A new diagnosis of cancer is difficult to give to a patient regardless of the type, prognosis, or treatment options. As extensive clinical research and new innovative therapies continue to arise, this type of discussion could potentially become one filled with more hope and reassurance than in the past.

One cancer with this type of potential is acute promyelocytic leukemia (APL), which, with the correct treatment plan, has a remission rate near 90%. However, as with any medical treatment, there are risks and benefits. APL is frequently treated with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as induction therapy. Although APL that is treated with ATRA and ATO has a high remission rate, it comes with the risk for differentiation syndrome (DS), which, if not considered early in the course of therapy, can cause serious complications.

DS is primarily caused by cytokines and their sequelae along with the maturation of promyelocytes induced by ATRA and ATO. DS can occur in up to 25% to 30% of patients with APL who are started on induction therapy with ATRA and ATO. Many studies have reported mixed results with respect to risk factors, but the patients at greatest risk for DS appear to be those with high WBC counts upon presentation and those who experience a dramatic increase in WBC during treatment, an increased BMI, greater than 70% blasts in the peripheral blood, and elevated LDH levels. DS can occur at any time during treatment with ATRA and ATO; however, it occurs most frequenty during the bimodal time distribution. Patients are most likely to experience DS during the first and third weeks of treatment with ATRA and ATO, with one study finding the median start of DS to be 12 days after the initiation of therapy. The more severe cases of DS manifest earlier during induction. Therefore, great vigilance is required in order to recognize the signs and symptoms of DS.

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A patient with DS will typically present with dyspnea, fever, peripheral edema, weight gain, and rash. Upon examination, these patients can be found to have hypoxemia, hypotension, pulmonary infiltrates and/or effusions, pericardial effusions, hepatic dysfunction, and renal dysfunction. Daily weights, trending WBC counts and renal function, pulse oximetry, and a thorough physical examination are all simple yet effective ways of evaluating your patients for DS. In addition to these steps, patients started on ATO should also have their electrolytes and EKGs routinely monitored, especially early in their treatment course to check for electrolyte abnormalities that could further complicate the clinical picture of DS.

Patients that are suspected to have DS based on their symptoms and objective work-up are usually treated with intravenous dexamethasone (DXM) 10 mg twice daily for at least 3 days until their symptoms resolve, and then are tapered off. Mortality rates for severe DS are between 25% and 30% when patients do not receive DXM; therefore, recognition of symptoms and timely initiation of DXM are crucial for survival. Several studies have examined the use of prophylactic steroids (both DMX and Prednisone) in patients with APL started on ATRA and ATO; however, the results vary and the data has not come from a large study population. More prospective clinical studies are needed in order to determine if steroid prophylaxis is beneficial in preventing DS.

Patients with APL appear to have a bright future with effective treatment regimens and high remission rates. With this promising scenario, clinicians need to be aware of both the side effects of the medications as well as the natural course of the cancer after induction therapy is started in order to help their patients with APL reach remission. Early recognition of the symptoms and objective trends associated with DS followed by treatment with DXM will hopefully continue to help APL patients maintain their 90% remission rate.

Questions to Readers

  • In your patients with APL, do you frequently prophylact them with dexamethasone to prevent DS?
  • Are there any other risk factors that you have experienced for your patients that develop DS?

Readers: We’d love to hear from you in the comments section below! If you have a case study or a more extended response to this subject, click here to submit an item for us to publish