scholarly journals The Addition of Rituximab to CHOP Improves Failure-Free and Overall Survival of Mantle-Cell Lymphoma Patients – a Pooled Trials Analysis of the German Low-Grade Lymphoma Study Group (GLSG)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1752-1752 ◽  
Author(s):  
Eva Hoster ◽  
Michael Unterhalt ◽  
Michael Pfreundschuh ◽  
Michael Hallek ◽  
Roswitha Forstpointner ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
Hazard Ratio ◽  
Adjusted Hazard Ratio ◽  
Low Grade ◽  
Mantle Cell ◽  
Lymphoma Study Group

Abstract Introduction: Immunochemotherapy has become the standard of care for patients with mantle-cell lymphoma (MCL) (Dreyling et al., ESMO recommendation for MCL, 2013). Previously, the German Low-Grade Lymphoma Study Group (GLSG) has shown in a randomized trial (GLSG2000) that the addition of rituximab to CHOP improves response rates in untreated advanced stage MCL patients (Lenz et al., JCO 2005). However, the trial was not powered to detect survival differences. Since 1996, patients with MCL have been included in the two consecutive randomized trials GLSG1996 (CHOP vs. MCP, Nickenig et al., Cancer 2006) and GLSG2000. Based on the mature pooled data of these trials we now aimed to compare the long-term clinical outcome of MCL patients treated with CHOP with or without rituximab. Methods: Induction treatment consisted of 4-6 cycles of MCP, CHOP, or R-CHOP. Patients younger than 66 years were subsequently randomized to either myeloablative consolidation and autologous stem cell transplantation, or interferon-alpha maintenance in the first European MCL Trial (Dreyling et al., Blood 2005), whereas older patients were designated to interferon-alpha maintenance. In 1998, randomization between CHOP and MCP (GLSG1996) was stopped due to superior response rates and more effective stem cell mobilization after CHOP, and all subsequently recruited patients were assigned to CHOP. Similarly, in 2002, randomization between CHOP and R-CHOP (GLSG2000) was stopped because of superior response rates after R-CHOP, and all subsequently recruited patients were assigned to R-CHOP. For the current evaluation, we included MCL patients prospectively assigned to either CHOP (GLSG1996 or GLSG2000) or R-CHOP (GLSG2000). We performed an intention-to-treat analysis comparing failure-free (failure: stable disease, progression, or death from any cause) and overall survival (OS) of patients prospectively assigned to R-CHOP versus CHOP, adjusting for potential imbalances in clinical risk profile based on the MIPI score (Hoster et al., JCO 2014). Results: From 1996 to 2004, 386 MCL patients have been prospectively assigned to R-CHOP (185) or CHOP (201). Clinical characteristics were comparable with median age 62 vs. 61 years for R-CHOP vs. CHOP groups, and 40% vs. 42% low risk, 38% vs. 36% intermediate risk, and 22% vs. 21% high risk MIPI. The R-CHOP group showed higher overall response (91% vs. 80%) and complete remission rates (25% vs. 15%). Median failure-free survival was 2.1 compared to 1.4 years (Figure 1, left panel) with adjusted hazard ratio 0.62 (95% CI 0.50-0.78, p<0.0001). After a median follow-up of 9.6 years, median OS was 5.9 vs. 4.8 years with adjusted hazard ratio 0.73 (95% CI 0.57-0.94, p=0.0166) and 5-year OS rates of 57% vs. 48% (Figure 1, right panel), confirming the randomized comparison (5-year OS rates, 59% vs. 47%, adjusted hazard ratio 0.74, 95% CI 0.50-1.09). OS curves of CHOP patients in GLSG1996 or GLSG2000 were overlapping as well as OS curves of patients with randomization or fixed assignment to R-CHOP in GLSG2000. Conclusions: After longer follow-up, pooled data of prospective GLSG trials showed prolonged survival by the addition of rituximab to CHOP induction in previously untreated MCL patients. Our results confirm the recommendation for immunochemotherapy as standard treatment for MCL. Compared to previous observations, clinical outcome for MCL patients has improved; however, further improvement by the introduction of more potent chemotherapy (e.g. high-dose cytarabine) or new targeted approaches is urgently warranted. Figure 1: Failure-free (left) and overall survival (right) of patients prospectively assigned to R-CHOP or CHOP in GLSG1996 or GLSG2000 trials Figure 1:. Failure-free (left) and overall survival (right) of patients prospectively assigned to R-CHOP or CHOP in GLSG1996 or GLSG2000 trials Figure 2 Figure 2. Disclosures Hoster: Roche: Travel Support Other. Off Label Use: Rituximab in mantle-cell lymphoma. Unterhalt:Roche: Travel Support Other. Hallek:Roche: Consultancy, Research Funding. Klapper:Roche: Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Autologous Stem Cell Transplantation and Addition of Rituximab Independently Prolong Response Duration in Advanced Stage Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 880-880 ◽  
Author(s):  
Eva Hoster ◽  
Bernd Metzner ◽  
Roswitha Forstpointner ◽  
Michael Pfreundschuh ◽  
Lorenz Trümper ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
Response Duration ◽  
Low Grade ◽  
Advanced Stage ◽  
Mantle Cell ◽  
Lymphoma Study Group

