Subscribe to RSS
How I Treat Acute Promyelocytic LeukemiaFunding None.
Discoveries and interventions in cancer are rarely so disruptive and exceptional that they cause dramatic advances in our understanding of the underlying mechanisms of a disease and immediately impact changes in treatment which lead to instant cures. Acute promyelocytic leukemia (APL) is an example of one such a disease.
Traditionally APL comprised of 10% of acute myeloid leukemia (AML) patients, presenting with bleeding diathesis and early fatal hemorrhage in 8 to 47% cases, complete remission (CR) rate was 60 to 80% with conventional anthracycline and cytosine arabinoside for patients who survived the initial induction, and a 5-year disease-free survival (DFS) which ranged between 35 and 45%. Yet, patient after patient bled during induction and succumbed in the wards 30 years ago.
The treatment of patients with APL has changed significantly in the past three decades and is now considered as one of the most curable cancers. The high sensitivity of APL cells to anthracycline chemotherapy and the introduction of a targeted therapy like all-transretinoic acid (ATRA) therapy has led to the deintensification of therapy. The initial studies showed that omission of cytarabine was feasible in standard-risk patients. An important milestone was achieved when arsenic trioxide (ATO) demonstrated substantial activity in relapsed APL. Thereafter, ATO emerged as one of the most potent agents in this disease with most patients achieving molecular remissions, as assessed by polymerase chain reaction (PCR) testing. Several strategies involving the use of the most effective agents early on in the course of treatment include the following: the use of ATO after patients achieved complete remission with an initial ATRA plus chemotherapy induction, monotherapy with ATO, ATRA and ATO combination therapy in induction followed by chemotherapy for consolidation, the addition of ATO to ATRA plus chemotherapy combination, and finally, a chemotherapy-free induction regimen with ATRA plus ATO and gemtuzumab ozogamicin (GO).        
This article attempts to address the following aspects of APL management: the initial approach of patients with suspected APL, management strategies, and supportive care measures; and assessment of molecular response and management of relapsed disease. We also share some of our experiences.
Begin treatment at suspicion of the diagnosis: A clinical suspicion of APL accompanied by the presence of characteristic findings can lead to a diagnosis. The review of peripheral blood (PB) and/or bone marrow (BM) aspirate smears of the patient by an experienced hematopathologist or hematologist enables a presumptive diagnosis. The PB smear of a patient typically shows circulating promyelocytes and leukopenia ( [Fig. 1A] ). Promyelocytes with abundant, irregular primary azurophilic granules and multiple auer rods are identified only in APL. The nucleus is bilobed or reniform in appearance. The promyelocytes are Myeloperoxidase positive ( [Fig. 1B] ). A nuanced appreciation of the morphology of APL is critical, as this subset of AML warrants immediate treatment. APL can be therapy-related rarely, and its outcomes are similar to a de novo APL. Considering the observations of appropriate sampling, occurrence of concomitant marrow changes and, occasionally, an unusual clinical presentation in APL patients, we recommend a BM test at the time of diagnosis. However, institutional policy and management protocols must guide BM testing practice (diagnosis and response assessment) in each center.
Once a diagnosis is suspected, ATO and/or ATRA must be started to initiate induction therapy and mitigate the attendant coagulopathy, even if the confirmatory cytogenetics and molecular test results are awaited.
Confirmation of the diagnosis: Several laboratory techniques can confirm diagnosis. Metaphase karyotyping is highly specific ( [Fig. 2A] ) and can detect variant translocations. However, karyotyping is time consuming and is often unsuccessful in detecting cryptic cytogenetic or molecular rearrangements. Reverse-transcriptase PCR (RT-PCR) for the PML-Retinoic Acid Receptor alpha fusion transcript is now a routine confirmatory test for diagnosis and considered the “gold standard.” Fluorescence in situ hybridization (FISH; [Fig. 2B] ) and the PML antibody methods are rapid tests to get a diagnosis in APL.
