Treatment of Acute Promyelocytic Leukemia Without Cytotoxic Chemotherapy
Treatment of Acute Promyelocytic Leukemia Without Cytotoxic Chemotherapy
ABSTRACT: The introduction of all-trans retinoic acid, or ATRA, in 1985, combined with anthracycline-based chemotherapy, has transformed acute promyelocytic leukemia (APL) from a fatal disease to one that is now highly curable. With appropriate contemporary therapy, more than 90% of patients achieve complete remission, and cure rates of approximately 80% and higher response and survival rates can be expected for patients at low and intermediate risk. The introduction of arsenic trioxide, or ATO, in 1994 has provided the opportunity to minimize and even eliminate standard cytotoxic chemotherapy from initial treatment regimens without compromising the excellent outcomes achieved by anthracycline-containing protocols. APL is a unique subtype of acute myeloid leukemia that is curable with targeted therapies and potentially without exposure to conventional DNA-damaging chemotherapy. The omission of conventional cytotoxic chemotherapy may reduce long-term complications such as cardiomyopathy and therapy-related myelodysplastic syndromes. Cure rates of APL may be further increased by adopting management strategies to reduce early hemorrhagic deaths, which now appear to be the major cause of treatment failure.
Acute promyelocytic leukemia (APL) is a rare distinct subtype of acute myeloid leukemia (AML) which accounts for 10%–15% of the approximately 12,330 adults diagnosed with AML in the United States each year. There has been dramatic progress in the management of APL during the past three decades. Important insights into the pathogenesis of the disease have come to light and effective treatment has been developed. APL has become highly curable and serves as a paradigm for development of effective therapies directed at a specific molecular abnormality. Modern treatment represents a departure from standard chemotherapeutic strategies applied to all other subtypes of AML, since all-trans retinoic acid (ATRA) induces differentiation of the malignant promyelocytes into mature granulocytes. The disease is characterized by distinctive morphology of blast cells, an associated life-threatening and often catastrophic bleeding disorder, and a specific balanced reciprocal translocation, t(15;17), which results in fusion of the PML (promyelocyte) gene on chromosome 15 to the RARα (retinoic acid receptor-α) gene on chromosome 17.
Prior to the introduction of ATRA as a treatment, APL was among the most fatal of AML subtypes at presentation or during induction, primarily because of an associated complex and often catastrophic bleeding disorder which is characterized by disseminated intravascular coagulation, fibrinolysis, and proteolysis. However, ATRA and arsenic trioxide (ATO) have changed the natural history of this disease from one that was characterized by a high mortality rate to one that is now associated with the highest curability rate among the AML subtypes in adults. Furthermore, multiple studies have demonstrated that combination of the two targeted agents ATRA and ATO is a highly effective and potentially curative treatment. Such a strategy has become the most exciting new treatment option for APL, potentially completely eliminating exposure to conventional cytotoxic chemotherapy in many, if not most, patients. Now that the relapse rate even among high-risk patients (white blood cell counts [WBCs] > 10 × 109/L at presentation) has decreased substantially, early hemorrhagic death prior to and during induction therapy remains the major cause of treatment failure. Almost every patient with APL achieves complete remission (CR) with either ATRA plus anthracycline-based induction or ATRA + ATO–based induction, and the relapse rate once a patient is in CR is very low; therefore, reducing early death has become the most important goal in the treatment of patients with APL and is likely the best strategy to apply towards the goal of curing virtually all patients with the disease. Given the unique natural history of APL, with some patients presenting with rapidly fatal bleeding before intervention is possible, clearly it will be impossible to cure every patient. However, the cure rate among patients with APL may be increased further through education of a wide variety of healthcare professionals about early recognition of the disease and introduction of ATRA and aggressive blood product support.
Evolution of Induction Therapy in APL
Prior to ATRA, induction therapy in APL was similar to that for all other subtypes of AML. Induction consisted of an anthracycline and cytarabine (also known as ara-C), which resulted in CR rates of 65%–80% among patients newly diagnosed with APL.[7-9] Historically, however, even among patients who achieved CR with initial chemotherapy, 50%–65% subsequently relapsed and only 30%–50% remained alive at 2 years—a rate somewhat higher than that often reported for patients with other subtypes of AML.[7,10] The recognition that ATRA could induce differentiation of leukemic promyelocytes into mature granulocytes had encouraged the evaluation of ATRA either as a single agent or in combination with chemotherapy, initially in relapsed and refractory disease and subsequently in patients with newly diagnosed APL. Although treatment with ATRA alone in induction results in CR rates of 72%–90%,[11-14] patients generally relapse if additional chemotherapy is not administered. Therefore, subsequent trials combined ATRA with chemotherapy. The European APL (EuroAPL) group demonstrated in a randomized study that concurrent ATRA plus chemotherapy (daunorubicin [Cerubidine] and cytarabine) resulted in a better outcome than sequential ATRA followed by chemotherapy, primarily by reducing the relapse rate at 2 years (6% vs 16%). This improvement was subsequently confirmed in other large multicenter trials.[15-18] Therefore, the concurrent administration of ATRA and anthracycline-based chemotherapy (an anthracycline plus cytarabine or an anthracycline alone, generally idarubicin [Idamycin]) is currently considered the standard of care for induction in newly diagnosed patients with APL. It is not known which anthracycline is best to administer, however. Although a retrospective analysis published only in a preliminary form has suggested that idarubicin is associated with an improved outcome compared with daunorubicin or amsacrine, there is no clear evidence that one anthracycline is clearly superior to another in APL.
Omitting Cytarabine in APL Induction
Two randomized trials have been conducted to investigate the role of cytarabine; the results have been conflicting. The National Cancer Research Institute (NCRI) in the United Kingdom (formerly the Medical Research Council, or MRC) reported no differences in response, relapse, or overall survival rates in patients randomized between ATRA plus idarubicin (AIDA) and ATRA with daunorubicin and cytarabine, but there was less myelosuppression with the regimen omitting cytarabine. In contrast, a randomized study by the EuroAPL group (APL 2000) showed a statistically significant increase in relapse risk (13.4% vs 29%) and decrease in overall survival (92.9% vs 83.3%) among patients in whom cytarabine was omitted from both induction and consolidation therapy.[21,22] The therapies likely were not comparable in other ways since, for example, the doses of the anthracyclines may not have been equivalent.
The cooperative groups Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) and Programa Espaol de Tratamientos en Hematologa (PETHEMA) have omitted cytarabine from induction, and demonstrated that AIDA is as effective in inducing remission as a cytarabine-containing regimen, with CR rates of 89%–95% regardless of the presenting WBC.[18,23] This discrepancy may be explained by differences in the consolidation regimens (ATRA vs no ATRA in EuroAPL trial), the number of consolidation courses, specific choice of anthracycline (idarubicin in the GIMEMA, PETHEMA, and NCRI trials vs daunorubicin in the EuroAPL trial), and the cumulative doses of anthracyclines. Treatment approaches that include cytarabine have the potential benefit of reducing the likelihood of extramedullary relapse, particularly in sanctuary sites such as the central nervous system (CNS), since relatively high doses of cytarabine are well-recognized to cross the blood–brain barrier and enter the CNS. Despite some reports of an increased incidence of extramedullary relapse since ATRA was introduced into routine clinical practice, the reported incidence of CNS relapses in APL in some studies is low, ranging from 0.6% to 2%,[24-26] and these relapses are invariably associated with marrow relapse.