- Email: [email protected]
Classification and Risk Stratification for Acute Promyelocytic Leukemia
Classification and Risk Stratification for Acute Promyelocytic Leukemia Steven Coutre Abstract Acute promyelocytic leukemia (APL) as a distinct clinical entity was first described only 50 years ago. The last twenty years are notable for rapid advances in understanding the molecular basis of the disease as well as dramatic improvements in treating APL. A new classification system that stratifies patients by risk has also lead to dramatic improvement in managing the disease. Molecular monitoring for minimal residual disease holds great promise for continued improvement in decreasing relapse risk. We are now able to tailor our therapy based on risk of relapse, and ongoing clinical trials use this risk-adapted framework in an attempt to further improve outcomes. Clinical Lymphoma, Myeloma & Leukemia, Vol. 10, Suppl. 3, S127-S129, 2010; DOI: 10.3816/CLML.2010.s.024 Keywords: Anthracycline- and ATRA-based treatment regimen, Molecular monitoring, Predictive modeling
Introduction Acute promyelocytic leukemia (APL) was first described as a distinct clinical entity only 50 years ago.1 For decades, it retained its distinction as the “most malignant form of acute leukemia,” a description included in the initial characterization of the disease. However, the past 20 years are notable for rapid advances in understanding the molecular basis of the disease as well as dramatic improvements in treating APL.2-5 It is fair to say that it is now the most curable acute leukemia in adults. A new classification system that stratifies patients by risk has also led to dramatic improvement in managing the disease. We are now able to tailor therapy for APL based on risk of relapse, and ongoing clinical trials use this risk-adapted framework in an attempt to further improve outcomes.
Predictors of Relapse Risk in Acute Promyelocytic Leukemia A predictive model for relapse-free survival (RFS) in APL was first described by Dr. Sanz and colleagues in a retrospective analysis of 2 large clinical trials.6 The Italian Gruppo Italiano per le Malattie Ematologiche dell’Adulto (GIMEMA) and Spanish Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) cooperative groups pooled their results from 2 clinical trials of chemotherapy regimens that were highly active in APL.7,8 Previous trials had demonstrated the importance of all-trans-retinoic acid (ATRA) in remission induction in patients with previously untreated APL.4,5 It is now understood that ATRA promotes the degradation of the proStanford University, CA Submitted: Sep 21, 2010; Revised: Oct 11, 2010; Accepted: Oct 11, 2010 Address for correspondence: Steven Coutre, MD, Stanford University, 875 Blake Wilbur Dr, Stanford, CA 94305-5820 Fax: 650-724-5203; e-mail: [email protected]
myelocytic leukemia (PML)–retinoic acid receptor α (RARα) fusion protein central to the pathogenesis of APL.9 The PETHEMA and GIMEMA clinical trials used consolidation regimens that differed not only in chemotherapy drugs but also in the intensity of treatment.7,8 The GIMEMA group initially reported a 95% complete response rate and a 79% 2-year event-free survival (EFS) rate with a regimen that included a large cumulative dose of anthracycline as well as additional intensive chemotherapy.7 The PETHEMA group reported similar results with an anthracycline-only consolidation regimen, with less treatment-related toxicity.8 The stated intent of the pooled analysis included an aim to “build a predictive model for relapse to be used in the design of improved risk-adapted protocols.”6 The analysis included 217 patients with newly diagnosed APL. Based on a multivariate analysis of clinical and laboratory findings, only white blood cell (WBC) and platelet counts at diagnosis retained predictive value, and a simplified predictive model was proposed. Three patient groups were identified: (1) low-risk group with initial WBC count ≤ 10 × 109/L and platelet count > 40 × 109/L; (2) intermediate-risk group with initial WBC count ≤ 10 × 109/L and platelet count ≤ 40 × 109/L; and (3) high-risk group with initial WBC count > 10 × 109/L. Figure 1 shows the difference in RFS between these 3 groups. Strikingly, only 1 of the 53 patients in the low-risk group experienced relapse.