FLT3 internal tandem duplications and its prognostic significant in APL patients given ATRA plus chemotherapy have generated a significant debate. Recent data, however, indicate that in patients treated with ATRA plus ATO, the presence of these gene rearrangements may not confer a worse outcome. Unlike other AML subtypes, the presence of recurrent mutations, such as in WT1, NRAS, and KRAS genes and their prognostic significance are not established. We do not recommend a routine screening of these gene rearrangements at diagnosis, outside a clinical study.
Article published online:
21 September 2021
© 2021. Indian Society of Medical and Paediatric Oncology. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
Thieme Medical and Scientific Publishers Private Ltd.
A-12, Second Floor, Sector -2, NOIDA -201301, India
- 1 Fenaux P, Pollet JP, Vandenbossche-Simon L. et al Treatment of acute promyelocytic leukemia: a report of 70 cases. Leuk Lymphoma 1991; 4 (04) 239-248
- 2 Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 2008; 111 (05) 2505-2515
- 3 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 (03) 1078-1084
- 4 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 (18) 3852-3860
- 5 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 (19) 3751-3757
- 6 Mathews V, George B, Chendamarai E. et al Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 2010; 28 (24) 3866-3871
- 7 Ghavamzadeh A, Alimoghaddam K, Rostami S. et al Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol 2011; 29 (20) 2753-2757
- 8 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 (15) 5328-5335
- 9 Iland HJ, Bradstock K, Supple SG. et al Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4. Blood 2012; 120 (08) 1570-1580 quiz 1752
- 10 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 (04) 504-510
- 11 Lo-Coco F, Avvisati G, Vignetti M. et al Gruppo Italiano Malattie Ematologiche dell’Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013; 369 (02) 111-121
- 12 Burnett AK, Russell NH, Hills RK. et al UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 2015; 16 (13) 1295-1305
- 13 Abaza Y, Kantarjian H, Garcia-Manero G. et al Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood 2017; 129 (10) 1275-1283
- 14 Bennett JM, Catovsky D, Daniel MT. et al Hypergranular promyelocytic leukemia: correlation between morphology and chromosomal translocations including t(15;17) and t(11;17. Leukemia 2000; 14 (07) 1197-1200
- 15 Rashidi A, Fisher SI. Therapy-related acute promyelocytic leukemia: a systematic review. Med Oncol 2013; 30 (03) 625
- 16 Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood 2009; 114 (25) 5126-5135
- 17 Sanz MA, Martín G, González M. et al Programa de Estudio y Traitmiento de las Hemopatías Malignas. 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 (04) 1237-1243
- 18 de Botton S, Chevret S, Coiteux V. et al European APL group. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia 2003; 17 (02) 339-342
- 19 Nasr R, Guillemin MC, Ferhi O. et al Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 2008; 14 (12) 1333-1342
- 20 Advani SH, Nair R, Bapna A. et al Acute promyelocytic leukemia: all-trans retinoic acid (ATRA) along with chemotherapy is superior to ATRA alone. Am J Hematol 1999; 60 (02) 87-93
- 21 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 (04) 1390-1398
- 22 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. PETHEMA group. Blood 1999; 94 (09) 3015-3021
- 23 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 (09) 3342-3347
- 24 Dai CW, Zhang GS, Shen JK. et al Use of all-trans retinoic acid in combination with arsenic trioxide for remission induction in patients with newly diagnosed acute promyelocytic leukemia and for consolidation/maintenance in CR patients. Acta Haematol 2009; 121 (01) 1-8
