Efficacy and safety of pixantrone for the treatment of multiply relapsed or refractory aggressive non‐Hodgkin B‐cell lymphomas

Abstract

Eur J Haematol. 2020;104:499-508. | 499 wileyonlinelibrary.com/journal/ejh 1 | INTRODUC TI ON Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL); between 30% and 58% of patients with NHL have DLBCL, which has a crude incidence in Europe of 3.81 cases per 100 000. 1,2 The incidence of both NHL and DLBCL varies considerably between European countries, with Italy and Spain having an incidence of NHL higher than the European average. 1-3 First-line therapy for intermediate-or high-risk B-cell NHL is an anthracycline-based regimen in combination with rituximab, such asAbstract Background and objective: Few treatment options exist for patients with relapsed/ refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who fail first-and second-line therapies. Pixantrone is a novel aza-anthracenedione agent with reduced potential for cardiotoxicity but maintained anti-tumour activity relative to anthracyclines. The current retrospective, observational, real-life study was undertaken in 79 patients who received pixantrone monotherapy for multiply R/R aggressive B-cell NHL in Spain and Italy.Results: Before pixantrone, patients had received a median of 3 prior therapies and 84.6% of them were refractory to the last regimen. Median progression-free survival (mPFS) was 2.8 months (95% confidence interval [CI] 2.1-3.6) and median overall survival (mOS) was 4.0 months (95%CI 5.6-7.9), with an objective response rate (ORR) of 29% (complete remission [CR]: 13.2%, partial remission [PR]: 15.2%). Patients receiving ≥2 cycles of pixantrone showed mPFS and mOS of 3.1 and 6.0 months, respectively, and an ORR of 36.8% (CR: 17.5%, PR: 19.3%). Overall, 63.3% of patients reported ≥1 adverse event (AE), most commonly haematological AEs. One patient developed grade 2 sinus tachycardia. Conclusion:Pixantrone was effective and well tolerated in a real-world population of multiply R/R patients with aggressive B-cell NHL, many of whom had very poor prognostic factors. K E Y W O R D Saggressive B-cell lymphoma, pixantrone, relapse, survival

Current Opinion on Pixantrone in the Treatment of Non-Hodgkin B-Cell Lymphoma

“…10,11 However, the phase III study PIX306, comparing the efficacy and safety of pixantrone with rituximab (PIX-R) versus gemcitabine with rituximab (GEM-R) in patients with relapsed (not refractory) aggressive B-cell NHL, deemed ineligible for ASCT (NTC01321541), failed to demonstrate any improvement in outcomes with pixantrone and rituximab as opposed to gemcitabine with rituximab. [12][13][14] In line with this were also findings of some real-world studies [15][16][17] which have shown overall disappointing outcomes of treatment with pixantrone and have therefore questioned the actual role of pixantrone in the current treatment of R/R aggressive lymphomas.…”

“…41,42 Following the pivotal PIX301 study, there were two real-life studies on pixantrone in monotherapy; one UKwide retrospective study of R/R DLBCL patients 15 and the other -the PIXA study conducted in Spain and Italy including the same patient population, that is, patients with aggressive relapsed or refractory B-cell NHL who had progressed after two or more prior therapies. 16 Patients from the Eyre and coworkers' study had poorer prognostic features than those from the PIX301 trial; 85% had refractory disease and 72% had an international prognostic index (IPI) value of 3 to 5 at commencement of pixantrone. The median PFS was 2.0 months and the median OS 3.4 months.…”

“…Even though the outcomes were numerically quite comparable to the outcomes of Eyre et al, Sancho et al concluded that pixantrone was effective in a realworld population of multiply R/R patients with aggressive B-cell NHL, many of whom had very poor prognostic factors. 16 This raises the question of definition, when can a certain drug be considered effective, as a median PFS of 2.8 months and a median OS of 4.0 months can hardly be considered as substantial evidence of effectiveness.…”

“…[46][47][48][49][52][53][54] Certain studies, 15,17,48 however, have stated its lesser activity in refractory patients compared to relapsed ones and most of real-world analyses have shown inferior results compared to trial results, ostensibly at least partly on account of inclusion of patients with poor risk characteristics. [15][16][17] Nevertheless, a good number of studies evaluated only clinical features of patients, with very few studies addressing the relation of histological characteristics of lymphomas to clinical outcome. 17 In the study of Novakovic et al, it was observed that all patient samples were BCL-2 positive, predicting a higher probability of resistance to systemic treatment and a lesser OS.…”

“…For none of the patient subgroups was the PIX-R arm statistically more beneficial in terms of survival. 14 These findings, together with the data from certain realworld studies, [15][16][17] raised a serious concern about the actual role of pixantrone in the R/R DLBCL setting, where it has been primarily approved. Regarding the emerging new treatment options mentioned above, 20,24,25,62,63 as well as some others cited it the BJH commentary by Eyre, 64 it is very likely that pixantrone will no longer be a part of the solution to the unmet need of patients with refractory (and relapsed) DLBCL.…”