Management of Acute Promyelocytic Leukemia

Eytan M. Stein¹ and Martin S. Tallman^1,2

¹Memorial Sloan Kettering Cancer Center, New York, NY, USA

²Weill Cornell Medical Center, New York, NY, USA

Case study 10.1

A 32-year-old Hispanic woman presents to the emergency room with severe menorrhagia, bruising, and shortness of breath for 6 days. The complete blood count shows a white blood cell (WBC) count of 8000/μL, hemoglobin of 6.5 g/dL, and platelets of 6000/μL. Further laboratory evaluation shows hypofibrinogenemia, with elevated prothrombin and partial thromboplastin times. You suspect acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) is started, and bone marrow examination is done. Several days into therapy, a noticeable improvement in the patient’s condition is noted. The bone marrow findings are suggestive of APL, but the cytogenetics are reported as normal.

• What should be the best management strategy at this time: to continue APL-focused therapy until molecular tests are available, discontinue ATRA and initiate acute myeloid leukemia (AML) induction therapy with “7+3,” or repeat bone marrow aspirate?

The correct answer is to continue APL-focused therapy until molecular tests are available. Acute promyelocytic leukemia is a unique subtype of AML characterized by a block at the promyelocyte stage of hematopoiesis. The original description and recognition of APL as a unique subtype of AML are credited to Leif Hillestad, a Scandinavian physician who reported three patients with rapidly progressive leukemia and a profound coagulopathy. This coagulopathy, similar to disseminated intravascular coagulation, produces a prolonged prothrombin time and partial thromboplastin time and hypofibrinogenemia. The patient described in this vignette has clearly developed a bleeding diathesis, with severe menorrhagia and shortness of breath that are attributable to anemia or perhaps pulmonary hemorrhage.

The sine qua non of APL is a recurrent reciprocal translocation between chromosomes 15 and 17. This translocation, first described by Janet Rowley and colleagues, fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha gene (RARα) and leads to the promyelocytic leukemia phenotype. In routine practice, this translocation is easily visualized with standard chromosomal analysis. However, cases have been described in the literature of cryptic translocations that fuse PML and RARα, but are nevertheless not detectable on standard chromosomal analysis.

Because of the high clinical suspicion of APL, the first test done was a bone marrow aspiration and biopsy. Although we are not told the results of the bone marrow examination, APL patients typically have an abundance of promyelocytes with multiple granules that often coalesce and take the appearance of a bundle of sticks (so-called faggot cells). Based on the clinical history and bone marrow examination, the physician chose to initiate ATRA at the first suspicion of APL. Although the cure rates for APL are remarkable, early death (often defined as death within 30 days of diagnosis) remains the major cause of treatment failure. In clinical trials, the induction death rate ranges between 5% and 9%. In population-based studies, the early death rate ranges between 17% and 30%, and it is considerably higher in older patients. Indeed, the early death rate has not changed significantly since the introduction of ATRA. Emerging data suggest that early death may be related to delays in receiving ATRA once patients present to the hospital. In a retrospective analysis of 194 patients, most patients (69%) had ATRA administered 2 days or more after presentation. Although the early death rate was not increased, the percentage of patients who died from hemorrhage was markedly increased when ATRA was delayed for more than 2 days. In addition, the results of this retrospective analysis confirmed that high-risk patients with APL who received their first dose of ATRA 3 or 4 days after they were suspected of having APL had an early death rate of 80%, compared with a rate of only 18% in high-risk patients who received ATRA on days 0, 1, or 2.

Because the patient is improving on ATRA-based therapy and the clinical picture is consistent with APL, the treating physician should wait for the results of sensitive molecular genetics tests for the PML–RARα fusion product.

Case study 10.2

A 45-year-old male presents with severe fatigue, shortness of breath, and epistaxis. Examination demonstrates diffuse petecchiae. The complete blood count shows a WBC count of 14,000/μL with 50% promyelocytes, hemoglobin of 5.3 g/dL, and platelets of 4000/μL. Further laboratory evaluation shows a fibrinogen level of 38, with prothrombin and partial thromboplastin times of 48 and 67, respectively. You plan to start APL induction therapy.

• Is there a preferred anthracycline for induction or consolidation therapy?

