Pearls in Preventing APL Differentiation Syndrome
After administering ATRA at the first clinical suspicion of APL, the astute physician must be vigilant for the APL differentiation syndrome. The differentiation syndrome, first described with the use of ATRA but also seen with the use of ATO, is manifested clinically as noncardiogenic pulmonary edema that can cause respiratory failure requiring intubation and mechanical ventilation. Its etiology is poorly understood. It is thought to be caused by a capillary leak syndrome induced by the rapid differentiation of leukemic promyelocytes. The treatment, dexamethasone(Drug information on dexamethasone) at 10 mg twice daily, should be prescribed immediately to patients who are thought to be developing the differentiation syndrome. In our practice, we administer dexamethasone prophylactically for 10 to 14 days to patients with high-risk disease. APL differentiation syndrome is an example of a situation in which a complication of treatment should be addressed at the very first suspicion and before its diagnosis is established.
Pearls in Maintenance
The question of whether to treat APL like other forms of AML and omit maintenance treatment after consolidation chemotherapy or to treat it instead like acute lymphoblastic leukemia (ALL) and prescribe maintenance therapy continues to be a matter of debate. As part of the AIDA 0493 trial, patients who were in a molecular CR after three courses of consolidation were randomized into one of four maintenance treatment arms: oral 6-MP at a dose of 90 mg/m2/d and intramuscular methotrexate(Drug information on methotrexate) at 15 mg/ m2/week, ATRA alone at a dose of 45 mg/m2 for 15 days every 3 months, alternating chemotherapy (with 6-MP and methotrexate) and ATRA, and observation.[ 8] After January 1997, the chemotherapy-only and observation arms were dropped and patients were randomized to one of the two ATRA treatment arms. When all four arms were analyzed, patients in the observation arm fared worse than those in the ATRA maintenance arms. Patients in both ATRA maintenance arms had similar rates of disease-free survival. In contrast, the APL97 study of the Japanese Acute Leukemia Study Group (JALSG) randomized patients who were in a molecular remission to 3 cycles of intensified maintenance chemotherapy or observation.[9] Patients who were molecularly positive were given ATRA for 4 weeks followed by the same 3 cycles of chemotherapy. Interestingly, disease-free survival did not differ significantly between the maintenance and no-maintenance groups, but overall survival was significantly worse in the maintenance chemotherapy arm.
The role of maintenance, therefore, is currently unclear. Our general recommendations are that patients should receive maintenance therapy, particularly if they are high-risk at the time of diagnosis or develop an elevated WBC count during treatment.
ATO in APL
Curing Patients Without Chemotherapy
The side effects of chemotherapy used in APL—cytopenias, neutropenic fever, and late cardiac toxicity—are significant. The holy grail of cancer therapy is to achieve remission and cure without the use of cytotoxic chemotherapy. In APL, this goal may be achievable. There are now a number of well-designed clinical trials demonstrating the efficacy of a combination of ATRA and ATO or even ATO alone (in very-lowrisk disease) used in induction, consolidation, or both (Table 2).[10,11]
Hu and colleagues treated 85 patients from April 2001 to December 2005 with an induction regimen of ATRA and ATO daily until documentation of CR.[12] Patients who developed WBC counts greater than 10,000/ μL before or during treatment were also given chemotherapy. After CR, patients received three courses of consolidation treatment with chemotherapy alone (no ATRA). They then received 5 cycles of maintenance therapy with ATRA/ ATO and low-dose chemotherapy. The trial showed an impressive 5-year survival rate of 91.7%.
Ravandi and colleagues, in 2009, published the updated results of a clinical trial of ATRA and ATO performed at the MD Anderson Cancer Center. [13] In this trial, 82 patients were given ATRA and ATO induction with the addition of gemtuzumab ozogamicin (Mylotarg) if they had high-risk disease at presentation, or if their WBC count increased to 30,000/μL or greater during treatment. Post-induction therapy was 7 cycles of consolidation that consisted of 4 cycles of combined ATRA and ATO and 3 cycles of ATRA alone. As with Hu's study, the results were impressive. The overall response rate of the entire group was 92%. Overall survival at 5 years was approximately 80%. However, the ability to replicate this study is limited because gemtuzumab ozogamicin was withdrawn from the commercial market because of increased liver toxicity seen in a Southwest Oncology Group trial, with no obvious clinical benefit.
Iland and colleagues have reported the results of the APML 4 study conducted by the Australasian Leukaemia and Lymphoma Group.[11] This study gave all patients a combination of ATRA, ATO, and the standard four doses of idarubicin(Drug information on idarubicin) in induction, followed by 2 cycles of consolidation with ATRA and ATO, followed by standard maintenance therapy with 6-MP, methotrexate, and ATRA given once every 3 months for 2 years. Of the 124 patients evaluated, the 5-year overall survival rate was 93%, and relapse-free survival was a remarkable 98%.
