There is no consensus on the optimal type and intensity of consolidation therapy. The benefit of ATRA when combined with chemotherapy for consolidation has not been demonstrated in randomized studies. However, historical comparisons of consecutive trials by the investigators of GIMEMA and PETHEMA demonstrated a statistically significant reduction in the relapse rate (8.7% vs 20.1%) and a higher disease-free survival (DFS) and OS when ATRA was given with chemotherapy in consolidation.
There is no clear consensus as to which specific chemotherapy regimen is best in consolidation. Major cooperative groups have used several consolidation approaches, and their investigations suggest a benefit of cytarabine(Drug information on cytarabine) in patients with the presenting WBC > 10 × 109/L. A study by the PETHEMA group (LPA2005), in which patients with a WBC > 10 × 109/L received cytarabine combined with ATRA and idarubicin(Drug information on idarubicin) in the first and third consolidation courses, reported a favorable impact on the 3-year relapse rate (11% vs 26%, P = .03) when cytarabine was added to the consolidation.
The GIMEMA group (AIDA2000) also reported a reduction in the relapse rate (49.7% vs 9.3%) when cytarabine was added to the consolidation in patients with a WBC > 10 × 109/L. In the GIMEMA study, however, ATRA was also added to the consolidation therapy, which may have contributed to the improved outcome observed. In contrast, a study by the NCRI, published only in abstract form, showed no benefit of cytarabine, irrespective of the initial WBC.
The majority of studies suggest a benefit of cytarabine in patients with a WBC > 10 × 109/L, possibly because of the synergistic effect of the combination of ATRA plus cytarabine. The GIMEMA group recently reported the outcome of high-risk patients treated with either the AIDA 0493 protocol, which did not include intermediate-dose ara-C, or AIDA 2000, with risk-adapted post remission therapy in which such patients received intermediate-dose ara-C. The DFS among high-risk patients was 49.6% for patients treated on AIDA 0493 and 84.5% for those treated on AIDA 2000 (see Figure 3). It appears that cytarabine can be omitted for patients with WBC ≤ 10 × 109/L, however, and excellent outcome is preserved.
Emerging Nonchemotherapy Consolidation Regimens
To reduce toxicity and chemotherapy exposure in non–high-risk patients, several cooperative groups have investigated the role of ATRA and ATO either in place of or combined with reduced doses of cytotoxic chemotherapy in consolidation.
The North American Intergroup investigated the role of ATO combined with ATRA in consolidation in a randomized trial in which patients received 2 cycles of consolidation of ATRA plus daunorubicin(Drug information on daunorubicin), either immediately following induction therapy or preceded by two 25-day cycles of ATO plus ATRA. Results from the trial demonstrated that addition of ATO as initial consolidation therapy significantly improves 3-year DFS (90% vs 70%) and OS (86% vs 81%) regardless of presenting WBC. In a phase II study, Gore et al reported a comparable outcome (DFS 90% and OS 88% at a median follow-up of 2.7 years) with a considerably reduced amount of anthracyclines combined with a single cycle (30 days) of ATO. Investigators at M.D. Anderson Cancer Center completely eliminated cytotoxic chemotherapy from consolidation in all patients and reported a 3-year survival of 85% using ATRA and ATO for 28 weeks as the only post-remission therapy. The ALLG administered two courses of consolidation with ATRA and ATO, and reported a 3-year OS and EFS rates of 93% and 87%, respectively. The Indian APML Study Group, IAPLSG, reported a clinical outcome comparable to that achieved with conventional combination chemotherapy in patients with WBC ≤ 10 × 109/L, using single-agent treatment with ATO during induction and consolidation. The majority of studies suggest a potential synergism between an ATRA and ATO combination and raise the possibility of minimizing or even eliminating chemotherapy in APL management, particularly in patients with WBC ≤ 10 × 109/L. Ongoing randomized trials by several cooperative groups comparing ATRA plus ATO to ATRA plus chemotherapy may establish a new standard of care in APL.
