Ibrutinib–rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial

Wang, Michael L.; Jain, Preetesh; Zhao, Shuangtao; Lee, Hun Ju; Nastoupil, Loretta J.; Fayad, Luis; Ok, Chi Young; Kanagal‐Shamanna, Rashmi; Hill, Holly A.; Yao, Yixin; Hagemeister, Fredrick B.; Westin, Jason R.; Fowler, Nathan; Samaniego, Felipe; Steiner, Raphaël; Nair, Ranjit; Iyer, Swaminathan Padmanabhan; Navsaria, Lucy; Badillo, Maria; Feng, Lei; Huang, Xuelin; González, Graciela M. Nogueras; Xu, Gelin; Wagner‐Bartak, Nicolaus A.; Thirumurthi, Selvi; Santos, David M. Cordas dos; Tang, Guilin; Lin, Pei; Wang, Sa A.; Jorgensen, Jeff; Yin, C. Cameron; Li, Shaoying; Patel, Keyur P.; Vega, Francisco; Medeiros, L. Jeffery; Flowers, Christopher R.; Wang, Linghua

doi:10.1016/s1470-2045(21)00638-0

Cited by 31 publications

(26 citation statements)

References 21 publications

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“…7 To minimize the exposure to chemotherapy, and resulting toxicity, WINDOW-1 regimen was reported. 119 Induction with rituximab another in North America, 122 the BR combination has become the standard first-line treatment for elderly MCL patients. In 2013,…”

Section: Prognostic Factorsmentioning

confidence: 99%

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Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

Jain

Wang

2022

American J Hematol

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The field of mantle cell lymphoma (MCL) has witnessed remarkable progress due to relentless advances in molecular pathogenesis, prognostication, and newer treatments. MCL consists of a spectrum of clinical subtypes. Rarely, atypical cyclin D1-negative MCL and in situ MCL neoplasia are identified. Prognostication of MCL is further refined by identifying somatic mutations (such as TP53, NSD2, KMT2D), methylation status, chromatin organization pattern, SOX-11 expression, minimal residual disease (MRD), and genomic clusters. Lymphoid tissue microenvironment studies demonstrated the role of B-cell receptor signaling, nuclear factor kappa B (NF-kB), colony-stimulating factor (CSF)-1, the CD70-SOX-11 axis. Molecular mechanism of resistance, mutation dynamics, and pathogenic pathways (B-cell receptor (BCR), oxidative phosphorylation, and MYC) were identified in mediating resistance to various treatments (bruton tyrosine kinase (BTK) inhibitors [ibrutinib, acalabrutinib]. Treatment options range from conventional chemoimmunotherapy and stem cell transplantation (SCT) to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti-CD19 chimeric antigen receptor therapy (CAR-T), and most recently bispecific antibodies against CD19 and CD20. MCL patients frequently relapse. Complex pathogenesis and the management of patients with progression after treatment with BTK/Bcl2 inhibitors and CAR-T (triple-resistant MCL) remain a challenge. Next-generation clinical trials incorporating newer agents and concurrent translational and molecular investigations are ongoing. 1 | INTRODUCTION Mantle cell lymphoma (MCL) is an uncommon subtype of aggressive B cell non-Hodgkin's lymphoma (B-NHL). In 1982, Weisenburger et al. 1 first described 12 cases of malignant lymphoma with lymph node biopsies showing widened mantle zones around germinal centers in the secondary lymphoid follicles. The diagnosis of MCL 2 is now well characterized. MCL is no longer considered a single disease but is a mixed bag of various subcategories with a spectrum of molecular and clinical features. MCL patients have varied clinical presentations (generally symptomatic to an asymptomatic indolent clinical course).Advances in MCL research have significantly enhanced our understanding of pathogenesis, tumor microenvironment, 3 risk factor prognostication, 4 and molecular categories. 5 With the available treatment modalities (chemoimmunotherapy, 6 stem cell transplantation [SCT], 7 covalent and noncovalent BTK inhibitors, 8,9 bispecific antibodies, 10 an ROR1 drug conjugate, 11 and Bcl2 antagonists 12 ), the response rates and patient survival have improved. 13 The FDA approval of anti-CD19-chimeric antigen receptor therapy (CAR-T)-brexucabtagene autoleucel 14 -is a landmark

