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Originally published as JCO Early Release 10.1200/JCO.2005.03.9503 on May 1 2006 © 2006 American Society of Clinical Oncology. Arsenic Trioxide in Patients With Myelodysplastic Syndromes: A Phase II Multicenter Study
From the Institut Paoli-Calmettes, Marseille; Groupe Français des Myélodysplasies, Paris; CHU Nancy Brabois, Vandoeuvre-Les Nancy; Universite Paris 7 –Denis Diderot; Hopital Cochin; Hopital Hotel Dieu, Paris; Institut Gustave Roussy, Villejuif; CHU de Nice-Hopital de l'Archet 1, Nice; Hopital Beaujon, Clichy, France; Cliniques Universitaires de Mont-Godinne, Yvoir; Hopital Erasme, Bruxelles, Belgium; Ninewells Hospital, Dundee; University Hospital of Wales, Cardiff; Christie Hospital NHS Trust, Manchester, United Kingdom Address reprint requests to Norbert Vey, MD, Institut Paoli-Calmettes, 232 Boulevard Sainte Marguerite, 13009 Marseille, France; e-mail: veyn{at}marseille.fnclcc.fr
PURPOSE: Evaluation of the safety and efficacy of arsenic trioxide in patients with myelodysplastic syndromes (MDS). PATIENTS AND METHODS: MDS patients diagnosed according to standard French-American-British criteria received a loading dose of 0.3 mg/kg per day of arsenic trioxide for 5 days followed by a maintenance dose of 0.25 mg/kg arsenic trioxide twice weekly for 15 weeks. Patients were divided into two cohorts: lower-risk MDS (International Prognostic Scoring System risk category low or intermediate 1) and higher-risk MDS (International Prognostic Scoring System risk category intermediate 2 or high). Modified International Working Group criteria were used for response evaluation. RESULTS: Of 115 patients enrolled and treated in the study, 67% of patients were transfusion dependent at baseline; median age was 68 years. Most treatment-related adverse events were mild to moderate. The overall rate of hematologic improvement (intent-to-treat) was 24 (19%) of 115, including one complete and one partial response in the higher-risk cohort. The hematologic response rates were 13 (26%) of 50 and 11 (17%) of 64 in patients with lower-risk and higher-risk MDS, respectively. Major responses were observed in all three hematologic lineages; 16% of RBC transfusion-dependent patients and 29% of platelet transfusion-dependent patients became transfusion independent. At data cut off, the median response duration was 3.4 months, with responses ongoing in nine patients. CONCLUSION: Arsenic trioxide treatment consisting of an initial loading dose followed by maintenance therapy has moderate activity in MDS, inducing hematologic responses in both lower- and higher-risk patients. This activity combined with a manageable adverse effect profile warrants the additional study of arsenic trioxide, particularly in combination therapy, for the treatment of patients with MDS.
Myelodysplastic syndromes (MDS) have emerged as one of the most common hematologic malignancies affecting adults. The incidence rate of MDS has been estimated to be 4 to 12 individuals per 100,000 per year in developed countries.1 The relative risk increases with age, as the incidence reaches 15 to 50 individuals per 100,000 per year in persons older than 70 years.2 As the age of the overall population of industrialized countries increases and as physician awareness and diagnostic recognition of MDS improve, the incidence of MDS can be expected to increase dramatically in the near future. MDS is characterized by ineffective hematopoiesis; patients typically present with symptoms related to cytopenias, including infections, fatigue, and bleeding. The majority of patients will become dependent on RBC or platelet transfusions during the course of their disease.3 MDS patients are also at heightened risk for transformation to acute myelogenous leukemia, which occurs in 20% to 40% of all cases.4 With the exception of allogeneic stem cell transplantation, there is currently no curative treatment for MDS, and progress in developing effective agents is hindered by the clinical heterogeneity of the disease. The development of an International Prognostic Scoring System (IPSS) represents an important tool for the stratification of MDS patients into clear and reproducible risk groups.5 The establishment of standardized response criteria is another significant step toward progress in the investigation of new treatment approaches for MDS.6,7 Survival rates are improved following stem-cell transplantation, but this treatment option is only applicable to a small subset of patients because of age, concomitant medical conditions, and donor availability.8,9 Intensive chemotherapy has been used to eradicate the abnormal MDS clone; however, the response duration is typically brief, and this type of treatment is poorly tolerated by most elderly patients.10 As the medical community's understanding of the complex biology underlying the disease has improved, newer therapeutic approaches have been developed that target the abnormal biologic features of MDS, such as impaired differentiation, excessive apoptosis, and angiogenesis.11
Arsenic trioxide (Trisenox; Cell Therapeutics Inc, Seattle, WA) has been approved in the United States and Europe for patients with relapsed or refractory acute promyelocytic leukemia (APL). Treatment with arsenic trioxide results in the degradation of promyelocytic leukemia gene retinoic acid receptor-alpha gene (PML-RAR The purpose of this open-label, multicenter, phase II study was to evaluate the efficacy and safety of arsenic trioxide in patients with MDS.