Designing Risk-Adapted Approaches to Therapy for Acute Promyelocytic Leukemia The PETHEMA group then applied this risk-adapted approach to their next clinical trial, the LPA99 study.10 Long-term results of 560 patients with a median follow-up of 5.67 years were recently reported. Figure 2 shows the cumulative incidence of relapse according to relapse risk group. The 5-year cumulative incidence of relapse (CIR) was only 3% in the low-risk patients and 8% in
Dr. Coutre has received research support from Bristol-Myers Squibb Company; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Hana Biosciences, Inc.; Pfizer Inc.; and Wyeth Pharmaceuticals. This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of arsenic trioxide in previously untreated APL and gemtuzumab ozogamicin in APL.
Clinical Lymphoma, Myeloma & Leukemia Supplement October 2010
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Classification and Risk Stratification for APL Figure 1 GIMEMA and PETHEMA Study Relapse-Free Survival by Risk Group
Figure 2 LPA99 Relapse Rate by Risk Group 100 High risk (n = 111) Low risk (n = 103) Intermediate risk (n = 295)
Probability of Relapse, %
Probability of Survival, %
100
80
60
40
20
Low Risk = WBC ≤ 10 × 109/L and Plt > 40 × 109/L Intermediate Risk = WBC ≤ 10 × 109/L and Plt ≤ 40 × 109/L High Risk = WBC > 10 × 109/L
P < .0001 60
40
20
0
P < .0001 0
80
20
40
60
80
12
24
36
48
60
72
84
96
108
Time, Months
Time, Months Abbreviations: Plt = platelets; WBC = white blood cell count
the intermediate-risk patients compared with 26% in the highrisk patients. This study emphasized the need to target high-risk patients in future studies of alternate treatment approaches. Other cooperative groups subsequently incorporated this riskstratification system, often called the Sanz score, into their trial designs. The French-Belgian-Swiss APL group compared the results of their randomized treatment APL 2000 trial that demonstrated the superiority of the addition of cytarabine to an ATRA/anthracycline-based regimen with the previous PETHEMA LPA99 trial outcomes.11 For low- and intermediate-risk patients, the 3-year CIR was significantly lower in the 294 evaluable patients in the LPA99 trial compared with the 95 patients in the APL 2000 trial (4% vs. 14%; P = .03). However, in high-risk patients, the addition of cytarabine improved overall survival at 3 years (91.5% vs. 80.8%; P = .026) and demonstrated a trend toward lower 3-year CIR (10% vs. 18.5%). The Italian GIMEMA AIDA-2000 trial also demonstrated the benefit of cytarabine when used in consolidation therapy for patients with high-risk disease.12 The positive results obtained with cytarabine in these 2 prospective, randomized trials reveals the power of risk-adapted approaches to consolidation therapy. Because of the recognition that high-risk patients need improved therapy, several groups have explored the use of arsenic trioxide (ATO) in the treatment of APL. Although arsenicals have long been used as medicinals, their mechanism of action in APL has only recently been elucidated.13,14 Direct binding to the PML gene leading to the proteasome-mediated degradation of the PML-RARα oncoprotein accounts for the exquisite sensitivity of APL to ATO. The North American Leukemia Intergroup recently published the results of a randomized trial that used a standard anthracyclineand ATRA-based treatment regimen.15 One treatment arm also received 2 courses of ATO consolidation. This trial revealed the benefit of adding ATO to the treatment of all patients with APL and confirmed the benefit of risk stratification. Disease-free survival at 3 years was 90% in the ATO consolidation arm compared with 70% in the other treatment arm. Both low/intermediate- and highrisk patient groups benefited from ATO. The French-Belgian-Swiss
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APL group has started a randomized trial, APL 2006, that incorporates ATO into the treatment course for high-risk patients.16 One question being addressed is whether use of ATO rather than cytarabine in consolidation therapy can lead to improved outcomes in high-risk patients.
Risk Stratification and Early Death Rates The risk-stratification system highlights the significant difference in early death rates between the risk groups. In the combined experience of the PETHEMA LPA96 and LPA99 trials, the early death rate was 7% in the low/intermediate-risk group compared with 15% in the high-risk group.17 In the North American trial, the early death rates were 4% in both the low- and intermediaterisk groups but 20% in the high-risk group.15 In each of these trials, the primary cause of early death was hemorrhage.15,17 In the APL 2000 study, only 2.8% of the high-risk patients experienced early death.11 This result is in contrast to the 15%-20% early death rate in high-risk patients reported by virtually every other large trial.11,15,17 The reasons why this study revealed such a low early death rate are not clear.
