Maintenance Therapy in Acute Promyelocytic Leukemia
The concept of maintenance therapy in acute leukemia has always appealed to investigators contemplating the idea that long-term nonintensive chemotherapy could eradicate residual leukemia cells that may have remained after previous intensive consolidation. Currently, the prevailing consensus is that maintenance therapy is mandatory in patients with acute lymphoblastic leukemia (ALL), whereas those with acute myeloid leukemia (AML) are unlikely to benefit.1 The only exception is acute promyelocytic leukemia (APL), which is the only AML subtype for which maintenance therapy is still routinely administered. Nevertheless, the efficacy and necessity of this approach in APL is uncertain because several clinical trials have shown contradictory results. Minimal residual disease (MRD) can be evaluated in patients with APL through polymerase chain reaction (PCR) analysis of the PML/RARα fusion gene product. In fewer than 2% of patients with APL, PCR results remain positive after completion of the consolidation course.2,3 It can be argued that the rationale for maintenance therapy is valid only in patients with positive PCR results because they have a target for continuation of therapy. Alternatively, the PCR technique has sensitivity limitations, and therefore perhaps even patients with negative PCR results may have a persistent leukemic clone, and maintenance therapy would be able to eradicate this clone.
The risks of maintenance therapy must also be considered. Long duration of treatment with 6-mercaptopurine (6-MP) and methotrexate (MTX) can suppress the bone marrow and expose patients to infections and even secondary malignancies.4
Maintenance Therapy Trials Before the All-Trans-Retinoic Acid Era
The first 2 reports of the efficacy of maintenance therapy in APL were published in the 1980s before the all-trans-retinoic acid (ATRA) era.5,6 These small series showed retrospectively that patients who were treated with 6-MP and MTX maintenance therapy experienced longer remission than those who were not treated with maintenance at all.5,6 The GIMEMA group was the first to prospectively address the question of the efficacy of maintenance in APL. Their LAP 0389 trial was initiated shortly before the availability of ATRA. They compared idarubicin (IDA) alone versus IDA/arabinosylcytosine (Ara-C) as induction. After 3 cycles of different chemotherapeutic regimens for consolidation, patients experiencing complete remission (CR) were randomized to either no treatment or maintenance treatment consisting of 6-MP and MTX for 2 years (Table 1). The 7-year disease-free survival (DFS) and overall survival (OS) rates were not statistically different between the maintenance and nonmaintenance groups (43% vs 38% and 51% vs 61%, respectively).7
Maintenance Therapy Trials in the ATRA Era
In the ATRA era, 4 trials8-13 examined this question prospectively through comparing 1 or more arms of maintenance therapy versus an observation arm. In another trial,14 maintenance therapy was added to the protocol later, and therefore the results of the years with and without maintenance therapy were compared. Of these 5 trials, 3 showed a benefit for maintenance treatment and 2 showed no benefit, and perhaps even a benefit in the observation arm (Table 1).
North American Intergroup Protocol I0129
The North American Intergroup APL study I0129 included induction followed by a consolidation cycle of either ATRA or daunorubicin (DNR)/Ara-C.8,9 Both arms received a second consolidation cycle of DNR and high-dose Ara-C (HiDAC). Patients experiencing CR were randomized to either maintenance with daily ATRA for 1 year or observation. The 5-year DFS rate was 61% in the maintenance group and 36% in the observation group (P<.0001). OS was not determined according to maintenance groups.
European APL93 Trial
The European APL93 trial compared induction treatment involving ATRA, DNR, and Ara-C given in 2 different schedules.10,11 The consolidation cycle involved 2 cycles DNR and Ara-C in different doses: DNR at 60 mg/m2 and Ara-C at 200 mg/m2 in the first cycle, and DNR at 45 mg/m2 and Ara-C at 1 g/m2 in the second cycle. The 2-year maintenance therapy included 4 arms: ATRA for 15 days every 3 months; 6-MP/MTX; ATRA/6-MP/MTX; and observation. The 10-year event-free survival rates were 63%, 73%, 80%, and 51%, respectively (P<.001). The 10-year OS rates were significantly better in those who were assigned to maintenance therapy, which includes chemotherapy (85.2% vs 79.2%; P=.02), but nonsignificant in those who were assigned to ATRA maintenance (82.7% vs 79.4%; P=.44).