Two randomized trials demonstrated a benefit of an ATRA-based maintenance therapy. The role of maintenance therapy remains unclear, however, particularly for non–high-risk patients and for those achieving molecular remission at the end of consolidation. Maintenance therapy in non–high-risk elderly patients may even be harmful, as shown by the EuroAPL group study that reported an 11% death rate in patients with CR, mainly from sepsis attributable to myelosuppression. Furthermore, introduction of ATO into first-line treatment for APL may reduce the significance of maintenance therapy.
The North American Intergroup study first reported a clinical benefit with the ATRA-based maintenance therapy for a year in terms of a reduction in relapse rate (22% vs 39%) and a higher 5-year DFS (61% vs 36%).[11,58] Similarly, the EuroAPL group confirmed the beneficial effect of adding ATRA to maintenance therapy in a randomized study of a regimen consisting of continuous low-dose 6-mercaptopurine and methotrexate(Drug information on methotrexate) in addition to intermittent ATRA. The EuroAPL group recently updated the results of their previous study and reported that the clinical benefit of maintenance therapy was mainly observed in high-risk patients, while only a marginal benefit was noted in non–high-risk patients. In contrast, two randomized trials by GIMEMA and the Japanese Adult Leukemia Study Group (JALSG) have reported no benefit from maintenance therapy if patients achieved molecular CR after consolidation.[60,61] However, the JALSG group trial included intensive chemotherapy and not ATRA as maintenance.
The discrepancy in these studies suggests that the benefit of maintenance treatment may depend on the specific prior induction and consolidation therapy, as well as PML/RARα status after consolidation, which has been shown to correlate with the relapse risk.[62,63] For example, both the JALSG and GIMEMA trials administered three cycles of consolidation therapy and used idarubicin as anthracycline for induction and consolidation chemotherapy, whereas the EuroAPL and North American Intergroup studies gave only two consolidation courses and used daunorubicin. Furthermore, while studies by the GIMEMA and JALSG groups were carried out in patients testing negative for PML/RARα at the end of consolidation, the North American Intergroup and EuroAPL studies did not examine molecular remission status at the end of consolidation, raising a question as to whether the observed benefit of maintenance therapy is largely attributable to responses in patients with minimal residual disease following consolidation.
These studies suggest that patients with a WBC ≤ 10 × 109/L and who achieve complete molecular remission after consolidation therapy may not benefit from the combination maintenance therapy. For high-risk patients, maintenance therapy for 1 to 2 years with intermittent ATRA and low-dose chemotherapy with 6-mercaptopurine and methotrexate are recommended. Given that there are no prospective trial data comparing 1 vs 2 years of maintenance therapy, the current recommendation is to continue maintenance therapy for 2 years unless toxicity develops.
Nonchemotherapy Maintenance Regimens
To investigate whether low-dose chemotherapy with 6-mercaptopurine and methotrexate can be safely omitted, investigators at M.D. Anderson Cancer Center used ATRA and ATO as the only postremission therapy following successful induction and reported a 3-year survival of 85%. One ongoing randomized trial is exploring the role of ATRA-based nonchemotherapy maintenance. A study by the JALSG is comparing ATRA to the synthetic retinoid tamibarotene. Several trials are also being conducted exploring nonchemotherapy maintenance regimens. The IAPLSG is conducting a phase II/III study wherein patients will receive ATO as a primary induction therapy followed by either 6 or 12 months of ATO maintenance. None of these trials includes an arm without maintenance, however. Future trials should address the role of maintenance therapy, particularly when ATO is incorporated into induction and consolidation.
Future Directions in APL
Now that cure rates are so high, the treatment of APL has focused recently of exploiting the synergism between ATRA and ATO in order to minimize cytotoxic chemotherapy and prevent both short-term and long-term toxicities. Cytarabine is not needed for induction in the majority of patients. Large cumulative doses of anthracyclines may result in cardiomyopathy. Therefore, the combination of ATRA and ATO has emerged as an attractive alternative approach. An oral formulation of ATO is under development. Tamibarotene is a novel retinoid with potential advantages compared with ATRA; its advantages include lower binding to the gamma receptor, which may result in less skin toxicity.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.