Arsenic and ATRA for APL Induction

Abstract & Commentary

By Andrew S. Artz, MD, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.

Synopsis: Although highly sensitive to a variety of agents, the need for prolonged therapy, particularly with anthracyclines in APL patients, may lead to significant toxicity and be contraindicated in others. In this study, standard chemotherapy was omitted. The combination of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) alone showed significant activity as induction and maintenance therapy for newly diagnosed low-risk (WBC < 10,000/uL) APL patients. The addition of gemtuzumab to ATO/ATRO for high-risk patients or relapse was also relatively effective. Early death remains problematic. Confirmatory studies are needed.

Source: Estey E, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107:3469-3473.

Acute promyelocytic leukemia (APL) has distinct biologic characteristics, clinical behavior, and responsiveness relative to other variants of AML. The majority of cases harbor the t(15:17)(q22;q12) which fuses the PML gene with the retinoic-acid receptor a gene (RAR), enabling molecular diagnosis and monitoring of PML/RAR transcripts. Bone marrow morphology often is suggestive, although it may be less obvious with the t(11:17) variant. White blood cell count > 10,000/uL represents an adverse prognostic factor.

Many chemotherapy agents have considerable activity in APL including anthracyclines, gemtuzumab ozogamicin (GO), arsenic trioxide (ATO), and all trans-retinoic acid (ATRA). APL now has the best long-term outcome owing to the leukemic sensitivity to these multiple agents. ATRA with an anthracycline with or without cytarabine has become a frequently employed induction regimen. Although ATRA may be considered a non-traditional chemotherapy agent, retinoic acid syndrome (RAS) is not uncommon and can be a life-threatening toxicity. Consolidation and maintenance regimens typically add ATRA and chemotherapy1 and employ molecular monitoring for minimal residual disease. ATO also has significant single-agent activity in newly diagnosed and relapsed patients.2 A recent study combining ATRA with ATO demonstrated enhanced activity over either agent alone in newly diagnosed APL.

Estey and colleagues devised a risk-adapted approach to identify low-risk APL patients where chemotherapy may be safely omitted. GO was added as chemotherapy for high-risk patients defined as: WBC was > 10,000/uL at diagnosis, positive PML/RAR PCR at 3 months from CR, relapse of disease by PCR, toxicity precluding further use of ATRA or ATO. Forty-four patients were treated on this schema.

For low-risk patients, ATRA was administered at 45 mg/m2 in 2 divided doses daily and ATO given at 0.15 mg/kg ATO intravenously over 1 hour daily on day 10. For high-risk patients at presentation GO at 9 mg/m2 was given on day 1.

Marrow samples were obtained weekly after 1 month. Therapy was discontinued when there were < 5% blasts and no abnormal promyelocytes. Once CR was obtained as defined by neutrophil and platelet recovery, ATO was given intravenously at 0.15 mg/kg daily on Monday through Friday of weeks 1 to 4, 9 to 12, 17 to 20, and 25 to 28. ATRA was given at 45 mg/m2 daily during weeks 1 to 2, 5 to 6, 9 to 10, 13 to 14, 17 to 18, 21 to 22, and 25 to 26. Therapy was stopped at 28 weeks after CR. PCR for PML/RAR was done every 3 months. In the event ATRA or ATO were discontinued, GO was given at 9 mg/m2 GO once monthly until 28 weeks after CR.

In the event of molecular relapse, 9 mg/m2 GO once monthly was given for 3 months while continuing ATO/ATRA or resuming or resuming ATO/ATRA if therapy completed. If molecular remission obtained, 3 more months of GO plus ATRA plus ATO was given. If not, 12 mg/m2 idarubicin daily for 3 days was substituted for GO and patients considered for allogeneic transplantation if PCR persistently positive.

The majority 39/44 achieved CR (39/44) overall, 96% in low-risk patients, and 79% in high-risk patients. Five patients had early therapy related mortality, four within 3 days of therapy. Toxicity eventually developed in 5 patients on ATO forcing discontinuation. None of the 24 low-risk patients and 3 of 15 high-risk patients relapsed. Two of the relapses were salvaged and one died from disease. Median follow-up overall was only 16 months. In patients 60 years and older, 10/12 achieved a CR; and 9 remain in molecular remission at a median of 17 months.

Commentary

Estey and colleagues report a prospective approach to limit the use of chemotherapy in newly diagnosed APL patients. The results confirm a high response rate to the combination of ATRA and ATO. Low-risk patients, defined as a white blood cell count < 10,000 /uL fared relatively well and had a reasonable rate of persistent molecular remission. GO added to ATRA and ATO appeared effective as well, although several patients relapsed within a year. A promising observation was 9 of 12 patients 60 years and older remain in remission at a median of 17 months.

The relatively short follow-up limits conclusions about long-term results. Also, 5 patients died early from treatment. Although not unusual, this remains a persistent problem for therapy of APL and may be one of the most important obstacles to enhance long-term outcomes.

These data require confirmation in a larger series since this was a single-institution series. The combination of ATRA and ATO appears a promising option, particularly for low risk patients for whom anthracycline and/or cytarabine chemotherapy may be contraindicated. The schedule employed for high-risk patients may potentially be less toxic than a standard consolidation and maintenance regimen so this also warrants further study.

Even better outcomes in the future may be anticipated with improved diagnostic techniques for risk adapted strategies. Further, the recent demonstration that 43% of APL cases showed a FLT-3 mutation offers another potential treatment pathway.3 APL remains a great success story for modern oncology and the future looks even brighter.

References

1. Fenaux P, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999;94:1192-1200.

2. Lu DP, et al. Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: a pilot report. Blood. 2002;99:3136-3143.

3. Gale RE, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood. 2005;106:3768-3776.