Abstract
Probably through inhibition of histone deacetylases, VPA ± ATRA has been associated with clinical responses in patients with myelodysplastic syndrome (MDS) or AML (Kuendgen, Blood 2004; Raffoux, Haematologica 2005). Interestingly, VPA/ATRA-induced differentiation of AML cells has been documented in vivo (Nervi, ASH 2004 #1805). On the other hand, the combination of VPA with a demethylating agent synergistically enhances its antileukemia activity in vitro (Yang, Leukemia Res 2005). In a pilot phase, we treated 5 high-risk AML patients with a sequential combination of 5-azacytidine, VPA, and ATRA. Each treatment cycle comprised 75 mg/m2/d 5-azacytidine SC from day 1 to 7, 20 mg/kg/d VPA (then adapted on serum concentration) from day 1 to 28, and 45 mg/m2/d ATRA from day 8 to 28. Six cycles were planned, each starting at day 29 of the previous one whatever the hematological status. High-risk AML (AML-M3 excluded) was defined as:
previously untreated de novo or post-MDS AML in patients aged 65+ unfit for intensive chemotherapy; or
post-MDS AML in first relapse or AML in second or subsequent relapse.
Eligibility criteria also comprised WBC<30 G/L, PS<2, no severe infection, liver enzyme levels ≤ 2xULN, and serum creatinine ≤ 1.5xULN. Main patient characteristics and response are indicated in the Table below:
| Patient . | Age . | AML . | Prior Tx . | BM blasts . | Cycles . | Response . | Time to response . |
|---|---|---|---|---|---|---|---|
| #1 | 71y | post-MDS | 4 | 41% | 6 | CRp | 4 cycles |
| #2 | 73y | post-MDS | 0 | 28% | 6 | CR | 4 cycles |
| #3 | 76y | de novo | 2 | 62% | 2 | Progression | – |
| #4 | 68y | post-MDS | 0 | 26% | 2 | Stable | – |
| #5 | 55y | de novo | 2 | 20% | 4+ | AML-free | 3 cycles |
| Patient . | Age . | AML . | Prior Tx . | BM blasts . | Cycles . | Response . | Time to response . |
|---|---|---|---|---|---|---|---|
| #1 | 71y | post-MDS | 4 | 41% | 6 | CRp | 4 cycles |
| #2 | 73y | post-MDS | 0 | 28% | 6 | CR | 4 cycles |
| #3 | 76y | de novo | 2 | 62% | 2 | Progression | – |
| #4 | 68y | post-MDS | 0 | 26% | 2 | Stable | – |
| #5 | 55y | de novo | 2 | 20% | 4+ | AML-free | 3 cycles |
Patient #3 progressed after the 2nd cycle. Treatment was also discontinued after the 2nd cycle in patient #4, because of ovarian carcinoma diagnosis. Response was observed after at least 3 cycles in the 3 remaining patients (1 CR, 1 CRp, 1 AML-free state with platelet count normalization), all treated as out-patients. Safety profile was excellent (no significant treatment-induced cytopenia). Main side effects were pain at 5-azacytidine injection sites and constipation. This treatment approach appearing promising in terms of efficacy versus toxicity, a formal multicenter Phase 2 study has been initiated.
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