Throughout the course of medical history, we have witnessed innovations that have initially been met with skepticism but have later revolutionized our management of patients with specific disorders. The recent history of oncology drug development is full of instances where a drug that was effectively used as salvage therapy was clearly demonstrated to be better than the established “standard” in the initial treatment of the same disease. Examples of this include tyrosine kinase inhibitors in Philadelphia chromosome–positive acute lymphoblastic leukemia, second-generation tyrosine kinase inhibitors in chronic myeloid leukemia, fludarabine in chronic lymphocytic leukemia, cladribine in hairy cell leukemia, and thalidomide (Thalomid) in multiple myeloma.
For obvious ethical reasons, the natural course of drug development in oncology follows the path from salvage to front-line therapy. An agent that is able to effectively salvage patients for whom the “standard” initial therapy has failed is likely to be more potent and associated with a higher likelihood of achieving a response in the front-line setting, particularly if used in combination with other established effective drugs.
All-trans Retinoic Acid and Arsenic Trioxide
The introduction of all-trans retinoic acid (ATRA) clearly revolutionized the treatment of acute promyelocytic leukemia (APL), improving response rates and disease-free and overall survival, particularly when ATRA was also used for maintenance.1 Single-agent ATRA is, however, associated with rapid development of resistance and relapse, and initial randomized trials clearly demonstrated that the combination of ATRA with chemotherapy was superior. However, despite the significant advantage of regimens combining chemotherapy and ATRA, relapses do occur in a proportion of patients, necessitating second-line therapy, namely arsenic trioxide (Trisenox).2
A brief look at recent trials involving the use of arsenic trioxide in the treatment of APL clearly demonstrates that the drug has followed the typical path from salvage to front-line therapy. Early studies in the salvage setting demonstrated arsenic trioxide to be very potent against this disease. In the U.S. multicenter phase II study that led to its approval, 85% of patients with relapsed APL treated with single-agent arsenic trioxide, achieved a complete response, with the majority achieving a complete molecular response.2 This compares favorably with the complete response rates achieved using single-agent anthracyclines (hitherto the most effective agents against APL cells) in earlier clinical trials, establishing arsenic trioxide as the most potent single agent against APL.
A number of studies have examined the potential role of arsenic trioxide in the initial treatment of patients with APL. In studies conducted by Indian and Iranian groups, the drug has proven to be highly effective in producing very durable remissions, particularly in patients with low-risk disease. Repeated treatment for consolidation has been shown to be beneficial. However, lack of universal success and modest long-term leukemia-free and overall survival rates have suggested a potential need to combine arsenic trioxide with other drugs.
Alternative Strategies
In the United States, one strategy has been to introduce arsenic trioxide in the consolidation setting. A large, randomized intergroup study showed better disease-free and overall survival for patients who received arsenic trioxide during consolidation compared to those who received chemotherapy alone (although not statistically significant for overall survival).3
Others, including our group at The University of Texas MD Anderson Cancer Center, have examined the possibility of eliminating or minimizing the role of chemotherapy. We conducted a phase II trial of arsenic trioxide plus ATRA with or without gemtuzumab ozogamicin (Mylotarg) in patients with high-risk disease, and have demonstrated the feasibility and efficacy of this strategy.4 Among the 82 patients first reported, 75 patients achieved complete remission and one patient achieved complete remission with incomplete recovery of platelets, for an overall response rate of 92%. These were durable responses with an estimated 3-year survival of 85%.
A group from China also conducted a study of ATRA plus arsenic trioxide for induction, but they used combination chemotherapy for consolidation in all patients. Another strategy, currently being explored by the European APL group in an ongoing study, is to combine arsenic trioxide with chemotherapy and ATRA to maximize their potential antileukemic effects, with the main concern for such a combination being toxicity.
Bleeding and Thrombosis
Despite significant advances in treating APL, the initial therapy of this disease remains fraught with danger, with a significant proportion of patients developing life-threatening complications of bleeding and thrombosis. Early diagnosis and initiation of therapy with ATRA is very important to reduce the risk of these complications.
The bleeding tendency is known to be exacerbated by the use of chemotherapy, which results in the breakdown of leukemic cells and release of procoagulant material into the circulation, and leads to the worsening of disseminated intravascular coagulation and consumptive coagulopathy—the hallmark of the disease. Therefore, a strategy that circumvents the use of chemotherapy may be desirable. Furthermore, many patients, particularly the elderly and those with cardiac dysfunction, may not be able or willing to tolerate the effects of combination chemotherapy. Although the potential long-term risks of chemotherapeutic agents (such as the development of secondary cancers) are limited, this can be cited as another potential advantage of a chemotherapy-free regimen.
With the withdrawal of gemtuzumab ozogamicin by the FDA, it is not clear whether a truly chemotherapy-free regimen will be feasible in all patients. We have substituted a dose of idarubicin for gemtuzumab in our regimen, so far with comparable results. However, ATRA plus arsenic trioxide is clearly an effective treatment, particularly for patients with low-risk disease and those unable to receive traditional cytotoxic chemotherapy. ■
Disclosure: Dr. Ravandi has been a member of advisory boards and has received honoraria from Cephalon.
References
1. Tallman MS, Andersen JW, Schiffer CA, et al: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337:1021-1028, 1997.
2. Soignet SL, Frankel SR, Douer D, et al: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:3852-3860, 2001.
3. Powell BL, Moser B, Stock W, et al: Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 116:3751-3757, 2010.
4. Ravandi F, Estey E, Jones D, et al: Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 27:504-510, 2009.
Dr. Ravandi is Associate Professor of Medicine, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.