Impact of Newer Noncytotoxic Treatment Regimens in Acute Promyelocytic Leukemia Alternate treatment strategies are being tested to both maintain the excellent outcomes observed in low-risk patients and decrease the toxicity of treatment. They are also being applied to current trials in highrisk patients. Investigators at The University of Texas MD Anderson Cancer Center conducted a trial in 82 patients with newly diagnosed APL using only ATRA, ATO, and, in some cases, gemtuzumab ozogamicin, completely eliminating the use of cytotoxic agents.18 Although the overall early death rate was only 8.5%, there was a disparity between the high- and low/intermediate-risk groups (19% vs. 4%), despite the absence of anthracycline therapy in either risk group. The EFS rate was 91% in the low/intermediate-risk group but only 58% in the high-risk group. Although the omission of anthracycline preserved the efficacy in low/intermediate-risk patients, there was no favorable impact on the early death rate in high-risk patients.
Steven Coutre In addition to risk stratification based on clinical variables at presentation, the use of molecular monitoring of treatment response has led to the concept of risk stratification for relapse. Prospective monitoring of real-time quantitative polymerase chain reaction (RQ-PCR) of PML-RARA transcripts was found to be the strongest predictor of RFS in the Medical Research Council AML 15 trial.19 Peripheral blood and bone marrow samples collected at various treatment and post-treatment time points from 406 patients with newly diagnosed APL treated with ATRA and anthracycline-based chemotherapy were used for minimal residual disease (MRD) monitoring. The MRD monitoring successfully identified 11 of the 20 patients with subsequent clinical relapse. Of the 9 patients whose relapse was not predicted by MRD monitoring, 7 patients did not have appropriate samples collected and 2 had samples of suboptimal quality. In a multivariate analysis, MRD monitoring was the strongest predictor of both clinical relapse and RFS, superior even to WBC count at diagnosis. Using this MRD information, the investigators preemptively treated with ATO, preventing clinical relapse in the majority of patients. The RFS rate 1 year from molecular relapse was 73%, and the overall 3-year cumulative incidence of clinical relapse was only 5%. Based on these results, the investigators raise the intriguing possibility of using sequential MRD monitoring by RQ-PCR and preemptive treatment as an alternative to more-intense up-front chemotherapy, particularly for high-risk patients.
Conclusion Breakthroughs in the understanding of the molecular basis of APL have led to a revolution in treatment of the disease. Treatment advance, including the addition of ATRA and ATO to the management of APL, is one of the great success stories in the management of acute leukemia in the past 2 decades. The introduction of a robust risk-stratification system has allowed investigators to not only focus on improved therapies for specific groups of patients but also to start asking if some patients can receive less therapy. Molecular monitoring for MRD is changing the treatment paradigm, allowing a more rational approach to treatment intensification. We have come a long way from the “most malignant” acute leukemia to the “most curable.” Now we can begin to address if less is more in the treatment of some patients with APL.
References 1. Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand 1957; 159:189-94. 2. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72:567-72. 3. Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med 1991; 324:1385-93. 4. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. European APL 91 Group. Blood 1993; 82:3241-9. 5. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100:4298-302. 6. Sanz MA, Coco FL, Martín G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000; 96:1247-53. 7. Mandelli F, Diverio D, Avvisati G, et al. Molecular remission in PML/RARalphapositive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 1997; 90:1014-21. 8. Sanz MA, Martín G, Rayón C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. Blood 1999; 94:3015-21. 9. Benedetti L, Levin AA, Scicchitano BM, et al. Characterization of the retinoid binding properties of the major fusion products present in acute promyelocytic leukemia cells. Blood 1997; 90:1175-85. 10. Sanz MA, Montesinos P, Vellenga E, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 2008; 112:3130-4. 11. Adès L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood 2008; 111:1078-84. 12. Lo-Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for [adult] patients younger than 61 years: results of the AIDA-2000 trial of the GIMEMA group. Blood 2010; July 19, 2010 [e-pub ahead of print]. 13. Zhang X-W, Yan X-J, Zhou Z-R, et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science 2010; 328:240-3. 14. Jeanne M, Lallemand-Breitenbach V, Ferhi O, et al. PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 2010; 18:88-98. 15. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and over-all survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup study C9710. Blood 2010; August 12, 2010 [e-pub ahead of print]. 16. Clinicaltrials.gov [Web site]. Acute promyelocytic leukemia 2006 (APL). Available at: http://clinicaltrials.gov/ct2/show/NCT00378365. Accessed: October 21, 2010. 17. Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103:1237-43. 18. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27:504-10. 19. Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct preemptive arsenic trioxide therapy. J Clin Oncol 2009; 27:3650-8.
