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Improving APL Outcomes
How Can We Further Improve Outcomes in Acute Promyelocytic Leukemia?

Released: June 18, 2015

Expiration: June 16, 2016

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Case, Part I: A 32-year-old Hispanic woman presented to her local hospital after several weeks of heavy menstrual bleeding and was investigated for menorrhagia. A week later, a full blood count showed her to be pancytopenic with a WBC count of 2.0 x 109/L, Hb of 6.7 g/dL, and a platelet count of 12 x 109/L. She was referred to a hematologist, and a bone marrow exam was performed several days later. Approximately 2 weeks after initial presentation, a diagnosis of acute promyelocytic leukemia (APL) was suggested by morphological examination, and the patient was transferred to a tertiary center. She was found to be coagulopathic with an INR of 3.2, fibrinogen of 85 mg/dL, and a platelet count of 8 x 109/L.

Treatment of patients with APL has changed dramatically during the past 2 decades, and with current treatment strategies, a cure is possible for most patients. Classical APL with the characteristic granules and multiple Auer rods (accounting for 80% of cases) can be easily recognized by trained pathologists. Other features such as the characteristic immunophenotype, a low WBC at presentation, and the usual concomitant coagulopathy also help with early recognition of the disease entity.

The definitive diagnosis requires detection of the pathognomonic translocation between chromosomes 15 and 17 and/or the resulting fusion transcript, PML-RARα, using standard karyotype analysis, FISH, or PCR, but this should not delay initiation of treatment with all-trans retinoic acid (ATRA) if the diagnosis is suspected. Rarely, a patient may have alternative partners for the RARa gene, which can result in insensitivity to ATRA. A rapid diagnostic test using anti-PML antibodies can be used to increase the speed of diagnosis.

Rapid Diagnosis and Treatment Essential
Rapid diagnosis and initiation of therapy with ATRA can significantly improve the outcome of patients with APL; most experts recommend initiating therapy with ATRA at the first suspicion of the diagnosis to avoid devastating complications such as pulmonary or intracranial hemorrhage. Aggressive correction of coagulopathy—with the use of blood products including platelets, fresh frozen plasma, and cryoprecipitate—is critical early in the course of treatment. Detection and management of infections, close attention to fluid status, and prevention and treatment of tumor lysis syndrome and differentiation syndrome are also important aspects of treatment.

Definitive therapy should be initiated as soon as the diagnosis is confirmed. Historically, this included the combination of ATRA and cytotoxic chemotherapy, with some regimens omitting cytarabine in order to deliver a higher dose of idarubicin (eg, the PETHEMA regimen). More recently, studies have incorporated arsenic trioxide (ATO) in the upfront treatment of APL, and several phase II studies have reported high responses with single-agent ATO. My colleagues and I have reported our trial of a chemotherapy-free regimen of ATRA plus ATO with the use of gemtuzumab ozogamycin in patients with high-risk disease (defined by WBC count at presentation above 10 x 109/L), and in patients with low-risk disease whose WBC count rises above 10 x 109/L during the course of therapy.

This led to a European randomized trial where the ATRA plus ATO regimen was compared with ATRA plus idarubicin in patients with low-risk APL (WBC ≤ 10 x 109/L, accounting for approximately two thirds of patients in most series). The chemotherapy-free regimen was associated with significant improvements in EFS and OS, establishing it as a standard of care in APL. A recent report from the US Intergroup presented at ASCO 2015 by Jeffrey Lancet, MD, has confirmed the feasibility and potential superiority of the triple combination of ATRA, ATO, and gemtuzumab ozogamycin over the traditional ATRA plus chemotherapy regimen in patients with high-risk disease. It should be noted that gemtuzumab ozogamycin was withdrawn from the US market due to toxicities and is only available in a clinical trial setting.

Using these strategies, the main mortality risk in patients with APL is delayed diagnosis and delay in the initiation of the life-saving treatments, as illustrated by the case.

Case, Part II: A confirmatory bone marrow examination was performed, and treatment with ATRA was initiated, with later addition of ATO when molecular confirmation of APL was established. The patient was complaining of a headache and mild altered consciousness; a CT scan of the brain demonstrated several large intraparenchymal hemorrhagic areas. This was not amenable to neurosurgical intervention and despite very aggressive correction of coagulopathy, her condition deteriorated, leading to her death.

This case demonstrates the necessity for the presence of a high degree of suspicion for APL in any patient with a hemorrhagic disorder, particularly when this is associated with cytopenias and an abnormal coagulation profile. Rapid diagnosis and initiation of ATRA at the first suspicion of APL can potentially avert catastrophic consequences.

For more information on best practices in APL management, please see Dr. Ravandi’s CCO program, “Clinical Focus on Acute Promyelocytic Leukemia: Optimal Use of Current Therapy,” by clicking here.

Your Thoughts?
Have you used chemotherapy-free regimens for your patients with APL? Why or why not? Let us know with your comments below and in the poll question on this page.

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In your current practice, which of the following do you use to treat patients presenting with low-risk APL (WBC less than 10 x 109/L)?
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