Before the introduction of ATRA, the paradigm for APL treatment was to use standard induction regimens with daunorubicin and cytarabine. The initial phase III trials of ATRA-based therapy sought to add ATRA to the standard induction regimen. The first trial to substitute idarubicin for daunorubicin was performed by the GIMEMA group and gave idarubicin on days 2, 4, 6, and 8 during induction chemotherapy. There are no randomized trials with a head-to-head comparison of idarubicin and daunorubicin. When using an anthracycline as a single agent with ATRA, some in the field prefer the use of idarubicin, as this is the regimen used successfully as monotherapy with ATRA in a number of clinical trials in Europe. When using an anthracycline in combination with cytarabine for induction and consolidation, experts generally prefer the use of daunorubicin (DNR) as was done in the North American Intergroup APL trials.

• What is the role of cytarabine in the management of APL?

The European APL group was the first to investigate the need for cytarabine during consolidation. The European APL 91 and APL 93 trials incorporated the use of DNR and cytarabine in consolidation, while the PETHEMA LPA 99 trial sought to eliminate cytarabine from induction and consolidation regimens. In order to test whether cytarabine could be eliminated from the treatment of APL, the European APL group designed a trial to determine the need for cytarabine in patients with low-risk disease. Patients younger than 60 years and with low-risk disease were randomized to the “standard” arm of ATRA, DNR, and cytarabine for induction followed by two cycles of consolidation with DNR and cytarabine, versus the investigational arm that eliminated cytarabine from consolidation. Patients with high-risk disease were not randomized.

Of the 356 patients enrolled on the trial, 196 patients were low risk and younger than age 60, and they were randomized to cytarabine versus no cytarabine. While the hematologic CR rates after induction and the molecular CR rates after consolidation were statistically equivalent in both treatment arms, the cumulative incidence of relapse (CIR) was significantly higher in the group not given cytarabine; the 2-year CIR was 15.9% in the no-cytarabine arm versus 4.7% in the group given cytarabine. In addition, the inclusion of cytarabine in this low-risk group of patients did not lead to a greater number of deaths as the overall survival (OS) of patients in the cytarabine arm at 2 years was 97.9% versus 89.6% in the no-cytarabine arm. While the results of this trial suggested that cytarabine is a necessary part of anti-APL therapy even for patients with low-risk disease, the absence of ATRA use in consolidation, as in the LPA 99 trial, made it difficult to interpret the results. Was cytarabine needed if ATRA was used in consolidation? Is it possible that cytarabine and ATRA in combination were only needed for high-risk disease?

To help determine the optimal role of cytarabine in APL, the PETHEMA group in conjunction with the Dutch HOVON group designed the LPA 05 trial. The design of this trial was similar to that of LPA 99, but patients with high-risk disease were given cytarabine in consolidation, with results compared to those of the historical control group of high-risk patients in the LPA 99 trial. While the CIR was higher in the historical control group with high-risk disease (14% in LPA 05 versus 27% in LPA 99 at 4 years), the disease-free survival (DFS) and OS were statistically equivalent, suggesting that patients who did relapse could be salvaged with subsequent therapy.

The GIMEMA group in the AIDA 2000 trial sought to answer similar questions as the PETHEMA group, specifically whether cytarabine could be eliminated from consolidation in low- and intermediate-risk patients and whether introducing ATRA during consolidation was an effective treatment strategy. In this study, patients received standard induction chemotherapy as given in the AIDA 0493 regimen (ATRA and idarubicin). Consolidation in the low- and intermediate-risk groups contained three cycles of monochemotherapy combined with ATRA, while in the high-risk group patients received three cycles of polychemotherapy (with cytarabine in cycles 1 and 3) with ATRA. Results were compared to the historical controls of the AIDA 0493 trial.

As would be expected from the results of prior trials, the outcomes in the AIDA 2000 among both low-risk and intermediate- or high-risk patients were improved over the AIDA 0493 trials. The 6-year DFS in the overall study cohort was 85.6% in AIDA 2000 versus 69.5% in AIDA 0493. The OS was 87.4% in AIDA 2000 versus 78.1% in AIDA 0493. Much of this was driven by improved outcomes in the high-risk group, with DFS of 84.5% in AIDA 2000 and 49.6% in AIDA 0493 and OS of 83.4% in AIDA 2000 and 61.3% in AIDA 0493.

• Bone marrow examination establishes the diagnosis of APL. Should a bone marrow biopsy be performed following induction therapy?

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10: Management of Acute Promyelocytic Leukemia

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