From rags to riches
http://www.100md.com
《血液学杂志》
Now that ATRA and anthracycline-based chemotherapy cure the majority of patients with newly diagnosed acute promyelocytic leukemia (APL), one major focus of research has been to minimize exposure to chemotherapy in order to reduce toxicity. In this issue of Blood, Estey and colleagues show that combination of the 2 most active agents, ATRA and arsenic trioxide (ATO), with either no or minimal chemotherapy, is an effective alternative to ATRA plus chemotherapy.
Historically, acute promyelocytic leukemia (APL) has been among the most rapidly fatal of all subtypes of acute myeloid leukemia (AML), with a high early death rate attributable to bleeding. However, with contemporary strategies, most patients with APL appear cured. Such success is achieved when all-trans retinoic acid (ATRA) is added to anthracycline-based chemotherapy.1 Leukemic promyelocytes are particularly sensitive to anthracyclines and also remarkably sensitive to arsenic trioxide (ATO)2 and gemtuzumab ozogamicin (GO).3 In addition, there appears to be synergy between ATRA and ATO.4 Of all of these, ATO appears to be the most active single agent in APL.2 No other subtype of AML has cells that are so highly sensitive to so many effective therapeutic agents. Estey and colleagues have exploited these observations in an attempt to minimize or even eliminate conventional cytotoxic chemotherapy in patients with newly diagnosed APL. In low- and intermediate-risk patients (white blood cell count < 10 x 109/L), relatively long complete molecular remission duration was achieved. Despite receiving chemotherapy with either GO or idarubicin in addition to ATRA and ATO, several high-risk patients relapsed at 9 to 12 months. Studies suggest that when ATRA is given with anthracycline-based induction and consolidation chemotherapy, cytarabine can be eliminated in most patients. The results reported here further suggest that perhaps even anthracyclines can be eliminated, at least in low- and intermediate-risk patients. Recent preliminary studies have suggested that patients who achieve molecular complete response (CR) may not benefit from maintenance therapy.
The approach of ATRA plus ATO may be an excellent alternative for older patients who appear to have a high rate of death in CR when treated with chemotherapy, patients with secondary APL who have received maximal doses of anthracyclines, and those with cardiac disease that precludes anthracycline exposure. It should be noted that toxicity (primarily cardiac arrhythmias) precipitated discontinuation of ATO in 5 patients in this study. Nevertheless, if further studies confirm the results reported here, this strategy may replace ATRA plus anthracycline-based chemotherapy for low- and intermediate-risk patients.
Several issues remain to be addressed in the treatment of patients with APL. The early death rate of approximately 10% remains difficult to tackle. Early diagnosis and institution of therapy without waiting for cytogenetic or molecular genetic confirmation of the diagnosis may be the best effective strategy at the present time. The retinoic acid syndrome is somewhat unpredictable and not preventable. High-risk patients remain the greatest challenge. While the outcome for such patients reported here is promising, new approaches are needed. Since up to 75% of high-risk patients may harbor mutations in the FLT3 gene, FLT3 inhibitors in consolidation may be yet another effective addition to the already rich armamentarium of therapeutic agents in APL.5
References
Tallman MS, Andersen JW, Schiffer CA, et al. Alltrans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337: 1021-1028.
Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17: 131-134.
Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004;104: 1995-1999.
Shen ZX, Shui Zz, Fang J, et al. All-trans retinoic acid/As203 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;1011: 5328-5335.
Gale RE, Hills R, Pizzey AR, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood. 2005;106: 3768-3776.(Martin S. Tallman)
Historically, acute promyelocytic leukemia (APL) has been among the most rapidly fatal of all subtypes of acute myeloid leukemia (AML), with a high early death rate attributable to bleeding. However, with contemporary strategies, most patients with APL appear cured. Such success is achieved when all-trans retinoic acid (ATRA) is added to anthracycline-based chemotherapy.1 Leukemic promyelocytes are particularly sensitive to anthracyclines and also remarkably sensitive to arsenic trioxide (ATO)2 and gemtuzumab ozogamicin (GO).3 In addition, there appears to be synergy between ATRA and ATO.4 Of all of these, ATO appears to be the most active single agent in APL.2 No other subtype of AML has cells that are so highly sensitive to so many effective therapeutic agents. Estey and colleagues have exploited these observations in an attempt to minimize or even eliminate conventional cytotoxic chemotherapy in patients with newly diagnosed APL. In low- and intermediate-risk patients (white blood cell count < 10 x 109/L), relatively long complete molecular remission duration was achieved. Despite receiving chemotherapy with either GO or idarubicin in addition to ATRA and ATO, several high-risk patients relapsed at 9 to 12 months. Studies suggest that when ATRA is given with anthracycline-based induction and consolidation chemotherapy, cytarabine can be eliminated in most patients. The results reported here further suggest that perhaps even anthracyclines can be eliminated, at least in low- and intermediate-risk patients. Recent preliminary studies have suggested that patients who achieve molecular complete response (CR) may not benefit from maintenance therapy.
The approach of ATRA plus ATO may be an excellent alternative for older patients who appear to have a high rate of death in CR when treated with chemotherapy, patients with secondary APL who have received maximal doses of anthracyclines, and those with cardiac disease that precludes anthracycline exposure. It should be noted that toxicity (primarily cardiac arrhythmias) precipitated discontinuation of ATO in 5 patients in this study. Nevertheless, if further studies confirm the results reported here, this strategy may replace ATRA plus anthracycline-based chemotherapy for low- and intermediate-risk patients.
Several issues remain to be addressed in the treatment of patients with APL. The early death rate of approximately 10% remains difficult to tackle. Early diagnosis and institution of therapy without waiting for cytogenetic or molecular genetic confirmation of the diagnosis may be the best effective strategy at the present time. The retinoic acid syndrome is somewhat unpredictable and not preventable. High-risk patients remain the greatest challenge. While the outcome for such patients reported here is promising, new approaches are needed. Since up to 75% of high-risk patients may harbor mutations in the FLT3 gene, FLT3 inhibitors in consolidation may be yet another effective addition to the already rich armamentarium of therapeutic agents in APL.5
References
Tallman MS, Andersen JW, Schiffer CA, et al. Alltrans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337: 1021-1028.
Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17: 131-134.
Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004;104: 1995-1999.
Shen ZX, Shui Zz, Fang J, et al. All-trans retinoic acid/As203 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;1011: 5328-5335.
Gale RE, Hills R, Pizzey AR, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood. 2005;106: 3768-3776.(Martin S. Tallman)