The introduction of all-trans retinoic acid, or ATRA, in 1985, combined with anthracycline-based chemotherapy, has transformed acute promyelocytic leukemia (APL) from a fatal disease to one that is now highly curable. With appropriate contemporary therapy, more than 90% of patients achieve complete remission, and cure rates of approximately 80% and higher response and survival rates can be expected for patients at low and intermediate risk. The introduction of arsenic trioxide, or ATO, in 1994 has provided the opportunity to minimize and even eliminate standard cytotoxic chemotherapy from initial treatment regimens without compromising the excellent outcomes achieved by anthracycline-containing protocols. APL is a unique subtype of acute myeloid leukemia that is curable with targeted therapies and potentially without exposure to conventional DNA-damaging chemotherapy. The omission of conventional cytotoxic chemotherapy may reduce long-term complications such as cardiomyopathy and therapy-related myelodysplastic syndromes. Cure rates of APL may be further increased by adopting management strategies to reduce early hemorrhagic deaths, which now appear to be the major cause of treatment failure.
Acute promyelocytic leukemia (APL) is a rare distinct subtype of acute myeloid leukemia (AML) which accounts for 10%–15% of the approximately 12,330 adults diagnosed with AML in the United States each year. There has been dramatic progress in the management of APL during the past three decades. Important insights into the pathogenesis of the disease have come to light and effective treatment has been developed. APL has become highly curable and serves as a paradigm for development of effective therapies directed at a specific molecular abnormality. Modern treatment represents a departure from standard chemotherapeutic strategies applied to all other subtypes of AML, since all-trans retinoic acid (ATRA) induces differentiation of the malignant promyelocytes into mature granulocytes. The disease is characterized by distinctive morphology of blast cells, an associated life-threatening and often catastrophic bleeding disorder, and a specific balanced reciprocal translocation, t(15;17), which results in fusion of the PML (promyelocyte) gene on chromosome 15 to the RARα (retinoic acid receptor-α) gene on chromosome 17.
Prior to the introduction of ATRA as a treatment, APL was among the most fatal of AML subtypes at presentation or during induction, primarily because of an associated complex and often catastrophic bleeding disorder which is characterized by disseminated intravascular coagulation, fibrinolysis, and proteolysis. However, ATRA and arsenic trioxide (ATO) have changed the natural history of this disease from one that was characterized by a high mortality rate to one that is now associated with the highest curability rate among the AML subtypes in adults. Furthermore, multiple studies have demonstrated that combination of the two targeted agents ATRA and ATO is a highly effective and potentially curative treatment. Such a strategy has become the most exciting new treatment option for APL, potentially completely eliminating exposure to conventional cytotoxic chemotherapy in many, if not most, patients. Now that the relapse rate even among high-risk patients (white blood cell counts [WBCs] > 10 × 109/L at presentation) has decreased substantially, early hemorrhagic death prior to and during induction therapy remains the major cause of treatment failure. Almost every patient with APL achieves complete remission (CR) with either ATRA plus anthracycline-based induction or ATRA + ATO–based induction, and the relapse rate once a patient is in CR is very low; therefore, reducing early death has become the most important goal in the treatment of patients with APL and is likely the best strategy to apply towards the goal of curing virtually all patients with the disease. Given the unique natural history of APL, with some patients presenting with rapidly fatal bleeding before intervention is possible, clearly it will be impossible to cure every patient. However, the cure rate among patients with APL may be increased further through education of a wide variety of healthcare professionals about early recognition of the disease and introduction of ATRA and aggressive blood product support.
Evolution of Induction Therapy in APL
Prior to ATRA, induction therapy in APL was similar to that for all other subtypes of AML. Induction consisted of an anthracycline and cytarabine (also known as ara-C), which resulted in CR rates of 65%–80% among patients newly diagnosed with APL.[7-9] Historically, however, even among patients who achieved CR with initial chemotherapy, 50%–65% subsequently relapsed and only 30%–50% remained alive at 2 years—a rate somewhat higher than that often reported for patients with other subtypes of AML.[7,10] The recognition that ATRA could induce differentiation of leukemic promyelocytes into mature granulocytes had encouraged the evaluation of ATRA either as a single agent or in combination with chemotherapy, initially in relapsed and refractory disease and subsequently in patients with newly diagnosed APL. Although treatment with ATRA alone in induction results in CR rates of 72%–90%,[11-14] patients generally relapse if additional chemotherapy is not administered. Therefore, subsequent trials combined ATRA with chemotherapy. The European APL (EuroAPL) group demonstrated in a randomized study that concurrent ATRA plus chemotherapy (daunorubicin [Cerubidine] and cytarabine) resulted in a better outcome than sequential ATRA followed by chemotherapy, primarily by reducing the relapse rate at 2 years (6% vs 16%). This improvement was subsequently confirmed in other large multicenter trials.[15-18] Therefore, the concurrent administration of ATRA and anthracycline-based chemotherapy (an anthracycline plus cytarabine or an anthracycline alone, generally idarubicin [Idamycin]) is currently considered the standard of care for induction in newly diagnosed patients with APL. It is not known which anthracycline is best to administer, however. Although a retrospective analysis published only in a preliminary form has suggested that idarubicin is associated with an improved outcome compared with daunorubicin or amsacrine, there is no clear evidence that one anthracycline is clearly superior to another in APL.
