Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

Abstract

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Choosing ibrutinib wisely

“…Median PFS was 4.6 months, and time to next treatment was 16 months. These results are consistent in terms of their duration of response and PFS when compared with those reported from other similar studies of novel agents such as idelalisib, 3 copanlisib, 4 umbralisib, 5 and venetoclax, 6 in patients with relapsed or refractory FL, which reflects the challenging clinical scenario.…”

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

“…30 In chronic lymphocytic leukemia, TP53 aberrations (mutations and deletions) have consistently been shown to confer poor prognosis and treatment resistance, and recently, the novel small molecule inhibitors, ibrutinib, venetoclax, and idelalisib, have been approved for first-line treatment in TP53-disrupted chronic lymphocytic leukemia, as they seem to partly overcome this deleterious effect. [31][32][33] Interestingly, ibrutinib and venetoclax have shown high response rates in relapsed MCLs, 34,35 and hence, it is tempting to speculate whether a similar approach could be applied in MCL. At this time, novel trials, including these targeted drugs, are appearing in both the frontline and relapse setting, and it will be interesting to investigate the responses in light of the TP53 status.…”

How I treat double-hit lymphoma

“…64 Bromodomains are conserved protein regions that recognize specific histone modifications. Bromodomain inhibition reduces tumor growth in lymphomas, in part through the disruption of myc-driven transcriptional networks.…”