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Arsenic Trioxide (Trisenox^®) Therapy for Acute Promyelocytic Leukemia in the Setting of Hematopoietic Stem Cell Transplantation

^a Division of Hematology, Norris Cancer Center, University of Southern California at Los Angeles, Los Angeles, California, USA; ^b St. Joseph’s Hospital, Orange, California, USA; ^c M.D. Anderson Cancer Center, Houston, Texas, USA; ^d Cedars-Sinai Medical Center, Los Angeles, California, USA; ^e Washington University, Saint Louis, Missouri, USA

Correspondence: Dan Douer, M.D., Bone Marrow Transplantation Program, USC/Norris Cancer Center, 1441 Eastlake Avenue, Room 3460, Los Angeles, California 90033, USA. Telephone: 323-865-3145; Fax: 323-865-0060; e-mail: douer_d{at}mikey.hsc.usc.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
After completing this course, the reader will be able to:

1. Explain how to treat patients with relapsed acute promyelocytic leukemia.
   
2. Describe how to use arsenic trioxide in acute promyelocytic leukemia and be familiar with drug’s side effects.
   
3. Identify the role of bone marrow transplantation in acute promyelocytic leukemia.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
The relapse-free survival of patients with acute promyelocytic leukemia (APL) has significantly increased during the last decade. The introduction of all-trans retinoic acid (ATRA) doubled the survival of patients with this disease. However, despite ATRA and anthracycline-based chemotherapy, 12%–30% of patients will still relapse. Arsenic trioxide (ATO) has demonstrated efficacy and safety in patients with first and subsequent relapsed or refractory APL, regardless of the disease-free interval. Treatment of relapsed and refractory patients with this novel therapy produces complete remission in 87% of patients and molecular remission in 83%. Studies have documented the efficacy of autologous and allogeneic transplantation as salvage therapy in relapsed and refractory APL. The introduction of ATO into the treatment regimen for APL has stimulated discussion on its role in the transplantation setting. Investigators recently met to discuss the issue and make recommendations regarding ATO therapy in patients who are in their second or subsequent complete remission and are candidates for transplantation. This article describes the pivotal studies of this novel agent, discusses risk factor stratification for relapse in patients with APL, and proposes protocols for treatment incorporating ATO therapy. In addition, it describes scientific issues in ongoing and proposed clinical trials of ATO therapy for this disease.

Key Words. Acute promyelocytic leukemia • Arsenic trioxide • Transplantation • Molecular remission

	INTRODUCTION

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
Acute promyelocytic leukemia (APL), designated by the French-American-British (FAB) classification as M3, is a subtype of acute myeloid leukemia (AML) with distinct clinical, hematopathologic, cytogenetic, and molecular features. In the U.S., approximately 10,600 patients are diagnosed with AML annually [1]. Of these, approximately 5%–15% will have the FAB M3 subtype [2]. In the vast majority of patients with APL, leukemic blasts express the aberrant protein product of a specific cytogenetic translocation, t(15;17)(q22;q21), a defect that fuses the promyelocytic leukemia (PML) gene on chromosome 15 with the retinoic acid receptor alpha (RAR) gene from chromosome 17 [3, 4]. The expression of the PML-RAR transcript is involved in the pathogenesis of the disease. APL cells expressing the PML-RAR chimeric protein are unable to undergo normal terminal differentiation and are blocked at a promyelocytic stage. The presence of PML-RAR can be used to diagnose and monitor therapeutic efficacy in patients with APL.

Significant improvements have occurred in the therapy of patients with APL throughout the last decade. Before 1990, patients with APL were treated with combination chemotherapy. In the late 1980s, however, investigators from China demonstrated that treatment with all-trans retinoic acid (ATRA) was highly effective in inducing remission [5]. The incorporation of ATRA into anthracycline-based APL treatment regimens since 1990 has more than doubled the number of survivors, compared with the results from chemotherapy alone [6–10].

Despite these advances, several studies demonstrate a relapse rate of 12%–30% in APL patients treated with combination chemotherapy and ATRA [8, 10–12]. The importance of maintenance therapy was demonstrated in recent reports. In an update of the North American Intergroup protocol, the 5-year disease-free survival rate among patients receiving chemotherapy with ATRA (both in induction and in maintenance) was 74% [13]. In that study, late relapses occurring after at least 2 years of continuous complete remission (CR) were reported in 9% of patients, but only one of those patients had received ATRA in induction and in maintenance. Two European studies reported a lower relapse rate at 3 years of 12.4% in patients receiving maintenance with ATRA plus oral low-dose chemotherapy [11]. The relapse rate has been reported to be higher in patients who present with a WBC above 10,000, ranging from 30%–47% [10, 11]. A recent report from the Spanish Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) Group suggested that increasing the doses of anthracyclines during consolidation could lower the relapse rate in this high-risk group of patients (20% relapse at 2 years) [14].