Patient Selection All patients were diagnosed with MDS according to standard criteria.20 Patients were confirmed to have adequate marrow iron stores before enrollment, and each patient's disease status was classified according to one of the French-American-British diagnostic groups for MDS: refractory anemia (RA), RA with ringed sideroblasts, RA with excess blasts (RAEB), RAEB in transformation, and chronic myelomonocytic leukemia. Patients were prohibited from receiving growth factors, cytotoxic agents, or experimental agents within 30 days before their first study treatment; patients who failed to respond to erythropoietin treatment within that time frame were permitted to enroll in the study. Other eligibility requirements included age  18 years; life expectancy 3 months; adequate hepatic and renal function defined by serum bilirubin, AST, and ALT 2.5x the upper limit of normal range, and serum creatinine 1.5x upper limit of normal range; absence of significant underlying cardiac dysfunction (New York Heart Association class II or greater); QTc interval less than 460 milliseconds; 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, except in cases of active malignancy or previous diagnosis of acute myelogenous leukemia. The protocol was approved by the institutional review boards of all of the participating institutes, and each patient provided written informed consent.
Treatment Regimen
Arsenic trioxide was administered by intravenous infusion (typically a 1- to 2-hour infusion, with durations up to 4 hours permitted in the event of vasomotor reactions). If nonhematologic treatment-related grade 2 or 3 toxicities persisted between doses, dosing was delayed for up to 4 weeks; patients with persistent grade
Evaluation During Study
Response Criteria
Statistical Methods Two separate patient cohorts with different end points of response were prospectively enrolled, and primary responses were defined separately for each cohort. A two-stage design was used based on the assumption that a 25% response rate would be of interest, and that additional testing should not be pursued if the response rates were less than 10%. For each cohort, 15 patients were accrued in stage I. If at least one patient of 15 had a response, 40 additional patients were to be enrolled for a total of 55 patients for each cohort. For patients with lower-risk MDS (IPSS risk category low or intermediate 1), the primary efficacy end point was defined as a major improvement in more than or equal to one of the hematologic lineages that were abnormal at baseline. For patients with higher-risk MDS (IPSS risk category intermediate 2 or high), the primary efficacy end point was defined as complete response, partial response, or a major hematologic improvement (HI) in more than or equal to one of the lineages that were abnormal at baseline. Secondary efficacy end points, such as minor HI in more than or equal to one of the lineages that were abnormal at baseline, were also assessed, as were the durability of the observed responses and overall survival. All of the patients that were enrolled in the study and received study drug were assessable for safety and efficacy analyses. Kaplan-Meier estimates were used to calculate probabilities of survival. Comparisons between overall survival of responders versus nonresponders by MDS risk category were made using log-rank and multivariate analyses. Response and toxicity were analyzed using data available through May 17, 2005.
Patient Characteristics Between February 2002 and February 2004, 115 eligible MDS patients were enrolled at a total of 19 sites in France, England, Germany, and Belgium. Patient characteristics are listed in Table 2, while a summary of the patients' baseline clonal cytogenetic characteristics are presented in Table 3. The median age of the study population was 68 years (range, 31 to 89). Most patients were diagnosed with RAEB (n = 70; 61%). Sixty-four patients (56%) had higher-risk MDS, while 50 patients (43%) had lower-risk MDS; due to the lack of required baseline information, risk category could not be assessed for one RAEB patient. Seventy-seven patients (67%) were determined to be RBC and/or platelet transfusion dependent at baseline. Twelve patients (10%) had therapy-related MDS, and 20 patients (17%) had been previously treated for the disease. Prior treatment included ara-c in the majority of these patients (11 patients); other prior treatments were thalidomide (four patients), melphalan (two patients), and decitabine, cladribin, all-trans-retinoic acid/valproic acid, and cyclophosphamide (one patient each).
Treatment Administration Eighty-eight patients (77%) received a minimum of 8 weeks of treatment. Patients who were unable to receive 8 weeks of therapy were discontinued due to adverse events (n = 18; 16%), disease progression or transformation (n = 6; 5%), or withdrawal of consent (n = 3; 3%). The median number of weeks on treatment was 15.6 (range, 1-39 weeks), and 30 patients (26%) were able to receive more than 16 weeks of treatment.
