Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

Casasnovas, Olivier; Follows, George; Zijlstra, Josée M.; Vermaat, Joost S.P.; Kalakonda, Nagesh; Choquet, Sylvain; Neste, Éric Van Den; Hill, Brian T.; Thiéblemont, Catherine; Cavallo, Federica; Cruz, Fátima De la; Kuruvilla, John; Hamad, Nada; Jaeger, Ulrich; Caimi, Paolo; Gurion, Ronit; Warzocha, Krzysztof; Bakhshi, Sameer; Sancho, Juan‐Manuel; Schuster, Michael W.; Egyed, Miklós; Offner, Fritz; Vassilakopoulos, Theodoros P.; Samal, Priyanka; Ku, Matthew; Ma, Xiwen; Chamoun, Kamal; Shah, Jatin J.; Canales, Miguel; Maerevoet, Marie; Shacham, Sharon; Kauffman, Michael; Goy, André

doi:10.1016/j.clml.2021.07.017

Cited by 7 publications

(6 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Patients who were previously treated for DLBCL had strong and durable responses when treated with single-agent selinexor, regardless of GCB or non-GCB subtype [25].…”

Section: Discussionmentioning

confidence: 96%

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study

Zijlstra

Follows

Casasnovas

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

Selinexor, an oral selective inhibitor of nuclear export, was evaluated in the Phase 2b SADAL study in patients with diffuse large B-cell lymphoma (DLBCL) who previously received two to five prior systemic regimens. In post hoc analyses, we analyzed several categories of patient characteristics (age, renal function, DLBCL subtype, absolute lymphocyte count, transplant status, number of prior lines of therapy, refractory status, Ann Arbor disease stage, and lactate dehydrogenase) at baseline, i.e., during screening procedures, to determine their potential contributions to the efficacy (overall response rate [ORR], duration of response [DOR], overall survival [OS]) and tolerability of selinexor. Across most categories of characteristics, no significant difference was observed in ORR or DOR. OS was significantly longer for patients < 65 vs. ≥65 years, and for those with lymphocyte counts ≥ 1000/µL vs. <1000/µL or lactate dehydrogenase ≤ ULN vs. >ULN. The most common adverse events (AEs) across the characteristics were thrombocytopenia and nausea, and similar rates of grade 3 AEs and serious AEs were observed. With its oral administration, novel mechanism of action, and consistency in responses in heavily pretreated patients, selinexor may help to address an important unmet clinical need in the treatment of DLBCL.

show abstract

“…Patients who were previously treated for DLBCL had strong and durable responses when treated with single-agent selinexor, regardless of GCB or non-GCB subtype [25].…”

Section: Discussionmentioning

confidence: 96%

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study

Zijlstra

Follows

Casasnovas

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…In another study, the ORR was estimated at 28%, the median PFS at 3.6 months, and the median OS at 9.1 months [53,54]. Notably, similar ORRs were achieved regardless of DLBCL subtype (germinal center B cell-like, non-germinal center B cell-like), but ORRs were lower for double-hit and triple-hit subtypes [55,56]. Patients with other non-Hodgkin lymphoma (NHL) types (follicular lymphoma, mantle cell lymphoma, and Richter transformation) also achieved an ORR of approximately 30% [50,55].…”

Section: Selinexor In R/r Dlbcl Nosmentioning

confidence: 93%

“…XPO1 overexpression was confirmed to worsen the prognosis of DLBCL patients with unfavorable cytogenetics (BCL-2 overexpression, double-hit, triple-hit) [56]. Moreover, targeting XPO1 with selinexor is only effective in the absence of the TP53 mutation.…”

Section: Selinexor In R/r Dlbcl Nosmentioning

confidence: 98%

Selinexor and Other Selective Inhibitors of Nuclear Export (SINEs)—A Novel Approach to Target Hematologic Malignancies and Solid Tumors

