CC BY-NC-ND 4.0 · Indian J Med Paediatr Oncol 2021; 42(03): 286-292
DOI: 10.1055/s-0041-1732942
How I Treat

How I Treat Acute Promyelocytic Leukemia

1   Department of Clinical Haematology Oncology, Hematopoietic Cell Transplantation, Tata Medical Center, Kolkata, West Bengal, India
,
1   Department of Clinical Haematology Oncology, Hematopoietic Cell Transplantation, Tata Medical Center, Kolkata, West Bengal, India
› Author Affiliations
Funding None.

Introduction

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%.[1] 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.[2] 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.[3] 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.[4] 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).[5] [6] [7] [8] [9] [10] [11] [12] [13]

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.[14] 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.[15] 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.

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Fig. 1 (A) The promyelocytes in the peripheral blood. (B) The Myeloperoxidase (MPO) staining in the BMA (Bone Marrow Aspiration).

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.[16]

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.

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Fig. 2 Characteristic Karyotype (2A) and Fluorescent In-Situ Hybridisation (2B) findings 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.



Publication History

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/).

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