Treatment with Amifostine, Topotecan and Cytarabine in 31 Consecutive Patients with High Risk Myelodysplastic Syndrome: A Phase II Trial.

Myelodysplastic syndromes are an heterogenous group of malignancies with a poor outcome. In order to improve the response rates and to prolong survival, many trials have been conducted including new scoring systems and using combination of new drugs.

We conducted a multicentric opened phase II trial with topotecan (1,5 mg/m² CI dy 1 to 5), cytarabine (1,0 mg/m² CI dy 1 to 5) and amifostine (200 mg/m² dy 1,3 &5) in 31 consecutive patients (M=33, F =8) with high risk myelodysplastic syndrome according to the FAB classification and defined as refractory anemia with excess of blasts (RAEB [18 pts]), RAEB in transformation (RAEBt [6 pts]), chronic myelomonocytic leukemia (CMML [6 pts]) and with an IPSS ≥1,5 (median = 2). The main characteristics of patients are summarized in table 1.

table 1: patient characteristics at diagnosis

The treatment plan consisted in two or three induction courses followed by two additional cycles at lower doses (half-dose) for those with partial response (PR), very good partial rsponse (VGPR) or hematological improvement (HI). Patients in CR or with progressive disease could receive consolidation therapy with either autologous or allognenic stem cell transplantation if eligible for intensive treatment. The main objective of the study was to evaluate the response rate after the induction courses. Three patients diden’t receive the treatment (2 for acute transformation, 1 death). The data study are analyzed by “intention to treat analysis” (ITT). The median follow-up is 14,5 months.

The post-induction CR and CR+PR rates are respectively of 38,7% and 45,2%. During the study 48% of patients achieved a CR (RAEB 61%, RAEBt 67%, CMML 0%). The median time to achieve CR is 2,9 months (95% CI, 1,1–4,8) with a probability of 59,1% (± 19,6).

The median duration of CR is 7 months (95% CI, 2,1–11,9). The median overall survival is 24 months (95% CI, 9,89-NR) [RAEB NR, RAEBt = 10,8, CMML = 5,3]. The probability of overall survival at 25 months is 47% (± 24,8) with the worst scores for patients with RAEB and RAEBt and those with IPSS ≥ 2,5 Twenty-four patients had an adverse event with grade > 2, mainly from infectious cause. Twelve patients died (5 from relapse, 2 from secondary leukemia, 4 miscellaneous). One toxic death occured during the srudy.

Nine patients were eligible forr intensification. Seven are alive of which 6 are in continuous CR with a median follow-up from transplant of 17 months. Two patients died respectively from aGVHD and relapse.

This combination is a safe procedure in patients with high risk myelodysplastic syndrome. In patients eligible for intensive treatment it could be an interesting regimen prior to transplantation since, per protocol, 53,5% of patients achieve a CR during the study, especially those with RAEB and RAEBt