Karaszewski,

Jędrzejczak

2023

DDC

View full text Add to dashboard Cite

Exportin 1 (XPO1) is a crucial molecule of nucleocytoplasmic transport. Among others, it exports molecules important for oncogenesis from the nucleus to the cytoplasm. The expression of XPO1 is increased in numerous malignancies, which contributes to the abnormal localization of tumor suppressor proteins in the cytoplasm and subsequent cell cycle dysregulation. Selective inhibitors of nuclear export (SINEs) are novel anticancer agents that target XPO1, arrest tumor suppressor proteins in the nucleus, and induce apoptosis in cancer cells. Selinexor, a first-in-class SINE, has already been approved for the treatment of relapsed/refractory multiple myeloma and relapsed/refractory diffuse large B cell lymphoma not otherwise specified. It has also been proven effective in relapsed/refractory and previously untreated acute myeloid leukemia patients. In addition, numerous studies have yielded promising results in other malignancies of the hematopoietic system and solid tumors. However, future clinical use of selinexor and other SINEs may be hampered by their significant toxicity.

show abstract

“…However, the study was designed to only include patients with slowly progressing, hence, "better-risk" relapse disease, which should be taken into consideration when interpreting these results. The preclinically reported efficacy of MYC + XPO-1 expressing DLBCL [102] could not be confirmed in a post hoc analysis of the SADAL trial, and the outcome was independent of the COO [104]. DLBCL patients with MYC and BCL2 overexpression had a shorter OS (median of 5.1 vs. 13.7 months) and a lower ORR (14.8% vs. 46.2%) compared to normal expression levels [104].…”

Section: Extension Of R-chop-like Soc By Other Small Molecules-new Ho...mentioning

confidence: 93%

“…The preclinically reported efficacy of MYC + XPO-1 expressing DLBCL [102] could not be confirmed in a post hoc analysis of the SADAL trial, and the outcome was independent of the COO [104]. DLBCL patients with MYC and BCL2 overexpression had a shorter OS (median of 5.1 vs. 13.7 months) and a lower ORR (14.8% vs. 46.2%) compared to normal expression levels [104].…”

Section: Extension Of R-chop-like Soc By Other Small Molecules-new Ho...mentioning

confidence: 93%

DLBCL 1L—What to Expect beyond R-CHOP?

Stegemann

Denker

Schmitt

2022

Cancers

View full text Add to dashboard Cite

The R-CHOP immunochemotherapy protocol has been the first-line (1L) standard of care (SOC) for diffuse large B-cell lymphoma (DLBCL) patients for decades and is curative in approximately two-thirds of patients. Numerous randomized phase III trials, most of them in an “R-CHOP ± X” design, failed to further improve outcomes. This was mainly due to increased toxicity, the large proportion of patients not in need of more than R-CHOP, and the extensive molecular heterogeneity of the disease, raising the bar for “one-size-fits-all” concepts. Recently, an R-CHP regimen extended by the anti-CD79b antibody–drug conjugate (ADC) Polatuzumab Vedotin proved superior to R-CHOP in terms of progression-free survival (PFS) in the POLARIX phase III trial. Moreover, a number of targeted agents, especially the Bruton’s tyrosine kinase (BTK) inhibitor Ibrutinib, seem to have activity in certain patient subsets in 1L and are currently being tested in front-line regimens. Chimeric antigen receptor (CAR) T-cells, achieving remarkable results in ≥3L scenarios, are being exploited in earlier lines of therapy, while T-cell-engaging bispecific antibodies emerge as conceptual competitors of CAR T-cells. Hence, we present here the findings and lessons learnt from phase III 1L trials and piloting phase II studies in relapsed/refractory (R/R) and 1L settings, and survey chemotherapy-free regimens with respect to their efficacy and future potential in 1L. Novel agents and their mode of action will be discussed in light of the molecular landscape of DLBCL and personalized 1L perspectives for the challenging patient population not cured by the SOC.

show abstract

Comparison of the Effectiveness and Safety of the Oral Selective Inhibitor of Nuclear Export, Selinexor, in Diffuse Large B Cell Lymphoma Subtypes

Cited by 7 publications

References 40 publications

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study

The Association between Patient Characteristics and the Efficacy and Safety of Selinexor in Diffuse Large B-Cell Lymphoma in the SADAL Study

Selinexor and Other Selective Inhibitors of Nuclear Export (SINEs)—A Novel Approach to Target Hematologic Malignancies and Solid Tumors

DLBCL 1L—What to Expect beyond R-CHOP?

Contact Info

Product

Resources

About