ATO: the forefront of APL treatment?
http://www.100md.com
《血液学杂志》
Arsenic trioxide (ATO) is the standard induction treatment of relapsed acute promyelocytic leukemia (APL).1 Now Mathews and colleagues from India show that single-agent ATO can induce and maintain a molecular remission in patients with newly diagnosed APL.
Several large randomized and nonrandomized trials established the combination of all-trans retinoic acid (ATRA) plus chemotherapy as the standard treatment for newly diagnosed APL, curing most of the patients.2 The high complete remission (CR) rate with ATO in relapsed APL led to its investigation in newly diagnosed patients. In fact, more than a decade ago investigators in China reported that single-agent ATO is effective in such patients.3 The studies were also supported by the observation that ATO is more efficient than ATRA in reducing the degree of minimal residual APL cells. In newly diagnosed patients, ATRA as a single agent induces hematologic complete remission (CR) in almost all patients, but very often fails to produce molecular remissions. In contrast, ATO induces molecular remission in almost all patients treated at relapse. Further, a study from study China showed, using quantitative polymerase chain reaction (PCR), that the number of PML/RAR transcript copies was significantly lower after induction treatment with ATO than with ATRA in a small group of newly diagnosed patients.4
ATO is being studied in newly diagnosed APL patients in 2 ways. One approach is adding ATO to the standard ATRA/chemotherapy regimen to improve the overall outcome. A small randomized trial from China suggested that the combination of all 3 modalities—chemotherapy, ATRA, and ATO in different treatment phases—resulted in significantly better outcome than chemotherapy plus ATRA.4 A much larger U.S. intergroup randomized trial studied whether adding 2 cycles of ATO consolidations to standard ATRA/chemotherapy would improve the overall outcome, but the results are pending. The second approach is that ATO may allow reducing or even eliminating chemotherapy and perhaps even ATRA, lowering the toxicity while maintaining the excellent outcome. Such an approach was taken by Matthew and colleagues using ATO as a single agent, and the results are reported in this issue.
Not surprisingly, ATO induced in 72 newly diagnosed patients a complete remission (CR) rate of 86% (although a minority of 8 patients received anthracycline for high white cell count), without evidence of disease resistance. Similar results were reported by a group in Iran.5 Prior to the next treatment cycle, most (76%) of the studied CR patients were PCR negative for PML/RAR. However, of greater interest is that ATO alone, given as consolidation plus maintenance of 10 doses per month for 6 cycles, was very effective in maintaining the molecular remission. The 3-year event-free survival was 75%. Further, using the white cell and platelet count at diagnosis, Mathews et al identified 2 risk groups that are different from those reported by Sanz et al.6 All 20 patients in the good-risk group were alive and in remission (see figure).
Although this approach is less toxic and the results are promising, single-agent ATO cannot yet be considered an alternative to well-studied standard APL treatment: the number of patients is much smaller and the duration of follow-up is relatively shorter than those studied with ATRA plus chemotherapy. Also, the outcome of those not considered good-risk patients may not be as positive as in the poor- and intermediate-risk patients classified by the criteria of Sanz et al2 despite the difficulty in a direct comparison (see figure).
An advantage of single-agent ATO was its limited toxicity, especially infrequent and very short occurrence of grade neutropenia. However, this is probably gained by eliminating the intensive chemotherapy, raising the question of whether ATRA also needs to be avoided. One might be concerned with using a single agent in a disease that is already highly curable. In fact, synergism between ATO and ATRA was demonstrated in APL animal models. Further, in newly diagnosed APL patients, minimal residual disease measured by quantitative PCR was significantly lower with ATRA plus ATO induction than with ATO alone.4 A smaller study showed a very high percentage of continued molecular remission even in high-risk patients with ATRA plus ATO, with the addition of gemtuzumab only for high-risk patients.7
Taken together, replacing standard chemotherapy with ATO in newly diagnosed APL will require larger studies. However, for selected patients who cannot tolerate anthracycline—for example those with cardiac dysfunction, older adults with poor performance status, and possibly Jehovah's Witnesses—ATO (probably still in combination with ATRA) would be a very reasonable alternative to the standard ATRA/chemotherapy. Of interest, in this report, patients were initially enrolled in the study because they could not afford standard therapy since the cost of single-agent ATO was much lower. In countries where cost would prohibit standard treatment of APL, a cheaper ATO, produced under good quality control, would be effective in curing many APL patients.
View larger version (27K):
Comparison of Kaplan-Meier product limit estimate of event-free survival. See the complete figure in the article beginning on page 2627.
The optimal use of ATO in newly diagnosed APL patients still needs to be established. Regardless, this study demonstrates that ATO is a very active—perhaps even the most active—single agent for treating APL.
Footnotes
Comment on Mathews et al, page 2627
References
Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication in hematological malignancies. J Clin Oncol. 2005;23: 2396-2410.[Abstract/Free Full Text]
Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood. 2005;105: 3019-3025.
Zhang P. The use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia. J Biol Regul Homeost Agents. 1999;13: 195-200.
Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101: 5328-5335.
Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia without ATRA and/or chemotherapy. Ann Oncol. 2006;17: 131-134.
Sanz MA, Lo Coco F, Martin G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000;96: 1247-1253.
Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid + arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood First Edition Paper, prepublished on December 22, 2005, as DOI: 10.1182/blood-2005-10-4006.(Dan Douer)
Several large randomized and nonrandomized trials established the combination of all-trans retinoic acid (ATRA) plus chemotherapy as the standard treatment for newly diagnosed APL, curing most of the patients.2 The high complete remission (CR) rate with ATO in relapsed APL led to its investigation in newly diagnosed patients. In fact, more than a decade ago investigators in China reported that single-agent ATO is effective in such patients.3 The studies were also supported by the observation that ATO is more efficient than ATRA in reducing the degree of minimal residual APL cells. In newly diagnosed patients, ATRA as a single agent induces hematologic complete remission (CR) in almost all patients, but very often fails to produce molecular remissions. In contrast, ATO induces molecular remission in almost all patients treated at relapse. Further, a study from study China showed, using quantitative polymerase chain reaction (PCR), that the number of PML/RAR transcript copies was significantly lower after induction treatment with ATO than with ATRA in a small group of newly diagnosed patients.4
ATO is being studied in newly diagnosed APL patients in 2 ways. One approach is adding ATO to the standard ATRA/chemotherapy regimen to improve the overall outcome. A small randomized trial from China suggested that the combination of all 3 modalities—chemotherapy, ATRA, and ATO in different treatment phases—resulted in significantly better outcome than chemotherapy plus ATRA.4 A much larger U.S. intergroup randomized trial studied whether adding 2 cycles of ATO consolidations to standard ATRA/chemotherapy would improve the overall outcome, but the results are pending. The second approach is that ATO may allow reducing or even eliminating chemotherapy and perhaps even ATRA, lowering the toxicity while maintaining the excellent outcome. Such an approach was taken by Matthew and colleagues using ATO as a single agent, and the results are reported in this issue.
Not surprisingly, ATO induced in 72 newly diagnosed patients a complete remission (CR) rate of 86% (although a minority of 8 patients received anthracycline for high white cell count), without evidence of disease resistance. Similar results were reported by a group in Iran.5 Prior to the next treatment cycle, most (76%) of the studied CR patients were PCR negative for PML/RAR. However, of greater interest is that ATO alone, given as consolidation plus maintenance of 10 doses per month for 6 cycles, was very effective in maintaining the molecular remission. The 3-year event-free survival was 75%. Further, using the white cell and platelet count at diagnosis, Mathews et al identified 2 risk groups that are different from those reported by Sanz et al.6 All 20 patients in the good-risk group were alive and in remission (see figure).
Although this approach is less toxic and the results are promising, single-agent ATO cannot yet be considered an alternative to well-studied standard APL treatment: the number of patients is much smaller and the duration of follow-up is relatively shorter than those studied with ATRA plus chemotherapy. Also, the outcome of those not considered good-risk patients may not be as positive as in the poor- and intermediate-risk patients classified by the criteria of Sanz et al2 despite the difficulty in a direct comparison (see figure).
An advantage of single-agent ATO was its limited toxicity, especially infrequent and very short occurrence of grade neutropenia. However, this is probably gained by eliminating the intensive chemotherapy, raising the question of whether ATRA also needs to be avoided. One might be concerned with using a single agent in a disease that is already highly curable. In fact, synergism between ATO and ATRA was demonstrated in APL animal models. Further, in newly diagnosed APL patients, minimal residual disease measured by quantitative PCR was significantly lower with ATRA plus ATO induction than with ATO alone.4 A smaller study showed a very high percentage of continued molecular remission even in high-risk patients with ATRA plus ATO, with the addition of gemtuzumab only for high-risk patients.7
Taken together, replacing standard chemotherapy with ATO in newly diagnosed APL will require larger studies. However, for selected patients who cannot tolerate anthracycline—for example those with cardiac dysfunction, older adults with poor performance status, and possibly Jehovah's Witnesses—ATO (probably still in combination with ATRA) would be a very reasonable alternative to the standard ATRA/chemotherapy. Of interest, in this report, patients were initially enrolled in the study because they could not afford standard therapy since the cost of single-agent ATO was much lower. In countries where cost would prohibit standard treatment of APL, a cheaper ATO, produced under good quality control, would be effective in curing many APL patients.
View larger version (27K):
Comparison of Kaplan-Meier product limit estimate of event-free survival. See the complete figure in the article beginning on page 2627.
The optimal use of ATO in newly diagnosed APL patients still needs to be established. Regardless, this study demonstrates that ATO is a very active—perhaps even the most active—single agent for treating APL.
Footnotes
Comment on Mathews et al, page 2627
References
Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication in hematological malignancies. J Clin Oncol. 2005;23: 2396-2410.[Abstract/Free Full Text]
Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood. 2005;105: 3019-3025.
Zhang P. The use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia. J Biol Regul Homeost Agents. 1999;13: 195-200.
Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101: 5328-5335.
Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia without ATRA and/or chemotherapy. Ann Oncol. 2006;17: 131-134.
Sanz MA, Lo Coco F, Martin G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000;96: 1247-1253.
Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid + arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood First Edition Paper, prepublished on December 22, 2005, as DOI: 10.1182/blood-2005-10-4006.(Dan Douer)