Ara-C is one of the most effective compounds in the treatment of AML. Strategies to increase therapeutic efficacy and overcome ara-C resistance have focused primarily on the enhancement of cellular accumulation and retention of ara-CTP, active metabolite of the drug. FAMP has been demonstrated one of the most effective modulators of ara-C cytotoxicity. Observation that a minimum dose of 15mg/sqm of FAMP produces cellular F-ara-ATP levels that maximise ara-CTP accumulation in AML blasts permits the intensification of FAMP+ara-C regimen giving FAMP twice daily with an intermediate dose of ara-C. Furthermore, all-trans retinoic acid (ATRA) was shown to reduce the expression of the antiapoptotic protoncogen bcl-2 and to increase ara-C cytotoxicity by a mechanism other than those with increase ara-CTP levels. We wished to test combination of ATRA and an intermittent schedule of ara-C preceded every 12 hours from FAMP administration in the poor setting of relapsed or resistant AML pts. Thirty three patients, 18 males, 15 females, with a median age of 44.3 years (range 16-60) have been enrolled into the study since march 1998 to date. Fifteen pts presented in first relapse, 2 in second relapse while 16 pts showed a resistance to the induction treatment (standard ICE schedule in 9 cases; idarubicin 12 mg/sqm x 3d+ ara-C 100 mg/sqm x 7 d, in 7 cases). At the time of treatment prognosis according to cytogenetic was: favourable in 6 pts, intermediate in 21 and unfavourable in 6 pts. Distribution according to FAB was: M0=1; M1=12; M2=10; M4=8; M5b=1; M6=1. Salvage therapy consisted of: FAMP 15 mg/sqm/12h x 5 d ara-C 1g/sqm/12h x 5 d; idarubicin 12mg/sqm x 3 d, ATRA 45 mg/sqm from day 1 to 10; G-CSF 300 mg from day 0-5 and from day 12 to PMN recovery, patients in PR after the first course received a second identical course. Two pts are not assessable for evaluation as still on treatment. Median time to PMN>500/ml was 17 d (range 10-31) and to PLT>20000/ml 18 d (range 9-60). Major toxicity consisted of infections: 11 sepsis, 2 sustained by GRAM- and 9 by GRAM+, were observed; eleven pts showed a pneumonia, microbiologically documented in 6 cases; four pts presented deep fungal infections (3 aspergillosis, 1 mucormicosis). As regards extra-hematological toxicity 2 according to WHO: 2 pts presented with jaundice grade 2 and 6 pts showed a grade 2 mucositis. The CR rate was of 58%, 18 of the 31 evaluable pts (12/16 resistant),in 3 cases obtained after the second course. Ten pts showed a resistant disease, 3 deaths (9%) due to infection during aplastic phase were observed. Both pts with extramedullary disease achieve a CR. According to cytogenetic CR was observed in 5/6 of the favorable prognostic group, 12/19 of the intermediate, 1/6 in the unfavorable group. Six pts relapsed after a median time of 7 months (3-24). Twelve pts (39%) are in continuos CR after a median time of 9.5 monhs (range 3-40) having received as post remission therapy chemotherapy alone (6 pts), autologous BMT (3 pts), allogeneic BMT (3 pts). These early data suggest that this combination is feasible with acceptable toxicity, the high response rate observed in primary resistant AML pts (75% ) warrant further studies in larger series.
Full conference title:
43rd American Society of Hematology (ASH) Annual Meeting
- ASH 43rd (2001)