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Originally published as JCO Early Release 10.1200/JCO.2005.03.7903 on May 1 2006 © 2006 American Society of Clinical Oncology. Phase II Multicenter Study of Arsenic Trioxide in Patients With Myelodysplastic Syndromes
From the UCLA Division of Hematology-Oncology, University of California Los Angeles; Norris Cancer Center, University of Southern California School of Medicine, Los Angeles; Scripps Cancer Center, San Diego, CA; Mayo Clinic, Scottsdale, AZ; Sarah Cannon Cancer Center, Nashville, TN; Georgia Cancer Specialists, Tucker, GA; Duke University Medical Center, Durham, NC; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL Address reprint requests to Gary J. Schiller, MD, UCLA Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, CA 90095; e-mail: garyjs{at}ucla.edu
PURPOSE: To evaluate the efficacy and safety of arsenic trioxide monotherapy in patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS: Patients received arsenic trioxide (0.25 mg/kg/d) on 5 consecutive days per week for 2 weeks, followed by 2 weeks’ rest (one cycle). Two patient cohorts were established according to International Prognostic Scoring System risk category: lower-risk (low or intermediate-1) or higher-risk MDS (intermediate-2 or high). For lower-risk MDS, hematologic improvement (HI) was the primary response end point. For higher-risk MDS, additional end points included complete or partial remission. Based on the expected time to response, patients receiving two or more cycles were prospectively evaluated.
RESULTS: Hematologic adverse events included neutropenia, thrombocytopenia, and febrile neutropenia. Two patients died during the study due to treatment-related toxicities. Most common grade 3/4 nonhematologic events were pneumonia, fatigue, hemorrhage, pain, and dyspnea. Among patients who received one or more doses (n = 70) or completed two or more cycles (n = 51), the HI rates were 34% and 39% in lower-risk patients, and 6% and 9% in higher-risk patients, respectively; the overall major HI rates were 20% and 22%. One higher-risk patient achieved a complete remission (3%). Major HIs were observed in all hematologic lineages; erythroid responses were the most common. Transfusion independence or reduction by CONCLUSION: Arsenic trioxide monotherapy has moderate activity against MDS, with a manageable adverse effect profile. The further study of arsenic trioxide in MDS, particularly in combination with other agents, is warranted.
Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem-cell malignancies characterized by ineffective hematopoiesis. Hematopoietic failure is attributed to a complex interaction between abnormal progenitor cells and the bone marrow microenvironment, resulting in premature apoptosis and impaired differentiation of blood cell precursors and their progeny.1 Five MDS subtypes are defined in the French-American-British (FAB) classification system.2 The prognosis for MDS varies with subtype: patients with refractory anemia (RA) and RA with ringed sideroblasts (RARS) generally survive longer than patients with RA with excess blasts and RA with excess blasts in transformation, for whom disease is characterized by transformation to acute myeloid leukemia. Recently, a more comprehensive prognostic scoring system was introduced that weighs a patient's prognosis by the number of cell lineages that are deficient, blast percentage, and the cytogenetic characteristics of the dysplastic clone.3 The International Prognostic Scoring System (IPSS) thus provides a more accurate estimate of clinical prognosis compared with morphologic classification alone.4 Management of patients with MDS remains largely supportive, including the administration of hematopoietic growth factors, antibiotics, and transfusions.5 Allogeneic stem-cell transplantation offers curative potential,6,7 but is limited by the patient's age and the availability of histocompatible donors. Intensive chemotherapy results in high rates of clinical remission, but the duration of remission is brief, and treatment is associated with significant toxicity.8
Arsenic trioxide is highly active in relapsed or refractory acute promyelocytic leukemia (APL).9 The cytotoxic effects of arsenic trioxide in APL are mediated by its ability to induce degradation of the APL fusion protein PML-RAR We conducted an open-label, multicenter, phase II study to evaluate the efficacy and safety of arsenic trioxide in patients with MDS.
