Emerging Strategies Combining ATRA and ATO and Minimizing or Eliminating Conventional Cytotoxic Chemotherapy
Minimizing treatment-associated toxicities observed with conventional cytotoxic chemotherapy may further improve the outcome and long-term complications of APL. Therapy-related myelodysplastic syndrome and AML in patients with APL have been reported, albeit at a low incidence; it is possible that omission of potentially leukemogenic cytotoxic chemotherapy, particularly anthracyclines, may reduce the incidence of this complication.[27-29]
Arsenic trioxide is extremely effective in patients with relapsed APL.[30,31] Several trials have investigated the role of ATO in previously untreated patients. As a single agent, ATO induces durable CR in 85%–86% of patients with untreated APL, comparable to that achieved by ATRA-based therapy.[32,33] The outcome for patients with a presenting WBC > 5 × 109/L at diagnosis, however, appears to be inferior to results for a similar patient subset treated with ATRA plus chemotherapy, with an event-free survival (EFS) of only 67% and a higher early death rate of 14.4%, mostly from hemorrhagic complications. Therefore, for many patients therapy with single-agent ATO does not appear sufficient as front-line therapy. Nevertheless, its ability to induce molecular remissions as a single agent in most patients and durable remissions in many makes it the most effective single agent in the armamentarium for APL.
The combination of ATRA and ATO is synergistic in inducing differentiation and apoptosis in vitro and in accelerating tumor regression in vivo,[34,35] providing the rationale for targeted therapy of APL without exposure to cytotoxic chemotherapy. Investigators at the Shanghai Institute of Hematology reported a randomized clinical trial in which patients were to receive ATRA, ATO, or the combination of ATRA plus ATO as induction therapy. All patients in CR after induction subsequently received intensive consolidation and maintenance chemotherapy. The combination treatment of ATRA and ATO resulted in the lowest rate of relapse, a faster CR rate, and a greater reduction in the number of PML/RARα transcripts, suggesting a deeper remission, with no apparent greater toxicity than each agent alone. More recently, the Australasian Leukaemia and Lymphoma Group (ALLG) reported the outcome of 124 patients with newly diagnosed APL treated with ATRA, ATO, and idarubicin(Drug information on idarubicin) for induction; two courses of consolidation with ATRA and ATO; and 2 years of maintenance with ATRA, methotrexate(Drug information on methotrexate), and 6-mercaptopurine. With a median follow-up of 20 months, the 3-year overall survival (OS) and EFS rates were 93% and 87%, respectively. This strategy showed that most patients with newly diagnosed APL can be effectively treated and likely cured with significant reduction in exposure to standard chemotherapy. Investigators at The University of Texas M.D. Anderson Cancer Center similarly demonstrated that the combination of ATRA and ATO is effective in untreated APL. A high CR rate of 96% was achieved with few late relapses even when chemotherapy was eliminated during consolidation, in patients with a presenting WBC < 10 × 109/L.[37,38] Patients with presenting WBC ≥ 10 × 109/L achieved an inferior CR rate of 79%–81%, however, owing to early treatment failure from fatal hemorrhage and APL differentiation syndrome despite the addition of either gemtuzumab ozogamicin (GO) or idarubicin during induction to control the WBC.[37,38]
These studies suggest that the combination of ATRA and ATO can effectively treat and potentially cure patients with standard-risk disease (defined as those with presenting WBC < 10 × 109/L), and it has emerged as the most exciting new treatment strategy in APL. Such a strategy is an excellent alternative for patients who are considered unfit for conventional treatment and those with severe comorbidities (eg, older adults, patients with cardiac dysfunction or other severe organ dysfunction).
In patients presenting with high WBC, however, concomitant use of cytotoxic drugs such as anthracyclines in induction and high- or intermediate-dose cytarabine(Drug information on cytarabine) in either induction or consolidation appears to be critical to prevent rapid development of leukocytosis and consequent APL differentiation syndrome and relapse. Several randomized trials are being conducted to address the question of whether the outcome among patients in whom chemotherapy is completely eliminated or minimized is as favorable as conventional ATRA plus anthracycline-based approaches.
Reducing Early Death in APL
Hemorrhage, often catastrophic in presentation and outcome, is the major cause of death during induction therapy in APL, despite the introduction of ATRA into routine clinical practice 15 years ago. Delayed diagnosis and treatment, together with an elevated WBC, were significantly associated with severe bleeding and early death. Multicenter cooperative group studies report a rate of approximately 5%–10% early deaths within 1 month after initiating treatment,[11,16-18,41] but several population-based observational studies report higher early death rates in unselected APL patients, with the largest study reporting a 17.3% overall early death rate despite ATRA and significantly higher in older adults at 24.2% (see Figures 1 and 2).[42-44] These findings indicate that the availability of ATRA has not eliminated the major cause of treatment failure in APL. They also emphasize the importance of immediate disease recognition and rapid intervention, since delayed treatment is associated with significant morbidity and mortality.
To implement immediate institution of the appropriate therapy in APL, however, it is critical that healthcare providers from a variety of disciplines, who may be the first to evaluate APL patients, understand that APL is a medical emergency requiring urgent initiation of ATRA at the first suspicion of the disease and before genetic confirmation, with concomitant aggressive supportive care to address the bleeding disorder. Because ATRA has been shown to rapidly reduce the severity of bleeding and decrease the amount of blood product consumption, it should be started immediately at the earliest hint of the diagnosis. Although the true impact of ATRA in reducing the early death rate is not known,[11,46] it is reasonable to presume it will be beneficial given the paucity of toxicities, particularly following one to two doses of treatment. The role of ATO in reducing early death rates is less clear, and more studies are required to better define the role of ATO with or without ATRA in reducing hemorrhagic complications during induction therapy.[38,47]
Aggressive supportive measures to counteract coagulopathy need to be instituted immediately. These include fresh frozen plasma, fibrinogen, cryoprecipitate, and multiple platelet transfusions to maintain the fibrinogen concentration and platelet count above 100–150 mg/dL and 50,000/µL, respectively, and post-transfusion values should be obtained to ensure adequate repletion of coagulation factors, platelets, and fibrinogen. Such replacement therapy should continue during induction therapy until disappearance of all clinical and laboratory signs of coagulopathy.
Since optimal treatment of APL is dependent on rapid access to unique specialized diagnostic tests and hospital facilities with immediate availability of ATRA and the appropriate blood products, patients with APL should be treated at specialized centers with an experienced multidisciplinary team. Breccia et al reported a significantly increased early death rate in patients who initially presented to nonspecialized primary care institutions with little experience in the treatment of acute leukemia. Therefore, the immediate and efficient access to experienced medical centers, to reduce the time span between the first signs and symptoms of APL and initiation of specific therapy, is critical to improve the clinical outcome.
While genetic confirmation of the specific lesion PML/RARα fusion is required to establish the definitive diagnosis of APL, test results from fluorescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) may not be immediately available at community hospitals and require a turnaround time of 1–2 days. Recently, immunostaining with anti-PML monoclonal antibodies on dry smears of bone marrow or even peripheral blood samples has been shown to establish a rapid diagnosis in less than 4 hours, with high sensitivity and specificity. This test may be particularly valuable in smaller centers lacking immediate access to a sophisticated molecular diagnostics laboratory. Such testing should not delay the initiation of ATRA if APL is suspected, however, and patients should immediately be transferred to more experienced centers with ATRA therapy, which should be started prior to patient transfer.