- Top of page
- PATIENTS AND METHODS
- FUNDING SOURCES
Acute promyelocytic leukemia (APL) accounts for 10%-15% of adult acute myeloid leukemias,1 with an incidence of 600-800 cases each year in the United States (US).2 APL is an important model for cancer therapy because it is the first neoplasm to have been effectively treated with a molecularly targeted drug, representing a change of paradigm in the treatment of cancer.3-7
For many years, APL had a dismal prognosis with a high rate of early mortality due to hemorrhage from coagulopathy, which often worsened during chemotherapy. In the 1970s, anthracycline-based therapies produced complete remission in 65%-80% of patients with APL and long-term survival in 15%-25% of patients.8-10 The introduction of all-trans retinoic acid (ATRA) in 1985,11 the first successful agent specifically targeting the PML-RARA oncogene, dramatically changed the management of APL. The clinical discovery of arsenic trioxide (ATO) in 1992 has been viewed as a second milestone in the treatment of APL.12-15
In the US, anthracyclines were introduced for APL treatment in the 1970s and were the standard therapy during the 1980s. Treatment of APL with ATRA was first introduced in the US in June 1990,16, 17 and ATO treatment was introduced in October 1997.1, 18 The US Food and Drug Administration (FDA) approved ATRA for the treatment of patients with APL in November 199519 and ATO for relapsed and refractory APL in September 2000.20 To evaluate the potential impact of introduction of ATRA and ATO on relative survival (RS), we used the years 1991 and 2000 as cutoff points. The aim of this study was to examine trends in short- and long-term survival of patients with APL before and after the introduction of molecularly targeted therapy and the incidence of APL in the US. We also examined the outcome of the patients treated in a tertiary referral center over approximately the same time interval to further confirm the potential impact of ATRA and ATO on survival in APL observed in the Surveillance, Epidemiology, and End Results (SEER) population-based study.
- Top of page
- PATIENTS AND METHODS
- FUNDING SOURCES
In this study, we noted a significant improvement in RS starting in 1991 (Figure 1 and Table 2). Several factors may have contributed to the observed improved clinical outcome in the latter calendar periods of study. These include better supportive care and increased use of anthracycline-based regimens, but most importantly the discovery and use of ATRA and ATO. Although the number of patients who underwent allogeneic SCT increased during this calendar period, this is unlikely to have a major role in the improvement, because the number of patients with APL who received allogeneic SCT was very small. It is also widely accepted that allogeneic SCT has a limited effect on the outcome of patients with acute myelogenous leukemia and favorable-risk cytogenetic in first remission, including those with APL.26
A dramatic improvement in survival for all age groups was observed in the calendar period 1991-1999. The 5-and 10-year RS rates for patients aged ≥40 years at diagnosis more than doubled in comparison to those in the previous calendar period (Figures 1 and 3, Table 3). Although the observed improvement could be partially due to better supportive care, this dramatic change in outcome can be clearly attributed to the increased use of ATRA. In the US, treatment of APL with ATRA was first introduced in June 1990.16, 17 Subsequently, the US Intergroup study, a multicenter clinical trial in 350 patients with newly diagnosed APL, was conducted during 1992-1995. Between June 1991 and November 1995, more than 1,500 patients with APL received ATRA on a compassionate-use basis.19 That is, at least ≈43% of the total number of patients with newly diagnosed APL in the US was treated with ATRA during this period. The high response rates reported in the clinical trials of ATRA in patients with APL led to its approval for the treatment of APL by the FDA.19 Subsequently, ATRA plus chemotherapy with daunorubicin (or idarubicin) and cytarabine became the standard induction regimen for this disease.9, 27, 28 Following the successful treatment of APL with ATO in China, a US pilot study was conducted in 12 patients with relapsed APL in October 1997,1, 18 and the first US multicenter trial was conducted in 40 patients with relapsed APL in 1998-1999.29 Soon after, the FDA approved ATO for relapsed and refractory APL in September 2000,20 so although its effect on survival during the calendar period prior to the year 2000 cannot be excluded, it is expected to be limited.
