Clinical outcome of Mantle Cell Lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression).pdf
ARTICLE OPEN LYMPHOMA Clinical outcome of Mantle Cell Lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression) Gabriel Scheubeck 1✉, Linmiao Jiang 2, Olivier Hermine3, Hanneke C. Kluin-Nelemans4, Christian Schmidt1, Michael Unterhalt1, Andreas Rosenwald5, Wolfram Klapper 6, Andrea Evangelista7, Marco Ladetto8, Mats Jerkeman 9, Simone Ferrero 10, Martin Dreyling1,11 and Eva Hoster 1,2,11 © The Author(s) 2023 Currently, treatment allocation of patients with Mantle Cell Lymphoma (MCL) is mainly based on age and medical ﬁtness. The combined MCL International Prognostic Index (MIPI-c) allows to predict prognosis using clinical factors (MIPI) and the Ki-67 index. However, high p53 expression as surrogate for TP53 alterations has demonstrated to be an independent predictor for poor outcome. We aimed to deﬁne a clear high-risk group based on the combination of MIPI, Ki-67 and p53 expression/TP53 alteration. A total of 684 patients from the prospective European MCL-Younger and MCL-Elderly trials were evaluable. The classiﬁcation of high- risk disease (HRD) as high-risk MIPI-c or p53 expression >50% versus low-risk disease (LRD) as low, low-intermediate or high- intermediate MIPI-c and p53 expression ≤50% allowed to characterize two distinct groups with highly divergent outcome. Patients with HRD had signiﬁcantly shorter median failure-free survival (FFS) (1.1 vs. 5.6 years, p < 0.0001) and overall survival (OS) (2.2 vs. 13.2 years, p < 0.0001) compared to those with LRD. These major differences were conﬁrmed in two validation cohorts from the Italian MCL0208 and the Nordic-MCL4 trials. The results suggest that this subset of HRD patients is not sufﬁciently managed with the current standard treatment and is asking for novel treatment strategies. Leukemia (2023) 37:1887–1894; https://doi.org/10.1038/s41375-023-01977-y INTRODUCTION Mantle cell lymphoma (MCL) is a rare and commonly aggressive subtype of B-cell lymphoma characterized by the translocation t(11;14) with consecutive cyclin D1 overexpression. The clinical course is heterogeneous and marked by recurring relapses. Novel therapeutic strategies such as the addition of high-dose cytar- abine to the induction treatment prior to autologous stem cell transplantation (aSCT), Rituximab (R) maintenance and the approval of Bruton’s tyrosine kinase inhibitors (BTKi) substantially improved the survival of patients [1–3]. Currently, patients are allocated for treatment mainly considering age, stage and performance status. The Mantle Cell Lymphoma International Prognostic Index (MIPI) allows for discriminating prognostic risk groups based on age, performance status, lactate dehydrogenase (LDH) and leukocyte count [4], the combined MIPI-c additionally incorporates the Ki-67 index [5]. In prospective trials, the biological risk factors Ki-67, blastoid or pleomorphic cytology [5], and TP53 alterations [6–8] were associated with inferior outcome independent of MIPI. The prognostic relevance of MCL cytology is closely correlated to the Ki-67 index, which is generally increased in blastoid MCL [5, 9, 10]. P53 expression is a widely applicable diagnostic method serving as surrogate marker for TP53 alterations [11, 12]. In univariate analyses TP53 alterations, such as mutations and deletions, were both validated as negative predictor for outcome in the Nordic MCL2, MCL3, and MCL4 as well as in the European MCL Younger and Elderly trial cohort [7, 8, 13]. Thus, even more intensive regimens including high-dose cytarabine and aPBSCT fail to overcome the dismal prognosis of TP53 alterations [7, 8]. New concepts are urgently needed to deﬁne a more reﬁned high-risk population and identify effective treatment strategies for these patients. In this study, we aimed to deﬁne a combination of MIPI, Ki-67 and p53 expression/TP53 alterations that reliably identiﬁes a high-risk group. Received: 5 March 2023 Revised: 28 June 2023 Accepted: 17 July 2023 Published online: 26 July 2023 1Department of Medicine III, LMU University Hospital, Munich, Germany. 