scholarly journals The impact of SAMHD1 expression and mutation status in mantle cell lymphoma: An analysis of the MCL Younger and Elderly trial

2020 ◽  
Vol 148 (1) ◽  
pp. 150-160
Author(s):  
Tobias Roider ◽  
Xi Wang ◽  
Katrin Hüttl ◽  
Carsten Müller‐Tidow ◽  
Wolfram Klapper ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Mutation Status ◽  
Mantle Cell ◽  
Samhd1 Expression ◽  
The Impact

scholarly journals Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era

2019 ◽  
Vol 37 (6) ◽  
pp. 471-480 ◽  
Author(s):  
James N. Gerson ◽  
Elizabeth Handorf ◽  
Diego Villa ◽  
Alina S. Gerrie ◽  
Parv Chapani ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Mantle Cell Lymphoma ◽  
Hematopoietic Cell Transplantation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large Cohort ◽  
Multivariable Regression Analysis ◽  
Mantle Cell ◽  
Multivariable Regression ◽  
The Impact

PURPOSE Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score–weighted (PSW) analysis were performed. RESULTS Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

Rituximab maintenance improves progression-free and overall survival rates after combined immuno-chemotherapy (R-FCM) in patients with relapsed follicular and mantle cell lymphoma: Final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7502-7502 ◽  
Author(s):  
M. Dreyling ◽  
R. Forstpointner ◽  
M. Gramatzki ◽  
H. Böck ◽  
M. Hänel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Remission Induction ◽  
Low Grade ◽  
Free Survival ◽  
Mantle Cell ◽  
The Impact

7502 Background: Rituximab (R) prolongs the progression-free survival (PFS) in patients with follicular lymphoma (FL) when given either simultaneously with or as maintenance after chemotherapy only. Methods: In the current study the impact of R maintenance after remission induction with an R-containing combined immuno-chemotherapy (R-FCM) was evaluated. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized 4 courses of chemotherapy with Fludarabine (25 mg/m2/d days 1–3), Cyclophosphamide (200 mg/m2/d days 1–3) and Mitoxantrone (8 mg/m2/d day 1) (FCM) ± Rituximab (375 mg/m2/d day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomization for R maintenance (4 weekly doses (375 mg/m2/d) at three and nine months after end of induction) or observation only. Randomization was stratified for histology, prior therapies (up to 2 lines vs. >2), induction (±R), and response (CR vs. PR). After improved outcome of the R-FCM arm had been observed in the initial 147 randomized patients, all subsequent patients received a combined immuno-chemotherapy induction. Results: 176 of 195 randomized cases are evaluable, 138 of whom had received an R-containing induction. In these patients (as well as the total group) the median PFS after end of induction has not been reached in the R-maintenance arm in contrast to 17 months in patients with no further treatment (p = 0.001). This improvement was seen both in FL (n = 81; p = 0,035) and MCL (n = 47; p = 0,049). More importantly, overall survival rate was also improved after R maintenance with borderline significance (3 y rate 82% vs. 55%; p = 0,056). No major sided effects of R maintenance have been observed and the rate of serious infections was similar in both study arms (p = 0.72). Conclusions: The final analysis of this study confirms that R maintenance after combined immuno-chemotherapy (R-FCM) is highly effective and improves the progression-free survival—with a strong trend towards improved overall survival—of patients with relapsed FL and MCL. [Table: see text]

Impact of rituximab on outcome of autologous transplantation for mantle cell lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7555-7555 ◽  
Author(s):  
A. Naing ◽  
J. Palmer ◽  
N. Tsai ◽  
N. Kogut ◽  
L. Popplewell ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Median Survival ◽  
Relapse Rate ◽  
Survival Probability ◽  
Cell Lymphoma ◽  
Disease Stage ◽  
Bulky Disease ◽  
Mantle Cell ◽  
The Impact ◽  
Disease Free