Tolerability
Analysis of Response Response results are presented in Table 6. In the intent-to-treat population, 24 patients (21%) responded to therapy. One patient achieved a complete response and one patient achieved a partial response; both were RAEB patients belonging to the high-risk cohort. At baseline, the partial response patient had a normal karyotype while the complete response patient had a deletion 13q, which remained after treatment. The additional 22 responding patients achieved HI according to the modified IWG criteria; 20 of these patients had a major HI. Responses were observed across all hematologic lineages: 19 patients achieved an erythroid response; 11 patients achieved a platelet response; and seven patients demonstrated a neutrophil response. Seven patients (6%) achieved responses in two hematologic lineages, and three patients demonstrated major improvements in all three lineages. No cytogenetic responses were observed. Of the 75 patients who were RBC-transfusion dependent, 12 (16%) became transfusion independent, and transfusion requirements in an additional three patients (4%) were reduced by more than 50%. Of the 28 patients who were platelet-transfusion dependent patients, eight (29%) became transfusion independent. The median time to response was 1.9 months. At the last assessment, the median duration of response was 3.4 months; however, responses were still ongoing in nine patients.
The overall HI rate in lower-risk patients was 26%. Most of these patients (12 of 13) achieved major responses. The overall HI rate in higher-risk patients was 17%; most of these patients (10 of 11) achieved major responses, including one complete response and one partial response. Comparison of the response rates between lower-risk and higher-risk patients revealed no statistically significant difference (P > .05). Additional comparison of the characteristics (ie, baseline blast percentage, French-American-British disease subtype, cytogenetic karyotype) of responding patients (n = 24) versus nonresponding patients (n = 91) yielded no statistically significant differences (P > .05).
Overall Survival
This multicenter, phase II study investigated the clinical activity of single-agent arsenic trioxide administration in patients with either lower-risk or higher-risk MDS. Twenty-one percent of the patients had HI according to modified IWG criteria. Responses were seen across all hematologic lineages, and major HIs were observed in 19% of the patients. Twelve of 75 patients who were RBC-transfusion dependent at the start of the study achieved durable RBC transfusion independence (16%). One patient had a complete response, and one had a partial response. The efficacy profile observed in this study is similar to that in the concurrent United States study,21 which used a different administration schedule of arsenic trioxide. The inclusion and response criteria were comparable in both trials. In the United States study, 27% of 51 patients that received at least 8 weeks of therapy achieved HI. As in this study, patients with lower-risk disease tended to respond more favorably to treatment with arsenic trioxide than those with higher-risk disease. Through the schedule used in this phase II study, the toxicity profile was easily managed and most patients could be treated on an outpatient basis. Myelosuppression was the most significant reported toxicity, but was to a large extent related to the underlying disease (Table 2). Interestingly, only three patients (3%) experienced QT/QTc interval prolongation, a proportion far below the 35% rate previously reported in patients with APL.22 While better management of serum potassium and magnesium in this study may have contributed to a reduction in the effects on cardiac function, the dose regimen used may be associated with reduced accumulation of the drug compared with that seen in prior studies.21 The concurrent United States study used a different dosing schedule associated with a higher cumulative dose of arsenic trioxide.21 Adverse events appeared to occur with greater frequency in the United States study, particularly QT/QTc prolongation, the rate of which was 24%. These results suggest that the adverse events induced by arsenic trioxide administration, including the effects on cardiac conduction, may be dose or schedule dependent, because those patients observed in other studies followed dosing regimens resulting in increased overall accumulation of the drug. The dosing schedule employed in this study, a loading dose of 0.3 mg/kg per day arsenic trioxide for 5 days followed by a maintenance dose of 0.25 mg/kg arsenic trioxide twice weekly, favored patient convenience and was associated with limited nonhematologic adverse effects.
The improvement of hematopoietic efficiency and subsequent relief of symptoms associated with cytopenias are important goals in the treatment of patients with MDS. Such ineffective hematopoiesis results from a reduced progenitor cell responsiveness to trophic signals and includes excess generation of pro-apoptotic cytokines, such as tumor necrosis factor- In conclusion, arsenic trioxide demonstrates activity in MDS as a single agent, and is well tolerated by this target population. It is anticipated that therapeutic regimens combining arsenic trioxide with agents having different mechanisms of action will produce synergistic efficacy in MDS while maintaining tolerable safety profiles. Future studies will concentrate on determining the optimal drug or drugs to administer in combination with arsenic trioxide to improve the survival and quality of life in patients with MDS.
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)
This manuscript was supported financially by Cell Therapeutics Inc, with editorial assistance from Scott Burke, Marjorie Murray, and Annemieke DeMaggio. We acknowledge the efforts of Norbert Gatterman, MD, Majid Kazmi, MD, Guy Laurent, MD, Beatrice Mahe, MD, Archibald Prentice, MD, and Christopher Ravoet, MD.
Supported by Cell Therapeutics Inc, Seattle, WA. Preliminary results of this study were presented at the 46th Annual Meeting of American Society of Hematology, San Diego, CA, December 4-7, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this 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
) transcripts, partial differentiation of promyelocytes, and induction of apoptosis.