Omitting Cytarabine in APL Induction
Two randomized trials have been conducted to investigate the role of cytarabine; the results have been conflicting. The National Cancer Research Institute (NCRI) in the United Kingdom (formerly the Medical Research Council, or MRC) reported no differences in response, relapse, or overall survival rates in patients randomized between ATRA plus idarubicin (AIDA) and ATRA with daunorubicin and cytarabine, but there was less myelosuppression with the regimen omitting cytarabine. In contrast, a randomized study by the EuroAPL group (APL 2000) showed a statistically significant increase in relapse risk (13.4% vs 29%) and decrease in overall survival (92.9% vs 83.3%) among patients in whom cytarabine was omitted from both induction and consolidation therapy.[21,22] The therapies likely were not comparable in other ways since, for example, the doses of the anthracyclines may not have been equivalent.
The cooperative groups Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) and Programa Espaol de Tratamientos en Hematologa (PETHEMA) have omitted cytarabine from induction, and demonstrated that AIDA is as effective in inducing remission as a cytarabine-containing regimen, with CR rates of 89%–95% regardless of the presenting WBC.[18,23] This discrepancy may be explained by differences in the consolidation regimens (ATRA vs no ATRA in EuroAPL trial), the number of consolidation courses, specific choice of anthracycline (idarubicin in the GIMEMA, PETHEMA, and NCRI trials vs daunorubicin in the EuroAPL trial), and the cumulative doses of anthracyclines. Treatment approaches that include cytarabine have the potential benefit of reducing the likelihood of extramedullary relapse, particularly in sanctuary sites such as the central nervous system (CNS), since relatively high doses of cytarabine are well-recognized to cross the blood–brain barrier and enter the CNS. Despite some reports of an increased incidence of extramedullary relapse since ATRA was introduced into routine clinical practice, the reported incidence of CNS relapses in APL in some studies is low, ranging from 0.6% to 2%,[24-26] and these relapses are invariably associated with marrow relapse.
1. Tallman MS, Altman JK. Curative strategies in acute promyelocytic leukemia. Hematology Am Soc Hematol Educ Program. 2008;391-9.
2. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33:451-8.
3. Tallman MS, Kwaan HC. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood. 1992;79:543-53.
4. Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet. 1977;1:549-50.
5. Grignani F, Ferrucci PF, Testa U, et al. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 1993;74:423-31.
6. 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 adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood. 2010;116:3171-9.
7. Cunningham I, Gee TS, Reich LM, et al. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood. 1989;73:1116-22.
8. Fenaux P, Degos L. Treatment of acute promyelocytic leukemia with all-trans retinoic acid. Leuk Res. 1991;15:655-7.
9. Head DR, Kopecky KJ, Willman C, Appelbaum FR. Treatment outcome with chemotherapy in acute promyelocytic leukemia: the Southwest Oncology Group (SWOG) experience. Leukemia. 1994;8(Suppl 2):S38-41.
10. Degos L, Dombret H, Chomienne C, et al. All-trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood. 1995;85:2643-53.
11. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021-8.
12. Chen ZX, Xue YQ, Zhang R, et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413-9.
13. Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990;76:1704-9.
14. 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.
15. Lengfelder E, Reichert A, Schoch C, et al. Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. German AML Cooperative Group. Leukemia. 2000;14:1362-70.
16. Mandelli F, Diverio D, Avvisati G, et al. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell’Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood. 1997;90:1014-21.
17. Asou N, Adachi K, Tamura J, et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Japan Adult Leukemia Study Group. J Clin Oncol. 1998;16:78-85.
18. Sanz MA, Martin G, Rayon 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. PETHEMA group. Blood. 1999;94:3015-21.
19. Berman E, Little C, Kher U, et al. Prognostic analysis of patients with acute promyelocytic leukemia (abstract). Blood. 1991;78(Suppl 1):43a.
20. Burnett AK, Hills RK, Grimwade D, et al. Idarubicin and ATRA is as effective as MRC chemotherapy in patients with acute promyelocytic leukaemia with lower toxicity and resource usage: preliminary results of the MRC AML15 trial (abstract). Blood. 2007;110:589.
