Approach Considerations

According to National Comprehensive Cancer Network (NCCN) guidelines, multidisciplinary testing (immonohistochemistry, cytochemistry, and molecular genetic analysis) are needed to diagnose APL in accordance with the 2016 WHO classification system. An APL diagnosis requires APL morphology and one of the following^[16]:

t(15:17) by cytogenetics, or
Promelocytic leukemia (PML)/retinoic acid receptor alpha (RARA) by molecular testing

Patients are further classified as low risk (white blood cell [WBC] count ≤10,000/μL) or high risk (WBC >10,000/μL)^[16]

If major neurologic signs or symptoms are present, appropriate brain imaging studies should be performed to detect meningeal disease, chloromas, or central nervous system (CNS) bleeding.^[16]

Laboratory Studies

The initial laboratory workup of acute promyelocytic leukemia (APL) should include the following:

Complete blood cell (CBC) count with differential
Peripheral blood smear
Comprehensive metabolic profile for baseline renal and liver function tests,
Electrolyte levels
Prothrombin time (PT) and activated partial thromboplastin time (aPTT)
Fibrinogen assay

Other Tests

Many authorities recommend lumbar puncture at diagnosis of acute promyelocytic leukemia (APL) in high-risk patients who present with a very high WBC count. In these cases, the CNS may serve as a sanctuary site warranting intrathecal therapy. Coagulopathy should be corrected first, and lumbar puncture may sometimes be delayed until after induction therapy.

The cerebrospinal fluid (CSF), in addition to undergoing routine chemical and hematologic studies, should be cytospun and examined by a pathologist trained in examination of fluid cytospins. Flow cytometry of CSF should be done to look for the abnormal clonal cells.

In addition, cardiac function should be examined by echocardiography or scintigraphy before the administration of anthracyclines.

Procedures

A bone marrow biopsy with aspirate should be performed immediately. The sample should be sent for flow cytometry and cytogenetics. Fluorescent in situ hybridization (FISH) for the translocation or reverse transcription–polymerase chain reaction (RT-PCR) for the PML-RAR alpha transcript should also be done. The typical phenotype of acute promyelocytic leukemia (APL) is myeloperoxidase positive and CD33 positive, human leukocyte antigen (HLA)-DR negative.

Histologic Findings

Acute promyelocytic leukemia (APL) has the following morphologic variants^[14]:

Hypergranular (classic M3)
Microgranular (M3v)
Hyperbasophilic
PLZF-RAR alpha (M3r)

The hypergranular subtype has frequent Auer rods, clumps of granular material containing lysosomes, peroxidase, lysosomal enzymes, and large crystalline inclusions (see the image below). Auer rods can be seen in other types of AML, but they are usually seen in APL. The nucleus is folded or bilobed, and the cytoplasm contains prominent azurophilic granules. The bone marrow is usually hypercellular. The cells stain intensely for Sudan black and myeloperoxidase, but not for periodic acid–Schiff (PAS) and HLA-DR.

Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.

View Media Gallery

The microgranular variant also has a folded nucleus, but the cytoplasm has fine, dusky granules and Auer rods are rare. It is seen in 25% of cases of APL.

The hyperbasophilic subtype shows an increased nucleocytoplasmic ratio and strongly basophilic cytoplasm with blebs. There are few granules and no Auer rods.

The PLZF-RAR alpha variant has regular, condensed chromatin in the nucleus. There are fewer granules and rare Auer rods compared with the hypergranular subtype.

