The treatment of acute promyelocytic leukemia (APL) is a success story of modern hematology. Characterized by a translocation fusing the promyelocytic leukemia gene (PML) on chromosome 15 with the retinoic acid receptor alpha gene (RARα) on chromosome 17, myeloid precursors in APL are blocked from differentiating past the promyelocyte stage, with subsequent inhibition of normal hematopoiesis. After introduction of all-trans retinoic acid (ATRA) into routine clinical practice, the survival of patients with APL dramatically improved. Indeed, in the first North American Intergroup trial (I0129), patients who received ATRA during both induction and maintenance had a disease-free survival rate of approximately 75%. Subsequent refinement of ATRA treatment schedules and the introduction of arsenic trioxide (ATO) allow cure of the majority of patients with APL. Patients who survive the first 30 days after diagnosis of their disease, when coagulopathy and the ATRA differentiation syndrome can cause morbidity and mortality, have an extraordinarily high rate of cure.
Given that most patients now survive and are cured, research efforts have shifted towards strategies to minimize early death and toxicity from treatment. In this brief review we address new “provocative pearls” in the diagnosis and treatment of APL. After discussing the generally agreed-upon international guidelines for treatment, we focus on the next generation of diagnostic and treatment strategies.
International Guidelines for Management of APL
ATRA was introduced into clinical practice in China in the early 1990s, and the first intergroup trial performed by the North American Intergroup was reported in 1997. This trial randomized APL patients to induction with ATRA or chemotherapy (daunorubicin and cytarabine [Ara- C]). Once remission was achieved, a second randomization assigned patients to ATRA maintenance or observation alone. The results were striking and anticipated the current age of targeted agents in cancer therapy. Clinically and statistically significant increases in overall and disease-free survival were observed among the patients who received ATRA, in either induction or maintenance, compared with the chemotherapy groups. Since 1997, findings from multiple welldesigned clinical trials in the United States, Europe, and elsewhere have led to an increase in the cure rate of APL, to more than 80%.[2-5]
Current guidelines advocate establishing a diagnosis of APL based on the morphology of a bone marrow aspirate and finding the characteristic translocation between chromo- somes 15 and 17 by cytogenetics, fluorescence in situ hybridization (FISH), or molecular testing. Patients are then risk-stratified based on their presentation white blood cell (WBC) count; those with a WBC count greater than 10,000/μL are considered high risk, and those with a WBC count lower than 10,000/μL are at either low or intermediate risk (based on the platelet count). Clinically, the low-/ intermediate-risk categories are now grouped together and receive identical treatment. As most regimens for APL include an anthracycline in induction and consolidation, the first clinical decision for practicing oncologists is whether the individual patient can tolerate an anthracycline. Patients with overt heart failure or borderline cardiac function, as well as elderly patients who may not be able to tolerate cytotoxic chemotherapy, should have an anthracycline omitted from their treatment regimen and can be given a combination of ATRA and ATO, which has shown excellent cure rates in phase II clinical trials. Patients who are able to tolerate anthracyclines, who have either high-risk or low-risk disease, are treated with ATRA at a dose of 45 mg/m2 in combination with an anthracycline, or ATRA at 45 mg/m2 in combination with an anthracycline and cytarabine, respectively. A number of cooperative groups and practicing physicians now omit cytarabine from the treatment of patients with low-risk disease. Following induction, consolidation is given for 2 to 3 cycles and incorporates ATRA with cytotoxic chemotherapy. There are multiple consolidation chemotherapy regimens; these reflect the different treatment strategies undertaken by different cooperative groups in clinical trials performed in Europe, the United States, and other parts of the world. The role of maintenance therapy, particularly in low-risk disease, continues to be a matter of active clinical investigation, but most experts agree that a combination of 6-mercaptopurine, methotrexate, and ATRA should be given to patients with high-risk disease.
Pearls in Diagnosis, Complete Remission, and Prognosis
For many patients, the most difficult part of the initial evaluation for acute leukemia is a bone marrow aspiration and biopsy. Even with adequate local anesthesia, many people experience significant procedural discomfort that leads to subsequent anxiety and in some cases, refusal of further bone marrow evaluation. There are several reasons for performing bone marrow biopsy in AML: assessment of bone marrow blast percentage (which forms the basis for a firm diagnosis of AML); evaluation of bone marrow morphology; use of immunohistochemical staining to assess leukemic lineage (lymphoid or myeloid); and the ability to obtain adequate numbers of myeloblasts for cytogenetic and, to a lesser extent, molecular genetic analysis. In AML, the initial bone marrow biopsy is crucial because the results of the cytogenetic and molecular genetic studies form the basis of treatment recommendations in consolidation—specifically regarding whether to proceed to allogeneic stem cell transplantation, or consolidate with multiple courses of high-dose cytarabine or a similar regimen.