Abstract Abstract 880 On behalf of the German Low-Grade Lymphoma Study Group (GLSG) and the European MCL Network Background: In younger patients with mantle cell lymphoma (MCL), autologous stem cell transplantation (ASCT) significantly prolonged response duration with a trend towards improved overall survival in a randomized trial of the European MCL Network (Dreyling et al., ASH 2008). A recently updated clinical trial of the German Low-Grade Lymphoma Study Group (GLSG) also reported a significantly prolonged response duration by the addition of Rituximab to first-line CHOP (Hoster et al., ASH 2008). By pooled analysis of these trials we investigated whether Rituximab and ASCT independently prolong response duration. Methods: The analysis included all advanced stage MCL patients of the trials “CHOP vs. MCP” (Nickenig et al., Cancer 2006), “CHOP vs. R-CHOP” (Lenz et al., JCO 2005) and European MCL trial 1 (Dreyling et al., Blood 2005) with complete or partial remission to either CHOP or R-CHOP first-line induction and randomization between ASCT and Interferon-α maintenance. Response duration was defined as time from the end of successful induction chemotherapy to relapse or death from any cause, overall survival from the end of successful induction chemotherapy to death from any cause. Stratified Kaplan-Meier curves for response duration and overall survival were calculated for the four treatment groups (CHOP without ASCT, CHOP with ASCT, R-CHOP without ASCT and R-CHOP with ASCT). By multiple Cox regression we tested whether the impact of Rituximab (R) and ASCT was independent and additive. Results: One-hundred and eighty patients with MCL were evaluable, 80 treated with R-CHOP, 78 with ASCT (CHOP without ASCT: 56, CHOP with ASCT: 46, R-CHOP without ASCT: 44 and R-CHOP with ASCT: 34). Median age was 55 years (range 34-65), the MIPI classified 71% as low risk, 22% as intermediate risk, and 6% as high risk, and baseline characteristics were comparable between treatment groups. With a median follow-up of 63 months, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT. In multiple Cox regression including R and ASCT, the hazard ratios of R (0.60, 95% CI 0.42-0.86, p = 0.0056) and ASCT (0.50, 95% CI 0.35-0.70, p = 0.0001) were independently significant. There was no interaction between R and ASCT (p=0.43). Median overall survival was 54 months after CHOP without ASCT, 66 months after R-CHOP without ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP with ASCT. The hazard ratios for OS were 0.70 (95% CI 0.44-1.12, p = 0.14) for R and 0.63 (95% CI 0.41-0.97, p = 0.0379) for ASCT. Conclusions: Our results indicate an additive effect of ASCT and Rituximab in combination with CHOP on response duration in advanced stage MCL patients and support strategies of several study groups to combine Rituximab-containing induction therapies with ASCT in younger MCL patients. However, even after combined treatment approaches, delayed relapses have been observed, supporting the use of maintenance therapy and the introduction of molecular targeted therapeutical strategies. Disclosures: Hoster: Roche: Travel Support. Off Label Use: Rituximab in Mantle Cell Lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees. Dührsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support. Dreyling:Roche: Honoraria, Research Funding.

Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 619-626 ◽  
Author(s):  
Roberto Chiarle ◽  
Leo M. Budel ◽  
Jeffrey Skolnik ◽  
Glauco Frizzera ◽  
Marco Chilosi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Protein Degradation ◽  
Mantle Cell Lymphoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Low Grade ◽  
High Grade ◽  
Ki 67 ◽  
Mantle Cell

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription–polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P = .001), the loss of p27 (P = .002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P = .002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626)

Whole Transcriptome Sequencing Reveals Recurrent NOTCH1 Mutations in Mantle Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 436-436 ◽  
Author(s):  
Robert Kridel ◽  
Barbara Meissner ◽  
Sanja Rogic ◽  
Merrill Boyle ◽  
Adele Telenius ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
The Other ◽  
Mantle Cell ◽  
Whole Transcriptome ◽  
Notch1 Mutations

Abstract Abstract 436 Background: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma that is characterized by the hallmark t(11;14)(q13;q32) translocation, as well as a high number of secondary chromosomal alterations. Further, a small number of genes such as TP53, ATM and CCND1 have been reported to be recurrently mutated in MCL, but do not fully explain the biology and do not adequately account for the wide spectrum of clinical manifestations, response to treatment and prognosis. The aim of this study was to discover new somatic mutations that could contribute to our understanding of the pathogenesis of MCL. Methods: In our discovery cohort, we sequenced the transcriptomes of 18 clinical samples (11 diagnostic and 7 progression biopsies) and 2 mantle cell lymphoma-derived cell lines (Mino and Jeko-1). For this purpose, whole transcriptome shotgun sequencing was performed on RNA extracted from fresh frozen tissue. We assembled an extension cohort of 103 diagnostic patient samples and 4 additional cell lines (Rec-1, Z-138, Maver-1, JVM-2), and performed Sanger sequencing of NOTCH1 exons 26, 27 and 34 on genomic DNA. We further exposed the 6 cell lines to 1 μM of the γ-secretase inhibitor XXI (compound E) for 7 days and measured cellular proliferation with an EdU incorporation assay. Survival analysis was carried out in the 113 patients with diagnostic biopsies and available outcome data. Results: NOTCH1 mutations were found in 14 out of 121 patient samples (11.6%) and in 2 out of 6 cell lines, Mino and Rec-1 (33.3%). The majority of these mutations (12 out of 14) lie in exon 34 that encodes the PEST domain of NOTCH1 and consist of either small frameshift-causing indels (10 cases) or nonsense mutations (2 cases). These mutations are predicted to cause truncations of the C-terminal PEST domain. To gain further insight into functional relevance, we treated 6 cell lines with compound E, an inhibitor of the γ-secretase complex that plays a critical role in the release of the intracellular domain of NOTCH1 after ligand-induced activation. In Rec-1, that harbours a NOTCH1 mutation, we observed a significant decrease in proliferation (mean percentage of cells in culture incorporating EdU decreasing from 47.5% to 1.4%, p<.001). No effect of compound E was observed in Mino, the other cell line with a NOTCH1 mutation, nor in the 4 cell lines that are wild type for NOTCH1. Outcome correlation analysis showed that NOTCH1 mutations are associated with poor overall survival (1.56 versus 3.86 years respectively, p=.001), but not with significantly shortened progression-free survival (0.88 versus 1.73 years respectively, p=.07). Discussion: We have identified recurrent mutations in NOTCH1 in a subset of patients with MCL (11.6%). The frequency and the pattern of mutations are strikingly similar to what has recently been reported in chronic lymphocytic leukemia, the other major CD5 positive B-cell malignancy (Nature, 2011 Jun 5, 475:101–105 and J Exp Med, 2011 Jul 4, 208:1389–1401). NOTCH1 mutations are associated with adverse prognosis as evidenced by shortened overall survival. This latter finding, however, should ideally be validated in a larger and uniformly treated cohort. Finally, the sensitivity of the Rec-1 cell line to compound E suggests that NOTCH1 mutations could serve as the target for tailored therapy in mantle cell lymphoma. Disclosures: Sehn: Roche/Genentech: Consultancy, Honoraria, Research Funding. Connors:Roche: Research Funding.

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]

CHOP Improves Response Rates but Not Overall Survival in Follicular and Mantle Cell Lymphoma (MCL)- Results of a Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 611-611 ◽  
Author(s):  
Christina Nickenig ◽  
Martin H. Dreyling ◽  
Eva Schiegnitz ◽  
Michael Pfreundschuh ◽  
Lorenz H. Truemper ◽  
...  
Keyword(s):  
Overall Survival ◽  
Follicular Lymphoma ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Low Grade ◽  
Study Group ◽  
Advanced Stage ◽  
Conventional Chemotherapy ◽  
Mantle Cell ◽  
Lymphoma Study Group

