- © 2011 by American Society of Clinical Oncology
Newly Diagnosed Acute Promyelocytic Leukemia: Arsenic Moves Front and Center
Treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA), anthracyclines, and increasingly, cytarabine (ara-C) is often prohibitively expensive in the developing world. This encouraged Ghavamzadeh et al1 in Iran to treat newly diagnosed APL without these standard drugs and rather to rely on arsenic trioxide (ATO), a drug with well-known activity in relapsed APL.2 As reported in the article that accompanies this editorial, Ghavamzadeh et al observed a complete remission (CR) rate of 86% in 197 patients. Typical of APL, failure to enter CR resulted essentially exclusively from death, most often resulting from hemorrhage before CR could occur (“early death”). As is usual, early death was more frequent (42% v 6%) in patients with a WBC count greater than 10,000/μL (hereafter high risk). Patients in CR continued receiving ATO, initially only for one 4-week course, but later, patients were given four such courses. With a median follow-up of 38 months of patients entering CR, 5-year disease-free survival (DFS) probability is 67% ± 4%, and 5-year overall survival (OS) probability is 64% ± 4% (± standard deviation). These rates will likely remain stable given that only one relapse was seen among 36 patients who were observed for more than 5 years. Patients given more than one consolidation course had a 5-year DFS of approximately 90% compared with the 5-year DFS of approximately 60% in patients given only one consolidation course; this observation appears somewhat self-fulfilling, given that patients had to remain in CR for more than 1 year to receive the third consolidation course and more than 2 years to receive the fourth.
Recently, Mathews et al3,4 in India administered ATO 10 mg daily until CR in 72 patients with newly diagnosed disease; 24% of these patients had a WBC count greater than 10,000/μL, and most could not afford standard therapy. Eleven percent received one to two doses of an anthracycline during induction, but once in CR, patients received only ATO 10 mg each day for one month and then 10 days per month for 6 months. The CR rate was 86%; with a median follow-up of 5 years, DFS and OS probabilities were 80% ± 5% and 74% ± 5%, respectively.4
It is natural to wonder how results with such ATO monotherapy compare with those with ATRA, anthracyclines, and ara-C as reported by large cooperative groups such as the Italian Group for Hematological Malignancies of the Adult (GIMEMA),5 the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA)/Hemato-Oncologie voor Volwassenen Nederland (HOVON),6 the European APL Group (EAPLG),7,8 and the North American Leukemia Intergroup.9 Table 1 suggests that DFS and OS rates are higher in these studies than in the Iranian and Indian studies, with largely nonoverlapping 95% CI or SEs. The shorter OS in the study of Ghavamzadeh et al1 may partially reflect a 42% early death rate in patients with high risk, which contrasts with CR rates of 83% to 98% reported in patients with high risk by PETHEMA/HOVON and EAPLG. The early death rate reported by Ghavamzadeh et al suggests suboptimal supportive care, more inclusive reporting of early death, or less effective therapy. Given that DFS, a composite of death in CR and relapse, was also lower and supportive care is much less critical in remission than during APL induction, I believe less effective therapy played some role. Of note, DFS was superior in the Indian study versus the Iranian study, possibly as a result of more prolonged use of ATO. The differences in DFS between treatment with ATO alone and the other studies might be even greater than suggested by Table 1 given that 15% to 33% of relapses in the GIMEMA, PETHEMA/HOVON, and EAPLG were molecular relapses compared with none in the Indian study and an unstated number in the Iranian study. Because it frequently precedes hematologic relapse, inclusion of molecular relapse will result in lower DFS. On the other hand, treatment of patients at the time of molecular, rather than only at hematologic, relapse might improve OS.
Comparison of Single-Agent ATO Trials With Cooperative Group Trials Using ATRA, Anthracyclines, and ara-C
The seeming superiority of standard treatment noted in the table could reflect administration of anthracyclines, ara-C, or maintenance therapy. In particular, accumulating data from historically controlled5,6 and randomized trials7,8 suggests, contrary to previous belief, a benefit for ara-C during induction and/or consolidation in both low-risk (WBC count < 10,000/μL) and high-risk patients. Similarly, on the basis of evidence from randomized trials, European LeukemiaNet guidelines recommend maintenance therapy with ATRA and 6-mercaptopurine plus methotrexate.10 It is possible, however, that use of higher doses of anthracyclines might obviate the need for ara-C and for maintenance.
Of course, response to treatment is influenced not only by treatment but by the mix of patients treated. Compared with the other studies in Table 1, the proportion of patients with high-risk disease was similar or lower in the Iranian and Indian studies, and the median age of patients in these studies was 15 to 20 years lower, presumably reflecting national demographics. Although not as important a factor as WBC count, increasing age has been found to increase early death5 and is better established as associated with deaths during standard consolidation; such deaths occur in 15% to 20% of patients age 60 years or older.11 Results of APL clinical trials may also be influenced by omission of patients who die before being enrolled onto a trial from the reports of that trial. As is almost invariably the case, such possible omissions were not reported by Ghavamzadeh et al.1
However, a narrow-minded focus on the possible inferiority of single-agent ATO compared with more standard regimens misses the seminal nature of the article by Ghavamzadeh et al,1 which documents that ATO is almost certainly a better drug in APL than is ATRA. It is generally thought implausible that single-agent oral ATRA would produce 5-year DFS rates of 65% as single-agent ATO did. Liposomal ATRA, a pharmacologically superior intravenous preparation that is not commercially available, was hypothesized to lower the relapse rate seen with single-agent oral ATRA. However, used alone, liposomal ATRA resulted in a 5-year DFS of only 40% in low-risk patients, whereas all eight high-risk patients either failed to enter CR or relapsed quickly12; in contrast, Ghavamzadeh et al reported little difference in DFS or OS between low- and high-risk patients.