Based on a total AML population of 10,600 [1], with an estimated 25% first-relapse rate (as per the North American Intergroup protocol), the number of relapsed APL patients can be estimated at 133–398 per year. The actual number may be higher when second and subsequent relapses are included. Reinduction therapy with single-agent ATRA alone has not provided long-term benefit, since second CRs achieved with ATRA alone lack durability and require consolidation with further chemotherapy [15, 16]. Therefore, promising novel agents such as arsenic trioxide (ATO) have been studied following initial reports of significant efficacy in relapsed or refractory APL patients.

This article provides a background on significant advances in APL therapy with ATO and discusses the integration of this novel agent into the treatment regimen of patients with APL in first or subsequent remission. Scientific issues in ongoing and proposed clinical trials of ATO therapy are also briefly described.

	ATO THERAPY FOR APL

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
In the 1990s, investigators from China reported that an herbal mixture containing ATO could induce CR in patients with APL [17, 18]. The mechanism of action of ATO in this disease appears to be unique and multifaceted and includes cytodifferentiation through degradation of the PML-RAR fusion protein, partial cellular differentiation, and induction of apoptosis [19, 20]. In clinical studies, the induction of apoptosis has been associated with caspase activation in leukemic cells, and it has been hypothesized that the PML-RAR fusion protein may be a substrate for caspase [20]. ATO can induce apoptosis of APL cells independently of the expression of the PML-RAR fusion protein, indicating other mechanisms of action [21–23]. Alternative mechanisms that have been suggested include downregulation of bcl2 expression or modulation of the intracellular content of reduced glutathione [23, 24].

	ATO FOR REINDUCTION AND CONSOLIDATION OF APL IN FIRST OR SUBSEQUENT RELAPSE

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
The Chinese results were replicated in a U.S. pilot study (n = 12) [20] and in a multicenter study (n = 40) [25] of purified ATO (Trisenox^®; Cell Therapeutics, Inc.; Seattle, WA) in patients with relapsed APL treated between October 1997 and May 2000 (Table 1). In those trials, all patients had relapsed following initial combination treatment with ATRA and anthracycline-based chemotherapy. The combined patient populations of these trials included patients in their first relapse (n = 26) and patients in their second or third relapse (n = 26). Among those, seven (13%) of the patients had undergone prior bone marrow transplantation (BMT). ATO was given daily until bone marrow remission was attained, to a maximum of 60 days. Patients who achieved CR were eligible for treatment with one consolidation course of therapy at the same daily dose used for induction, starting 3–5 weeks after completing the first course and given for a cumulative total of 25 days, and were also eligible for a maintenance protocol of up to four 25-day courses.

ATO was well tolerated. Treatment with ATO was not associated with bone marrow hypoplasia or alopecia, which is commonly seen with cytotoxic chemotherapy. APL differentiation syndrome was observed in 12 (23%) of the 52 patients [20, 25]. This syndrome was initially observed in ATRA-treated patients and described as the retinoic acid syndrome; it manifests as pulmonary infiltrates, dyspnea, and weight gain and appears to be related to the biologic response of APL to treatment, in particular the induction of cellular differentiation, which may lead to release of cytokines and increased production of integrins [27]. This syndrome has since been reported during induction therapy with ATRA or ATO and responds well to early treatment with systemic corticosteroids. Prolongation of the QT/QTc interval is a common side effect of ATO therapy. Therefore, during treatment, patients should undergo frequent electrocardiographic monitoring and vigilant monitoring; serum potassium and magnesium levels should be maintained as described in the Trisenox^® prescribing information. Extensive safety analyses show that adverse effects of ATO can be managed with proper monitoring and treatment [28, 29]. On the basis of these trials, the U.S. Food and Drug Administration approved Trisenox^® in September 2000 for the induction and consolidation therapy of patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy and whose APL is characterized by the presence of t(15;17) and/or PML-RAR gene expression. Trisenox^® was also approved in March 2002 by the European Agency for the Evaluation of Medical Products for the treatment of adult patients with relapsed APL. The systemic availability of an oral formulation of ATO has recently been reported, but its role in the treatment of hematologic malignancies remains unknown [30].