2Institute for Medical Information Processing, Biometry, and Epidemiology, LMU Munich, Munich, Germany. 3University Hospital, Paris, France. 4Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. 5Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany. 6Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. 7Unit of Clinical Epidemiology, Azienda Ospedaliera Universitaria Città della Salute e della Scienza and CPO Piemonte, Turin, Italy. 8Hematology, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. 9Skane University Hospital, Lund, Sweden. 10Division of Hematology, Department of Molecular Biotechnologies and Health Sciences University of Torino/AOU “Città della Salute e della Scienza di Torino”, Turin, Italy. 11These authors contributed equally: Martin Dreyling, Eva Hoster. Presented in abstract form at the 61st American Society of Hematology (ASH 2019) Annual Meeting. ✉email: gabriel.scheubeck@med.uni-muenchen.de www.nature.com/leu Leukemia 1234567890();,: METHODS Patients A total of 1183 MCL patients with conﬁrmed MCL and Ann Arbor stage II to IV were registered in the MCL Younger [14] (NCT00209222) and MCL- Elderly trial [15] (NCT00209209) of the European MCL Network from 2004–2010 serving as training cohort. Patients without available Ki-67 and p53 data were excluded from this analysis. All patients gave written informed consent to participation in the trials. Two independent series of 300 patients from the MCL0208 trial [16] and 51 patients from the Nordic-MCL4 trial [17] were included in this study as validation cohort. The MCL0208 cohort considered TP53 mutation or del(17p) and the Nordic-MCL4 cohort only TP53 mutation status instead of p53 expression data. Immunohistochemistry Immunohistochemistry was performed centrally on either tissue micro- arrays or whole tissue sections. P53 was stained with a mouse monoclonal antibody (Leica/NovoCastra clone DO7) and scored as negative (0%), low (1–10%), intermediate (10–50%) or high (>50%) by one observer based on visual assessment as described [6]. Ki-67 index was centrally assessed in accordance with established guidelines [18]. Pathology Formalin-ﬁxed parafﬁn-embedded (FFPE) diagnostic biopsy material was classiﬁed as classical or pleomorphic/blastoid variant by cytomorphological features conﬁrmed by the central pathology review of a pathology reference center (European MCL Pathology Panel). Risk variables Biological risk variables Ki-67 and p53 expression along with the clinical prognostic tool MIPI were investigated in various combinations. MIPI score is the weighted sum of MIPI prognostic factors weighted by the regression coefﬁcients from the deﬁning Cox regression model [4]. The equally weighted combination of MIPI with the dichotomized Ki-67 index at the validated 30% cutoff deﬁnes the MIPI-c [5]. It was previously reported that none of the patients in the MCL Younger and Elderly cohort with complete absence of p53 expression did display TP53 deletions [6, 8]. For this reason, we focused on the cutoff for p53 expression at 50% serving as biomarker indicating a TP53 mutation with altered functions [11, 19]. Combinations tested to deﬁne high-risk disease (HRD) were p53 expression >50% or Ki-67 ≥30% (deﬁnition 1), p53 expression >50% or high, high-intermediate MIPI-c (deﬁnition 2), or p53 expression >50% or high MIPI-c (deﬁnition 3). Accordingly, low-risk disease (LRD) was deﬁned by p53 expression ≤50% and Ki-67 < 30% (deﬁnition 1), p53 expression ≤50% and low, low-intermediate MIPI-c (deﬁnition 2) or p53 expression ≤50% and low, low-intermediate, high-intermediate MIPI-c (deﬁnition 3). For the validation cohort, presence of TP53 mutation and del(17p) (only MCL0208 cohort) deﬁned HRD instead of high p53 expression. Statistical methods Cases with missing data for both Ki-67 and p53 expression or TP53 mutation/deletion, respectively, were excluded from the analysis. If one high-risk feature applies, missing data for