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E. Campo et al.
continued from the previous page
Study/treatment Sponsors
MURANO: a randomized, open-label, phase 3 trial evaluating venetoclax plus rituximab versus bendamustine plus rituximab in R/R CLL
NCT02005471
AbbVie Genentech, Inc.
Population
Adult patients with R/R CLL (n=389): Venetoclax plus rituximab (n=194) Median age (range): 64.5 (28–83) years ECOG score n (%)
0: 111 (57.2%) 1: 82 (42.3%) 2: 1 (0.5%)
Number of prior therapies n (%): 1: 111 (57.2%) 2: 57 (29.4%) 3: 22 (11.3%) >3: 4 (2.1%)
BR (n=195)
Median age (range): 66 (22–85) years ECOG score n (%)
0: 108 (55.7%) 1: 84 (43.3%) 2: 2 (1.0%)
Number of prior therapies n (%): 1: 117 (60.0%)
2: 43 (22.1%) 3: 34 (17.4%) >3: 1 (0.5%)
TP53 aberrations at baseline
del(17p) only Venetoclax plus rituximab: 24 (14%) BR 18 (11.4%)
TP53 mutation only Venetoclax plus rituximab: 19 (11.1%) BR 23 (14.6%)
del(17p) and
TP53 mutated Venetoclax plus rituximab: 22 (12.9%)
BR 22 (13.9%)
Overall response
in del(17p)/TP53 mutated population
Not reported
PFS in del(17p)/ TP53 mutated
population
del(17p)
Median PFS not reached with venetoclax plus rituximab at 2-year follow-up
Median PFS 15.4 months with BR
TP53 mutation
Median PFS not reached with venetoclax plus rituximab at 2-year follow-up
Median PFS 12.9 months with BR
OS in del(17p)/ TP53 mutated
population
Not reported
Safety Reference (experimental arm,
overall population)
Grade 3–4 AE in patients (120) receiving venetoclax plus rituximab: 82.0%
Grade 3–4 AE in patients receiving BR 70.2%
AE: adverse events; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BD: twice daily; BR: bendamustine plus rituximab; CLL: chronic lymphocytic leukemia; ECOG: Eastern Cooperative Oncology Group; HR: hazard ratio; IQR: interquartile range; OD: once daily; ORR: overall response rate; OS: overall survival; PD: progressive disease; PFS: progression-free survival; R/R: relapsed/refractory; SLL, small lymphocytic leukemia; TEAE: treatment emergent adverse events.
overall limited efficacy and a high risk of opportunistic infectious complications.16 Allogeneic hematopoietic stem cell transplantation is a potentially curative therapeutic option for patients with TP53 aberrations, but is only fea- sible for highly selected younger, physically fit patients and those who have obtained a good therapeutic response.13,15,17
Therapies with p53-independent mechanisms of action
Recent developments in the treatment options for patients with CLL harboring TP53 aberrations include small-molecule kinase inhibitors that target the BCR path- way (ibrutinib and idelalisib)18-22,26 and the anti-apoptotic protein BCL2 (venetoclax).24,91-93 Ibrutinib is an inhibitor of Bruton tyrosine kinase,94,95 whereas idelalisib is an inhibitor of the PI3K p110δ isoform,19,96 both of which are involved in mediating intracellular signaling from several receptors including the BCR. Venetoclax is a BH3-mimetic inhibitor of BCL2, an anti-apoptotic protein with constitu- tively elevated expression in CLL.92,97 An overview of the clinical evidence from phase 2/3 trials for these treatments in patients with CLL harboring TP53 aberrations is shown in Table 3. The studies were carried out in varying patient populations, but overall, these novel therapies produced responses and favorable survival times in a high propor- tion of patients harboring TP53 aberrations and represent a significant advance for this high-risk population com- pared to chemoimmunotherapy regimes.18-26 It is impor-
tant to note that such therapies achieved similar responses in patients with relapsed or refractory CLL, irrespective of risk factors that are associated with poorer responses to chemoimmunotherapy.92,98-100
Given the improvements seen with these therapies, accelerated approval programs have made the therapies available for CLL treatment in the clinic. Currently in Europe, ibrutinib is licensed as monotherapy for first-line treatment and for relapsed/refractory patients with CLL, or in combination with bendamustine plus rituximab in the relapsed/refractory setting.94 Idelalisib is indicated in combi- nation with an anti-CD20 monoclonal antibody (rituximab or ofatumumab) for relapsed/refractory CLL therapy, and as first-line therapy in patients with del(17p)/TP53 mutations not suitable for other therapies.96 Venetoclax is currently licensed in Europe for patients with relapsed/refractory CLL in whom both chemoimmunotherapy and a BCR inhibitor have failed, or for patients with del(17p) or a TP53 mutation who are not suitable for BCR inhibitors or in whom BCR inhibitor treatment has failed.97 Although limited data are available for all these agents in the treatment-naïve setting, the approvals as first-line therapy reflect the high level of unmet need for patients with TP53 aberrations. Moreover, the development of these novel therapies has produced a change in therapeutic goals. In particular, frail patients with progressive CLL can now be treated with the aim of effec- tively controlling the disease, whereas previously palliative care would have been the only option.19
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haematologica | 2018; 103(12)