	OUTCOMES OF ATO-TREATED PATIENTS WHO ACHIEVED CR: A RETROSPECTIVE ANALYSIS

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
The outcomes of the 45 patients who achieved CR in the ATO clinical trials were analyzed retrospectively and are summarized in Figure 1. Of the 45 patients who achieved CR, 39 patients (87%) received consolidation beginning 3–4 weeks after their initial course of induction therapy. Most of those patients (n = 25) also received at least one 25-day cycle of ATO as maintenance therapy. Of the six patients who did not receive ATO consolidation or maintenance therapy after CR, three underwent BMT after induction (two while still in CR) and the remaining three patients discontinued treatment for various reasons [25].

View larger version (24K): [in this window] [in a new window]   Figure 1. Outcomes of ATO-treated patients achieving complete remission. Abbreviations: Allo = allogeneic stem cell transplantation; auto = autologous stem cell transplantation; rel = relapse after stem cell transplantation; SCT = stem cell transplantation.

Although still preliminary, the data from the above studies suggest that patients in first or subsequent relapse following ATRA/anthracycline therapy will benefit when they are treated with ATO either alone or before transplantation. In view of the small sample sizes, further studies are needed to confirm that administration of two cycles of ATO (induction plus consolidation) prior to stem cell transplantation is sufficient for an optimal outcome. The details of how best to use ATO to achieve optimal efficacy, however, are unknown at this time. Future clinical trials will undoubtedly answer the important questions concerning the frequency, duration, timing, and sequencing of ATO therapy.

	MAINTENANCE OF SECOND OR SUBSEQUENT CR

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
In an effort to reach a consensus on the management of patients with APL in second or subsequent remission (CR2), a panel of hematologists/oncologists, many of whom had served as clinical investigators, met in December 2001. This group discussed prognostic factors associated with a greater risk of relapse, treatment regimens that could reduce the risk of relapse, and transplantation strategies that could be applied to maintain remissions in this population in the era of ATO therapy. These topics are discussed in the remainder of this article. The panel members agreed with the opinion that, while CR is an important end point, the overall success of therapy for relapsed APL is dependent on postremission strategies that best provide for long-term disease-free survival [10].

	PROGNOSTIC FACTORS ASSOCIATED WITH A GREATER RISK OF RELAPSE

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
Certain clinical and laboratory features are useful as prognostic indicators of risk of relapse.

Clinical Prognostic Factors
Patient age at diagnosis appears to be an important clinical prognostic factor, as demonstrated in several trials [9, 13, 31]. For example, in a large European trial, survival at 2 years was 67% for patients older than 65 years compared with 82% for younger patients [9]. In a multicenter study of patients treated with ATRA followed by chemotherapy, an age of <30 years was associated with a greater event-free survival (p = 0.0003) [31]. Another study [32] demonstrated a superior event-free survival rate for individuals <70 years of age receiving anthracycline-based consolidation therapy. Other investigations did not demonstrate an effect of age on outcome [8, 11].

Laboratory Features
At the time of initial diagnosis of APL, a WBC of >10,000/µl and a platelet count of <40,000/µl have been shown to be adverse prognostic features in a number of studies [8, 9, 11, 13, 30–33]. Multivariate analyses [11] of the PETHEMA trial and the trial of the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) using these two variables indicated that risk of relapse can be stratified accordingly, into low-risk (WBC 10,000/µl, platelet count >40,000/µl), intermediate-risk (WBC 10,000/µl, platelet count 40,000/µl), and high-risk (WBC >10,000/µl) groups. In those studies, significant differences in relapse-free survival could be discerned among the three risk groups (p < 0.0001).

Molecular studies that detect minimal residual disease also provide useful prognostic information in APL patients [34]. Among APL patients in CR, conversion from negative to positive status for the PML-RAR mRNA transcript on RT-PCR testing is likely the most important predictor of relapse and may be an indicator for early and more aggressive therapy [35, 36]. In a serial study of 47 patients with newly diagnosed APL treated with ATRA monotherapy, 40 (85%) of the patients had molecular evidence of residual disease [37]. However, after three cycles of consolidation therapy with idarubicin and cytosine arabinoside, molecular evidence of residual disease remained in only 4 (10%) of the 40 patients. The investigators then correlated relapse rates with the results of these molecular studies. Only 3 (7%) of 41 patients who had two or more negative RT-PCR tests for PML-RAR relapsed, while all four patients with two or more positive tests relapsed. Thus, the persistence of the APL clone indicates a high probability of relapse.

