Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial

Trněný, Marek; Lamy, Thierry; Walewski, Jan; Belada, David; Mayer, Jiřı́; Radford, John; Jurczak, Wojciech; Morschhauser, Franck; Alexeeva, Julia; Rule, Simon; Afanasiev, Boris; Kaplanov, Kamil; Thyss, Antoine; Кузьмин, А. В.; Voloshin, S.; Kuliczkowski, Kazimierz; Giza, Agnieszka; Milpied, Noël; Stelitano, Caterina; Marks, Reinhard; Trümper, Lorenz; Biyukov, Tsvetan; Patturajan, Meera; Bravo, Marie Laure Casadebaig; Arcaini, Luca

doi:10.1016/s1470-2045(15)00559-8

Cited by 140 publications

(69 citation statements)

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“…The median follow‐up for all surviving patients was 41·3 months, which was an additional 20 months from the initial assessment and published report (Trneny et al , 2016). Lenalidomide continued to show longer median PFS than IC (8·6 vs. 5·4 months, respectively; P = 0·006; Fig 1A).…”

Section: Resultsmentioning

confidence: 96%

“…Patients had received a median of 2 (range, 1–5) prior treatment regimens, of which 19% had received prior SCT. As previously reported, the treatment arms were balanced in baseline characteristics except for high‐risk MIPI score, high tumour burden, bulky disease, and high lactate dehydrogenase (LDH) concentration, which were more prevalent among patients randomized to lenalidomide versus IC (Trneny et al , 2016). Also, compared with the IC treatment arm, more patients in the lenalidomide arm had received a higher number of previous anti‐lymphoma treatments and had been refractory to their last previous therapy.…”

Section: Resultsmentioning

confidence: 99%

“…The primary analysis of MCL‐002 demonstrated that lenalidomide significantly improved PFS compared with single‐agent IC therapy in patients with relapsed/refractory MCL, resulting in a significant risk reduction in PD or death (Trneny et al , 2016). The current exploratory subgroup and multivariate analyses extend these findings by uncovering an improved clinical benefit with lenalidomide compared with IC in patients with a wide range of demographic and baseline clinical characteristics.…”

Section: Discussionmentioning

confidence: 99%

“…The methodology for MCL‐002 (ClinicalTrials.gov identifier, NCT00875667) has been previously described (Trneny et al , 2016). Key inclusion criteria were minimum age 18 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, histologically confirmed MCL with cyclin D1 overexpression by immunohistochemistry, measurable disease ≥2 cm in the longest diameter, refractory to prior therapy or ≤3 relapses and had documented progressive disease after ≥1 prior combination chemotherapy regimen with an alkylating agent and an anthracycline, cytarabine and/or fludarabine (with or without rituximab); and ineligibility for intensive chemotherapy or stem cell transplantation (SCT).…”

Section: Methodsmentioning

confidence: 99%

“…Subsequently in the single‐arm, phase II MCL‐001 (EMERGE) study in 134 patients with MCL who had relapsed during treatment with, or developed disease refractory to, bortezomib, lenalidomide treatment resulted in an overall response rate (ORR) of 28%, with a median response duration of 16·6 months (Goy et al , 2013, 2015). More recently, in the randomized, open‐label, multicentre, phase II MCL‐002 (SPRINT) study, the lenalidomide arm showed a statistically significant and clinically meaningful improvement in the primary endpoint of PFS compared with investigator's choice (IC) of single‐agent therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine), with a manageable safety profile (Trneny et al , 2016). This primary analysis of MCL‐002, which had a cut‐off date of 7 March 2014 and a median follow‐up of 15·9 months for the overall study population, found a median PFS of 8·7 months for lenalidomide versus 5·2 months for IC (hazard ratio [HR] 0·61, 95% confidence interval [CI] 0·44–0·84; P = 0·004).…”

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confidence: 99%

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Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

et al. 2017

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SummaryIn the mantle cell lymphoma (MCL)‐002 study, lenalidomide demonstrated significantly improved median progression‐free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long‐term follow‐up data and results of preplanned subgroup exploratory analyses from MCL‐002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL‐002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1–21; 28‐day cycles) or single‐agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent‐to‐treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single‐agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

et al. 2017

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Patient Experience Captured by Quality-of-Life Measurement in Oncology Clinical Trials

et al. 2020

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IMPORTANCE Quality of life (QoL) is an important consideration in cancer medicine, especially because drugs are becoming more costly and may only result in modest gains in overall survival.However, there has been no descriptive analysis for the points at which QoL is measured in cancer trials.OBJECTIVE To estimate the prevalence of studies that measure QoL at different points and see how many studies measure QoL for the entirety of a patient's life. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional analysis includes all articles ononcology clinical trials in the 3 highest-impact oncology journals, published between July 2015 and June 2018, that reported QoL outcomes. MAIN OUTCOMES AND MEASURESData were abstracted on when QoL was assessed and the characteristics of these studies. RESULTSFor all 149 studies that met inclusion criteria, QoL assessment was high during treatment (104 articles [69.8%]), during follow-up (81 articles [54.4%]), and after the end of the intervention (68 articles [45.6%]). In 5 of the 149 studies (3.4%), QoL was assessed until death, including in only 1 of the 74 studies on metastatic or incurable cancers. Among these 5 studies, only 1 (20%) used a drug intervention, 1 (20%) used a behavioral intervention, and 2 (40%) used a radiation intervention; only 1 of 5 was in the metastatic setting. The number of studies that reported a positive QoL outcome (ie, QoL outcome was more favorable in the intervention group than in the control group) was between 42 of 81 articles (51.9%) and 16 of 28 articles (57.1%) for most QoL assessment points but only 1 of 5 articles (20%) for studies measuring QoL until death. CONCLUSIONS AND RELEVANCEThis study found that most clinical trials assessed QoL during the treatment or intervention and often during a given amount of follow-up but infrequently assessed QoL on disease progression and rarely followed QoL until the end of the patient's life. Most studies reporting QoL until the end of life reported worse QoL outcomes for the intervention group than the control group. Future research and policy recommendations should consider not just short-term QoL outcomes but QoL outcomes throughout the patient's cancer care. Question How often do oncology studies assess quality of life (QoL) throughout a patient's disease course? Findings This cross-sectional analysis of 149 oncology studies published in highimpact medical and oncology journals found that most studies (69.8%) assessed QoL during the intervention, whereas only 3.4% of studies assessed QoL until the time of death. Meaning These findings suggest that many oncology studies only assess QoL during the intervention; future research should consider the long-term outcomes throughout the patient's life.Oncology, and JAMA Oncology. For each of the journals, we searched for the term quality of life on the journal's website, and we limited the search to research articles only. Selected articles needed to (1) be an RCT, (2) have performed the analysis in the originally randomized groups, (3) have evaluated QoL in ...

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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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Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial

Cited by 140 publications

References 26 publications

Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

Patient Experience Captured by Quality-of-Life Measurement in Oncology Clinical Trials

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

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