At the very least then, the article by Ghavamzadeh et al1 indicates that there is much more reason to give ATO than to give ATRA to patients with newly diagnosed APL. However, a broader reading would, I hope, suggest that ATO be used with ATRA and/or other drugs. Support for this approach comes from the DFS and OS rates of 85% to 90% that are noted in the North American Leukemia Intergroup study, which were obtained in patients who were randomly assigned to receive consolidation with two courses of single-agent ATO (administered 5 days weekly for 5 weeks) in addition to two courses of daunorubicin and ATRA rather than consolidation with only daunorubicin and ATRA, which produced inferior DFS (P < .001) and OS (P = .07).
Perhaps a more appealing possibility would be to administer ATO and ATRA simultaneously. Randomly assigning patients with newly diagnosed disease to ATRA alone, ATO alone, or both for induction and maintenance, Shen et al13 found lower levels of the pathognomonic promyelocytic leukemia (PML) retinoic acid receptor α (RARα) transcript at CR in patients treated with the combination. Although all patients received consolidation chemotherapy probably decreasing any differences between ATO, ATRA, and ATO plus ATRA, the combination was associated with superior DFS. These results motivated an MD Anderson Cancer Center study14 in which patients with newly diagnosed low-risk disease received ATO plus ATRA exclusively unless molecular relapse ensued. In CR, patients were treated for 6 months with ATO on a 4 weeks on, 4 weeks off schedule and with ATRA for 2 weeks of every 4. High-risk patients received identical treatment except for the addition on day 1 of gemtuzumab ozogamicin, an active drug in untreated and molecularly relapsed APL.15,16 The CR rate was 98% in 104 patients (median age 46 years; 30% high risk).17 With a median follow-up of 115 weeks—with 36 patients observed for more than three and 23 for more than 5 years—five relapses (molecular and hematologic) have been observed (all in high-risk patients and all occurring within the first 2 years), leading to 5-year probabilities of 95% for remission duration and 88% for OS.17 Production of such results without chemotherapy prompted an ongoing GIMEMA/British Medical Research Council trial that randomly assigns low-risk patients to ATO plus ATRA or to standard ATRA plus idarubicin. Although ATO plus ATRA might have unknown delayed complications, its use might reduce the 2% to 5% 6-year cumulative incidence of therapy-related myeloid neoplasms in patents given anthracyclines18; median OS was 10 months after development of such therapy-related myeloid neoplasms. Omission of chemotherapy might be particularly beneficial in older patients who, as noted earlier, experience a 15% to 20% incidence of death during consolidation.11 Accordingly, the GIMEMA/British Medical Research Council trial assigns all patients age ≥ 65 years to ATO plus ATRA.
The biggest problems in management of APL, however, remain early deaths and continued relapses in high-risk patients. Findings by Breccia et al19 stress the importance of prompt diagnosis and institution of therapy. In their study, five of 105 consecutive patients died resulting from hemorrhage within 24 hours of arrival at a tertiary center, despite administration of ATRA within 2 to 5 hours of arrival. The patients who died within 24 hours had higher WBC counts (P = .001), more frequent coagulation abnormalities (P = .04), and most strikingly, a longer time between admission to general hospitals and arrival at the tertiary center (median, 7 v 1.5 days; P = .001)). Once APL is suspected morphologically in patients with WBC counts greater than 10,000/μL, benefit/risk considerations suggest immediate administration of not only ATRA but also ATO and, given the unavailability of gemtuzumab ozogamicin, an anthracycline and ara-C. Specifically, less would be lost by administering ATO plus ATRA if the diagnosis is not APL than might be gained by addition of ATO if APL is diagnosed. Similar considerations might argue for immediate use of dexamethasone, which, together with immediate administration of chemotherapy, might reduce the incidence of APL differentiation syndrome, an adverse effect of both ATO and ATRA.20 Of course, the more rapid the diagnosis, the less critical this discussion becomes. In fact, an immunohistochemical test that relies on the abnormal PML distribution pattern consequent to formation of PML-RARα can diagnose APL within a few hours.21 Although availability of this test might be impractical for community hospitals, such hospitals should be encouraged to have adequate supplies of ATO and ATRA on hand. Prophylactic administration of platelets and clotting factors is essential; inability to do this routinely was suggested to at least partially underlie the 32% induction death rate observed in Brazil despite the use of ATRA plus anthracyclines.22
Reports of clinical trials have led to the belief that modern treatment cures more than 90% of patients with APL. However, by using data from 1,400 patients in the Surveillance, Epidemiology, and End Results program and from 721 patients in the New York State Cancer Registry, Park et al23 found that more than 25% of patients die as a result of their disease; 10% to 20% died within 1 month of diagnosis. There was no significant improvement in either figure between 1997 and 2001 and between 2002 and 2007. Although they provide more evidence regarding selection bias in clinical trials, these results also indicate the magnitude of the APL problem. I hope the article by Ghavamzadeh et al1 will motivate wider use of ATO in combination with other drugs in patients with newly diagnosed disease, with the eventual possibility of administering ATO by mouth.24,25
AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