the other variable is allowed. For the classiﬁcation of LRD all variables must be available. The percentages of HRD in the study population were estimated based on complete cases, where patients with missing data in either Ki-67 or p53 expression were excluded in order to minimize bias. The number of complete cases is signiﬁcantly smaller but is more reliable to estimate the true proportion of MCL patients with HRD. Analyses for the outcomes were performed on all the classiﬁable patients with available outcome data. In addition, we performed sensitivity analyses with complete cases. We estimated and compared failure-free survival (FFS, deﬁned as time from treatment start to stable disease, progression, or death from any cause, whichever occurred ﬁrst) and overall survival (OS, deﬁned as time from study registration to death from any cause) stratiﬁed by Ki-67 index (</≥30%), cytology (blastoid versus non blastoid), p53 expression (≤/>50%), the combination of Ki-67 and p53 and MIPI-c and p53 using Kaplan-Meier-plots, logrank tests, and Cox regression. Five-year FFS and OS probabilities were reported along with median FFS and OS times. Quantiﬁcation of follow-up was done by the reversed Kaplan-Meier method. Status of the clinical data was that of July 08, 2021, the latest available time point of medically reviewed data from MCL Younger and MCL-Elderly trials. RESULTS Six hundred eighty-four patients (MCL Younger n = 390, MCL Elderly n = 294) out of 1183 registered study patients with MCL from the training cohort had evaluable data either for Ki-67 or p53 (Supplemental Fig. 1). Among these, low-risk MIPI was more frequent (43% vs. 27%), whereas high-risk MIPI was signiﬁcantly less frequent (24% vs. 44%, p < 0.0001) compared to those without evaluable data (Table 1). Accordingly, median FFS and OS was superior in the subgroup of patients with available data (4.4 vs. 3.2 years, p = 0.0066 and 9.6 vs. 6.6 years, p = 0.0013) (Supplemental Fig. 2). This difference is mainly explained by an overrepresenta- tion of patients with available pathology data from the MCL Younger trial (57% vs 45%) who had a better overall outcome. Of note, there was no difference in outcome of patients with a high MIPI comparing those with available data for Ki-67/p53 vs. unavailable data for Ki-67 and p53. Apart from MIPI parameters, patient characteristics were equally distributed among the two groups (Table 1). High MIPI-c was seen in 63 of 612 cases (10%) and high p53 expression in 54 of 348 (16%) cases. High p53 expression was associated with inferior median FFS (1.5 vs. 4.6 years; p < 0.0001) and OS (2.8 vs. 10.7 years, p < 0.0001) compared to p53 expression ≤50% (data not shown). Blastoid cytology was no negative predictor in patients with low Ki-67 (Supplementary Fig. 3). Using Ki-67 ≥30% or high p53 expression to deﬁne HRD (deﬁnition 1) resulted in a relatively large high-risk group with 37% of complete cases. Median FFS and OS was 1.8 vs. 6.0 years (HR 2.01, p < 0.0001) and 4.0 vs. 14.4 years (HR 2.57, p < 0.0001) compared to LRD (Supplemental Fig. 4). Considering also clinical factors, we tested the impact of high, high-intermediate MIPI-c or high p53 expression (deﬁnition 2) on outcome. This high-risk deﬁnition includes 41% of complete cases and revealed similar results (median FFS: 1.7 vs. 6.0 years, HR 2.40, p < 0.0001; median OS: 3.6 vs. 15.4 years, HR 3.24, p < 0.0001) (Supplemental Fig. 5). The combination of high MIPI-c or high p53 expression (deﬁnition 3) deﬁned the smallest group of high-risk patients and had the highest discriminatory power between HRD and LRD in terms of the hazard ratios for FFS and OS, why we chose that deﬁnition for further analyses. Based on the selection process of deﬁnition 3, 22% complete cases could be assigned to the HRD group (n = 60) and 78% (n = 216) had conﬁrmed LRD. After a median follow-up of 9.6 (FFS) and 9.4 (OS) years the median FFS (1.1 years vs. 5.6 years; HR 2.97, p < 0.0001; Fig. 1A) and OS (2.2 vs. 13.2 years, HR 3.69, p < 0.0001; Fig. 1B) was signiﬁcantly decreased in the high-risk compared with the low-risk group. 