Australian APML3 Trial
The Australian APML3 trial showed the high efficacy of the combination of ATRA/IDA.14 The trial did not include maintenance therapy in the beginning, but was subsequently amended to have 3 different single-agent maintenance arms: ATRA, 6-MP, and MTX for 2 years. The statistical analysis compared the 2 periods and showed that the 4-year DFS rate was significantly better (P<.001) in the patients who were treated after the amendment (ie, with maintenance; 78.9%) compared with those who were treated before the amendment (ie, without maintenance; 46.9%). Details regarding the different maintenance groups were not reported, probably because of the small number of patients.
In contrast to these studies, 2 other trials12,13 showed opposite results (Table 1).
AIDA 0493 Trial
In the AIDA 0493 trial, patients received ATRA/IDA as induction and 3 cycles of different chemotherapeutic regimens of consolidation.12 These regimens included IDA, Ara-C, mitoxantrone (mitox), etoposide, and 6-tioguanine without ATRA. The maintenance was composed of 4 arms of 2 years of treatment: ATRA for 15 days every 3 months; 6-MP/MTX; ATRA/6-MP/MTX; and observation. In the first period after randomization, a significant decrease in DFS was seen in the no-maintenance arm compared with the 3 other arms. As a result, the protocol was amended and, beginning in February 1997, patients experiencing molecular CR were randomized only to the 2 ATRA-containing options (ATRA only and alternating chemotherapy/ATRA). However, with longer follow-up, the initial differences disappeared, and the 12-year DFS probabilities were very similar among the 4 groups (70.4%, 69.0%, 67.6%, and 69.1%). The OS of the no-maintenance arm and the 3 other groups was also similar (P=.3317, the numbers were not reported). Adding the patients after the amendment did not change the results. Comparison of the 2 remaining arms (ATRA-only and alternating chemotherapy/ATRA) also did not reveal any differences.12
Maintenance Therapy in Acute Promyelocytic Leukemia: A Summary of the Trials That Compare Maintenance With No Maintenance
Japan Adult Leukemia Study Group APL97 Study
In the Japan Adult Leukemia Study Group (JALSG) APL97 study, induction therapy involved ATRA with or without IDA and Ara-C, depending on the patient’s leukocyte count. Consolidation therapy included 3 different regimens with several combinations of mitox, DNR, etoposide, Ara-C, and IDA. Randomization was between intensified maintenance or none. The maintenance consisted of different combinations of drugs, including behenoyl Ara-C, DNR, 6-MP, etoposide, mitox, vindesine, and aclarubicin. After a median follow-up of 49 months, the predicted 6-year DFS rate was 63% in the maintenance group compared with 80% in the observation group (P = not significant). The OS rate was significantly better (P=.014) in the observation group (99%) than in the treated group (86%).13
These 5 trials have several differences, which may explain the different results. In the AIDA 0493 and Japanese trials (the trials that did not find an advantage in maintenance therapy), there was molecular or cytogenetic confirmation of the diagnosis of APL and of remission, in contrast to the North American and European trials (which found a maintenance advantage), in which the assessment relied only on morphology. It is possible that some of the patients with APL in the American and European trials who were considered to be experiencing CR and were randomized to maintenance therapy were, in fact, not experiencing molecular CR. In addition, the AIDA 0493 and Japanese trials used IDA and 3 cycles of consolidation, in contrast to the North American and European trials, which used daunorubicin and only 2 cycles of consolidation. The possibility exists that more-intensive consolidation and/or using IDA overcome the advantage of maintenance therapy.12 Similarly, the Australian trial included limited initial therapy, which possibly provided a milieu in which maintenance therapy was beneficial.
Maintenance Therapy in the ATO Era
ATO is considered the most potent anti-APL agent. Its use, which was traditionally reserved for patients experiencing relapse, has expanded and become more a part of induction-consolidation therapy.15,16 Recently, primary results of the APL 0406 study of the Italian-German Cooperative Groups were presented.17 This trial compared the use of ATRA/ATO without chemotherapy versus IDA/ATRA in non-high-risk patients with newly diagnosed APL. After a median follow-up of 31 months, the investigators reported CR rates of 100% versus 95% (P=.12), event-free survival rates of 97.0% versus 86.7% (P=.03), and OS rates of 98.7% versus 91.1% (P=.03). This outstanding response of APL to ATO raises the question of whether all patients who receive ATO as part of their induction-consolidation therapy require maintenance therapy.
