Combination Therapy with Vorinostat and Bortezomib in Patients with High Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes

Patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) refractory to or progressive on standard therapies present a challenging population of patients to treat and warrant novel therapy. Investigational combination therapy with vorinostat and bortezomib may synergistically target additive aberrant cellular processes and may modulate NK cell mediated killing.

Patients with refractory/relapsed AML (non-M3) and high risk MDS progressive on hypomethylating agents or lenalidomide were eligible. Karnofsky Performance Status (KPS) of > 60, creatinine < 2, ALT/AST < 3X ULN, and bilirubin < 2, ejection fraction > 40%, absence of central nervous system disease, and < grade 2 peripheral neuropathy were required for enrollment. Cycles consisted of vorinostat 400 mg/day Day 1–14 and bortezomib 1.3 mg/m2 IV Days 1,4,8, and 11 of a 21 day cycle. Pre therapy bone marrow biopsy and transfusion requirements were documented. Disease response was planned after 3 cycles. Clinical responses were defined as complete morphologic remission (CR), partial remission (PR), hematologic improvement (HI), stable disease (SD), or progressive disease (PD) as defined by IWG criteria. (Cheson et al 2003 and 2006) Completion of 1 full cycle was required for analysis of clinical response. All patients were included in toxicity assessment. Patients achieving a CR, PR, or HI after 3 cycles of therapy could proceed with an additional 3 cycles of therapy in the absence of dose limiting toxicity.

Twelve patients (AML=9, MDS-3), median age of 66 (range 48–88), median KPS of 80, and predominantly male (n=7) have been treated. AML patients were primary induction failures (n=1), an untreated elderly unfit for standard induction (n=1), relapsed/refractory (n=3), and with progressive disease after response to azacitidine (n=1). Cytogenetics were complex (n=4), 7q- (n=1), normal with FLT3+ (n=1) or miscellaneous abnormalities (n=3). Median blast burden at the time of therapy was 66%. All MDS patients had progressive disease after prior hypomethylating agents and were RAEB-2 with complex cytogenetics (n=2). Comorbidites for the entire group included vascular disease (predominantly cardiac n=4), COPD (n=1), prior GI bleed (n=1), prior fungal infection (n=1)

A total of 9 patients were evaluable for clinical response. The remaining three patients failed to complete the first full round of chemotherapy due to transition to hospice (n=2) and unrelated fall/hip fracture (n=1). Five patients completed all 3 cycles with the majority requiring dose reduction, 2 patients completed therapy through cycle 2, and 2 patients completed cycle 1 before disease progression.

The overall clinical response (CR, PR, HI, and SD) was 56% (n=1 morphologic CR, n=4 SD). The remaining 4 patients had PD. All of responding patients had AML, and none of the patients requiring initial hydroxyurea control of WBC responded to therapy.

Toxicity was common with fatigue, anorexia, dehydration, nausea, and neuropathy the most common side effects. Severe adverse effects included fevers, pulmonary infection, QT prolongation that lead to syncope, and infection with or without neutropenia. Two deaths occurred during or soon after completion of therapy. One patient with extensive prior cardiac disease status post numerous cardiac stents died after cardiac arrest when admitted for neutropenic fever. Another patient hospitalized for high fevers related to possible pulmonary fungal infection was found unresponsive and died. While these events were felt to have causes unrelated to drug therapy, they were classified as toxicity that was possibly treatment related. The overall toxicity rate was 50%.

The combination of vorinostat and bortezomib produced disease stability in a subset of patients and a complete morphologic remission in one suggesting clinical activity in myeloid diseases. Toxicity limited additional cycles of therapy in some responding patients and protocol therapy dose adjustments have been made to address this issue so that extended therapy is feasible. While toxicity was frequent, the majority of therapy was tolerated in the outpatient setting. The combination of vorinostat and bortezomib may be a clinically promising therapy with the potential for disease stabilization if toxicity issues can be improved by our current plan for tailoring dose based on patient tolerance.

No relevant conflicts of interest to declare.