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Section: Prognostic Factorsmentioning

confidence: 99%

“…To minimize the exposure to chemotherapy, and resulting toxicity, WINDOW‐1 regimen was reported 119 . Induction with rituximab (IR) (Part A) followed by short‐course four cycles of R‐HCVAD‐methotrexate/ara‐C (Part B) was investigated in 131 patients in a single‐arm phase 2 clinical trial.…”

Section: Introductionmentioning

confidence: 99%

Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

Jain

Wang

2022

American J Hematol

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“…39 Several phase II, single-arm studies have demonstrated impressive results with ASCT consolidation after intensive induction, reporting 4-5 year PFS and OS rates of 56%-73% and 64%-81% respectively (Table 2). 33,39,40,[44][45][46][47][48][49][50][51][52][53] A previous EMCLN randomised prospective trial compared ASCT to interferon-α maintenance after CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like induction with or without rituximab. 54 With 14 years follow-up, there was significantly superior PFS and OS in the ASCT group; however, on subgroup analysis the difference in both PFS and OS was restricted only to rituximab-naïve patients.…”

Section: Intensive Chemoimmunotherapy and Autologous Stem Cell Transp...mentioning

confidence: 99%

“…For patients eligible for intensive chemotherapy and ASCT, the recent WINDOW-1 single-centre phase II study recently reported results with the use of front-line IR, prior to chemoimmunotherapy. 45 IR was given for up to 12 cycles, followed by four cycles of R-HCVAD (rituximab/cyclophosphamide/vincristine/doxorubicin/dexamethasone) in those with CR or a more intensive combination of R-HCVAD with methotrexate-cytarabine in those not in CR. Although the responses from IR alone (98% ORR) were promising and raise the question of whether chemotherapy is needed at all in the front-line setting, patients with TP53 mutations and/ or blastoid morphology had a lower CR rate compared to those without (Table 2).…”

Section: Novel and Cellular Therapies In Front-linementioning

confidence: 99%

How I manage mantle cell lymphoma: indolent versus aggressive disease

et al. 2023

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Summary Mantle cell lymphoma (MCL) is a mature B‐cell lymphoma with a variable clinical course and historically poor prognosis. Management is challenging in part due to the heterogeneity of the disease course, with indolent and aggressive subtypes now well recognised. Indolent MCL is often characterised by a leukaemic presentation, SOX11 negativity and low proliferation index (Ki‐67). Aggressive MCL is characterised by rapid onset widespread lymphadenopathy, extra‐nodal involvement, blastoid or pleomorphic histology and high Ki‐67. Tumour protein p53 (TP53) aberrations in aggressive MCL are recognised with clear negative impact on survival. Until recently, trials have not addressed these specific subtypes separately. With the increasing availability of targeted novel agents and cellular therapies, the treatment landscape is constantly evolving. In this review, we describe the clinical presentation, biological factors, and specific management considerations of both indolent and aggressive MCL and discuss current and potential future evidence which may help move to a more personalised approach.

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“…It should be noted that the efficacy of this combination may be reduced in the context of TP53-mutation and Ki-67 high expression [ 171 , 237 ]. Ibrutinib–rituximab induction followed by shortened R-HCVAD CIT regime induced an extremely high rate of overall response (98%) as frontline treatment in young MCL patients, with reduced chemotherapy-related AEs [ 172 ]. The addition of bendamustine [ 238 ] or lenalidomide [ 175 ] into the ibrutinib–rituximab regime showed promising activity and tolerability.…”

Section: Btk Inhibitors In Hematological Malignanciesmentioning

confidence: 99%

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Alu

Han

et al. 2022

J Hematol Oncol

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Bruton’s tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

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Ibrutinib–rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trial

Cited by 31 publications

References 21 publications

Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments

How I manage mantle cell lymphoma: indolent versus aggressive disease

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

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