What is known about the role of maintenance therapy after ATO treatment? In the C9710 trial, the North American Leukemia Intergroup investigated different maintenance regimens in ATO-treated patients, but did not include an observation arm.18,19 In that trial, all patients received 1 cycle of ATRA/DNR/Ara-C as induction and another 2 cycles of DNR/ATRA as consolidation. The investigational group also received 2 ATO cycles at the beginning of their consolidation. The maintenance groups included 7 days of ATRA every other week for 1 year versus ATRA/6-MP/MTX (Table 2). After a median follow-up of 6.2 years, DFS and OS were not statistically different for the 2 maintenance arms, but only 5 patients who received ATO consolidation experienced relapse, which represents too few events to provide the desired power to detect statistical significant difference.19
Maintenance Therapy in Acute Promyelocytic Leukemia: A Summary of the Trials That Compare Maintenance Options Without A No-Maintenance Arm
In the S0521 trial, the North American Leukemia Intergroup investigated the question of whether low- and intermediate-risk patients require maintenance therapy (ClinicalTrials.gov identifier: NCT00492856). The same induction-consolidation therapy was used as in the ATO arm of the C9710 trial protocol, but patients who did not experience CR were given gemtuzumab ozogamicin. After experiencing CR, patients were randomized to 2 arms of ATRA/6-MP/MTX for 1 year versus observation only (Table 1). The results of this study have not yet been published.
Another question that arises in the ATO era is whether ATO is effective as maintenance therapy. No study has compared ATO versus ATRA or chemotherapy as maintenance therapy, or observation only. A group from Hong Kong examined different ATO maintenance protocols. In their trial, patients received induction with ATRA/DNR/Ara-C and, if they were younger than 65 years, 2 more cycles of DNR/Ara-C as consolidation. Maintenance included 3 arms, each including oral ATO: ATO alone; ATO/ATRA; and ATO/ATRA/ascorbic acid. No observational arm was included (Table 2). The 3-year DFS rate was not significantly different among the 3 arms (85%, 84%, and 94%, respectively), but the numbers of patients on each were too small for the results to be conclusive.20
Maintenance Therapy According to Risk Group
It is well established that patients with APL can be divided into low- and high-risk groups according to their initial WBC count. The common definition for high-risk is a WBC count greater than 10,000/μL.21 A retrospective analysis of the APL93 trial found that patients with a WBC count greater than 5000/μL had particularly benefited from maintenance therapy.11 Currently, clinical trials in APL are mostly designed with a risk-adapted approach. In these trials, the induction and/or consolidation part of the protocol apply risk stratification of the patient. In contrast, it does not appear that any study has prospectively examined the maintenance question according to risk stratification; this remains to be explored in future APL trials. An example of this approach is the phase II trial conducted by Memorial Sloan-Kettering Cancer Center, in which only high-risk patients receive 2 years of ATRA/ATO maintenance therapy (ClinicalTrials.gov identifier: NCT01404949).
The Optimal Maintenance Regimen and Duration
Whether maintenance therapy is indicated in patients with APL is unclear. It is even more questionable in low-risk patients who received ATRA and chemotherapy as part of their induction-consolidation therapy, and particularly in patients treated with ATO.
In accordance with the literature supporting the use of maintenance therapy, the important question remains regarding which regimen is preferred: chemotherapy alone, ATRA, or the combination.
The existing data are inconsistent. In the North American I0129 trial, maintenance with ATRA alone, the only maintenance regimen that was investigated, improved DFS dramatically.8,9 In contrast, in the APL93 trial, maintenance with chemotherapy, either alone or with ATRA, significantly improved OS (10-year survival rate, 85.2% vs 79.2%; P=.02), but long-term survival was not significantly modified by maintenance with ATRA (10-year survival, 82.7% vs 79.4%; P= .44).10,11 It is reasonable that the benefit of maintenance therapy depends on the regimen that was chosen for the induction and consolidation therapies. Therefore, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML recommend “to use maintenance therapy in conjunction with treatment protocols in which it has been shown to confer benefit”22 (to view the most recent version of these guidelines, visit NCCN.org). One can also conclude from the clinical trials mentioned earlier that if IDA is used during the induction-consolidation phase, as opposed to DNR, maintenance therapy might have no benefit. Until the data are clarified further, common practice and treatment guidelines recommend the use of maintenance therapy.