Treatment & Management

Cingam SR, Koshy NV. Acute Promyelocytic Leukemia. 2021 Jan. [QxMD MEDLINE Link]. [Full Text].
Bernard J. History of promyelocytic leukaemia. Leukemia. 1994. 8 suppl 2:S1-5. [QxMD MEDLINE Link].
Lo-Coco F, Cicconi L, Voso MT. Progress and criticalities in the management of acute promyelocytic leukemia. Oncotarget. 2017 Nov 21. 8 (59):99221-99222. [QxMD MEDLINE Link]. [Full Text].
Tan Y, Wang X, Song H, Zhang Y, Zhang R, Li S, et al. A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia. Blood. 2021 Mar 18. 137 (11):1503-1516. [QxMD MEDLINE Link]. [Full Text].
Vahdat L, Maslak P, Miller WH Jr, et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood. 1994 Dec 1. 84(11):3843-9. [QxMD MEDLINE Link]. [Full Text].
Yin CC, Jain N, Mehrotra M, Zhagn J, Protopopov A, Zuo Z, et al. Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia. J Natl Compr Canc Netw. 2015 Jan. 13(1):19-22. [QxMD MEDLINE Link].
Cao Y, Yuan R, Wang Y, Chen R, Huang M, Zhou J. A New Chromosome Translocation t(7;16)(q31,q22) Change during an Acute Promyelocytic Leukemia Relapse. Cytogenet Genome Res. 2013 May 4. [QxMD MEDLINE Link].
Jurcic JG, Soignet SL, Maslak AP. Diagnosis and treatment of acute promyelocytic leukemia. Curr Oncol Rep. 2007 Sep. 9(5):337-44. [QxMD MEDLINE Link].
Ribeiro RC, Rego E. Management of APL in developing countries: epidemiology, challenges and opportunities for international collaboration. Hematology Am Soc Hematol Educ Program. 2006. 162-8. [QxMD MEDLINE Link]. [Full Text].
Douer D. The epidemiology of acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2003 Sep. 16(3):357-67. [QxMD MEDLINE Link].
Matasar MJ, Ritchie EK, Consedine N, Magai C, Neugut AI. Incidence rates of acute promyelocytic leukemia among Hispanics, blacks, Asians, and non-Hispanic whites in the United States. Eur J Cancer Prev. 2006 Aug. 15(4):367-70. [QxMD MEDLINE Link].
Cicconi L, Lo-Coco F. Current management of newly diagnosed acute promyelocytic leukemia. Ann Oncol. 2016 Aug. 27 (8):1474-81. [QxMD MEDLINE Link]. [Full Text].
Xu F, Wang C, Yin C, Jiang X, Jiang L, Wang Z, et al. Analysis of early death in newly diagnosed acute promyelocytic leukemia patients. Medicine (Baltimore). 2017 Dec. 96 (51):e9324. [QxMD MEDLINE Link]. [Full Text].
Hou J, Wang S, Zhang Y, Fan D, Li H, Yang Y, et al. Causes and prognostic factors for early death in patients with acute promyelocytic leukemia treated with single-agent arsenic trioxide. Ann Hematol. 2017 Dec. 96 (12):2005-2013. [QxMD MEDLINE Link].
Zhao H, Zhao Y, Zhang Y, Hou J, Yang H, Cao F, et al. Difference in causes and prognostic factors of early death between cohorts with de novo and relapsed acute promyelocytic leukemia. Ann Hematol. 2018 Mar. 97 (3):409-416. [QxMD MEDLINE Link].
[Guideline] National Comprehensive Cancer Network. Acute Myeloid Leukemia. NCCN. Available at http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Version 3.2021 — March 2, 2021; Accessed: March 19, 2021.
Testa U, Lo-Coco F. Prognostic factors in acute promyelocytic leukemia: strategies to define high-risk patients. Ann Hematol. 2016 Apr. 95 (5):673-80. [QxMD MEDLINE Link].
Tallman MS, Kim HT, Montesinos P, et al. Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood. 2010 Dec 16. 116(25):5650-9. [QxMD MEDLINE Link].
Montesinos P, González JD, González J, Rayón C, de Lisa E, Amigo ML, et al. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic Acid and anthracycline-based chemotherapy. J Clin Oncol. 2010 Aug 20. 28(24):3872-9. [QxMD MEDLINE Link].
Cashen AF. Acute Leukemias. Govindan R, Morgensztern D, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology: Review. 4th ed. Philadelphia, Pa: Wolters Kluwer; 2016. 293-304.
Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999 Apr 1. 340(13):994-1004. [QxMD MEDLINE Link]. [Full Text].
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 Dec 15. 100(13):4298-302. [QxMD MEDLINE Link]. [Full Text].
Shigeno K, Naito K, Sahara N, et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol. 2005 Oct. 82(3):224-9. [QxMD MEDLINE Link].
Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, 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 Apr 13. 101(15):5328-35. [QxMD MEDLINE Link]. [Full Text].
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11. 369(2):111-21. [QxMD MEDLINE Link]. [Full Text].
Sanz MA, Martin G, Gonzalez M, et al, for the Programa de Estudio y Traitmiento de las Hemopatias 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 Feb 15. 103(4):1237-43. [QxMD MEDLINE Link]. [Full Text].
Fenaux P, Chastang C, Chevret S, et al, for the The European APL Group. 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. Blood. 1999 Aug 15. 94(4):1192-200. [QxMD MEDLINE Link]. [Full Text].
Sanz MA, Lo Coco F, Martin 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 Aug 15. 96(4):1247-53. [QxMD MEDLINE Link]. [Full Text].
Ades 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 Feb 1. 111(3):1078-84. [QxMD MEDLINE Link]. [Full Text].