7555 Background: Currently, Mantle Cell Lymphoma (MCL) is an incurable disease. Patients treated with chemotherapy alone experience only transient responses, with no long-term improvement in disease-free/overall survival. While autologous hematopoietic stem cell transplantation (ASCT) in MCL patients has demonstrated prolonged survival, relapse remains the major issue. We evaluate the impact of rituximab (Rituxan, Rtx) on relapse and survival following ASCT. Method: A case-series of 83 MCL patients treated with ASCT at City of Hope (from 02/1991 to 04/2005) were examined; a total of 52 patients received Rtx (with-Rtx) as part of their induction/salvage treatment (pre-ASCT) and/or maintenance therapy (post-ASCT), 31 patients did not receive Rtx (no-Rtx) at any point pre-/post-ASCT. An assessment of baseline patient and disease characteristics (gender, age, KPS, % of pts with bone marrow involvement at diagnosis, disease stage/status at ASCT, % of pts with bulky disease B-symptoms at ASCT, and # of regimens administered prior to ASCT) showed no significant differences among the two groups. Result: To date, 23 patients have relapsed/progressed post-ASCT; 61% of the patients in the no-Rtx group remain disease free at last contact, while 79% in the with-Rtx group remain disease free. The median survival in the no-Rtx group is 77.63 months; the median survival time point for the with-Rtx group has not been reached due to shorter follow-up period. The 2-yr relapse rate for the with-Rtx/no-Rtx groups among 1st CR/PR patients were 19% (95% CI: 10–33%) and 26% (95% CI: 14–43%) (p > 0.05) respectively and the 2-yr relapse rate for the with-Rtx/no-Rtx groups among the beyond 1st CR pts were 33% and 40% respectively (p > 0.05). The survival endpoint showed similar results. The 2-yr survival probability for the with-Rtx/no-Rtx groups among the 1st CR/PR patients were 91% (95% CI: 76–97%) and 82% (95% CI: 64–91%) (p > 0.05) respectively and the 2-yr survival probability for the with-Rtx/no-Rtx groups among the patients beyond 1st CR/PR were 59% and 63% respectively (p > 0.05). Conclusion: Using Rtx as induction/salvage and/or maintenance before and after ASCT therapy may not be associated with decreased relapse and improved survival. Nevertheless, our data indicate that outcome is better when ASCT is carried out at 1st CR/PR. No significant financial relationships to disclose.

The Impact of Histological Subtypes on Outcome in Patients with Mantle Cell Lymphoma Treated with or without Autologous Stem Cell Transplant.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1904-1904
Author(s):  
Muhammad I. Zulfiqar ◽  
Dennis D. Weisenburger ◽  
Fausto R. Loberiza ◽  
Julie M. Vose ◽  
Philip J. Bierman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Mantle Cell Lymphoma ◽  
Stem Cell Transplant ◽  
Cell Lymphoma ◽  
Cell Transplant ◽  
Histological Subtypes ◽  
Mantle Cell ◽  
Hodgkin's Lymphomas ◽  
The Impact

Abstract Mantle cell lymphoma (MCL) accounts for 7% of all non-Hodgkin’s lymphomas, with median overall survival in most series of 3–4 years. MCL has been classified into three histological subtypes which include diffuse MCL, nodular MCL, and blastic MCL. A relatively small number of studies have examined the prognostic importance of histology in MCL. The aim of this study was to determine if the progression free survival (PFS) and overall survival (OS) rates in mantle cell lymphoma differ among histological subtypes. A total of 102 patients with MCL, treated by the Nebraska Lymphoma Study Group between January 1986 and June 2006, with a median age of 60 years (range 32–89 years) were available for study. Patients were treated with HyperCVAD or a CHOP like regimen with or without rituximab and autologous hematopoetic stem cell transplant (ASCT). All cases were confirmed using cyclin D1 staining. Regardless of treatment, our study failed to show a significant difference in PFS (p=0.26) or OS (P=0.06) among histological subtypes. There was a trend for better survival in patients with nodular MCL. However, in patients receiving ASCT, there was a significantly higher PFS (P=0.0001) and OS (p=0.0005) compared to patients not receiving ASCT. The 3 year PFS for patients receiving HyperCVAD followed by ASCT was 64% compared to the 3 year PFS for HyperCVAD alone of 0 (p=0.008). In conclusion, we failed to show association between histological subtypes of MCL with outcomes regardless of treatment. However, the use of ASCT improved survival.