However, APL has unique associations that raise the question of whether a bone marrow biopsy at diagnosis is actually needed. The morphology of leukemic promyelocytes (if they are present in the peripheral blood) is distinctive and consists of promyelocytes with abundant granules that form bundles resembling collections of sticks (so called faggot cells). In addition, the presence of the t(15;17) translocation, identified by cytogenetics, FISH, or molecular genetics, is unique to APL and confirms the diagnosis. Often, review of the peripheral blood in patients with APL reveals the characteristic leukemic promyelocytes, and if these are present, the cytogenetics are also clear. Although additional cytogenetic abnormalities aside from t(15;17) exist in about one-third of patients with APL, these have not been consistently associated with disease outcome and are not included in risk stratification. In fact, the prognosis is based solely on peripheral WBC count and age, and as mentioned earlier, treatment strategy is based on risk status and ability to tolerate anthracyclines. Novel molecular genetic abnormalities have an important influence on prognosis in other subtypes of AML, but no clear influence in treatment and outcome in APL.
In other forms of AML, a day 14 nadir bone marrow aspirate and biopsy are obtained. In APL this is not needed because it often takes more than 14 days for the leukemic promyelocytes to differentiate. Furthermore, a day 14 marrow in APL is characteristically replete with differentiating leukemia cells, and there is very often no typical marrow aplasia. As the incidence of primary ATRA resistance during induction therapy is vanishingly small, a patient whose peripheral blood counts normalize with ATRA plus anthracycline-based therapy can be presumed to be in a complete remission (CR). An initial CR can be verified using sensitive molecular genetic tests for the PML-RAR fusion product in peripheral blood. Therefore, it may be that a bone marrow aspirate and biopsy in first CR are not needed. Once a CR is confirmed, periodic monitoring with molecular genetic testing of peripheral blood are all that are needed to confirm continued disease remission. Thus, it is conceivable that in many patients for whom the diagnosis is clear from the history, physical examination, and laboratory studies, a bone marrow aspirate and biopsy are not needed at diagnosis, at the nadir, or once the patient enters a hematologic CR.
APL is also distinguished from other subtypes of AML in that there are no modifications in therapeutic approach, even in patients with additional cytogenetic abnormalities, therapy-related disease, the FLT3-ITD mutation (commonly present in APL), the PML isoform, and the microgranular variant (M3V).
Pearls in Minimizing Early Death
While the cure rates for APL are remarkable, early death (defined as death within 30 days of diagnosis) continues to be a major cause of treatment failure. In clinical trials, the induction death rate ranges between 5% and 9%.[1,4] In population-based studies (including patients who never enrolled in trials), the early death rate ranges between 17% and 30% and is considerably higher in older patients (Table 1).[2,6] Indeed, the early death rate has not changed significantly since the introduction of ATRA. The major cause of early death is hemorrhage, usually pulmonary or intracerebral, caused by the characteristic coagulopathy associated with this disease. What accounts for early death? An abstract presented at the 2011 meeting of the American Society of Hematology suggested that early death may be related to delays in receiving ATRA once patients present to the hospital. The authors hypothesized that early death could be reduced with the rapid administration of ATRA—without waiting for the results of bone marrow aspiration and confirmation of t(15;17). In this retrospective analysis of 194 patients, most patients (69%) had ATRA administered 2 days or more after presentation (Figure 1). While 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. Results of this retrospective analysis also 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.
While these results are preliminary and need to be confirmed in larger series, we advocate administration of ATRA at the earliest suspicion of APL. ATRA is a relatively innocuous drug with few side effects. If the diagnosis of APL is not confirmed, ATRA can be discontinued. This requires vigilance by hematologists and medical oncologists, and participation and awareness of emergency department and general internal medicine physicians, who often have the first clinical contact with newly diagnosed patients. Also, hospital pharmacies should have ATRA readily available or the ability to obtain a supply of ATRA rapidly. It may be that further improvement in the outcome of APL may come from aggressive blood product support and early administration of ATRA rather than identification of new treatments for the disease.
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