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Originally published as JCO Early Release 10.1200/JCO.2005.05.4759 on May 1 2006 © 2006 American Society of Clinical Oncology.
Is Intravenous Arsenic Trioxide a Useful Therapy in Myelodysplastic Syndromes?Dana-Farber Cancer Institute, Boston, MA How do we know when a new agent represents a therapeutic advance for patients with myelodysplastic syndromes (MDS)? The disease is heterogeneous in the extreme. First, from a clinical standpoint, prognosis can range from many years for patients with normal chromosomes, no excess myeloblasts in the bone marrow specimen, and minimal derangements of the blood counts to less than 1 year for patients with pantocytopenia, an excess number of marrow myeloblasts, and/or chromosomal abnormalities. The aforementioned features are indeed the three critical components of the widely accepted International Prognostic Scoring System.1 The ability to discern prognosis among MDS patients using a model not solely based on histology was a major advance. Unfortunately, the International Prognostic Scoring System is only tangentially responsive to the real problem in clinical development in MDS. The biologic basis for the vast majority of patients who have this disease is unknown, except for those relatively rare patients with chronic myelomonocytic leukemia whose blasts contain an activating rearrangement of the platelet derived growth factor receptor ß gene on chromosome 5 for whom imatinib represents excellent therapy.2 Though patients whose bone marrow blasts contain an abnormality of the long arm of chromosome 5 with or without additional abnormalities respond well to lenalidomide,3 we have no clear understanding of the mechanism. The development of targeted therapies in MDS rests mainly on presumptive biologic features, which distinguish abnormal from normal marrow growth. For example, MDS has been said to be characterized by a block in normal hematopoietic differentiation; this notion lead to the use of differentiation-inducing agents, such as low-dose ara-C4 or retinoic acid.5 Differentiation-associated genes are silenced on an epigenetic basis, due to DNA overmethylation or histone under acetylation.6 This nascent understanding has led to a drug approval for the only agent thought to have activity in all subtypes of MDS, 5-azacitidine.7 Unfortunately, the response rate to this drug is fairly low and the actual mechanism of its action remains uncertain. Other alleged biologic features of MDS include disordered cell signaling, especially in the pro-proliferative direction for those subtypes of MDS characterized by excess numbers of blasts and overabundant apoptosis, especially in the more indolent types of MDS to explain low blood counts despite a hypercellular marrow.8 Pro-angiogenic signaling between bone marrow stem cells and their microenvironment has also been proposed as another mechanism of MDS pathophysiology. Other strategies include the use of cytotoxic agents, immunosuppression, augmenting anti-MDS autoimmunity, or stimulation with hematopooietic growth factors. Available therapies include lenalidomide for those with 5q– karyotypic abnormalities, 5-azacitidine for any patient with MDS who is deemed worthy of treatment, and immunosuppressive strategies for those subtypes of MDS more closely associated with aplastic anemia. Allogeneic hematopoietic stem cell transplantation remains the only known curative modality, but is not available for many MDS patients and must be judiciously employed.9
Into this rather variegated and confusing mix of available and developmental therapies arrives arsenic trioxide. Arsenic trioxide is an intravenously administered agent which is fantastically useful in patients with relapsed acute promyelocytic leukemia (APL), in which an 85% complete remission rate was noted even in a very advanced group of patients.10 The vast majority of the remissions occur at a level where the qualitative polymerase chain reaction test could not detect evidence of the disease based on assays for the PML-RAR The American trial11 enrolled MDS patients with any histologic subtype and used an arsenic trioxide regimen of 0.25 mg/kg administered daily by intravenous infusion for 5 consecutive days per week, for 2 weeks in a 4 week period. The European study12 had essentially identical eligibility criteria and enrolled 115 patients with treatment consisting of loading doses of 0.3 mg/kg of arsenic for 5 consecutive days in the first week, followed by a maintenance dose of 0.25 mg/kg arsenic twice weekly. Given the similarities between these two studies, it is perhaps not surprising, especially since they both used modified versions of the International Working Group criteria to assess response,13 that the results were reassuringly similar. Twenty-five of 76 patients enrolled in the American study failed to complete the desired two cycles of therapy. In order to obtain a realistic appraisal of the drug's activity, it is probably best to look at results with a denominator including all 76 patients: the actual intent to treat analysis reveals an 18% response rate. Most of these responses were major improvements in the erythroid lineage in low-risk patients, although there was one complete remission in a patient with chronic monomyelocytic leukemia. In the 115 MDS patients who were enrolled throughout Europe, the response rate was 21%, again with one complete remission and one partial remission with each of these patients having refractory anemia with excess blasts and belonging to the high-risk cohort. Most of the responses were characterized by a major improvement in erythroid lineage with only 10 patients achieving responses in two or more lineages. A major erythroid response requires that transfusion-dependent patients become transfusion independent or that the hemoglobin rises by greater than 2 g/dL in those patients who are transfusion independent at the outset. It is highly questionable whether a 20% response rate with an intravenously administered drug with significant adverse effects is worth using as a single agent. Although we are not told if these patients had failed the use of a hematopoietic growth factor, such agents are associated with a 20% to 25% response rate, which may be higher if there is a baseline erythropoietin level. Complete remissions, partial remissions, and/or multilineage responses are rare with arsenic trioxide. Even in the more somewhat more reasonable European schedule, the