Patient Selection Patients with a diagnosis of MDS according to FAB criteria19 and adequate marrow iron stores (as determined by Prussian blue stain for hemosiderin in bone marrow) were eligible to participate. Hematopoietic growth factors, cytotoxic therapy, or experimental agents were prohibited within 30 days before first study treatment, except for patients whose disease failed to respond to erythropoietin treatment. Other eligibility requirements included age  18 years; life expectancy 3 months; adequate hepatic and renal function defined by serum bilirubin, ALT and AST  2.5x upper limit of normal, and serum creatinine 1.5x upper limit of normal; absence of significant underlying cardiac dysfunction (New York Heart Association Class II or greater); QTc interval less than 460 ms; serum potassium greater than 4.0 mEq/L; and serum magnesium greater than 1.8 mg/dL. Patients with a history of prior malignancy were eligible. The protocol was approved by the institutional review boards of each participating institution, and patients provided written informed consent.
Treatment Regimen Each treatment cycle consisted of arsenic trioxide 0.25 mg/kg daily for 5 consecutive days per week for 2 weeks during every 4-week period. If study drug–related grade 2 or 3 toxicities were present at the scheduled start of a treatment cycle, that cycle was delayed for as long as 4 weeks; patients with persisting treatment-related symptoms were withdrawn from the study. Patients continued on study treatment as long as they derived clinical benefit.
Evaluations During Study
Response Criteria
Statistical Methods Two separate patient cohorts with different primary end points of response were prospectively enrolled. For patients with lower-risk MDS, the primary efficacy end point was major HI in one or more of the lineages that were abnormal at baseline. For patients with higher-risk MDS, the primary efficacy end points were CR, PR, or major HI in one or more of the lineages that were abnormal at baseline. Secondary efficacy end points included minor HI in one or more of the lineages that were abnormal at baseline, response duration, and duration of progression-free and overall survival. All patients who received study drug were included in the safety analysis. For the efficacy analysis, response percentages were calculated by comparing the number of patients with disease responses to (1) the number of patients enrolled in the study; (2) the number of patients who received at least one dose of arsenic trioxide; and (3) the number of patients who completed two or more cycles of therapy (as defined in the design of the trial).
Patient Characteristics Between May 2001 and March 2004, 76 eligible MDS patients were enrolled. This multicenter study included 13 centers; the median enrollment per center was five patients (range, one to 19). Seventy patients received at least one dose of arsenic trioxide. Response and toxicity profiles were analyzed using data available through March 14, 2005. Patient demographics and clinical characteristics are listed in Table 2.
Study Withdrawals Before 8 Weeks of Treatment Of 76 patients enrolled in this study, six received no study drug, and 19 discontinued before completing two cycles of therapy. The reasons for early withdrawal are summarized in Table 3. While serious adverse events (SAEs) were the most common reason for withdrawal, SAEs considered drug-related were limited to three patients and included acute toxic hepatitis, pleural effusion/bronchitis, and hypoalbuminemia. Non–drug related SAEs included infections, hemorrhage, respiratory failure, and fatigue; these could be attributed to the diagnosis of MDS, highlighting the difficulty of conducting studies in a disease state in which remittive agents require adherence for a minimum of 2 months, especially in higher-risk patients.
