Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax

被引:148
作者
Anderson, Mary Ann [1 ,3 ,4 ]
Tam, Constantine [3 ,4 ,5 ]
Lew, Thomas E. [2 ]
Juneja, Surender [4 ]
Juneja, Manu [1 ,2 ]
Westerman, David [4 ,5 ]
Wall, Meaghan [3 ,6 ,7 ]
Lade, Stephen [4 ,5 ]
Gorelik, Alexandra [8 ]
Huang, David C. S. [2 ,3 ]
Seymour, John F. [3 ,4 ,5 ]
Roberts, Andrew W. [1 ,2 ,4 ]
机构
[1] Royal Melbourne Hosp, Dept Clin Haematol & Bone Marrow Transplantat, Parkville, Vic, Australia
[2] Walter & Eliza Hall Inst Med Res, Div Canc & Haematol, 1G Royal Parade, Parkville, Vic 3052, Australia
[3] Univ Melbourne, Fac Med Dent & Hlth Sci, Parkville, Vic, Australia
[4] Victorian Comprehens Canc Ctr, Parkville, Vic, Australia
[5] Peter MacCallum Canc Ctr, Parkville, Vic, Australia
[6] St Vincents Hosp, Victorian Canc Cytogenet Serv, Fitzroy, Vic, Australia
[7] St Vincents Inst Med Res, Fitzroy, Vic, Australia
[8] Royal Melbourne Hosp, Melbourne Epicentre, Parkville, Vic, Australia
基金
英国医学研究理事会;
关键词
CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTITUMOR-ACTIVITY; IBRUTINIB; THERAPY; FLUDARABINE; NAVITOCLAX; APOPTOSIS; RITUXIMAB; TRIAL;
D O I
10.1182/blood-2017-01-763003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The BCL2 inhibitor venetoclax achieves responses in similar to 79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) (P = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (>= 400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P = .002 and 6.6 [1.5-29.8]; P = .005, respectively), whereas del(17p) and/or TP53 mutation were not (P = .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy.
引用
收藏
页码:3362 / 3370
页数:9
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