drug is cumbersome to administer and requires many visits to the clinic for this generally elderly and frequently infirm group of patients. Moreover, the toxicity is not trivial. In the American study, two of three patients experienced fatigue, although only 13% experienced a severe or life-threatening version of the symptom. Mild and moderate adverse events such as rash, pain, edema, and nausea and vomiting were common; severe life-threatening events were fairly uncommon. Although there was no quality of life analysis accompanying these trials, it seems certain that the vast majority of patients experienced a decline in their quality of life. Even for those patients who responded, one wonders whether a couple of grams per deciliter of hemoglobin rise was worth the adverse effects. Let us assume that responding patients could manage the adverse effects in exchange for some improvement in hematopoietic function. One of the primary ways to justify such a trade-off would be to be able to identify which patients were likely to respond to this agent at the outset. Such was the fortuitous outcome for treatment of MDS patients with lenalidomide for whom those with a 5q– abnormality had an 80% response rate. This is different from the arsenic trioxide case since there was no discernible way to tell who was going to respond and who was not. Responses were seen both in low- and high-risk patients, although there were more responses in the low-risk group. Those patients who had complete or partial remissions did not have any recurring chromosomal abnormalities. Incidentally, given the proposed mechanism of actions of arsenic apoptosis promotion it is entirely unclear why those patients with low-risk disease (generally < 5% blasts) seem to respond with at least as high a frequency as those with excess blasts. Fortunately, QT prolongation did not appear to be as a common problem as it was in certain arsenic-treated patients with APL. Not only is arsenic trioxide cumbersome and associated with significantly bothersome, if not occasionally life threatening toxicities, it does not compare well against currently available therapies. According to the International Working Group–based reanalysis of the original phase III data14 of Cancer and Leukemia Group B study 9221, which compared 7 days of 5-azacitidine to observation in MDS patients, the complete remission rate was 7%, the partial remission rate was 16%, and the hematologic improvement rate was 20%. The overall response rate of 43% is higher than was observed in the Schiller et al and Vey et al studies. The results with lenalidomide in non5q– patients also appears to be superior (55% response rate, with a more favorable adverse effect profile) to those reported in this issue11,12 for arsenic trioxide. Lenalidomide is not approved for non5q– MDS patients and arsenic trioxide is not approved for any MDS patient. As it is inappropriate to routinely recommend an approved drug for an unapproved indication, the use of arsenic trioxide in the off-protocol setting should be limited or nonexistent. In summary, while the authors of these two studies with arsenic trioxide in MDS ought to be commended for evaluating a novel agent in a disease for which there are few available therapies, it must be stressed that arsenic trioxide remains investigational for this indication.11,12 The response, efficacy, and toxicity data do not support the routine use of arsenic trioxide in MDS. The concluding sentences for both of these articles argue for the evaluation of the addition of arsenic trioxide to other agents in MDS. Which other agents would optimally be added to arsenic is unclear. Author's Disclosures of Potential Conflicts of Interest The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997; erratum appears in Blood 91:1100,1998 2. Apperley JF, Gardembas M, Melo JV, et al: Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347:481-487, 2002 3. List A, Kurtin S, Roe DJ, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549-557, 2005 4. Cheson BD, Jasperse DM, Simon R, et al: A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes. J Clin Oncol 4:1857-1864, 1986[Abstract] 5. Abrahm J, Besa EC, Hyzinski M, et al: Disappearance of cytogenetic abnormalities and clinical remission during therapy with 13-cis-retinoic acid in a patient with myelodysplastic syndrome: Inhibition of growth of the patient's malignant monocytoid clone. Blood 67:1323-1327, 1986 6. Egger G, Liang G, Aparicio A, et al: Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457-463, 2004[CrossRef][Medline] 7. Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol 20:2429-2440, 2002 8. Raza A, Qawi H, Lisak L, et al: Patients with myelodysplastic syndromes benefit from palliative therapy with amifostine, pentoxifylline, and ciprofloxacin with or without dexamethasone. Blood 95:1580-1587, 2000 9. Cutler CS, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104:579-585, 2004 10. Soignet SL, Maslak P, Wang ZG, et al: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339:1341-1348, 1998 11. Schiller GJ, Slack J, Hainsworth JD, et al: A phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol 24:2456-2464, 2006 12. Vey N, Bosly A, Guerci A, et al: Arsenic trioxide in patients with myelodysplastic syndromes: A phase II multicenter study. J Clin Oncol 24:2465-2471, 2006 13. Cheson BD, Bennett JM, Kantarjian H, et al: Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671-3674, 2000 14. Silverman R, McKenzie DR, Peterson B, et al: Response rates in patients with acute myeloid leukemia (AML), treated with azacitidine, using WHO and International Working Group (IWG) critieria for myelodysplastic syndrome (MDS). Blood 106:525a, 2005 (abstr 1848) Related Articles
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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fusion transcript, the product of the t(15;17) translocation that defines this disease. However, aside from relapsed (or possibly early complete remission) APL, there is no other known utility for this agent. Arsenic trioxide generally requires administration for a prolonged period of time and has some interesting and concerning adverse effects including prolongation of the Q-T interval. Both phase II studies analyzing arsenic trioxide in MDS in this issue of Journal of Clinical Oncology claim that the mechanism of action could be related to activation of apoptosis in malignant cells from MDS.
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