5-year and 10- year FFS probabilities were 18% vs. 51% and 10% vs. 37%; 5-year and 10-year OS probabilities were 31% vs. 72% and 15% vs. 59% for HRD vs. LRD, respectively. Sensitivity analyses in complete cases showed similar results to the analyses in classiﬁable cases. These aforementioned signiﬁcant differences were observed consistently across both trial groups, regardless of whether patients received conventionally dosed immunochemo- and maintenance therapy in MCL Elderly (median FFS: 0.8 vs. 3.9 years, p < 0.0001; median OS: 1.9 vs 9.7 years, p < 0.0001) or received induction with intention to high-dose chemotherapy followed by aSCT in MCL Younger (median FFS: 1.9 vs. 6.7 years, p < 0.0001; median OS: 3.0 years vs. median not reached, p < 0.0001) (Fig. 2). Subgroup analyses showed that R-CHOP compared to R-FC in MCL Elderly (median OS 1.1 vs. 2.3 years; HR 3.61 vs. 3.50) as well as R-CHOP/R-DHAP induction compared to R-CHOP induction in MCL Younger (median OS 1.5 vs. 5.6 years; HR 5. 94 vs. 3.06.) could partially mitigate the dismal prognosis of HRD. However, the G. Scheubeck et al. 1888 Leukemia (2023) 37:1887 – 1894 transplantation was carried out in some patients of the Younger trial, only a minority received targeted therapies such as a BTKi (1–3% in the MCL Younger, 7–10% in the MCL-Elderly trial) [24, 25]. Hence, the efﬁcacy of novel therapies in HRD patients can hardly be inferred from these trials as the numbers are too small. Of note, also the immunomodulatory drug lenalidomide trial did not overcome the adverse impact of TP53 mutations in combination with R-bendamustine [13]. The general validity of the biology-based HRD model was conﬁrmed in the FIL-MCL0208 and the Nordic-MCL4 trial with signiﬁcant inferior PFS and higher risk for death in high-risk patients. Interestingly, in relapsed or refractory MCL even the potent BTKi ibrutinib does not overcome the poor prognosis that is linked to TP53 mutations and high MIPI-c [26–28]. A beneﬁt of ibrutinib for progression-free survival in the ﬁrst line treatment of elderly patients was recently reported in the SHINE study (ClinicalTrials.- gov Identiﬁer: NCT01776840) [29]. However, the addition of ibrutinib to rituximab and bendamustine did not show a clear beneﬁt in patients with TP53 mutations or a MIPI score indicating high-risk [29]. The beneﬁt of ibrutinib in combination with chemotherapy in treatment-naive transplant eligible patients has been recently reported for the TRIANGLE study, but longer follow- up is required to evaluate whether this combination fully overcomes the biological risk factors [30]. Of note, neither Ki- 67 ≥50%, TP53 mutation, nor intermediate or high MIPI had any negative prognostic value for 6-months PFS in relapsed or refractory patients treated with the novel CD19 directed CAR-T- cell therapy KTE-X19 [31], suggesting that cellular immunotherapy might overcome the poor prognosis in high-risk patients. As MCL patients with HRD deﬁned by high MIPI-c or high p53 expression/TP53 alteration had a dismal clinical course of the disease, we recommend to incorporate these factors in routine diagnostic practice as suggested by the WHO 5th edition and the International Consensus Classiﬁcation (ICC) to identify patients with need for novel therapeutic strategies [32, 33]. At present, HRD MCL patients should be treated with ibrutinib-containing induction based on the SHINE and TRIANGLE data [29, 30]. However, we think that this approach will not completely overcome the dismal prognosis of high MIPI-c or high p53/TP53 mutation and clinical trials are needed that particularly address HRD patients. In conclusion, the combination of the prognostic MIPI index with the biological risk factors TP53 mutation and high Ki-67 expression reliably deﬁnes a subset of MCL patients with dismal prognosis. On the other hand, patients without these high-risk features achieve an excellent outcome with an overall survival over a decade with