	TREATMENT STRATEGIES TO REDUCE THE RISK OF RELAPSE IN HIGH-RISK PATIENTS

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
The optimal strategy for reducing the risk of relapse is still unknown. BMT, although not without risk, may decrease the relapse rate in patients who are in first molecular relapse [36]. This approach may play a role in preventing a relapse in high-risk patients who are in first CR. However, the high-risk population needs to be well defined and identified, and the timing of transplantation is subject to debate. Other treatment strategies that are in early development may prove to be useful in the high-risk population. One such strategy is the inclusion of gemtuzumab ozogamicin (Mylotarg^®; Wyeth Ayerst; Madison, NJ) in the treatment regimen [38].

Monitoring for Molecular Relapse
The results of monitoring for the presence of the PML-RAR transcript by RT-PCR have prognostic significance and can be used to guide therapy. Repeated negative results are associated with long-term survival, whereas the persistent presence of the transcript is highly predictive of relapse [39]. Diverio et al. reported the results of a prospective study of 163 patients with APL who were treated with ATRA and chemotherapy and then monitored by RT-PCR [40]. Twenty (95%) of the 21 patients who remained RT-PCR positive relapsed within a 3-month interval. The relapse rate was <10%, however, among patients with at least two negative test results following consolidation. Thus, the investigators recommended that molecular monitoring be conducted at regular intervals and that patients with a second positive test result within 2–4 weeks be treated for relapse. Identification of molecular relapse is an indication for the early administration of salvage therapy, although the optimal therapeutic approach has not yet been established [36]. Intervention at that time reduces the most serious disease- and treatment-related risks of clinically overt APL.

Bone Marrow or Stem Cell Transplantation
Bone marrow or peripheral blood stem cell transplantation is routinely employed as postconsolidation therapy for patients with APL in CR2. Because of the excellent response with ATRA plus chemotherapy, stem cell transplantation generally is not indicated in first CR (CR1) but might be considered for the few very high-risk patients in CR1. Most studies of stem cell transplantation in CR1 were performed before the introduction of ATO, and since patients with relapsed or refractory APL can now be treated successfully with ATO without introducing transplantation-limiting toxicity, the optimal timing for transplantation is unclear.

Allogeneic Transplantation
In a series of patients who underwent transplantation before 1994, the European Group for Bone Marrow Transplantation (EBMT) reported a relapse rate of 64% and a transplant-related mortality of 40% in patients undergoing allogeneic BMT in CR2 [41]. An update report from the registry, including data from patients who underwent transplantation after 1993, showed the 6-year estimated relapse rate to be 15% for allogeneic stem cell transplantation. However, the transplantation-related mortality estimate was 33% [42]. The authors agreed with The European APL group, reporting that allogeneic stem cell transplantation in patients in second or subsequent relapse is too toxic after salvage regimens that include ATRA and intensive chemotherapy. In that study, 8 (40%) of 20 patients treated with ATRA died from transplant-related complications [43].

Autologous Transplantation
In a report from the EBMT published in 1994, patients undergoing autologous BMT before 1994 had a relapse rate of 54% and a probability of transplantation-related mortality of 23% [41]. In a later report by the registry issued in 2000, patients in CR2 who underwent stem cell transplantation after 1993 had a relapse rate of 44%, although the transplantation-related mortality was 25% [42]. In 2002 the European APL group reported a 16% relapse rate in 45 patients after autologous stem cell transplantation and a transplantation-related mortality of 4% [43]. Prolonged clinical and molecular remissions have been obtained in patients undergoing BMT, even in the presence of initial RT-PCR-positive results for PML-RAR [44, 45]. The success of autologous transplantation contaminated by APL cells may reflect the antileukemic effect of the conditioning regimen; however, the presence or absence of minimal residual disease in the autologous harvested cells can influence the outcome after transplantation. Meloni et al. sought to determine whether remission could be maintained in patients with marrow harvests that were RT-PCR positive for PML-RAR. In a series of 15 patients undergoing transplantation in CR2, all seven patients who were transplanted with RT-PCR-positive marrow relapsed within 5 months; among the eight patients transplanted with RT-PCR-negative marrow, six patients (75%) remained in remission after a median of 28 months following autologous transplantation [46]. The relatively good outcome and low transplantation-related mortality are features that support the use of autologous transplantation, especially in the absence of minimal residual disease, in patients in CR2.

	GUIDELINES FOR THE USE OF ATO TO MAINTAIN REMISSION IN THE TRANSPLANTATION SETTING

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
With the approval of ATO as a treatment option in patients with relapsed and refractory APL, clinicians must now determine how the drug can be used to optimize therapy and prevent relapse in the transplantation setting.