Mathews in 2010 reported the long-term outcomes of a trial of arsenic monotherapy induction (although chemotherapy was allowed at the investigators' discretion to control elevated WBC counts) followed by 4 weeks of ATO consolidation, followed by 10 days of ATO once a month for 6 months as maintenance therapy.[14] The 5-year overall survival in the cohort of 72 patients enrolled on the trial was 74.1%. In a “good-risk” group, defined by the authors as patients presenting with a WBC count lower than 5,000/μL and platelet count higher than 20,000/μL, the overall survival at 5 years was 100%. The event-free survival at 5 years was 90% in the low-risk group and 60% in the high-risk group.
Ghavazmadeh and colleagues subsequently reported results of a phase II trial of 197 patients treated with arsenic monotherapy in post-induction and consolidation treatment.[15] Overall survival was 64.4% at 5 years.
What can we learn from these trials? It seems clear that arsenic monotherapy for induction and consolidation is not sufficient to produce the high overall survival seen for the majority of patients treated with ATRA and chemotherapy. However, a combination of ATRA and ATO without chemotherapy or with minimal chemotherapy to control the WBC count may be effective. There are active clinical trials and trials in development to further study the use of ATRA and ATO without chemotherapy. Therefore, APL represents both the only subtype of AML for which current therapy is directed at less cytotoxic chemotherapy and the only subtype that can be cured with minimal and, in fact, no chemotherapy.
APL in Older Adults
Several recent cooperative group studies demonstrate that the CR rate among older adults with APL is as high as that among younger patients (approximately 85%). Similarly, the relapse rate is quite low, at 10% to 20%, and the early death rate is approximately 15%. Therefore, APL appears to be one of the few subtypes of AML in which the disease appears as sensitive among older adults as it is among younger patients. Furthermore, APL is one of the few subtypes of AML in which improvements in outcome among older adults may depend more on decreasing toxicity than on increasing the amount of anti-leukemia therapy.
Oral Arsenic Trioxide(Drug information on arsenic trioxide)
Introducing oral ATO into routine clinical practice follows the general trend in hematology and medical oncology to deliver oral medications in place of IV formulations. In addition to the convenience for patients, the benefits of oral arsenic are a reduction in the need for long-term venous access devices such as medi-ports and PICC lines. These permanent-access devices are associated with risks of infection and of deep and superficial vein thromboses, with concomitant health care costs associated with inpatient hospital stays, IV antibiotics, and therapeutic anticoagulation.
The safety and efficacy of oral arsenic have been investigated in prior studies undertaken in China. Lu et al published the clinical results and safety data from 129 patients with newly diagnosed or relapsed APL treated from 1994 to 2000 using oral arsenic at a dose of 50 mg/kg per day, divided into four doses, until the patients had a documented hematologic complete remission.[16] Although not directly compared, complete remission and disease-free survival rates were similar to those seen in studies of IV arsenic. Oral arsenic was well tolerated, with the most frequent adverse events being asymptomatic prolongation of QTc (33%), transaminitis (10.5%), gastrointestinal discomfort (3.2%), rash (3.2%), and pericardial effusion (1%), side effects that are also typical of IV administration. Of note, despite the prolongation in QTc, arsenic continued to be administered without any evidence of ventricular arrhythmia.
In a separate report by Au et al, 12 consecutive patients with relapsed APL were treated with single-agent oral arsenic in a formulation slightly different from that used by Lu et al (As2O3 vs As4S4).[17] All patients achieved a CR. The most frequent adverse events were leukocytosis (related to administration when patients had initial relapsed disease), liver function abnormalities, and skin rash. The liver function abnormalities resolved with temporary cessation of treatment, and patients were successfully re-challenged with oral arsenic.
Clinical trials are evaluating the use of oral arsenic in combination with ATRA. Should this combination therapy be successful, APL will become the only subtype of acute leukemia that can be cured with all-oral therapy.
Conclusion
The treatment of APL in the modern era is a success of modern hematology. In this review we have attempted to plant the seeds of understanding regarding how diagnosis and treatment of APL will be pursued over the next decade. It is our hope that this will include rapid diagnostic assessment with a simple venipuncture, swift administration of ATRA- and ATO-based therapies that minimize exposure to cytotoxic chemotherapy, and the performance of well-designed clinical trials that elucidate the role of maintenance in APL treatment.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
A hematologically stable CML patient developed a solitary, exquisitely painful ulceration, 7 cm × 5 cm, located on the mid-medial foreleg. There was never any evidence of venous insufficiency. The patient denied the possibility of a spider bite. What is the likely cause of this lesion?
