Treatment of relapsed or refractory acute promyelocytic leukemia in adults
- Richard A Larson, MD
Richard A Larson, MD
- Editor-in-Chief — Hematology
- Section Editor — Leukemia
- Professor of Medicine
- University of Chicago Pritzker School of Medicine
Acute promyelocytic leukemia (APL) is a clinically and biologically distinct variant of acute myeloid leukemia (AML). It was classified as AML-M3 in the older French-American-British (FAB) classification system, and acute promyelocytic leukemia with t(15;17)(q24.1;q21.1);PML-RARA in the WHO classification system. (See "Classification of acute myeloid leukemia".)
The vast majority of patients with newly diagnosed APL can obtain a complete remission with induction therapy that incorporates all-trans retinoic acid (ATRA; tretinoin) followed by a molecular complete remission after consolidation therapy. It is extremely uncommon to have primary drug resistance in APL, and in general, the predominant cause of induction failure (5 to 10 percent) is death from hemorrhage or infection. Despite this, relapse occurs in 10 to 15 percent of patients with APL and in about 20 to 30 percent of those with high-risk APL as defined as those who present with a white blood cell count above 10,000 and a platelet count less than 40,000. Using arsenic trioxide (ATO) during consolidation of first complete remission may markedly reduce the relapse rate even in high-risk APL.
The treatment of relapsed or refractory APL will be reviewed here. The clinical features, diagnosis, and prognosis of APL in adults are presented separately, as is the initial treatment of APL. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)
Resistant or refractory acute promyelocytic leukemia (APL) is diagnosed in those patients who either fail to attain a cytologic complete remission with induction chemotherapy or fail to attain a complete molecular remission following several cycles of consolidation chemotherapy. Response criteria are presented separately. (See "Remission criteria in acute myeloid leukemia and monitoring for residual disease".)
We consider patients to have relapsed disease if, after attainment of complete molecular remission, subsequent analyses confirm the loss of such molecular remission or identify extramedullary disease.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- de Botton S, Fawaz A, Chevret S, et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 2005; 23:120.
- Douer D, Zicki L, Schiffer CA, et al. Late relapses following all-trans retinoic acid for acute promyelocytic leukemia are uncommon, respond well to salvage therapy and occur independently of prognostic factors at diagnosis: Long-term follow-up of North American Intergroup Study 10129 (abstract 83). Blood 2011; 118:40.
- Gallagher RE, Moser BK, Racevskis J, et al. Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia. Blood 2012; 120:2098.
- Zhu HH, Qin YZ, Huang XJ. Resistance to arsenic therapy in acute promyelocytic leukemia. N Engl J Med 2014; 370:1864.
- Au WY, Tam S, Fong BM, Kwong YL. Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy. Blood 2008; 112:3587.
- Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94:3315.
- Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997; 89:3354.
- Soignet SL, Maslak P, Wang ZG, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998; 339:1341.
- Camacho LH, Soignet SL, Chanel S, et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol 2000; 18:2620.
- Kwong YL, Au WY, Chim CS, et al. Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukaemia: clinicopathological and molecular features of a pilot study. Am J Hematol 2001; 66:274.
- Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19:3852.
- Yanada M, Tsuzuki M, Fujita H, et al. Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood 2013; 121:3095.
- Raffoux E, Rousselot P, Poupon J, et al. Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 2003; 21:2326.
- Aribi A, Kantarjian HM, Estey EH, et al. Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia. Cancer 2007; 109:1355.
- Unnikrishnan D, Dutcher JP, Garl S, et al. Cardiac monitoring of patients receiving arsenic trioxide therapy. Br J Haematol 2004; 124:610.
- Chiang CE, Luk HN, Wang TM, Ding PY. Prolongation of cardiac repolarization by arsenic trioxide. Blood 2002; 100:2249.
- Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol 2003; 21:3609.
- Ohnishi K, Yoshida H, Shigeno K, et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med 2000; 133:881.
