ILLUSTRATIVE CASE SERIES

Case Management: Acute Promyelocytic Leukemia

By Jerome W. Yates, MD, Vice President for Research (Emeritus), American Cancer Society, Senior Scientist, National Institute on Aging, NIH. Dr. Yates reports no financial relationships relevant to this field of study.

A 44-year-old male patient is seen in the emergency room because of intractable nose bleed, hematuria, and ecchymoses — all first noted within the past 48 hours. Previously he had been well, without known medical illness, and was taking no prescription drugs. He had no prior history of bleeding, nor had he any family member with bleeding disorder. He had no knowledge of exposure to toxic chemicals or drugs and had not traveled or eaten any unusual foods over the past year. He was not experiencing pain, confusion, or shortness of breath, although he had had diarrhea over the past week and noted fatigue and decreased appetite.

Physical exam revealed persistent posterior nasal bleeding and ecchymoses over the arms and trunk. He was afebrile and blood pressure was 110/72, pulse 88, and regular and oxygen saturation was 98% on room air. There was no palpable lymphadenopathy splenomegaly or hepatomegaly. Abdomen was soft without mass or tenderness.

Laboratories in the emergency room indicated a hemoglobin of 10.1 g/dL, a white blood count of 8,000/cu mm, and a platelet count of 78,000/cu mm. White blood differential revealed 11% neutrophils, 3% band forms, 4% lymphocytes, and approximately 80% large hypergranular cells interpreted by the laboratory technician as promyelocytes with irregular appearing primary azurophilic granulocytes and Auer rods. Serum chemistries were essentially within normal limits. Prothrombin time and partial thromboplastin times (PT and PTT) were both > 2 times the normal limit.

Discussion

Although by no means confirmed, the patient's diagnosis is most likely the promyelocytic variant of acute myelogenous leukemia. This scenario is one of the true "oncologic emergencies" because failure to institute prompt therapy can result in rapid demise, particularly from hemorrhage into the central nervous system. In fact, this is a situation in which you must rely on clinical judgment. Order confirming laboratory studies but do not wait for the results of those studies before initiating therapy.1

Acute promyelocytic leukemia (APL) accounts for approximately 10% of acute leukemia in adults and is somewhat more common in children. It results from a balanced reciprocal translocation between chromosomes 15 and 17, producing a fusion transcript of the PML and RAR-a genes.2,3 Leukemic cells of this type have the unique ability to undergo differentiation with exposure to either retinoic acid or arsenic trioxide.

In the current case, the initial approach would be to review the peripheral blood smear with an experienced hematopathologist, if available. Bone marrow aspirate and biopsy should also be obtained and should include both cytogenetic and molecular studies, if this can be arranged in a timely fashion, but should not delay therapy.

Response rates in APL are excellent. However, a great risk for catastrophic outcomes remains without aggressive early management. In the case under discussion, the white count of > 10,000 places the patient in the "high-risk" group,4 and treatment with all-trans retinoic acid (ATRA) (45 mg/m2 in divided doses) should be initiated very early, even while in the emergency room, if possible. For those in the high-risk category, the addition of an anthracycline concurrent with ATRA is advisable to reduce the risk that ATRA alone might be associated with additional leukocytosis. However, for those with low or intermediate risk, ATRA alone is recommended for a few days prior to additional chemotherapy.

Additional, aggressive, early supportive measures can be life-saving. Platelet counts should be maintained above 30,000/cu mm and cryoprecipitate administered to maintain the fibrinogen level above 150 mg/dL. If ATRA is administered promptly, there is no clear benefit for the use of heparin, except perhaps for those who have recognized deep vein thrombosis or who are on antifibrinolytic therapy. The placement of a central line and lumbar puncture, typical early measures in the management of acute leukemia, should be delayed until adequate coagulation parameters are reached.

For patients with high-risk APL, particularly for those with presenting WBCs of > 30,000/cu mm, therapy may result in what has been termed APL differentiation syndrome,5 manifested predominantly by pulmonary insufficiency; the incidence of this may be reduced with preemptive corticosteroids.

Although deaths continue to occur in the early phase of management of APL, for those in whom coagulation is promptly controlled and full treatment (induction, consolidation, and maintenance) administered, long-term, disease-free outcomes are likely. Clinical trials are currently addressing the optimal management for those with high-risk disease to determine the most effective combinations of ATRA, arsenic trioxide, and anthracycline in initial therapy, as well as those or other agents in consolidation or maintenance. Nonetheless, prompt and aggressive early diagnosis and management are critical in achieving a successful outcome for these patients.

References

1. de la Serna J, 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;111:3395-3402.

2. Grignani F, et al. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell. 1993;74:423-431.

3. Rowley JD, Golomb HM, Dougherty C. 15/17 translocation, a consistent chromosomal change in acute promyelocytic leukaemia. Lancet. 1977;1:549-550.

4. Sanz MA, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103:1237-1243.