- 25 Dally N, Hoffman R, Haddad N, Sarig G, Rowe JM, Brenner B. Predictive factors of bleeding and thrombosis during induction therapy in acute promyelocytic leukemia-a single center experience in 34 patients. Thromb Res 2005; 116 (02) 109-114
- 26 Tallman MS, Andersen JW, Schiffer CA. et al Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood 2000; 95 (01) 90-95
- 27 Ajay B, Reena N, Advani SH. Retinoic acid syndrome in Acute Promyelocytic Leukemia. Ind J Med Ped Oncol 1997; 18: 46-50
- 28 Wiley JS, Firkin FC. Australian Leukaemia Study Group. Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Leukemia 1995; 9 (05) 774-778
- 29 Devdas SK, Jain H, Bhausaheb B, Sengar M, Dangi U. Khattry, et al Sequential treatment of arsenic trioxide followed by all trans retinoic acid with anthracyclines has an excellent long term cure in acute promyelocytic leukemia. Indian J Hematol Blood Transfus 2020; 37 (01) 30-36
- 30 Platzbecker U, Avvisati G, Cicconi L. et al Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol 2017; 35 (06) 605-612
- 31 Russell N, Burnett A, Hills R. et al NCRI AML Working Group. Attenuated arsenic trioxide plus ATRA therapy for newly diagnosed and relapsed APL: long-term follow-up of the AML17 trial. Blood 2018; 132 (13) 1452-1454
- 32 Döhner H, Estey E, Grimwade D. et al Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129 (04) 424-447
- 33 Schuurhuis GJ, Heuser M, Freeman S. et al Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 2018; 131 (12) 1275-1291
- 34 Avvisati G, Lo-Coco F, Paoloni FP. et al GIMEMA, AIEOP, and EORTC Cooperative Groups. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 2011; 117 (18) 4716-4725
- 35 Breccia M, Diverio D, Noguera NI. et al Clinico-biological features and outcome of acute promyelocytic leukemia patients with persistent polymerase chain reaction-detectable disease after the AIDA front-line induction and consolidation therapy. Haematologica 2004; 89 (01) 29-33
- 36 Grimwade D, Jovanovic JV, Hills RK. et al Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol 2009; 27 (22) 3650-3658
- 37 Sanz MA, Fenaux P, Tallman MS. et al Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood 2019; 133 (15) 1630-1643
- 38 Yanada M, Yano S, Kanamori H. et al Autologous hematopoietic cell transplantation for acute promyelocytic leukemia in second complete remission: outcomes before and after the introduction of arsenic trioxide. Leuk Lymphoma 2017; 58 (05) 1061-1067
- 39 Ganzel C, Mathews V, Alimoghaddam K. et al Autologous transplant remains the preferred therapy for relapsed APL in CR2. Bone Marrow Transplant 2016; 51 (09) 1180-1183
- 40 Thirugnanam R, George B, Chendamarai E. et al Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant 2009; 15 (11) 1479-1484
- 41 Hashmi H, Nishihori T. Role of hematopoietic cell transplantation in relapsed acute promyelocytic leukemia. Clin Transplant 2020; 34 (09) e14009
- 42 Gardner KM, Dorcy KS. et al Use of gemtuzumab ozogamicin for the treatment of relapsed or refractory acute myeloid leukemia (AML) or acute promyelocytic leukemia (APL) in an expanded access setting at our cancer consortium. Blood 2018; 132 (supplement 1) 2710
- 43 Kulkarni U, Ganesan S, Alex AA. et al A phase II study evaluating the role of bortezomib in the management of relapsed acute promyelocytic leukemia treated upfront with arsenic trioxide. Cancer Med 2020; 9 (08) 2603-2610
- 44 Gupta S, Bagel B, Gujral S. et al Parenthood in patients with acute promyelocytic leukemia after treatment with arsenic trioxide: a case series. Leuk Lymphoma 2012; 53 (11) 2192-2194
- 45 Stein EM, Tallman MS. Does arsenic trioxide impact fertility. ? Leuk Lymphoma 2012; 53 (11) 2099-2100
- 46 Abhyankar D, Nair R, Menon H, Kapoor B, Advani S. Avascular necrosis of head of femur in a patient with acute promyelocytic leukemia. Leuk Lymphoma 2000; 37 (5,6) 635-637