scholarly journals Prognostic significance of p53, Sox11, and Pax5 co-expression in mantle cell lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Caixia Jing ◽  
Yuhuan Zheng ◽  
Yu Feng ◽  
Xia Cao ◽  
Caigang Xu
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Progression Free Survival ◽  
Tissue Array ◽  
Ki 67 ◽  
Mutation Status ◽  
Mantle Cell

AbstractMantle cell lymphoma (MCL) is a relatively rare subtype of non-Hodgkin’s lymphoma. To identify molecular biomarkers in MCL, we performed immunohistochemistry tissue arrays using biopsies from 64 MCL patients diagnosed in West China Hospital from 2012 to 2016. TP53 mutation status in those patients was also examined by sequencing. The sequencing results showed TP53 mutations were highly heterogeneous in MCL. We identified four novel TP53 mutations in MCL: P151R, G199R, V218E, and G325R. The MCL patients with TP53 mutations had inferior progression-free survival (PFS, p = 0.002) and overall survival (OS, p = 0.011). Tissue array results showed the expression of p53, Sox11, or Pax5 alone did not correlate with the patient PFS and OS. However, the MCL patients with triple-positive expression of p53/Sox11/Pax5 had inferior PFS (p = 0.008) and OS (p = 0.002). Such risk stratification was independent to the mantle cell lymphoma international prognostic index (MIPI), Ki-67 value, and TP53 mutation status of the patients. The triple-positive patients might represent a subtype of high-risk MCL. Our findings might indicate a novel way to stratify MCL and predict patients’ prognosis.

scholarly journals Bortezomib (Btz) Dose Intensity Is the Strongest Predictor for Overall Survival (OS) in Mantle Cell Lymphoma (MCL) Patients (Pts) Not Considered for Transplantation, Receiving Frontline Btz Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) Therapy in the Phase 3 LYM-3002 Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4412-4412
Author(s):  
Tadeusz Robak ◽  
Huiqiang Huang ◽  
Jie Jin ◽  
Jun Zhu ◽  
Ting Liu ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Dose Intensity ◽  
Newly Diagnosed ◽  
Mantle Cell ◽  
Response Status ◽  
Treatment Changes ◽  
Ecog Ps ◽  
The Impact