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Introduction Acute promyelocytic leukemia (APL) was first described as a distinct clinical entity only 50 years ago.1 For decades, it retained its distinction as the “most malignant form of acute leukemia,” a description included in the initial characterization of the disease. However, the past 20 years are notable for rapid advances in understanding the molecular basis of the disease as well as dramatic improvements in treating APL.2-5 It is fair to say that it is now the most curable acute leukemia in adults. A new classification system that stratifies patients by risk has also led to dramatic improvement in managing the disease. We are now able to tailor therapy for APL based on risk of relapse, and ongoing clinical trials use this risk-adapted framework in an attempt to further improve outcomes.
Predictors of Relapse Risk in Acute Promyelocytic Leukemia A predictive model for relapse-free survival (RFS) in APL was first described by Dr. Sanz and colleagues in a retrospective analysis of 2 large clinical trials.6 The Italian Gruppo Italiano per le Malattie Ematologiche dell’Adulto (GIMEMA) and Spanish Programa para el Tratamiento de Hemopatías Malignas (PETHEMA) cooperative groups pooled their results from 2 clinical trials of chemotherapy regimens that were highly active in APL.7,8 Previous trials had demonstrated the importance of all-trans-retinoic acid (ATRA) in remission induction in patients with previously untreated APL.4,5 It is now understood that ATRA promotes the degradation of the proStanford University, CA Submitted: Sep 21, 2010; Revised: Oct 11, 2010; Accepted: Oct 11, 2010 Address for correspondence: Steven Coutre, MD, Stanford University, 875 Blake Wilbur Dr, Stanford, CA 94305-5820 Fax: 650-724-5203; e-mail: [email protected]
myelocytic leukemia (PML)–retinoic acid receptor α (RARα) fusion protein central to the pathogenesis of APL.9 The PETHEMA and GIMEMA clinical trials used consolidation regimens that differed not only in chemotherapy drugs but also in the intensity of treatment.7,8 The GIMEMA group initially reported a 95% complete response rate and a 79% 2-year event-free survival (EFS) rate with a regimen that included a large cumulative dose of anthracycline as well as additional intensive chemotherapy.7 The PETHEMA group reported similar results with an anthracycline-only consolidation regimen, with less treatment-related toxicity.8 The stated intent of the pooled analysis included an aim to “build a predictive model for relapse to be used in the design of improved risk-adapted protocols.”6 The analysis included 217 patients with newly diagnosed APL. Based on a multivariate analysis of clinical and laboratory findings, only white blood cell (WBC) and platelet counts at diagnosis retained predictive value, and a simplified predictive model was proposed. Three patient groups were identified: (1) low-risk group with initial WBC count ≤ 10 × 109/L and platelet count > 40 × 109/L; (2) intermediate-risk group with initial WBC count ≤ 10 × 109/L and platelet count ≤ 40 × 109/L; and (3) high-risk group with initial WBC count > 10 × 109/L. Figure 1 shows the difference in RFS between these 3 groups. Strikingly, only 1 of the 53 patients in the low-risk group experienced relapse.
Designing Risk-Adapted Approaches to Therapy for Acute Promyelocytic Leukemia The PETHEMA group then applied this risk-adapted approach to their next clinical trial, the LPA99 study.10 Long-term results of 560 patients with a median follow-up of 5.67 years were recently reported. Figure 2 shows the cumulative incidence of relapse according to relapse risk group. The 5-year cumulative incidence of relapse (CIR) was only 3% in the low-risk patients and 8% in
Dr. Coutre has received research support from Bristol-Myers Squibb Company; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Hana Biosciences, Inc.; Pfizer Inc.; and Wyeth Pharmaceuticals. This article includes discussion of investigational and/or unlabeled uses of drugs, including the use of arsenic trioxide in previously untreated APL and gemtuzumab ozogamicin in APL.
