Arsenic Trioxide and Tretinoin, With or Without Chemotherapy

In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.[22]

In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.[22]

The 3-year overall survival (OS) rate was 94%, and the event-free survival (EFS) rate was 91%.

In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.[22]

Patients with standard-risk APL had an OS rate of 98% and an EFS rate of 95%.

In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.[22]

Patients with high-risk APL had an OS rate of 86% and an EFS rate of 83%. This lower survival compared with standard-risk patients was primarily caused by early death events.

In children and adolescents with newly diagnosed APL treated on the COG AAML0631 (NCT00866918) trial, two consolidation cycles of arsenic trioxide were incorporated into a chemotherapy regimen with lower cumulative anthracycline doses compared with historical controls.[22]

The relapse risk after arsenic trioxide consolidation was 4% and was similar for standard-risk and high-risk APL.

The concurrent use of arsenic trioxide and tretinoin in newly diagnosed patients with APL results in high rates of CR.[23-25] Early experience in children with newly diagnosed APL showed high rates of CR to arsenic trioxide, either as a single agent or given with tretinoin.[26][Level of evidence C1] Results of a meta-analysis of seven published studies in adult patients with APL suggested that using a combination of arsenic trioxide and tretinoin may be more effective than using arsenic trioxide alone to induce CR.[27]

The concurrent use of arsenic trioxide and tretinoin in newly diagnosed patients with APL results in high rates of CR.[23-25] Early experience in children with newly diagnosed APL showed high rates of CR to arsenic trioxide, either as a single agent or given with tretinoin.[26][Level of evidence C1] Results of a meta-analysis of seven published studies in adult patients with APL suggested that using a combination of arsenic trioxide and tretinoin may be more effective than using arsenic trioxide alone to induce CR.[27]

In early trials in children, the impact of arsenic added to induction (either alone or with tretinoin) on EFS and OS had appeared promising.[26,28,29]

Arsenic trioxide was evaluated as a component of induction therapy with idarubicin and tretinoin in the APML4 clinical trial, which enrolled both children and adults (N = 124 evaluable patients).[20] Patients received two courses of consolidation therapy with arsenic trioxide and tretinoin (but no anthracycline) and maintenance therapy with tretinoin, mercaptopurine, and methotrexate.[30]

Arsenic trioxide was evaluated as a component of induction therapy with idarubicin and tretinoin in the APML4 clinical trial, which enrolled both children and adults (N = 124 evaluable patients).[20] Patients received two courses of consolidation therapy with arsenic trioxide and tretinoin (but no anthracycline) and maintenance therapy with tretinoin, mercaptopurine, and methotrexate.[30]

The 2-year freedom-from-relapse rate was 97.5%, the failure-free survival rate was 88.1%, and the OS rate was 93.2%.

Arsenic trioxide was evaluated as a component of induction therapy with idarubicin and tretinoin in the APML4 clinical trial, which enrolled both children and adults (N = 124 evaluable patients).[20] Patients received two courses of consolidation therapy with arsenic trioxide and tretinoin (but no anthracycline) and maintenance therapy with tretinoin, mercaptopurine, and methotrexate.[30]

These outcome results were superior to those reported for patients who did not receive arsenic trioxide in the predecessor clinical trial (APML3).

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

The median duration of induction therapy for all patients (standard risk and high risk) was 47 days which included a 14-day rest period before starting consolidation therapy. All standard-risk and high-risk patients who completed their induction therapy achieved a hematologic CR or a CR with incomplete hematologic recovery before day 70.

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

During induction therapy, one standard-risk patient died of complications from coagulopathy, differentiation syndrome, and subsequent organ failure. No high-risk patients died of complications.

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

All patients who received quantitative polymerase chain reaction (PCR) testing after completing their second round of consolidation therapy were in molecular remission.

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

No patients experienced a relapse while on therapy. One standard-risk patient (1%) and two high-risk patients (4%) experienced relapses after therapy completion. These patients were successfully salvaged.

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

Standard-risk patients had equivalent 2-year EFS rates (98% vs. 97%) and OS rates (99% vs. 98.5%).

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

High-risk patients who enrolled in the AAML1331 trial had a significantly improved 2-year EFS rate (96.4% vs. 82.9%; P = .05) and OS rate (100% vs. 85.7%; P = .02).

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

In the AAML1331 trial, only a few patients with CNS symptoms or hemorrhage were examined and treated using triple intrathecal chemotherapy, whereas in the AAML0631 study, all standard-risk patients received three prophylactic doses of intrathecal chemotherapy, and all high-risk patients received four prophylactic doses of intrathecal chemotherapy.

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

The length of therapy was significantly shorter in the AAML1331 trial (9 months) than in the AAML0631 trial (>2 years).

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

Hospitalizations during consolidation therapy were significantly reduced in the AAML1331 trial, when compared with the AAML0631 trial (0 days vs. 13 days, respectively; P < .001).

The historically controlled noninferiority COG AAML1331 (NCT02339740) trial was conducted between 2015 and 2019. The study included pediatric patients (age range, 1–21 years) with APL. The study examined whether the addition of arsenic trioxide to induction therapy, and continued through consolidation, could sustain the excellent outcomes seen in the AAML0631 (NCT00866918) trial. Additionally, chemotherapy was eliminated entirely, except when patients with high-risk APL were given short courses of idarubicin during induction therapy. Patients with standard risk APL, compared to past trials, had idarubicin eliminated from the induction cycle. Mitoxantrone, high-dose cytarabine, and idarubicin were eliminated from the consolidation cycles. Then, mercaptopurine and methotrexate were eliminated from the maintenance cycles. Intrathecal doses of cytarabine were also eliminated. The AAML1331 study included 154 patients, 98 of whom were classified as standard risk and 56 of whom were classified as high risk.[3] Standard-risk patients received tretinoin plus arsenic trioxide on days 1 to 28, with the possibility of continuing treatment up to day 70 to achieve a hematologic CR. High-risk patients received the same induction therapy schedule as standard-risk patients, with the addition of idarubicin on induction days 1, 3, 5, and 7. High-risk patients also received daily dexamethasone as a prophylactic treatment to prevent differentiation syndrome on days 1 to 14. All patients received the same consolidation therapy, which consisted of tretinoin on days 1 to 14 and days 29 to 42. Patients were also given arsenic trioxide 5 days each week for 4 consecutive weeks in every 8-week consolidation cycle for four cycles, although the fourth consolidation therapy cycle concluded on day 28. There was no maintenance therapy phase.[3]The AAML1331 and AAML0631 trials were compared and the following was reported:

In the AAML1331 trial, early death was significantly lower in high-risk patients (0 vs. 4 in AAML0631; P = .02), and not significantly different for standard-risk patients (1 vs. 0 in AAML0631; P = .16).