Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Abstract

PURPOSE Patients with transplantation-ineligible relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) fare poorly, with limited treatment options. The antibody-drug conjugate polatuzumab vedotin targets CD79b, a B-cell receptor component. METHODS Safety and efficacy of polatuzumab vedotin with bendamustine and obinutuzumab (pola-BG) was evaluated in a single-arm cohort. Polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) was compared with bendamustine and rituximab (BR) in a randomly assigned cohort of patients with transplantation-ineligible R/R DLBCL (primary end point: independent review committee [IRC] assessed complete response [CR] rate at the end of treatment). Duration of response, progression-free survival (PFS), and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression methods. RESULTS Pola-BG and pola-BR had a tolerable safety profile. The phase Ib/II pola-BG cohort (n = 27) had a CR rate of 29.6% and a median OS of 10.8 months (median follow-up, 27.0 months). In the randomly assigned cohort (n = 80; 40 per arm), pola-BR patients had a significantly higher IRC-assessed CR rate (40.0% v 17.5%; P = .026) and longer IRC-assessed PFS (median, 9.5 v 3.7 months; hazard ratio [HR], 0.36, 95% CI, 0.21 to 0.63; P < .001) and OS (median, 12.4 v 4.7 months; HR, 0.42; 95% CI, 0.24 to 0.75; P = .002; median follow-up, 22.3 months). Pola-BR patients had higher rates of grade 3-4 neutropenia (46.2% v 33.3%), anemia (28.2% v 17.9%), and thrombocytopenia (41% v 23.1%), but similar grade 3-4 infections (23.1% v 20.5%), versus the BR group. Peripheral neuropathy associated with polatuzumab vedotin (43.6% of patients) was grade 1-2 and resolved in most patients. CONCLUSION Polatuzumab vedotin combined with BR resulted in a significantly higher CR rate and reduced the risk of death by 58% compared with BR in patients with transplantation-ineligible R/R DLBCL.

Antibody–Drug Conjugates for Cancer Therapy

“…Monomethyl auristatin E (MMAE) is used as a warhead in approved ADCs brentuximab vedotin, polatuzumab vedotin and enfortumab vedotin while monomethyl auristatin F (MMAF) was used in depatuxizumab mafodotin. Further development of depatuxizumab mafodotin has been ceased owing to disappointing results in a phase III trial [ 47 , 48 , 49 , 50 ]. Maytansinoids are derived from the naturally occurring maytansine, which was originally isolated from the bark of the shrub Maytenus ovatus [ 51 ].…”

“…In a multicenter phase Ib/II clinical trial among patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL), addition of polatuzumab vedotin to anti-CD 20 antibody rituximab and chemotherapy bendamustine showed improved mPFS (9.5 vs. 3.7 months, HR 0.36, 95% CI 0.21–0.63; p < 0.001) and mOS (12.4 vs. 4.7 months, HR 0.42, 95% CI 0.24–0.75; p = 0.002) [ 48 ]. Polatuzumab vedotin received accelerated approval from the FDA in 2019 for treatment of relapsed or refractory DLBCL.…”

“…The most common side effects noted with polatuzumab vedotin are myelosuppression, peripheral neuropathy. Polatuzumab vedotin has also been associated with progressive multifocal leukoencephalopathy (PML) [ 48 ].…”

Drug Resistance in Non-Hodgkin Lymphomas

“…In 2017, brentuximab-vedotin was approved also for patients with cutaneous T-cell lymphomas [24]. Polatuzumab-vedotin, anti-CD79B antibody with MMAE, was approved in 2019 for the therapy of R/R DLBCL [25]. In addition, anti-CD22 ADCs inotuzumab-ozogamicin and moxetumomab-pasudotox were granted approval for patients with R/R B-cell acute lymphoblastic leukemia (2017), and R/R hairy cell leukemia (2018), respectively [26,27].…”

Neue Therapien für Patienten mit Non-Hodgkin-Lymphomen

“…Kürzlich wurde Polatuzumab Vedotin (▶ Abb. 1, ⑩), ein CD79b-ADC zur Therapie des r/r-DLBCL in Kombination mit Rituximab und Bendamustin zugelassen[28].…”