Clinical Lymphoma, Myeloma & Leukemia Supplement October 2010
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Classification and Risk Stratification for APL Figure 1 GIMEMA and PETHEMA Study Relapse-Free Survival by Risk Group
Figure 2 LPA99 Relapse Rate by Risk Group 100 High risk (n = 111) Low risk (n = 103) Intermediate risk (n = 295)
Probability of Relapse, %
Probability of Survival, %
100
80
60
40
20
Low Risk = WBC ≤ 10 × 109/L and Plt > 40 × 109/L Intermediate Risk = WBC ≤ 10 × 109/L and Plt ≤ 40 × 109/L High Risk = WBC > 10 × 109/L
P < .0001 60
40
20
0
P < .0001 0
80
20
40
60
80
12
24
36
48
60
72
84
96
108
Time, Months
Time, Months Abbreviations: Plt = platelets; WBC = white blood cell count
the intermediate-risk patients compared with 26% in the highrisk patients. This study emphasized the need to target high-risk patients in future studies of alternate treatment approaches. Other cooperative groups subsequently incorporated this riskstratification system, often called the Sanz score, into their trial designs. The French-Belgian-Swiss APL group compared the results of their randomized treatment APL 2000 trial that demonstrated the superiority of the addition of cytarabine to an ATRA/anthracycline-based regimen with the previous PETHEMA LPA99 trial outcomes.11 For low- and intermediate-risk patients, the 3-year CIR was significantly lower in the 294 evaluable patients in the LPA99 trial compared with the 95 patients in the APL 2000 trial (4% vs. 14%; P = .03). However, in high-risk patients, the addition of cytarabine improved overall survival at 3 years (91.5% vs. 80.8%; P = .026) and demonstrated a trend toward lower 3-year CIR (10% vs. 18.5%). The Italian GIMEMA AIDA-2000 trial also demonstrated the benefit of cytarabine when used in consolidation therapy for patients with high-risk disease.12 The positive results obtained with cytarabine in these 2 prospective, randomized trials reveals the power of risk-adapted approaches to consolidation therapy. Because of the recognition that high-risk patients need improved therapy, several groups have explored the use of arsenic trioxide (ATO) in the treatment of APL. Although arsenicals have long been used as medicinals, their mechanism of action in APL has only recently been elucidated.13,14 Direct binding to the PML gene leading to the proteasome-mediated degradation of the PML-RARα oncoprotein accounts for the exquisite sensitivity of APL to ATO. The North American Leukemia Intergroup recently published the results of a randomized trial that used a standard anthracyclineand ATRA-based treatment regimen.15 One treatment arm also received 2 courses of ATO consolidation. This trial revealed the benefit of adding ATO to the treatment of all patients with APL and confirmed the benefit of risk stratification. Disease-free survival at 3 years was 90% in the ATO consolidation arm compared with 70% in the other treatment arm. Both low/intermediate- and highrisk patient groups benefited from ATO. The French-Belgian-Swiss
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APL group has started a randomized trial, APL 2006, that incorporates ATO into the treatment course for high-risk patients.16 One question being addressed is whether use of ATO rather than cytarabine in consolidation therapy can lead to improved outcomes in high-risk patients.
Risk Stratification and Early Death Rates The risk-stratification system highlights the significant difference in early death rates between the risk groups. In the combined experience of the PETHEMA LPA96 and LPA99 trials, the early death rate was 7% in the low/intermediate-risk group compared with 15% in the high-risk group.17 In the North American trial, the early death rates were 4% in both the low- and intermediaterisk groups but 20% in the high-risk group.15 In each of these trials, the primary cause of early death was hemorrhage.15,17 In the APL 2000 study, only 2.8% of the high-risk patients experienced early death.11 This result is in contrast to the 15%-20% early death rate in high-risk patients reported by virtually every other large trial.11,15,17 The reasons why this study revealed such a low early death rate are not clear.
Impact of Newer Noncytotoxic Treatment Regimens in Acute Promyelocytic Leukemia Alternate treatment strategies are being tested to both maintain the excellent outcomes observed in low-risk patients and decrease the toxicity of treatment. They are also being applied to current trials in highrisk patients. Investigators at The University of Texas MD Anderson Cancer Center conducted a trial in 82 patients with newly diagnosed APL using only ATRA, ATO, and, in some cases, gemtuzumab ozogamicin, completely eliminating the use of cytotoxic agents.18 Although the overall early death rate was only 8.5%, there was a disparity between the high- and low/intermediate-risk groups (19% vs. 4%), despite the absence of anthracycline therapy in either risk group. The EFS rate was 91% in the low/intermediate-risk group but only 58% in the high-risk group. Although the omission of anthracycline preserved the efficacy in low/intermediate-risk patients, there was no favorable impact on the early death rate in high-risk patients.