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 Apr 1. 111(7):3395-402. [QxMD MEDLINE Link]. [Full Text].
Montesinos P, Gonzalez JD, Gonzalez J, et al. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic Acid and anthracycline-based chemotherapy. J Clin Oncol. 2010 Aug 20. 28(24):3872-9. [QxMD MEDLINE Link].
Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11. 116(19):3751-7. [QxMD MEDLINE Link]. [Full Text].
Grimwade D, Howe K, Langabeer S, et al. Minimal residual disease detection in acute promyelocytic leukemia by reverse-transcriptase PCR: evaluation of PML-RAR alpha and RAR alpha-PML assessment in patients who ultimately relapse. Leukemia. 1996 Jan. 10(1):61-6. [QxMD MEDLINE Link].
Avvisati G, Lo-Coco F, Paoloni FP, et al. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood. 2011 May 5. 117(18):4716-25. [QxMD MEDLINE Link].
Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM. The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. Cancer. 2016 Apr 15. 122 (8):1160-8. [QxMD MEDLINE Link].
Soignet SL, Frankel SR, Douer D, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001 Sep 15. 19(18):3852-60. [QxMD MEDLINE Link]. [Full Text].
Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010 Aug 20. 28(24):3866-71. [QxMD MEDLINE Link].
Tomita A, Kiyoi H, Naoe T. Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As₂O ₃) in acute promyelocytic leukemia. Int J Hematol. 2013 May 14. [QxMD MEDLINE Link].
Lo Coco F, Ammatuna E, Noguera N. Treatment of acute promyelocytic leukemia with gemtuzumab ozogamicin. Clin Adv Hematol Oncol. 2006 Jan. 4(1):57-62, 76-7. [QxMD MEDLINE Link].
Lo-Coco F, Cimino G, Breccia M, et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood. 2004 Oct 1. 104(7):1995-9. [QxMD MEDLINE Link]. [Full Text].
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 Jun 1. 99(11):4222-4. [QxMD MEDLINE Link]. [Full Text].
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 Jan 1. 23(1):120-6. [QxMD MEDLINE Link]. [Full Text].
Kharfan-Dabaja MA, Abou Mourad YR, Fernandez HF, Pasquini MC, Santos ES. Hematopoietic cell transplantation in acute promyelocytic leukemia: a comprehensive review. Biol Blood Marrow Transplant. 2007 Sep. 13(9):997-1004. [QxMD MEDLINE Link].
Fenaux P, Chastang C, Chevret S, et al, for the European APL Group. 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. Blood. 1999 Aug 15. 94(4):1192-200. [QxMD MEDLINE Link]. [Full Text].
Sanz MA, Vellenga E, Rayon C, et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood. 2004 Dec 1. 104(12):3490-3. [QxMD MEDLINE Link]. [Full Text].
Lengfelder E, Hofmann WK, Nolte F. Management of elderly patients with acute promyelocytic leukemia: progress and problems. Ann Hematol. 2013 May 22. [QxMD MEDLINE Link].
Braun T, Cereja S, Chevret S, Raffoux E, Beaumont M, Detourmignies L, et al. Evolving characteristics and outcome of secondary acute promyelocytic leukemia (APL): A prospective analysis by the French-Belgian-Swiss APL group. Cancer. 2015 Apr 6. [QxMD MEDLINE Link].
[Guideline] Sanz MA, Fenaux P, Tallman MS, Estey EH, Löwenberg B, Naoe T, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood. 2019 Apr 11. 133 (15):1630-1643. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Bone marrow aspirate hybridized with the RARA dual color break-apart probe set (Abbott-Vysis). The cell to the left shows a normal cell with 2 fusion signals, as the 5'RARA probe (orange) and the 3'RARA probe (green) are not separated. The cell on the right shows split signals for one RARA gene, indicating a chromosomal rearrangement disrupting the RARA gene. Image courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
Bone marrow aspirate hybridized with PML/RARA dual color translocation probe set (Abbott-Vysis). The cell to the right shows a normal cell with 2 separate PML (orange) and RARA (green) signals each. The cell to the left shows an abnormal cell characterized by a single fusion signal juxtaposing the PML and RARA signals, suggestive of a translocation of the 2 genes. Images courtesy of Dr. Tina Edmonston from the Department of Pathology at Thomas Jefferson University Hospital.
Hypogranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.
Regularly hypergranular subtype of acute promyelocytic leukemia. Image courtesy of Dr. William Kocher.

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Author

Sandy D Kotiah, MD Director of the Neuroendocrine Center, Hematology and Medical Oncology, Mercy Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Ronald A Sacher, MD, FRCPC, DTM&H Professor Emeritus of Internal Medicine and Hematology/Oncology, Emeritus Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center

Ronald A Sacher, MD, FRCPC, DTM&H is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Additional Contributors

Clarence Sarkodee Adoo, MD, FACP Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program

Clarence Sarkodee Adoo, MD, FACP is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Society of Hematology, American Society of Clinical Oncology

Disclosure: Nothing to disclose.