The hypomethylating agent decitabine has significant activity in AML. We previously demonstrated a novel epigenetic mechanism of action for the proteasome inhibitor bortezomib in AML cells (Liu, Blood 2008). Bortezomib induced hypomethylation of leukemic cells in vitro and in vivo via disruption of the Sp1/NF-kB transcriptional activation complex on the DNA methyltransferase 1 (DNMT1) gene promoter, which resulted in down-regulation of DNMT1 mRNA and protein levels, DNA hypomethylation, and re-expression of otherwise hypermethylated target genes. Based on this, we designed a phase 1 dose escalation trial of decitabine in combination with bortezomib.
Adults with high risk AML who had preserved organ function and ECOG ≤2 were eligible. High risk AML included relapsed/refractory AML or age>60 years with previously untreated disease (if ineligible for or refused standard induction therapy). Patients received decitabine at 20mg/m2 IV daily for days (d) 1–10 of 28 d cycles with dose modification in subsequent cycles based on response and myelosuppression. Bortezomib (given immediately after decitabine) was gradually dose escalated in standard 3+3 fashion from 0.7mg/m2 on d 5 and 8 to the target dose of 1.3mg/m2 on d 5, 8, 12, and 15. Cycles were repeated every 28 d, regardless of count recovery. The plan was to administer 3 cycles if possible before discontinuation due to lack of response. For responding pts, therapy was continued indefinitely. Six additional pts were treated at the recommended phase 2 dose. Dose limiting toxicities (DLT) were assigned for cycle 1 of therapy. Given the high likelihood of infection in this population regardless of therapy, infection was not considered a DLT unless toxicity exceeded that expected with conventional therapy.
19 pts were enrolled with a median age of 69 years (range, 32–83). 12 pts were age>70. 10 pts were previously untreated. Median presenting WBC count was 3,900/uL (range, 1,300-69,200/uL); median bone marrow blast was 34%. Patients received a median of 2 cycles of therapy (range, 1–14 cycles). Two pts received combination therapy beyond 3 cycles of treatment; one received combination for 8 cycles, then decitabine alone for 6 additional cycles, and the other received combination for 4 cycles, then decitabine alone for 6 additional cycles. Dose escalation was halted once the target bortezomib dose was reached; the MTD was decitabine at 20mg/m2 d 1–10 plus bortezomib 1.3mg/m2 d 5, 8, 12, and 15. One DLT of death due to sepsis occurred in dose level 3. Febrile neutropenia and infectious complications were frequent. Death within 8 weeks occurred in 4 pts (21%). Neuropathy attributable to bortezomib, though not meeting DLT criteria, was problematic with repetitive cycles of administration. Specifically, two pts had Grade 3 neuropathy requiring discontinuation of treatment. Responses occurred in 4/10 previously untreated pts: 3 had complete remission (CR) and one had CR with incomplete blood count recovery (CRi). One 84 year old pt with complex karyotype discontinued therapy after one cycle due to fatigue with persistent disease (non-responder). Notably, the pt subsequently had complete count recovery and lived for 14 months with no additional treatment, refusing further marrow evaluation of response. Response durations for the 3 CR were as follows: 12 months, 9 months, and the last patient died in CR after 10 months response duration due to unrelated and preexisting cardiac disease. The CRi lasted 3 months before relapse. Responses occurred in 2/9 relapsed/refractory pts. Both had CRi. Response duration for one patient was only 2 months. The other had allogeneic transplant in first remission 22 months ago before recently expiring in remission with transplant-related complications. In 3/6 responders with abnormal karyotype, two achieved cytogenetic CR.
The combination of decitabine and bortezomib was reasonably well tolerated and active in high risk AML. Neuropathy beyond cycle 1 limited prolonged exposure to both agents. Given recent data suggesting equivalent efficacy with weekly dosing of bortezomib in multidrug treatments for myeloma, modification of the bortezomib schedule may facilitate more prolonged exposure to the combination. A phase 2 study of this combination is being planned, with bortezomib modification as noted. Correlative studies are ongoing.
NCI U01 CA 76576, NIH/NCI K23CA120708.
Blum:Celgene: Research Funding. Off Label Use: decitabine and bortezomib in AML.
Asterisk with author names denotes non-ASH members.