- Unnikrishnan D, Dutcher JP, Varshneya N, et al. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood 2001; 97:1514.
- Westervelt P, Brown RA, Adkins DR, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood 2001; 98:266.
- Roboz GJ, Ritchie EK, Carlin RF, et al. Prevalence, management, and clinical consequences of QT interval prolongation during treatment with arsenic trioxide. J Clin Oncol 2014; 32:3723.
- Singer JW. Cardiac toxicity of arsenic trioxide. Blood 2001; 98:1633; author reply 1633.
- Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113:1875.
- Au WY, Cheung GT, Yuen TW, et al. Successful treatment of relapsed acute promyelocytic leukemia in a patient receiving continuous ambulatory peritoneal dialysis with oral arsenic trioxide. Arch Intern Med 2005; 165:1067.
- Petti MC, Pinazzi MB, Diverio D, et al. Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg CMA-676). Br J Haematol 2001; 115:63.
- Lo Coco F, Ammatuna E, Noguera N. Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin. Clin Adv Hematol Oncol 2006; 4:57.
- Breccia M, Cimino G, Diverio D, et al. Sustained molecular remission after low dose gemtuzumab-ozogamicin in elderly patients with advanced acute promyelocytic leukemia. Haematologica 2007; 92:1273.
- Estey EH, Giles FJ, Beran M, et al. Experience with gemtuzumab ozogamycin ("mylotarg") and all-trans retinoic acid in untreated acute promyelocytic leukemia. Blood 2002; 99:4222.
- Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004; 104:1995.
- Thomas X, Anglaret B, Thiebaut A, et al. Improvement of prognosis in refractory and relapsed acute promyelocytic leukemia over recent years: the role of all-trans retinoic acid therapy. Ann Hematol 1997; 75:195.
- Meloni G, Diverio D, Vignetti M, et al. Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene. Blood 1997; 90:1321.
- Linker CA, Owzar K, Powell B, et al. Auto-SCT for AML in second remission: CALGB study 9620. Bone Marrow Transplant 2009; 44:353.
- Sanz MA, Labopin M, Gorin NC, et al. Hematopoietic stem cell transplantation for adults with acute promyelocytic leukemia in the ATRA era: a survey of the European Cooperative Group for Blood and Marrow Transplantation. Bone Marrow Transplant 2007; 39:461.
- Sainty D, Liso V, Cantù-Rajnoldi A, et al. A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Blood 2000; 96:1287.
- Lo-Coco F, Romano A, Mengarelli A, et al. Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia: results in patients treated in second molecular remission or with molecularly persistent disease. Leukemia 2003; 17:1930.
- Zompi S, Legrand O, Bouscary D, et al. Therapy-related acute myeloid leukaemia after successful therapy for acute promyelocytic leukaemia with t(15;17): a report of two cases and a review of the literature. Br J Haematol 2000; 110:610.
- Pecci A, Invernizzi R. A therapy-related myelodysplastic syndrome with unusual features in a patient treated for acute promyelocytic leukemia. Haematologica 2001; 86:102.
- Au WY, Lam CC, Ma ES, et al. Therapy-related myelodysplastic syndrome after eradication of acute promyelocytic leukemia: cytogenetic and molecular features. Hum Pathol 2001; 32:126.
- 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.
- ACHIEVING A SECOND RESPONSE
- Arsenic trioxide
- - Efficacy
- - Toxicity
- Chemotherapy and ATRA for relapse
- Autologous transplantation
- Allogeneic transplantation
- MANAGEMENT OF EXTRAMEDULLARY DISEASE
- Central nervous system involvement
- Myeloid sarcoma
- MONITORING DURING THERAPY AND SUPPORTIVE CARE
- THERAPY RELATED MYELOID NEOPLASMS AFTER APL
- CLINICAL TRIALS
- SUMMARY AND RECOMMENDATIONS