21. Ades L, Chevret S, Raffoux E, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol. 2006;24:5703-10.
22. Ades L, Raffoux E, Chevret S, et al. Is araC required in the treatment of standard risk APL? Long term results of a randomized trial (APL 2000) from the French Belgian Swiss APL Group (abstract). Blood. 2010;116:13.
23. Avvisati G, Lo Coco F, Diverio D, et al. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) pilot study. Blood. 1996;88:1390-8.
24. Specchia G, Lo Coco F, Vignetti M, et al. Extramedullary involvement at relapse in acute promyelocytic leukemia patients treated or not with all-trans retinoic acid: a report by the Gruppo Italiano Malattie Ematologiche dell’Adulto. J Clin Oncol. 2001;19:4023-8.
25. de Botton S, Sanz MA, Chevret S, et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006;20:35-41.
26. Montesinos P, Diaz-Mediavilla J, Deben G, et al. Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis. Haematologica. 2009;94:1242-9.
27. Andersen MK, Pedersen-Bjergaard J. Therapy-related MDS and AML in acute promyelocytic leukemia. Blood. 2002;100:1928-9.
28. Garcia-Manero G, Kantarjian HM, Kornblau S, Estey E. Therapy-related myelodysplastic syndrome or acute myelogenous leukemia in patients with acute promyelocytic leukemia (APL). Leukemia. 2002;16:1888.
29. Latagliata R, Petti MC, Fenu S, et al. Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem. Blood. 2002;99:822-4.
30. Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:
31. Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;
32. Mathews V, George B, Lakshmi KM, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006;107:2627-32.
33. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17:131-4.
34. Zheng PZ, Wang KK, Zhang QY, et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005;102:7653-8.
35. Gianni M, Koken MH, Chelbi-Alix MK, et al. Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells. Blood. 1998;91:4300-10.
36. Shen ZX, Shi ZZ, Fang J, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101:5328-35.
37. Ravandi F, Estey EH, Cortes JE, et al. Phase II study of all-trans retinoic acid (ATRA), arsenic trioxide (ATO), with or without gemtuzumab ozogamicin (GO) for the frontline therapy of patients with acute promyelocytic leukemia (APL) (abstract). Blood. 2010;116:1080.
38. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107:3469-73.
39. de la Serna J, Montesinos P, Vellenga E, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395-402.
40. Breccia M, Latagliata R, Cannella L, et al. Early hemorrhagic death before starting therapy in acute promyelocytic leukemia: association with high WBC count, late diagnosis and delayed treatment initiation. Haematologica. 2010;95:853-4.
41. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999;94:1192-200.
42. Alizadeh AA, McClellan JS, Gotlib JR, et al. Early mortality in acute promyelocytic leukemia may be higher than previously reported (abstract). Blood. 2009;114:1015.
44. Micol JB, Raffoux E, Boissel N, et al. Do early events excluding patients with acute promyelocytic leukemia (APL) from trial enrollment modify treatment result evaluation? Real-life management of 100 patients referred to the university Hospital Saint-Louis Between 2000 and 2010 (abstract). Blood. 2010;116:1083.
45. Di Bona E, Avvisati G, Castaman G, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000;108:689-95.
46. Visani G, Gugliotta L, Tosi P, et al. All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia. Eur J Haematol. 2000;64:139-44.
47. Hu J, Liu YF, Wu CF, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009;106:3342-7.
49. Dimov ND, Medeiros LJ, Kantarjian HM, et al. Rapid and reliable confirmation of acute promyelocytic leukemia by immunofluorescence staining with an antipromyelocytic leukemia antibody. Cancer. 2010;
50. Sanz MA, Martin G, Gonzalez 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.
51. Sanz MA, Montesinos P, Rayon C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood. 2010;115:5137-46.
53. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751-7.
54. Gore SD, Gojo I, Sekeres MA, et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol. 2010;28:1047-53.
56. Iland H, Firkin F, Supple S, et al. Interim analysis of the APML4 trial incorporating all-trans retinoic acid (ATRA), idarubicin, and intravenous arsenic trioxide (ATO) as initial therapy in acute promyelocytic leukaemia (APL): an Australasian Leukaemia and Lymphoma Group (ALLG) study (abstract). International Oral Arsenic Union 38th Annual Scientific Meeting of the Hong Kong Society of Haematology. 2010;16:6.
58. 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.
59. Ades L, Guerci A, Raffoux E, et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood. 2010;115:1690-6.
60. Asou N, Kishimoto Y, Kiyoi H, et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Blood. 2007;110:59-66.
63. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia. 2002;16:1959-73.