Abstract In advanced stage follicular lymphoma conventional chemotherapy is non-curative and no major improvement in overall survival has been achieved by different regimens. Similarly, MCL, a lymphoma subtype with an especially poor clinical outcome, cannot be cured by conventional chemotherapy. In 1996, the German Low Grade Lymphoma Study Group (GLSG) started a randomized trial to evaluate the efficacy of two different anthracycline/anthrachinon containing regimens comparing CHOP (cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 2, adriamycine 50 mg/m2 day 1, prednisone 100 mg/m2 days 1–5) and MCP (mitoxantrone 8 mg/m2 days 1–2, chlorambucil 3x3 mg/m2 days 1–5; prednisone 25 mg/m2 days 1–5). 415 previously untreated patients with advanced stage indolent lymphoma were prospectively randomized to receive either 6–8 cycles of CHOP or MCP and are evaluable for induction therapy. 277 patients (67%) had a follicular lymphoma, 86 (21%) had a mantle cell lymphoma and 52 (13%) patients had another indolent histology. Responders up to 60 years were subsequently assigned to either myeloablative radiochemotherapy and autologous stem cell transplantation or to interferon-a maintenance (IFNa ), all other patients received IFNa. As stem cell mobilization was hampered in the MCP arm (only 44% sucessful mobilisations after MCP, 93% after CHOP; p=0.0003), from July 1998 all younger patients were asssigned to the CHOP arm. 86% complete and partial remissions (18% CR) were observed in the CHOP arm, whereas after MCP an overall response rate of 77% was obtained (14% CR, p=0.0094). In subgroup analysis similar improvement of remission rates were detected in follicular lymphoma (91% vs 82%, p=0.026) and mantle cell lymphomas (87% vs 73%, p=0.080). No differences, were observed, however, between both regimens for progression-free survival in both lymphoma subtypes. Overall survival was comparable for FL in both study arms (74% vs 69% at five years, p=0.29). In MCL, overall survival was slightly higher in the CHOP arm (5y OS: 57% vs. 31%; p=0.0578), but this difference was mostly due to unbalanced patient characteristics (IPI). In conclusion, CHOP appears superior to MCP in achieving a higher initial response rate but has no long term impact on response duration or overall survival.

Deferred Treatment Is Associated with Improved Overall Survival in Patients with Newly Diagnosed Mantle Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2717-2717
Author(s):  
Jonathon B. Cohen ◽  
Xuesong Han ◽  
Xin Hu ◽  
Ahmedin Jemal ◽  
Elizabeth Ward ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Early Stage ◽  
Cohort Analysis ◽  
Newly Diagnosed ◽  
Early Stage Disease ◽  
Deferred Treatment ◽  
Mantle Cell