ATO For APL in First or Subsequent Relapse Before Transplantation
Since ATO has been shown to be an excellent therapy for relapsed/refractory patients previously exposed to ATRA and it can induce a significant number of CRs, it may be an appropriate intervention before transplantation. In contrast, ATRA retreatment of APL patients relapsing after a first ATRA-induced CR has been of limited utility [15, 16]. Although the data described on the use of ATO therapy before transplantation are limited, they seem to indicate that ATO does not produce the toxicities seen with conditioning regimens involving aggressive chemotherapy. ATO thus appears to reduce the risk of transplantation-related complications. Among transplant recipients who were previously treated with ATO, 14 are still alive at last follow-up (Cell Therapeutics, Inc., data on file, 2002).

After the induction of CR by ATO, patients should be tested for minimal residual disease by RT-PCR for the presence of the PML-RAR transcript. Patients who test negative may be eligible for autologous transplantation even if they have an HLA-identical sibling. Allogeneic BMT in these patients carries a higher toxicity burden, and the overall rate of survival is not superior to that achieved with autologous transplantation [43]. ATO maintenance therapy following autologous transplantation may be an effective way of treating minimal residual disease, since APL cells that are not detected in the stem cell harvest may still be sensitive to ATO. The optimal dose and duration of the maintenance regimen are unclear at this time.

Also unclear is to what extent patients in CR2 would ultimately be cured with ATO alone. For this reason, autologous transplantation after an initial two or three cycles of ATO may be a preferable option. In patients who cannot undergo autologous transplantation or choose not to, ATO may be administered in consolidation and maintenance approaches, followed by close RT-PCR monitoring. In the pivotal ATO trial, the few patients with hematologic CR who did not achieve a molecular remission after induction became RT-PCR negative after one or two additional treatment cycles [25]. This suggests that patients who are in hematologic CR but remain PML-RAR positive after ATO induction and consolidation may still become PML-RAR negative after additional cycles of ATO maintenance. Autologous transplantation remains an option at this point, since patients in CR, even if transplanted with PML-RAR-positive harvests, still may be cured or experience extended relapse-free survival [44].

Patients who fail autologous transplantation may be considered for allogeneic transplantation if a suitable donor exists. Ultimately, the patient in hematologic CR who remains PML-RAR positive after ATO therapy can be considered for enrollment in a clinical trial involving interventions aimed at converting the RT-PCR status.

Transplant Safety Concerns in Patients Who Have Received Prior ATO Therapy
Although ATO therapy is generally very well tolerated, certain precautions should be taken, based upon known pharmacologic issues, when the drug is used before or after transplantation. ATO therapy can prolong the QT/QTc interval. Therefore, it is wise to restrict ATO therapy in the 30 days immediately before and after transplantation. This recommendation is based upon the potential for transient cardiac disturbances or electrolyte abnormalities that may occur in the peritransplantation period and the associated increased risk of arrhythmias, including torsade de pointes. Furthermore, ATO therapy has the potential to worsen or prolong cytopenias in the immediate posttransplantation interval. Therefore, a reduction in the ATO dose may need to be considered [47].

	CURRENT AND PROPOSED TRIALS OF ATO IN PATIENTS WITH APL

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 
Clinical trials to further evaluate the effectiveness of ATO in APL are under way or in the planning stage. Most of these trials will study the role of this drug in the initial treatment or nonsalvage setting. For example, ATO will be evaluated in patients in molecular relapse and also as first-line treatment during induction or consolidation. It is likely, and appropriate, that future trials will be designed to evaluate the role of ATO as maintenance therapy to eliminate any minimal residual disease following autologous transplantation in patients in CR2 (Fig. 2). In addition, the Cancer and Leukemia Group B and the U.S. North American Intergroup are conducting a randomized phase III trial studying ATRA, cytarabine, and daunorubicin with or without ATO as induction/consolidation therapy in patients with previously untreated APL. Such proposed trials will require a large effort by many institutions in order to collect sufficient information, since few relapsed APL patients are seen at any one institution.

View larger version (17K): [in this window] [in a new window]   Figure 2. Proposed trial design. Trial will compare the effects of ATO maintenance with observation following autologous transplantation on overall survival and relapse-free survival of APL patients in CR2. Abbreviation: FISH = fluorescence in situ hybridization.

	CONCLUSION

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

	REFERENCES

Top Learning Objectives Abstract Introduction ATO Therapy for APL ATO for Reinduction and... Outcomes of ATO-Treated Patients... Maintenance of Second or... Prognostic Factors Associated... Treatment Strategies to Reduce... Guidelines for the Use... Current and Proposed Trials... Conclusion References

 

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