Analysis of Safety Myelosuppression is one of the clinical characteristics of MDS and most patients entered the trial with preexisting cytopenias (Table 2); consequently, the distinction between disease-related and drug-induced cytopenias is difficult to make. Table 4 summarizes the occurrence of all hematologic adverse events; grade 3/4 neutropenia and thrombocytopenia occurred in 36% and 44% of patients, respectively, and febrile neutropenia was reported in 11%. The most common nonhematologic toxicities are listed in Table 4; most events were moderate and manageable. Two treatment-related deaths occurred: one patient experienced acute toxic hepatitis on Study day 17, with grade 4 hypoxia and dyspnea before succumbing to multiple organ failure on day 36; a second patient experienced respiratory failure, diffuse alveolar damage, pleural effusion, and bronchitis leading to the patient's death on day 33. Severe or life-threatening events were infrequent; grade 4 events were limited to pneumonia (three patients); hemorrhage and hypoxia (two patients each); and pain, dyspnea, and pyrexia (one patient each). Grade 3 adverse events such as asthenia/fatigue or pneumonia (nine patients each); hemorrhage, hyperglycemia, or pain (five patients each); and catheter-related infection or dyspnea (four patients each), were reported. Among the mild or moderate adverse events, 17 patients experienced QT/QTc prolongation; however, these events were transient, no patients had accompanying clinical symptoms, and the events were easily managed by correcting concomitant electrolyte imbalances and by delaying dosing until the patient's QT interval returned to an acceptable value.
Analysis of Response Hematologic improvement. Responses are summarized in Table 5, and HIs by lineage for responding patients are presented in Table 6. Ten of the lower-risk patients achieved erythroid responses; seven were major improvements. In higher-risk patients, two major erythroid responses were observed, including one associated with a CR in a patient with chronic myelomonocytic leukemia, and a baseline blast percentage of 18%. Of the 33 patients dependent on RBC transfusions and who completed two cycles of therapy, eight became transfusion-independent, and an additional three patients had transfusion requirements reduced by 50%. The median time to response was 3.3 months, with a median duration of 4.4+ months; responses are still ongoing in six of the 12 patients.
In the platelet lineage, two patients demonstrated major responses. One of these patients (a lower-risk–category patient) also achieved a major erythroid response during the study. The other responding patient's risk category could not be determined due to lack of sufficient background information. Of the 11 platelet-transfusion–dependent patients who completed two cycles of therapy, one became transfusion-independent. The median time to response was 2.8 months, while the median duration of response was 8.6 months. In the neutrophil lineage, one major response was observed in a lower-risk patient. The time to response for this patient was 3.8 months, and the response lasted for 27.5 months. The tabulation of responses according to the demographic characteristics of assessable patients is presented in Table 7. Multivariate analyses of the results indicated that the arsenic trioxide dosing regimen used in this study was more effective in patients with lower blast percentages at baseline (P = .0473), patients with lower-risk MDS (P = .0227), and to a lesser extent, patients with RA or RARS disease subtypes (P = .100). The study drug regimen did not seem to favor patients of a specific age category or sex, nor did it favor patients with specific cytogenetic aberrations or secondary MDS.
Overall, HI was achieved in 39% of assessable lower-risk patients. The majority of these responses were major HIs (eight of 11). HIs were achieved in 9% of assessable patients with higher-risk MDS. Both responses were major erythroid improvements and included one CR. In addition, one patient whose risk category could not be determined demonstrated a major platelet response. Progression-free and overall survival. Progression-free and overall survival were assessed for each patient by determining the length of time from the patient's entry into the study until patient withdrawal due to disease progression or death. Table 8 provides a comparison of median survival for higher- and lower-risk patients who received one or more doses versus patients who completed two or more treatment cycles, as well as lower-risk patients who responded to arsenic trioxide therapy versus lower-risk patients who did not respond to treatment. The median survival for patients with higher-risk disease who received one or more cycles was 149 days, while the median survival for higher-risk patients who were able to receive two or more cycles was 227 days. The median survival for all patients with lower-risk disease was not yet reached at last follow-up; the median survival for nonresponders with lower-risk disease was 348 days.