Abstract Background: The phase 3, randomized LYM-3002 study compared VR-CAP (n=243) vs R-CHOP (n=244) as frontline therapy in newly diagnosed MCL pts who were ineligible or not considered for bone marrow transplantation (NCT00722137). In the primary analysis after a median follow-up of 40 mos, progression-free survival (PFS) as assessed by independent radiology review committee (IRC) (median 24.7 vs 14.4 mos; hazard ratio [HR] 0.63; p<0.001) or by investigator (median 30.7 vs 16.1 mos; HR 0.51; p<0.001) was significantly prolonged with VR-CAP vs R-CHOP. A trend for improved OS (a pre-specified secondary endpoint) was also seen with VR-CAP vs R-CHOP (median not reached vs 56.3 mos; HR 0.80; p=0.173) and 4-yr OS rates were 64.4% vs 53.9% (Cavalli et al. ASCO 2014, Abs 8500; Robak et al. EHA 2014, Abs S1345). An association between higher Btz cumulative dose and improved OS has been observed in newly diagnosed multiple myeloma pts (Mateos et al. ASH 2013, Abs 1968). This post-hoc analysis of LYM-3002 evaluated the impact of Btz dose intensity on OS in newly diagnosed MCL pts receiving VR-CAP. Methods: In the VR-CAP arm, pts with measurable stage II–IV MCL and an ECOG performance status (ECOG PS) of 0–2 received 6–8 × 21-d cycles of Btz 1.3 mg/m2 IV on d 1, 4, 8, and 11, plus rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, all IV on d 1, and prednisone 100 mg/m2 PO on d 1–5. Btz dose adjustments for toxicities were permitted using established dose modification guidelines per the drug prescribing information. OS was estimated by Kaplan-Meier methodology. For this analysis, Btz dose intensity (total Btz dose received per cycle) during cycles 1–6 was calculated. The median value was selected as a cut-off for dichotomization of pts to be included in lower or higher (<4.6 vs ≥4.6 mg/m2/cycle) dose intensity groups. OS was then compared between groups, among pts who had received ≥6 cycles of Btz (n=181) in a landmark analysis from the end of cycle 6. The impact of potential confounding factors (baseline factors and on-treatment changes in response status, ECOG PS, and nadir platelet/neutrophil counts pre-landmark) was evaluated in multivariate analysis using Cox proportional hazards modeling. Results: From the landmark, OS was found to be significantly longer in the higher (n=93) vs lower (n=88) Btz dose intensity group in univariate analysis (HR 0.43 [0.23, 0.80]; p=0.0059; Figure). 4-yr OS rates were 79.5% and 57.1%. In multivariate analysis adjusted for potential confounding baseline patient/disease characteristics that may have been imbalanced between the dose groups (age [≤65 vs >65 yrs], sex, race [white vs non-white], ECOG PS [≤1 vs >1], disease stage [II/III vs IV], extranodal involvement [≤1 vs >1], LDH level, white blood cell count, bone marrow involvement, albumin level, platelet count), Btz dose intensity remained the most significant predictor of OS (HR 0.40 [0.20, 0.79]; p=0.009). After selection for the most significant covariates (Btz dose intensity, ECOG PS, LDH level), dose intensity remained the strongest predictor of OS of all variables considered in the model (HR 0.38 [0.20, 0.71]; p=0.003). Dose intensities of other drugs in the VR-CAP regimen showed no association with OS due to infrequent dose modification. After adjusting for achievement of complete response (CR)/unconfirmed CR (CR/CRu) by investigator assessment (per International Lymphoma Workshop Criteria) by the end of cycle 6 (yes [n=28] vs no [n=151]), which showed no impact on OS (HR 0.36 [0.11, 1.17]; p=0.09), the impact of Btz dose intensity on OS remained highly significant (HR 0.43 [0.23, 0.80]; p=0.007). Similar findings were observed after adjusting for achievement of CR/CRu by IRC. Adjusting for change from baseline to landmark in ECOG PS (worsening [n=26] vs non-worsening [n=153]; HR 0.88 [0.40, 1.95]; p=0.76), and worst on-treatment platelet count (≥25 [n=120] vs <25 [n=59] x109/L; HR 0.72 [0.38, 1.37]; p=0.31) or neutrophil count (≥0.75 [n=38] vs <0.75 [n=141] x109/L; HR 1.47 [0.59, 3.68]; p=0.41), showed no significant impact on OS of these variables, but demonstrated continued prognostic significance of Btz dose intensity. Conclusions: Higher Btz dose intensity was the strongest predictor of OS in newly diagnosed MCL pts receiving frontline VR-CAP. The association was independent of baseline characteristics, dose intensity of co-administered drugs, or on-treatment changes in response status or hematologic parameters. Figure 1 Figure 1. Disclosures Robak: Janssen Research & Development: Consultancy, Research Funding. Off Label Use: The proteasome inhibitor bortezomib is approved in the US for the treatment of multiple myeloma and for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. In the present study, bortezomib is being investigated in combination with immunochemotherapy for previously untreated patients with mantle cell lymphoma, an indication for which it is currently not approved.. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Pei:Janssen: Employment. Rooney:Johnson & Johnson: Equity Ownership; Janssen: Employment. van de Velde:Johnson & Johnson: Equity Ownership; Janssen: Employment. Cavalli:Roche: Research Funding; Takeda: Consultancy; Pfizer: Research Funding; Mundipharma: Research Funding; Novartis: Consultancy.

scholarly journals SAMHD1 Is Variably Expressed in Mantle Cell Lymphoma and Correlated to SOX11 but Not to Survival

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4136-4136
Author(s):  
Agata Magdalena Wasik ◽  
Elin Marin ◽  
Magali Merrien ◽  
Joana de Matos Rodrigues ◽  
Martin Lord ◽  
...  
Keyword(s):  
T Cells ◽  
Mantle Cell Lymphoma ◽  
Correlation Coefficient ◽  
Cell Lymphoma ◽  
Mrna Levels ◽  
Spearman Correlation ◽  
Significant Difference ◽  
Mantle Cell ◽  
Samhd1 Expression ◽  
Sox11 Expression