The findings in the SEER population-based study are in line with those for the MD Anderson study group. During 1991-2001, 87 patients with newly diagnosed APL were treated with ATRA plus idarubicin at MD Anderson. OS was significantly increased over that in the 70 patients with APL treated without ATRA in 1980-1990 (P<.001; Figure 1B).Therefore, the introduction of ATRA clearly contributed to the observed overall RS of 0.65 at 1 year and 0.52 at 5 years for patients treated during the same period (1991-1999) in the SEER population-based study.
Recent studies have suggested that ATO is more effective than ATRA in eradicating leukemic stem cells.30 Clinical trials have demonstrated that single-agent ATO can induce durable remissions in patients with previously untreated APL,31, 32 and the addition of ATO to standard induction and consolidation therapies may improve clinical outcomes in adults with newly diagnosed APL.27, 33, 34 In the present study, we observed improvement in RS in the last calendar period; overall RS increased from 0.52 in 1991-1999 to 0.64 in 2000-2008 (Table 2). Our findings in a population-based study are in accordance with results of the North American Leukemia Intergroup Study C9710.27 In this randomized trial of 481 patients with previously untreated APL from 1999 to 2005, it was reported that 3-year OS was better for patients assigned to receive an ATO-containing regimen than for those assigned to a regimen of ATRA in combination with daunorubicin for consolidation (86% versus 81%; P = 0.06). The observed improvement in RS in this latest calendar period is also likely to be due to a more widespread use of ATO for relapsed APL resulting in the improved RS in relapsed patients. However, other potential factors that may have contributed to this improvement include improvement of supportive care measures as well as increased knowledge and experience of teams who care for patients with APL, and more widespread use of ATRA for maintenance therapy. Early detection of relapse through monitoring for the fusion transcript PML-RARA using polymerase chain reaction, and prompt initiation of therapy with ATO for relapsed patients also have some effect. Furthermore, our observations in the SEER population-based study are consistent with the results from an MD Anderson trial of ATO in combination with ATRA (±GO) in 85 newly diagnosed patients with APL treated between 2002 and 2008, suggesting that such a combination may improve OS compared with ATRA plus idarubicin or GO (n = 87) during the period 1991- 2001 (P<.001; Figure 1B),34 although part of this improvement must be attributed to better overall care of the patients.
All patients with available long-term follow-up data for our population-based study were obtained from SEER registries with no selection biases. Limitations of the SEER database include a lack of treatment information for individual patients. It is impossible to know whether or not the patients received chemotherapy and/or other agents; therefore, the proportion of patients who actually received various treatments, and more specifically ATRA and ATO, is unknown. Clearly, the conclusions of this study are based on the assumption of changing patterns of treatment with the FDA approval of ATRA and ATO in the US, and availability of data from related publications. However, the inclusion of the single-institution data serves to confirm that these patterns may well reflect the actual practice and that the improved outcomes are clearly related to the changed practice.
We also observed that the incidence of APL has increased in the US over the past several decades. The incidence rate was 0.27 per 100,000 in 2000-2008 compared with 0.11 in 1975-1990, and 0.06 in the population aged ≤20 years compared with 0.36 per 100,000 among those aged ≥60 years in the latter period (Table 1). Similar incidence rates of 0.16 in 1992-1995, 0.22 in 1996-2001, and 0.28 in 2002-2007 were reported in another recent report.35 The reasons behind this apparent increase are unclear. Although the use of better diagnostic tools (eg, molecular techniques) may have increased the diagnostic accuracy over the years, this is unlikely to be the sole explanation for the increased incidence, because APL can be diagnosed reliably by the presence of typical presenting features, distinctive bone marrow morphology, and chromosome abnormality.
In conclusion, in this large population-based study of 1397 patients diagnosed with APL between 1975 and 2008, we found that the incidence of APL increased over time, especially in the last decade; the RS of patients with APL increased, with the most improvement occurring in 1991-1999 for all age groups, presumably because of increased use of the molecularly targeted agent ATRA. Future studies with longer observation periods are needed to evaluate the impact of the introduction of ATO and its inclusion earlier in the course of treatment on outcomes in APL. The combination of ATRA and ATO has shown the potential to eliminate standard cytotoxic chemotherapy for APL.36, 37 ATO alone or in combination with ATRA is an excellent option for older patients, who often cannot tolerate anthracycline-based therapy.31-33, 38-40 It will also be interesting to see the impact of ATO on the survival of this particular population in the future.