The ineffective hematopoiesis characteristic of MDS results from a reduced progenitor cell responsiveness to trophic signals and includes excess generation of pro-apoptotic cytokines, such as tumor necrosis factor alpha and interleukin-1ß.20-24 Thus, malignant progenitors produce signals that not only reinforce self-renewal, but also promote apoptosis in long-term initiating cells as well as committed progenitors.25-28 Restoring hematopoiesis in MDS is dependent on reducing the proapoptotic and proliferative effects of the abnormal MDS clone. The exposure of bone marrow cells from patients with advanced MDS to therapeutic concentrations of arsenic trioxide promotes apoptosis in short-term cultures.29 An important mechanism in arsenic trioxide–induced apoptosis is the generation of oxidative stress.14-16 Because abnormal MDS cells are characterized by increased oxidative stress,24 these cells may be especially vulnerable to additional oxidative insults. In clinical studies of patients with MDS, the median time to therapeutic response, 9 to 13 weeks, seems to be similar regardless of the treatment modality.30,31 Given this information, we prospectively analyzed disease response in patients who received at least two 28-day cycles of arsenic trioxide therapy; 27% of these patients achieved HI, including one CR. Nineteen patients did not receive a second treatment cycle; withdrawal was due to disease progression in two patients and treatment-related SAEs in three patients, indicating that discontinuation was not necessarily related to toxicity or lack of activity. The median time from first dose to response was 3.2 months, confirming the requirement for multiple cycles to obtain benefit. In general, most treatment-related toxicities were mild to moderate in severity; most of the observed toxicities either resolved without intervention or were manageable with medication. The response criteria used in this study (Table 1) follow the IWG guidelines defined by Cheson et al in 2000, with some important modifications that we believe should be incorporated into future studies. Transfusion dependence is not defined by the IWG guidelines; these criteria are clearly defined in this study, because diminishing dependence on RBC and/or platelet transfusions represents a clear response to therapy, while an increased dependence denotes disease progression. For this study, the criteria for CR or PR are identical to IWG parameters. Guidelines for determining major and minor HIs are similar to the IWG criteria, but were modified to reflect the patient's clinical status at baseline. For example, several patients met the criteria for major platelet responses because they appeared to become transfusion-independent. On further review however, these apparent responses were excluded because the patients' platelet counts remained consistently low whether they received transfusions or not. In these cases, platelet transfusions were discontinued because the patient derived no clinical benefit, and not because the patient was responding to therapy. Results from the current study are comparable with those from a concurrent study of arsenic trioxide monotherapy in MDS that was conducted in Europe32; Vey et al33 reported that 21% of the patients achieved HI. However, on further comparison of the results of these studies, some variant trends emerge. For example, in this study, arsenic trioxide appeared to be more effective in patients with lower-risk disease, patients with the RA or RARS disease subtypes, and patients with lower blast percentages at baseline. In the European study, however, comparable results were observed in patients with different MDS risk categories, different disease subtypes, and varied baseline blast percentages. Differences can also be seen when comparing the tolerability profile of arsenic in both studies. Particularly, QT/QTc interval prolongation was observed in 17 patients (24%) in this study, but only three patients experienced similar events in the European study. The differences observed in both the efficacy and tolerability profiles from these studies could be attributed to their respective dosing regimens. In the European study, patients received a loading dose of 0.3 mg/kg/d arsenic trioxide for 5 days, followed by a maintenance dose of 0.25 mg/kg arsenic trioxide twice weekly, which is associated with a lower cumulative dose of arsenic trioxide compared with the current regimen. Patients with more aggressive courses of MDS or those with advanced stages of the disease, such as patients with higher-risk MDS or patients with higher blast percentages at the beginning of the study, probably experienced greater difficulty in tolerating the current dosing regimen, as their clinical condition was already compromised. As a result, those patients were less likely to obtain benefit