The desired duration of maintenance therapy is also unclear. The North American Intergroup study prescribed 1 year of maintenance and noted a statistically significant advantage for this treatment.8,9 In contrast, the European study used 2 years of maintenance therapy and found that the risk of relapse significantly decreased when maintenance treatment was given for more than 1 year (hazard ratio, 0.16; 95% CI, 0.10-0.28; P<.001) compared with less than 1 year.10,11 Practically, the recommendation is to use the maintenance regimen as defined in the protocol-driven regimen that is chosen. Even in protocols that include 2 years of maintenance, shortening duration of therapy might be considered in individual patients if maintenance drugs interact with other drugs or toxicity develops.
Postconsolidation Monitoring
In addition to considering maintenance after consolidation, long-term monitoring for MRD has been studied particularly in APL. The rationale is the excellent correlation between the presence of MRD and subsequent relapse using the APL-specific PML/RARα fusion gene product. This correlation is being studied with other AML genetic markers, such as NPM1, but the correlation with outcome is still too premature to apply this strategy routinely for clinical purposes. In ALL, MRD is routinely tested in children and limarrokely to be used in adults in the near future.23,24
In the early 1990s, several retrospective studies showed that reverse transcriptase-PCR (RT-PCR) analysis of the PML/RARα fusion gene product can detect residual leukemic cells during hematologic remission in patients with APL.25-28 Furthermore, it was shown retrospectively that patients who remain PCR-positive after consolidation therapy29 or who transformed from PCR-negative to PCR-positive30 almost always experience a relapse. The GIMEMA group was the first to report prospectively about the natural history of molecular relapse. They showed that of 21 patients who converted from PCR-negative to PCR-positive, 20 experienced a hematologic relapse at a median of 3 months from the first PCR-positive result.31 Follow-up of patients with APL in molecular CR for the possibility of PCR conversion allows molecular relapse to be detected before it evolves into frank hematologic relapse. It should be emphasized that most of the patients who experience relapse do so despite having negative PCR results at the end of the consolidation. Treatment of patients with APL during molecular relapse without waiting for the development of hematologic relapse has several potential advantages. It might reduce the risks of bleeding caused by coagulopathy, of having hyperleukocytosis, and of developing differentiation syndrome while using ATRA and/or ATO. This early intervention while the patient is in molecular relapse has been shown to improve both relapse-free survival32,33 and OS32,34 compared with treatment during hematologic relapse. Therefore, a negative postconsolidation PCR result became the main goal of APL treatment, and follow-up with repeated PCR tests became the standard of care in these patients.
RT-PCR, Real-Time Quantitative PCR, and Fluorescence In Situ Hybridization
Despite being the most common monitoring method, RT-PCR has several limitations. It is prone to contamination, may fail to identify poor-quality samples, and lacks the ability to distinguish between decreasing and increasing levels of leukemia-specific transcripts. Real-time quantitative PCR (RQ-PCR) for detection of PML/RARα has a significant advantage in all of these aspects and tends to be a more sensitive tool. In a prospectively analysis of 6727 serial blood and marrow samples from 406 patients with newly diagnosed APL who were receiving ATRA and anthracycline-based chemotherapy, a British group showed that serial molecular monitoring with RQ-PCR to detect an increasing trend in PML/RARα transcripts provides the strongest predictor of relapse-free survival in APL.33
Fluorescence in situ hybridization (FISH) is being used as a diagnostic test in patients with suspected APL. It has the advantage of being relatively rapid and specific but provides no information about the isoform of PML/RARα, which is required for molecular monitoring of MRD, and might be misleading and appear normal in situations in which PML/RARα is formed as a result of small insertion events. FISH has been shown to be a reliable MRD target35-37 but is probably not as sensitive and specific as PCR.38
In conclusion, both the European LeukemiaNet and NCCN Guidelines recommend either RT-PCR or RQ-PCR as the preferred monitoring tool in patients with APL.22,39
PML/RARα Analysis in a Patient Treated With ATO
The kinetics of leukemia cell clearance after the use of ATO is significantly different from that of ATRA-based therapy. Thus, a group from India tried to explore, prospectively, the most informative time point for measuring MRD after a single-agent ATO treatment. Using a multivariate analysis, they reported that a positive RT-PCR result at the end of a single-agent ATO induction therapy was significantly associated with an increased risk of relapse (relative risk, 4.9; P=.034).40 Because first-line treatment with ATO/ATRA is likely to become more routinely used, similar studies will clarify the preferred schedule for MRD examination.
