3000 mg/m2; doses of 1000 mg/m2 are considered intermediate and doses above that are considered high, Dr. Löwenberg explained. The differences in dosing go back to early studies in the United States, he said. "If patients presented with relapsed leukemia, physicians tried to rescue these patients" with dosages as high as 3000 mg/m2. These studies, from the early 1980s, all showed responses in patients with relapses. "This moved these high dose levels to front-line treatment," he said.
A landmark study, published by the Cancer and Leukemia Group B in the New England Journal of Medicine (1994;331:896-903), set high dose levels as the standard. The study compared 100 mg/m2, 400 mg/m2, and 3000 mg/m2 for consolidation therapy, and showed the best overall survival with the highest dose. "Since then, the 3000 mg/m2 dose level has [been used in] clinical practice in the front-line treatment of newly diagnosed patients," Dr. Löwenberg explained. Two other studies — 1 from Australia and 1 from the United States — showed prevention of relapse with high dosages.
The high dose levels were accepted, but presented big problems. "It's a very toxic treatment, and in patients over 60 years of age, it was not possible to administer these dose levels because it was just too toxic," Dr. Löwenberg said. "Patients would die from it."
Two Doses of Cytarabine Compared
The Dutch study randomly assigned newly diagnosed AML patients (n = 860), between the ages of 18 and 60 years, to 1 of 2 induction regimens — containing the same doses of anthracycline but different doses of cytarabine — to test the efficacy and safety of lower doses. A lower-dose group (n = 431) received 200 mg/m2 by continuous intravenous infusion (CIV) for 24 hours on days 1 to 7 during cycle 1 of induction therapy, and 1000 mg/m2 CIV for 3 hours twice daily on days 1 to 6 during cycle 2. An escalated-dose group (n = 429) received 1000 mg/m2 every 12 hours on days 1 to 5 in cycle 1, followed by 2000 mg/m2 twice daily on days 1,2, 4, and 6 during cycle 2. Patients achieving a complete response received a third cycle of chemotherapy, consisting of only mitoxantrone and etoposide, or underwent an autologous or allogeneic stem cell transplant.
The 2 groups were well matched for age (median, 49 years; range, 17 to 60 years) and karyotype classification.
No Difference in Survival
The complete remission rate was 80% in the lower-dose group and 82% in the escalated-dose group after 2 cycles of induction therapy. Most of the remissions occurred during the first cycle (60% vs 66%). "The survival is also exactly the same; no difference," Dr. Löwenberg reported. At 5 years, event-free survival was 34% vs 35%, and overall survival was 40% vs 42%, respectively (P = .79 and P = .87 by log-rank test, respectively).
However, those in the lower-dose group experienced significantly less toxicity. "The [escalated] dose prolongs neutropenia (32 vs 27 days) and prolongs thrombocytopenia; . . . even after cycle 3, this disadvantage of retarded hematological recovery is maintained," Dr. Löwenberg reported. In addition, the escalated-dose group had longer hospitalizations.
Dr. Löwenberg concluded that a dose level above 1,000 mg/m2 confers excess toxicity with no gain in benefit. "In fact, if you go higher, it is overdosing. It is above the plateau of the dose–response relationships, and we think this will have an impact on the standard of care of patients with acute myeloid leukemia," he said.
The results also have a financial impact, which will differ in each country. Dr. Löwenberg calculated that in Holland, use of lower doses would result in a savings of "at least €7000 per treatment."
He noted that the study involved interim analyses of the data by an independent committee to be sure that lower doses were effective and that patients were not being undertreated. It is possible that even lower doses could be effective, but such a large study would be difficult to repeat. The investigators now suggest a dose of 1000 mg/m2. "One thousand is at the plateau" of the dose–response curve, Dr. Löwenberg emphasized.
Same Results With Half the Dose
Robin Foà, MD, head of the division of hematology at Sapienza University in Rome, Italy, and past president of the EHA, said: "By halving the doses, you can get more or less the same results. . . . What is unfortunate is that AML in adults is still having a poor prognosis." In the Dutch study, overall survival was only about 40% in each group.
Dr. Foà told Medscape Medical News that in a larger context, the management of hematologic disorders has changed over time, and doses need to be retested. Some may need to go up, and others could possibly go down. Furthermore, regimens need to be individualized on the basis of age, performance status, and risk. Although the majority of patients in clinical trials tend to be younger and fitter, typical patients are often older and more debilitated.
After a suggestion that treatment registries would allow clinicians to follow more patients and more forms of therapy, Dr. Foà said the gold standard for judging the efficacy, safety, and even the quality of life associated with a particular treatment is still the randomized clinical trial, but overly stringent regulations can get in the way of carrying them out. He said the EHA is working with European Commission authorities in Brussels, Belgium, to simplify procedures, allowing more randomized trials to be done.
The study did not receive any commercial funding. Dr. Löwenberg and Dr. Foà have disclosed no relevant financial relationships.
16th Congress of the European Hematology Association (EHA).Presented June 10, 2011.
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