from the therapy. Conversely, patients enrolled in the European study received a lower, and potentially more tolerable, overall dose of arsenic trioxide, increasing the likelihood that they would adhere to its administration. The combined data suggest that the appropriate dose of arsenic trioxide for lower-risk patients may be different from that for higher-risk patients, and this possibility should be evaluated in future studies. Patients with MDS characterized by complex cytogenetic abnormalities were generally insensitive to arsenic trioxide therapy; however, no specific cytogenetic abnormality was found to be predictive of potential sensitivity or resistance. Of the two higher-risk patients whose disease responded to study therapy, one (who achieved CR) had a normal diploid karyotype; the other patient (who achieved a major erythroid response) had complex cytogenetic aberrations (46, XY, der[2], t[2;11] [q33;q13], –11, +MAR [four cells] 47, IDEM, +MAR [six cells]). Differentiating agents, immunosuppressive drugs, and immunomodulatory compounds have all had some success in MDS. Lenalidomide, a high-potency thalidomide analog, induces major erythroid improvement in approximately 70% of patients with lower-risk MDS (particularly those with the 5q– syndrome) who failed therapy with recombinant erythropoietin; only 21 of 55 patients screened achieved a major erythroid response.32,34 5-azacytidine, a DNA methyltransferase inhibitor, was recently approved for treatment of MDS; in pivotal trials, response rates were 13% to 19%, though hematologic improvement is achieved in nearly 40% of patients.35 In conclusion, arsenic trioxide demonstrates activity in MDS as a single agent, with a manageable safety profile. Combination studies are required to improve clinical efficacy in MDS therapy; clinical studies evaluating the addition of arsenic trioxide to other agents, particularly those active in patients with higher-risk disease and with different mechanisms of action, are warranted.
Although all authors completed the disclosure declaration, the following authors or their 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)
Supported by Cell Therapeutics Inc, Seattle, WA. Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Sierra J, Perez WS, Rozman C, et al: Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood 100:1997-2004, 2002 8. Beran M, Shen Y, Kantarjian H, et al: High-dose chemotherapy in high-risk myelodysplastic syndrome: Covariate-adjusted comparison of five regimens. Cancer 92:1999-2015, 2001[CrossRef][Medline] 9. 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 10. Miller WH Jr, Schipper HM, Lee JS, et al: Mechanisms of action of arsenic trioxide. Cancer Res 62:3893-3903, 2002 11. Zhang W, Ohnishi K, Shigeno K, et al: The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms. Leukemia 12:1383-1391, 1998[CrossRef][Medline] 12. Rojewski MT, Baldus C, Knauf W, et al: Dual effects of arsenic trioxide (As2O3) on non-acute promyelocytic leukaemia myeloid cell lines: Induction of apoptosis and inhibition of proliferation. Br J Haematol 116:555-563, 2002[CrossRef][Medline] 13. Zhu XH, Shen YL, Jing YK, et al: Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst 91:772-778, 1999 14. Jing Y, Dai J, Chalmers-Redman RM, et al: Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 94:2102-2111, 1999 15. Woo SH, Park IC, Park MJ, et al: Arsenic trioxide induces apoptosis through a reactive oxygen species-dependent pathway and loss of mitochondrial membrane potential in HeLa cells. Int J Oncol 21:57-63, 2002[Medline] 16. Chen YC, Lin-Shiau SY, Lin JK: Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. 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Raza A, Buonamici S, Lisak L, et al: Arsenic trioxide and thalidomide combination produces multi-lineage hematological responses in myelodysplastic syndromes patients, particularly in those with high pre-therapy EVI1 expression. Leuk Res 28:791-803, 2004[CrossRef][Medline] 32. Cazzola M, Malcovati L: Myelodysplastic syndromes–coping with ineffective hematopoiesis. N Engl J Med 352:536-538, 2005 33. 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 34. List A, Kurtin S, Roe DJ, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549-557, 2005 35. Kaminskas E, Farrell AT, Wang YC, et al: FDA drug approval summary: Azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 10:176-182, 2005 Submitted August 9, 2005; accepted December 16, 2005. Related Article
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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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ABSTRACT
INTRODUCTION
, allowing APL cells to overcome the differentiation block that is the hallmark of the disease. Arsenic trioxide also induces apoptosis via mechanisms independent of its effects on PML-RAR