Steven Coutre In addition to risk stratification based on clinical variables at presentation, the use of molecular monitoring of treatment response has led to the concept of risk stratification for relapse. Prospective monitoring of real-time quantitative polymerase chain reaction (RQ-PCR) of PML-RARA transcripts was found to be the strongest predictor of RFS in the Medical Research Council AML 15 trial.19 Peripheral blood and bone marrow samples collected at various treatment and post-treatment time points from 406 patients with newly diagnosed APL treated with ATRA and anthracycline-based chemotherapy were used for minimal residual disease (MRD) monitoring. The MRD monitoring successfully identified 11 of the 20 patients with subsequent clinical relapse. Of the 9 patients whose relapse was not predicted by MRD monitoring, 7 patients did not have appropriate samples collected and 2 had samples of suboptimal quality. In a multivariate analysis, MRD monitoring was the strongest predictor of both clinical relapse and RFS, superior even to WBC count at diagnosis. Using this MRD information, the investigators preemptively treated with ATO, preventing clinical relapse in the majority of patients. The RFS rate 1 year from molecular relapse was 73%, and the overall 3-year cumulative incidence of clinical relapse was only 5%. Based on these results, the investigators raise the intriguing possibility of using sequential MRD monitoring by RQ-PCR and preemptive treatment as an alternative to more-intense up-front chemotherapy, particularly for high-risk patients.
Conclusion Breakthroughs in the understanding of the molecular basis of APL have led to a revolution in treatment of the disease. Treatment advance, including the addition of ATRA and ATO to the management of APL, is one of the great success stories in the management of acute leukemia in the past 2 decades. The introduction of a robust risk-stratification system has allowed investigators to not only focus on improved therapies for specific groups of patients but also to start asking if some patients can receive less therapy. Molecular monitoring for MRD is changing the treatment paradigm, allowing a more rational approach to treatment intensification. We have come a long way from the “most malignant” acute leukemia to the “most curable.” Now we can begin to address if less is more in the treatment of some patients with APL.
References 1. Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand 1957; 159:189-94. 2. Huang ME, Ye YC, Chen SR, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72:567-72. 3. Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med 1991; 324:1385-93. 4. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. European APL 91 Group. Blood 1993; 82:3241-9. 5. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100:4298-302. 6. Sanz MA, Coco FL, Martín G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000; 96:1247-53. 7. Mandelli F, Diverio D, Avvisati G, et al. Molecular remission in PML/RARalphapositive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood 1997; 90:1014-21. 8. Sanz MA, Martín G, Rayón C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. Blood 1999; 94:3015-21. 9. Benedetti L, Levin AA, Scicchitano BM, et al. Characterization of the retinoid binding properties of the major fusion products present in acute promyelocytic leukemia cells. Blood 1997; 90:1175-85. 10. Sanz MA, Montesinos P, Vellenga E, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 2008; 112:3130-4. 11. Adès L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood 2008; 111:1078-84. 12. Lo-Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for [adult] patients younger than 61 years: results of the AIDA-2000 trial of the GIMEMA group. Blood 2010; July 19, 2010 [e-pub ahead of print]. 13. Zhang X-W, Yan X-J, Zhou Z-R, et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science 2010; 328:240-3. 14. Jeanne M, Lallemand-Breitenbach V, Ferhi O, et al. PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3. Cancer Cell 2010; 18:88-98. 15. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and over-all survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup study C9710. Blood 2010; August 12, 2010 [e-pub ahead of print]. 16. Clinicaltrials.gov [Web site]. Acute promyelocytic leukemia 2006 (APL). Available at: http://clinicaltrials.gov/ct2/show/NCT00378365. Accessed: October 21, 2010. 17. Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103:1237-43. 18. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27:504-10. 19. Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct preemptive arsenic trioxide therapy. J Clin Oncol 2009; 27:3650-8.
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