MDS- אזציטידין

להלן מאמר שפורסם במדסקייפ על תוצאות עבודה חדשה בטיפול ב- MDS באזציטידין Journal of Clinical Oncology May 15, 2002 (Volume 20, Number 10) Azacitidine for Patients With Myelodysplastic Syndromes Silverman LR, Demakos EP, Peterson BL, et al. Journal of Clinical Oncology. 2002;20(10):2429-2440 Although a number of agents have been studied for the treatment of patients with myelodysplastic syndromes (MDS), none has been shown, so far, to alter the natural history of the disease. Therefore, supportive care with transfusions and antibiotics is still considered the standard of care. Azacitidine is a pyrimidine nucleoside analog that was first studied in the treatment of acute myeloid leukemia (AML) in the 1970s. In 1985, the Cancer and Leukemia Group B (CALGB) conducted a phase 2 study with continuous-infusion azacitidine in patients with poor-risk MDS and observed a response rate of 49%. A subsequent study using subcutaneous dosing showed similar results. These results prompted the current phase 3 trial comparing subcutaneous azacitidine with supportive care.[1] Patients diagnosed with MDS according to the French-American-British (FAB) classification were eligible for this open-label, multicenter study. Subjects with the low-risk subtypes, refractory anemia and refractory anemia with ringed sideroblasts, had to meet additional criteria of significant bone marrow dysfunction. Patients with secondary (therapy-related) MDS were also included in the trial. Patients were stratified according to FAB subtype and randomized to receive either supportive care or azacitidine 75 mg/m2/day subcutaneously for 7 days, repeated every 28 days. After 4 months, patients in the supportive care arm who had worsening disease were permitted to cross over to the azacitidine arm. Patients who had progressed to AML were also allowed to cross over, provided that the blast count in the bone marrow was not greater than 40%. A total of 191 patients were enrolled. Subsequent evaluation revealed that 20 patients had AML at the time of enrollment. These patients were excluded only from the analysis of time to leukemic transformation. In the supportive care arm, no patients achieved a complete response (CR) or partial response (PR). Improvement (defined as a mono- or bilineage response or >/= 50% decrease in transfusion requirements from baseline) was seen in 5 patients (5%). All of these "responses" were a result of rising white blood cell or platelet counts in the process of transformation to acute leukemia. In the azacitidine arm, 60% of patients responded to treatment (P < .0001 vs supportive care), with 7% achieving a CR, 16% a PR, and 37% showing an improvement. Of the patients categorized as having improvement, 35% had increases in all 3 cell lines (but not enough to classify them as PR), 30% had increases in 2 cell lines, and the remaining 35% had only a single cell line response. No cases of improvement were due to transformation to AML. The response to azacitidine was independent of MDS classification. The median times to initial and best responses were 64 and 93 days, respectively, and the median duration of response was 15 months. A total of 49 patients initially randomized to the supportive care arm crossed over to the azacitidine treatment. The response rate in this group was 47%, with 10% achieving a CR, 4% PR, and 33% improvement. The median time to leukemic transformation or death in the supportive care arm was 12 months compared with 21 months in the azacitidine arm (P = .007). For patients with high-risk FAB subtypes (RAEB, RAEB-T, or CMML) the median time to transformation or death was 8 months in the supportive care arm and 19 months in the azacitidine arm (P = .004). As would be expected, the median survival of patients who had transformed to AML was significantly shorter than that of patients who had not undergone transformation, as determined by a landmark analysis at 12 months. While the red blood cell transfusion requirement in the azacitidine arm increased in the first month of treatment, there was an overall decease in transfusion requirements in these patients. By definition, all patients with a CR or PR were transfusion independent. Of the patients classified as improved, 22% had an elimination of all red blood cell transfusion requirements and 16% had a 50% decrease in transfusion requirements. The median survival was 14 months for patients randomized to the supportive care arm compared with 20 months for those in the azacitidine arm (P = .10). This analysis is complicated by the fact that 50% of the patients randomized to supportive care crossed over to receive azacitidine. When the azacitidine group was compared with patients who never crossed over or who crossed over late, the difference in survival was statistically significant (18 vs 11 months). Overall, azacitidine was well tolerated, with myelosuppression being the most common toxicity. Because of the nature of the disease, it is often difficult to separate drug and disease toxicity. In general, however, toxicity was transient and patients recovered in time to receive their next scheduled treatment cycle. Infection occurred in 20% of patients, and there was 1 treatment-related death. Details were not provided in the report. The mechanism of action for azacitidine in the treatment of MDS is thought to be multifactorial. Azacitidine may act as a biologic response modifier, acting through suppression of the MDS clone or a cytotoxic effect on regulator T-cells or other modulating cells involved in inhibiting hematopoiesis. The authors speculated that while the regimen examined in this study is active, other doses and schedules may improve on the efficacy. In addition, they suggested combination studies to further evaluate the role of this agent in the treatment of patients with MDS, but proposed consideration of azacitidine as the treatment of choice in patients similar to the study population. In an accompanying report, the results from the quality-of-life (QOL) studies from this CALGB study were presented.[2] Patients were assessed at baseline (before randomization), at day 50 (after completing 2 cycles), at day 106, and at day 182 (approximately 6 months after entry into the study). The QOL tools used to assess patients were the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30, which is a measure of general physical symptoms, physical functioning, fatigue, and social and emotional functioning; the Mental Health Inventory, which is a measure of psychological state; and a visual analog scale to assess patients' perception of improvement of their condition. There were significant improvements in fatigue, dyspnea, physical functioning, positive affect, and psychological distress in the azacitidine arm compared with the supportive care arm. Furthermore, in those patients who crossed over from supportive care to azacitidine, the QOL was found to be either stable or worsening while on the supportive care arm, but showed a significant improvement after the cross over. There was a significant interrelationship detected between patients' physical status and psychosocial well-being, suggesting that physical improvement was the likely cause for the psychological improvement seen in patients receiving azacitidine. The authors dismissed the possibility of a placebo or Hawthorne effect (QOL improvement as a result of increased medical attention associated with the treatment) based on post-hoc testing that demonstrated no improvements in nonresponders on the azacitidine arm compared with the supportive care arm. Consistently, no significant differences between treatment arms were found on all measures as might be expected from a "blanket" placebo effect. References 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. 2002;20:2429-2440. Kornblith AB, Herndon JE, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002;20:2441-2452.

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