Bortezomib+Chemotherapy Based Salvage Combinations in Refractory AML, Preliminary Results

Bortezomib (Velcade) proved to be the standard element of refractory myeloma 2^nd and 3^rd line treatment, while many studies are suggesting excellent results in 1^st line. Proteasome inhibition, the block of angiogenesis, modification of the NF-kappa-B system seems to be a challenging target in other malignant diseases, including refractory acute myeloid leukemia (AML), as well. In vitro data clearly support, that bortezomib exerts antiproliferative and pro-apoptotic effects in different AML cell-lines, along with human AML cell cultures, and moreover bortezomib was able to restore, or at least improve anthracyclin and possibly ARA-C sensitivity in different cell-lines (including AML). More recently, a Phase I trial showed bortezomib monotherapy efficient (only in few percents) in childhood refractory acute leukemia. Some case reports were shown at ASH 2007. We have tried bortezomib containing first or second line combinations in 27 (14 female, 13 male, mean age 57.6 years) patients with refractory or poor risk AML, in a small retrospective survey. The combinations were as follows: HAM or Flag-Ida, combined with bortezomib 1,3 mg pro sqm, day O and seven). The following groups were considered as refractory or poor risk AML:

De novo AML, 2^nd line: No response/remission to first line standard treatment (“3+7”), n=2 (Velcade- Flag-Ida treatment)

De novo AML 1^st line: bilineal or biphenotypic (flow-cytometry) n=2 (Velcade-Flag- Ida treatment)

De novo AML with complex (numerical or more than 3 abnormalities) karyotype or normal karyotype with flt-3 TKD mutation, n=9, 1^st line (Velcade-Flag-Ida n=6, Velcade- HAM protocol, n=3)

Secondary AML or AML with evidence of previous more than 6 mo duration high grade MDS, n=14, 1^st line: (Velcade-Flag-Ida n=9, Velcade-HAM n=5)

RESULTS: Complete remission (CR) 12/27, partial remission (PR) 9/27, no remission 5/27, progression during treatment: 1/27.Best responses were seen in de novo cases. CR had been achieved in all patients of group 1 (two standard risk patients not responding to 3+7 protocol), and group 2 (biphenotypic, bilineal). The CR rate was quite appreciable in group 3, i.e. 6/9 (complex karyotype or normal karyotype with FLt-3 mutation – the response rate was excellent with flt-3 mutated cases). In group 4. (MDS, secondary AML) the results were less impressive. There were no major differences according to protocol (Flag-Ida or HAM)

Allogeneous stem cell transplantation could have been performed in 1^st CR in two patients (one from group 1. and another from group 2.). One of them died due to relapse, the other one is in CR since then.

The combinations seem to be relatively safe. Induction related death rate was low (1 elderly patient acute thrombocytopenic bleeding with refractory MDS-AML). 5 other patients had severe neutropenic sepsis (2 with fatal outcome). Pulmonary syndrome, which may follow Velcade+ARA-C had not been documented. Other adverse events did not differ from the pattern observed with standard induction therapies.