A Maintenance Therapy with Differentiating Agents and Low-Dose Chemotherapy Increases Remission Duration and Survival in High Risk AML and MDS Patients.

Abstract

Acute myeloid leukemia (AML) patients above the age of 60 or with secondary AML generally have an unfavourable outcome. The same is true for high risk myelodysplastic syndrome (MDS) patients ineligible to bone marrow transplantation. Indeed, in spite of an improved CR rate after intensive chemotherapy (about 60–65%), median CR duration and survival remain short (9–12 months in most studies), due to early relapses. (Sekeres MA et al.: Curr Opin Oncol 2002; 14:24–30. Verbeek W et al.: Ann Hematol 2001; 80:499–509).On the basis of our previous clinical trials with differentiative agents + low dose chemotherapy in MDS/AML patients unsuitable to intensive treatments, (Ferrero D et al.: Leuk Res 1996; 20:867–876; Haematologica 2004; 89:619–620), we adopted the same strategy as a post-remission maintenance therapy to patients with AML or MDS at high risk of relapse and ineligible to allogeneic transplant. Thirty-six patients (27 AML and 9 high risk MDS) who had obtained a CR after different schemes of intensive chemotherapy were scheduled to receive the maintenance treatment with 13-cis-retinoic acid (20–40 mg/day) + 1,25-di-hydroxy-vitamin D3 (1 microgram /day) in association to intermittent, low dose chemotherapy: 6-thioguanine 40 mg/day x 21 days every 5 weeks, alternated every 2–3 months, in 24 patients, to a 14 day course of ARA-C 8 mg/m2 s.c. x 2/day + 6-mercaptopurine 50 mg/day. Patients' median age was 64 years (range 27–76), with only 9 below the age of 60. Cytogenetic analysis was performed successfully in 27 cases, and an unfavourable karyotype was found in 10. All patients presented at least one poor prognosis determinant, including age >60 (27), previous AML relapse after autologous BMT (1), therapy-related disease (5), AML secondary to MDS (7), resistance to 1st induction therapy (4), hyperleukocytosis (8), RAEB-2 (8), abnormal karyotype (10). Twenty six had received 1 - 4 courses of consolidation treatment, including autologous stem cell transplantation in 2 MDS patients, before starting the maintenance program. Three patients underwent a very early relapse before maintenance start and 1 patient refused to prosecute the therapy after the first 2 months. The other 32 patients received the treatment as outpatients, with good tolerance and no major toxicity, until relapse, death or 4 years of continuous CR. After a median follow up for alive patients of 23 months (6–76), median disease-free (dfs) and overall survival, based on "intention to treat analysis" are 22 (1–74+) and 23 (5–76+) months, respectively, with a 28% 4 year actuarial survival. Inclusion of ARA-C in the maintenance treatment did not significantly prolong CR duration. The 17 patients with a normal karyotype enjoyed better median dfs (43 months) and overall survival (50,5 months) compared to the 10 patients with abnormal cytogenetics (12,5 and 15,5 months respectively); however, the differences are not significant, probably due to sample exiguity.In conclusion, our patients evidenced quite longer dfs and overall survival than expected from literature data on AML/MDS patients with similar features. However some late relapses (after 3–4 years) occurred. Therefore, our maintenance program seems worthy to be evaluated on larger casistics in randomised trials.