the current standard of care. Furthermore, these results will allow risk stratiﬁcation in clinical trials, to hopefully develop innovative therapies especially for the high-risk MCL population which has the greatest medical need. Fig. 3 Prognostic impact of high MIPI-c or high p53 expression on overall survival stratiﬁed by treatment groups of the MCL Younger and the MCL Elderly trial. Kaplan–Meier estimates of OS among patients treated with R-CHOP induction and aPBSCT (A), alternating R-CHOP/ R-DHAP induction and aPBSCT (B), R-FC and IFN maintenance (C) and R-CHOP + R maintenance (D) stratiﬁed by the presence of high MIPI-c or p53 expression >50% (high-risk disease) compared to low, low-intermediate or high-intermediate MIPI-c and p53 expression <50% (low-risk disease). The number at risk is based on all classiﬁable patients. G. 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FUNDING Open Access funding enabled and organized by Projekt DEAL. COMPETING INTERESTS GS, LJ, OH, HCK-N, CS, MU, AR, WK, ML, AE and EH: None. MJ—Honoraria: Abbvie, Astra Zeneca, BMS, Genmab, Gilead, Pierre Fabre, Janssen, Roche. Research support: Abbvie, Astra Zeneca, BMS, Gilead, Janssen, Roche. SF—Research funding: Janssen, Morphosys, Gilead, Beigene. Consultancy: EusaPharma, Janssen, Sandoz, Abbvie. Advisory Board: EusaPharma, Janssen, Clinigen, Incyte, Italfarmaco. Speakers Honoraria: Janssen, EusaPharma, Servier, Gentili. MD—Research Support (institution): Abbvie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche. - Employee: -Major Stockholder: -Speakers Bureau: -Speakers Honoraria: Amgen, Astra Zeneca, Gilead/ Kite, Janssen, Lilly, Novartis, Roche. - Scientiﬁc Advisory Board: Astra Zeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, Roche. G. Scheubeck et al. 1893 Leukemia (2023) 37:1887 – 1894 ADDITIONAL INFORMATION Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41375-023-01977-y. Correspondence and requests for materials should be addressed to Gabriel Scheubeck. Reprints and permission information is available at http://www.nature.com/ reprints Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional afﬁliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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Title: Clinical outcome of Mantle Cell Lymphoma patients with high-risk disease (high-risk MIPI-c or high p53 expression) ​
Authors: Gabriel Scheubeck, Linmiao Jiang, Olivier Hermine, Hanneke C. Kluin-Nelemans, Christian Schmidt, Michael Unterhalt, Wolfram Klapper, Andrea Evangelista, Marco Ladetto, Mats Jerkeman, Simone Ferrero, Martin Dreyling, and Eva Hoster ​
Publisher: Nature
Date: July 26, 2023 ​
Abstract: Currently, treatment allocation of patients with Mantle Cell Lymphoma (MCL) is mainly based on age and medical fitness. ​ The combined MCL International Prognostic Index (MIPI-c) allows predicting prognosis using clinical factors (MIPI) and the Ki-67 index. ​ However, high p53 expression as a surrogate for TP53 alterations has demonstrated to be an independent predictor for poor outcome. ​ We aimed to define a clear high-risk group based on the combination of MIPI, Ki-67, and p53 expression/TP53 alteration. ​ A total of 684 patients from the prospective European MCL-Younger and MCL-Elderly trials were evaluable. ​ The classification of high-risk disease (HRD) as high-risk MIPI-c or p53 expression >50% versus low-risk disease (LRD) as low, low-intermediate, or high-intermediate MIPI-c and p53 expression ≤50% allowed characterizing two distinct groups with highly divergent outcomes. ​ Patients with HRD had significantly shorter median failure-free survival (FFS) (1.1 vs. 5.6 years, p < 0.0001) and overall survival (OS) (2.2 vs. 13.2 years, p < 0.0001) compared to those with LRD. ​ These major differences were confirmed in two validation cohorts from the Italian MCL0208 and the Nordic-MCL4 trials. ​ The results suggest that this subset of HRD patients is not sufficiently managed with the current standard treatment and is asking for novel treatment strategies. ​