Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial

Jerkeman, Mats; Eskelund, Christian Winther; Hutchings, Martin; Räty, Riikka; Wader, Karin Fahl; Laurell, Anna; Toldbod, Helle; Pedersen, Lone Bredo; Niemann, Carsten Utoft; Dahl, Christina; Kuitunen, Hanne; Geisler, Christian H.; Grønbæk, Kirsten; Kolstad, Arne

doi:10.1016/s2352-3026(18)30018-8

Cited by 116 publications

(86 citation statements)

References 23 publications

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“…Patients with high Ki‐67% (>50%) and blastoid cytomorphology had inferior outcomes compared to patients with low Ki‐67% and non‐blastoid cytomorphology. The combination of IR with lenalidomide was also reported from a European phase II multicenter trial with 50 previously treated MCL patients, which demonstrated an ORR of 76% with 56% CR after a median follow up of 17.8 months. In that trial, 38% of patients had grade 3‐4 neutropenia.…”

Section: Advances In the Treatment Of MCLmentioning

confidence: 66%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX‐11 expression. Cyclin‐D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki‐67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long‐term follow‐up on chemo‐immunotherapy studies has demonstrated durable remissions in some patients; however, long‐term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy‐free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine‐microenvironmental milieu, incorporation of positron emission tomography‐computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next‐generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

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Section: Advances In the Treatment Of MCLmentioning

confidence: 66%

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

2019

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“…Reduced intensity conditioning allograft as part of frontline consolidation has demonstrated no survival benefit in unselected MCL cohorts [22], though further prospective trials examining TP53-mutated patients are warranted. In contrast, preliminary data incorporating novel agents report (phase II PHILEMON trial combining ibrutinib, lenalidomide, and rituximab in relapsed/refractory patients) a similar PFS for TP53-mutated and unmutated patients [23]. Combination ibrutinib and venetoclax in a small phase II study of heavily pretreated young MCL patients achieved CR in 50% of TP53mutated patients included [24], supporting the potential efficacy of novel agent combinations in this poor-performing group of patients.…”

Section: Treating High-risk Patientsblastoid Variant and Tp53 Alteratmentioning

confidence: 95%

Optimal frontline management of mantle cell lymphoma: can we agree?

Tang

Kuruvilla

2018

Expert Review of Hematology

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“…This combination also induced an ORR of 95% in untreated FL in a phase 1 trial (NCT01829568), as well as an ORR of 76% (CR 56%) in relapsed or refractory MCL in a phase 2 trial (NCT02460276). 200,201 In untreated CD20 + B-NHLs, ibrutinib plus R-CHOP achieved an ORR of 100% in a phase 1 study (NCT01569750). 202 In addition, in a phase 3 study (NCT01855750) in untreated non-GCB DLBCL, ibrutinib plus R-CHOP produced a CR rate of 67.3%, and placebo plus R-CHOP produced a CR rate of 68.0%, with no statistically significant difference.…”

Section: Bcr-btkmentioning

confidence: 99%

Advances in targeted therapy for malignant lymphoma

Wang

Qin

Huo

et al. 2020

Sig Transduct Target Ther

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The incidence of lymphoma has gradually increased over previous decades, and it ranks among the ten most prevalent cancers worldwide. With the development of targeted therapeutic strategies, though a subset of lymphoma patients has become curable, the treatment of refractory and relapsed diseases remains challenging. Many efforts have been made to explore new targets and to develop corresponding therapies. In addition to novel antibodies targeting surface antigens and small molecular inhibitors targeting oncogenic signaling pathways and tumor suppressors, immune checkpoint inhibitors and chimeric antigen receptor T-cells have been rapidly developed to target the tumor microenvironment. Although these targeted agents have shown great success in treating lymphoma patients, adverse events should be noted. The selection of the most suitable candidates, optimal dosage, and effective combinations warrant further investigation. In this review, we systematically outlined the advances in targeted therapy for malignant lymphoma, providing a clinical rationale for mechanism-based lymphoma treatment in the era of precision medicine.Signal Transduction and Targeted Therapy (2020) 5:15; https://doi.

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Ibrutinib, lenalidomide, and rituximab in relapsed or refractory mantle cell lymphoma (PHILEMON): a multicentre, open-label, single-arm, phase 2 trial

Abstract: Janssen and Celgene.

Cited by 116 publications

References 23 publications

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

Optimal frontline management of mantle cell lymphoma: can we agree?

Advances in targeted therapy for malignant lymphoma

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