| Abstract: |
BACKGROUND: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. Copyright © 2015 Massachusetts Medical Society. |
| Keywords: |
adult; controlled study; treatment response; aged; aged, 80 and over; disease-free survival; middle aged; major clinical study; fludarabine; clinical trial; constipation; fatigue; neutropenia; area under the curve; diarrhea; dose response; drug efficacy; drug safety; unspecified side effect; antineoplastic agents; drug targeting; disease free survival; flow cytometry; antineoplastic agent; protein bcl 2; progression free survival; controlled clinical trial; anemia; nausea; thrombocytopenia; vomiting; cohort analysis; recurrence; dose-response relationship, drug; drug selectivity; cancer resistance; arthralgia; coughing; drug dose escalation; febrile neutropenia; fever; hyperglycemia; pneumonia; prostate cancer; tumor lysis syndrome; acute kidney failure; drug fatality; survival time; nonhodgkin lymphoma; immunoglobulin heavy chain; minimal residual disease; sulfonamide; multicenter study; sulfonamides; peripheral edema; remission; remission induction; single drug dose; recurrent disease; open study; idiopathic thrombocytopenic purpura; headache; maximum tolerated dose; phase 1 clinical trial; drug half life; leukemia relapse; chromosome deletion; chronic lymphatic leukemia; fused heterocyclic rings; bicyclo compounds, heterocyclic; proto-oncogene proteins c-bcl-2; leukemia, lymphocytic, chronic, b-cell; lymphocytoma; upper respiratory tract infection; leukemia remission; chromosome 17p; cancer prognosis; small lymphocytic lymphoma; hypervolemia; very elderly; humans; human; male; female; priority journal; article; antagonists and inhibitors; venetoclax; 4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-n-((3-nitro-4-((tetrahydro-2h-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1h-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide; bcl2 protein, human
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