Abstract Introduction Mantle cell lymphoma (MCL) is an incurable disease with a median survival of 3-5 years. Most cases express SOX11, a transcription factor associated with MCL pathobiology, which serves as a diagnostic marker. Current standard first-line therapy for younger MCL patients is rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and cytarabine (Ara-C), consolidated with high dose chemotherapy with autologous stem cell transplantation (ASCT), which is associated with prolonged survival (Eskelund et al. Br J Haematol 2016). Ara-C metabolizes into its active triphosphate form Ara-CTP which inhibits proliferation of the malignant cells. Recent reports suggest that the expression of the mammalian dNTPs hydrolase SAMHD1 determines response to Ara-C in acute myeloid leukemia (AML) by hydrolyzing Ara-CTP and thus by diminishing the anti-proliferative properties of Ara-C. Consequently, in vitro downregulation of SAMHD1 resulted in sensitization of AML cells to Ara-C (Herold et al., Nat Med 2017). SAMHD1 also exhibits anti-tumor properties via regulation of dNTP pool and is recurrently mutated in CLL (Clifford et al. Blood 2014) and T-PLL (Johansson et al. Blood Cancer J. 2018). In CLL a role in DNA-repair has been suggested (Clifford et al. Blood 2014). Thus, SAMHD1 may function as a tumor suppressor. In this study, we investigated for the first time the expression patterns of SAMHD1 in MCL and its association to clinical outcome, especially in patients receiving Ara-C as part of induction for ASCT. Methods SAMHD1 and SOX11 expression was investigated by qPCR, WB and IHC on whole tissue sections or tissue microarrays. MCL cell lines were treated with gene-specific siRNA for SAMHD1 or SOX11. Data on overall survival (OS) was retrieved from patient records. For patients included in the Nordic MCL2 and MCL3 trials data on progression free survival (PFS) and OS were retrieved. Results Initial IHC showed that expression of SAMHD1 is high in normal T-cells and macrophages and low in cells in the mantle zones of reactive tonsils. Co-staining with CD20 in a heterogeneously treated cohort of primary MCL (n=104) showed a large variation between cases (median 73.15%, range: 0.4%-99.6%) and the staining intensity was lower than in T-cells. Sixty two/104 samples were also evaluated for SOX11 expression and the percentage of SOX11 positive cells moderately correlated with SAMHD1 expression (Spearman correlation coefficient 0.27, p=0.036). Analysis of mRNA expression (normalized to mRNA levels of respective genes in Granta519 cell line) of SAMHD1 (median RFI: 2.09, range: 0.18-10.69) and SOX11 (median RFI: 2.00, range: 0.00-7.11) in flow cytometry sorted primary MCL cells (n=19) showed a trend for correlation (Spearman correlation coefficient 0.45, p=0.053). However, downregulation of SOX11 by siRNA did not alter the expression of SAMHD1 and neither did downregulation of SAMHD1 by siRNA change the expression of SOX11 suggesting that the observed correlation is not due to a mutual regulation. We investigated the relation of SAMHD1 expression to clinical and pathological parameters in this cohort and found no correlation to OS, blastoid morphology, proliferation (% Ki67+ tumor cells) nor p53 positivity (>20% positively stained cells). Further, a cohort of patients treated within the Nordic MCL2 and MCL3 protocols (n=51) were investigated for SAMHD1 expression by IHC. Interestingly the distribution of SAMHD1 expression was different in this cohort (median 34.9%, range: 2.2%-97.1%; Mann-Whitney p=0.0019). Survival analysis showed a trend for better PFS and OS in patients with high (>75% SAMHD1 positive cells) and low (<25% positive cells) SAMHD1, although the differences were not significant (Kaplan-Meier with log rank test, p=0.053). Conclusions In MCL the expression of SAMHD1 varies over a broad range and correlates to expression of SOX11. However, no significant difference in PFS or OS among patients receiving Ara-C containing induction chemotherapy is found in this study. Disclosures No relevant conflicts of interest to declare.

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