Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study.
Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study.
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DOI：
10.1200/jco.20.00948
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发表时间：
2020-12-01
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影响因子：
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通讯作者：
Seymour JF
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作者：
Kater AP;Wu JQ;Kipps T;Eichhorst B;Hillmen P;D'Rozario J;Assouline S;Owen C;Robak T;de la Serna J;Jaeger U;Cartron G;Montillo M;Dubois J;Eldering E;Mellink C;Van Der Kevie-Kersemaekers AM;Kim SY;Chyla B;Punnoose E;Bolen CR;Assaf ZJ;Jiang Y;Wang J;Lefebure M;Boyer M;Humphrey K;Seymour JF
在先前的MURANO研究分析中，与苯达莫司汀+利妥昔单抗（BR）相比，固定持续时间的维奈托克+利妥昔单抗（VenR）在复发或难治性慢性淋巴细胞白血病（CLL）患者中改善了无进展生存期（PFS）。在4年的随访中，我们报告了长期结果、对后续治疗的反应以及分子和遗传特征的预测价值。CLL患者被随机分配至2年的维奈托克（前6个周期为VenR）或6个周期的BR。评估PFS、总生存期（OS）、外周血微小残留病（MRD）状态、基因组复杂性（GC）和基因突变。在389例患者中，194例分配至VenR，195例分配至BR。VenR组的4年PFS和OS率高于BR组，分别为57.3%和4.6%（风险比[HR]，0.19; 95% CI，0.14 - 0.25）以及85.3%和66.8%（HR，0.41; 95% CI，0.26 - 0.65）。与低MRD阳性（HR，0.50）和高MRD阳性（HR，0.15）相比，联合治疗结束（EOCT）时未检出MRD（uMRD）与上级PFS相关。VenR组中接受伊鲁替尼作为进展后首次治疗的患者（n = 12）报告的缓解率为100%（10/10例可评价患者）;随后接受基于维奈托克的方案治疗的患者（n = 14）报告的缓解率为55%（6/11例可评价患者）。对于VenR，GC患者治疗结束（EOT）时的uMRD率低于无GC患者（P = 0.042）; GC越高，PFS越短。EOCT时BIRC 3和BRAF突变以及EOT时TP 53、NOTCH 1、XPO 1和BRAF突变的MRD阳性率较高。在达到uMRD的患者中，固定持续时间VenR的疗效获益持续，尤其持久。在VenR后使用伊曲替尼的挽救治疗获得了高应答率。基因突变和GC影响MRD率和PFS。
In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (P = .042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with BIRC3 and BRAF mutations at EOCT and with TP53, NOTCH1, XPO1, and BRAF mutations at EOT. Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.