Frequency and Duration of MRD Monitoring
The optimal frequency of PCR testing in patients with APL is unknown, but it should reflect the likelihood of relapse. In low-risk patients (WBC at diagnosis ≤10,000/μL), the risk of relapse is very low (≈7%),21 and therefore the advantage of PCR monitoring is questionable. In these cases, it seems reasonable that once negative postconsolidation PCR results are achieved, additional PCR tests are likely not justified. On the other hand, in high-risk patients (WBC at diagnosis >10,000/μL), the relapse risk is significantly higher (≈10%-20%), and thus testing should continue beyond establishing postconsolidation molecular remission. The APL European LeukemiaNet guidelines recommend that MRD testing be performed every 3 months.39 Sanz et al41 recommend that high-risk patients should be monitored every 1 to 2 months for the first year after consolidation and every 3 months for the next 2 years. The NCCN Guidelines leave the decision to “the discretion of the treating physician to determine the appropriate frequency of monitoring for individual patients”22 (to view the most recent version of these guidelines, visit NCCN.org). According to this recommendation, patients who are high risk, are elderly, had interruptions during the consolidation courses, and are unable to tolerate maintenance therapy should be monitored more frequently.22
The duration of PCR monitoring tests should also be determined according to the risk of relapse. Low-risk patients probably do not need monitoring PCR at all. For high-risk patients, in whom the rate of relapse is higher, monitoring should be performed for a long period. The different recommendations for the duration of monitoring with PCR, taken together, are for a 2- to 3-year period. However, late relapses, beyond 3 years, can occur in APL, although these are rare. The European group (APL91 and APL93) and North American Intergroup APL trials that were conducted at the beginning of the ATRA era reported that 12.3% and 1.0%, respectively, of relapses occurred 4 years or more after achievement of CR.42,43 Interestingly, the patients experiencing late relapse in the European trials were not characterized as high risk at diagnosis.
Bone Marrow Versus Peripheral Blood Testing
Using peripheral blood rather than bone marrow to monitor PML/RARα MRD with PCR is more convenient for patients and their physicians. The large British study mentioned earlier evaluated pairs of samples of peripheral blood and bone marrow.33 The investigators reported that, despite having a high correlation in RQ-PCR results during the early stages of treatment, this was not the case in sequential monitoring of prerelapse samples. In the latter, molecular conversion of bone marrow samples preceded that of peripheral blood in 7 of 12 patients evaluated by a median of 29 days (range, 14-72 days). Bone marrow afforded a median increment in sensitivity of 1.50 logs (range, 0.34-2.15 logs) compared with peripheral blood.33 The APL guidelines of the European LeukemiaNet recommend testing the bone marrow for MRD every 3 months for a total of 3 years after completion of consolidation therapy.39 A delay of 1 month in the diagnosis of molecular relapse seems to have a negligible clinical impact. Thus, the NCCN Guidelines, taking into consideration the convenience and accuracy of testing, recommend that a postconsolidation test be performed on a bone marrow sample, but that subsequent PCR monitoring can be performed on peripheral blood samples22 (to view the most recent version of these guidelines, visit NCCN.org). If PCR positivity is detected, in view of the rapid kinetics, a bone marrow test should be repeated as soon as possible and in no more than 2 to 4 weeks.22,39 In the time that the results are pending, using ATRA to prevent the development of frank disease might be considered.
Finally, looking forward, ATO promises to become a primary component of induction therapy in APL and a new standard of care. The outcome from initial therapy with ATO-containing regimens may well reduce the need for prolonged maintenance. MRD monitoring, using the PML/RARα transcripts, is well established in APL. In that respect, APL serves as a model for other AML subtypes in which the role of molecular genetics as a tool for MRD monitoring is being actively investigated.
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