Abstract Background: Although mantle cell lymphoma (MCL) has traditionally been considered an aggressive lymphoma with shortened survival, the long-term outcomes and initial presentation can be heterogeneous. Martin et al (JCO 2009) reported that 32% of patients with MCL at an academic referral center deferred therapy for at least 3 months, with a median overall survival (OS) of 64 months for patients treated within 90 days of diagnosis and median OS not reached for those who deferred therapy. We used the National Cancer Database (NCDB) to perform a national cohort analysis of the impact of deferred therapy in MCL. Methods: The NCDB is a nationwide oncology outcomes database sponsored by the Commission on Cancer of the American College of Surgeons and the American Cancer Society, capturing nearly 70% of all newly diagnosed cases of cancer in the United States. We included all patients ≥18 years old who received initial treatment for newly diagnosed MCL in 2004-2011. MCL patients were identified by the International Classification of Diseases for Oncology code 9673 and variables of interest were captured using the Facility Oncology Registry Data Standards. Patients were determined to have received deferred therapy if their time to initial treatment was > 90 days. Chi-square tests were used as appropriate to compare baseline characteristics between immediate and deferred treatment groups, and OS was estimated using the Kaplan-Meier method. Log-binomial regression models were developed to identify characteristics associated with deferred treatment and multivariable Cox proportional hazard models were fit to evaluate the relationship between deferred treatment and OS. Results: Of 8209 patients with MCL, 492 (6.1%) received therapy > 90 days from diagnosis with a median time to treatment for this group of 121 days (range 91-1152). Among all patients, 64% were > 60 years of age, 73% were male, 85% were stage III/IV, and 83% had primarily nodal disease. Additional comorbidities were identified in 22% of patients, and 28% of patients presented with B-symptoms at diagnosis. Approximately 1/3 of patients received therapy in a high volume teaching/research institution. Compared to patients treated within 90 days of diagnosis, patients receiving deferred therapy were more likely to have early stage disease (22% vs 15% p<0.0001), extranodal presentation (24% vs 17%, p<0.0001), to be located in the Northeast region (26% vs 20%, p<0.0001), and to be treated at a high volume teaching/research institution (41% vs 33%, p=0.005). Patients treated within 90 days of diagnosis more commonly had B-symptoms (29% vs 16%, p<0.0001). There were no significant differences between the two groups with regard to gender, age, year of diagnosis, socioeconomic status (based on location of residence), or primary payer. When analyzed in a multivariable model, lack of B-symptoms (RR 1.67, 95% CI 1.38-2.03, p < 0.0001) and extra-nodal status (RR 1.24, 95% CI 1.00-1.53, p = 0.0468) were two strong clinical predictors of deferred therapy. Multivariable analysis demonstrated improved OS for patients who received deferred therapy (HR 0.79: 95% CI 0.67-0.93, p = 0.005; See Figure 1). Additional significant predictors of improved OS included age ≤ 60 years (HR 0.60: 95% CI 0.54-0.66, p < 0.0001), early stage disease (HR 0.66: 95% CI 0.59-0.74, p < 0.0001), lack of B-symptoms (HR 0.75: 95% CI 0.70-0.81, p < 0.0001), and lack of comorbidities (HR 0.63: 95% CI 0.58-0.68, p < 0.0001). Non-Hispanic black patients had inferior OS compared to the other racial/ethnic groups. Among patients who deferred therapy, male gender (p=0.046), age ≤ 60 years (p=0.0002) and lack of comorbidities (p<0.0001) were associated with improved OS, while remaining variables including region, stage, race, B-symptoms, and extranodal presentation were not. Discussion: This national cohort analysis supports prior reports that deferred therapy in MCL is safe for a subgroup of patients with MCL. We found that deferred therapy > 90 days was associated with improved OS and that lack of B-symptoms was a strong predictor for deferred therapy. Predictors of improved survival for patients deferring therapy included young age and lack of comorbidities. These data support use of watchful waiting approach for well-selected newly diagnosed MCL patients. Figure 1. Overall survival for newly diagnosed patients with mantle cell lymphoma based on time to initiation of therapy. Figure 1. Overall survival for newly diagnosed patients with mantle cell lymphoma based on time to initiation of therapy. Disclosures Cohen: BMS: Research Funding; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Millennium: Consultancy; Celgene: Consultancy; Janssen: Research Funding. Flowers:Infinity Pharmaceuticals: Research Funding; Acerta: Research Funding; Millennium/Takeda: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Onyx Pharmaceuticals: Research Funding; Janssen: Research Funding; OptumRx: Consultancy; Spectrum: Research Funding; Seattle Genetics: Consultancy; Infinity Pharmaceuticals: Research Funding; Genentech: Research Funding; Millennium/Takeda: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Onyx Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Pharmacyclics: Research Funding; AbbVie: Research Funding; Seattle Genetics: Consultancy; Celegene: Other: Unpaid consultant, Research Funding; OptumRx: Consultancy.

The Addition of Rituximab to Fludarabine and Cyclophosphamide (FC) Improves Overall Survival in Newly Diagnosed Mantle Cell Lymphoma (MCL): Results of the Randomised UK National Cancer Research Institute (NCRI) Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 440-440 ◽  
Author(s):  
Simon Rule ◽  
Paul Smith ◽  
Peter W Johnson ◽  
Simon Bolam ◽  
George A Follows ◽  
...  
Keyword(s):  
Overall Survival ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
End Of Treatment ◽  
Mantle Cell ◽  
Experienced Grade ◽  
Grade Iii

Abstract Abstract 440 Background: Rituximab is widely used in combination with chemotherapy for treating B cell lympho-proliferative disorders. In MCL, two randomised trials explored the addition of Rituximab to standard initial therapy. Neither demonstrated a significant improvement in either PFS or OS. In 2002 the NCRN initiated a phase II randomised trial of FC chemotherapy with or without Rituximab to evaluate response rates. In 2006 this was extended to a phase III study with overall survival as the primary end point. Trial: Newly diagnosed patients with MCL requiring therapy received up to 8 cycles of oral FC (Fludarabine 40mg/m2 and Cyclophosphamide 250mg/m2 both daily × 3) given every 4 weeks with a randomisation to the addition of Rituximab 375mg/m2 on day 1. There was no age limit to the study, no risk stratification and no consolidation of responses with transplantation or maintenance therapy. Results: 370 patients were randomised. Median age was 66 years (range 36 – 88) with 76% male patients. The arms were well balanced by Mantle Cell International Prognostic Index (MIPI); 77% in the FCR arm and 71% in the FC arm were in the intermediate or high risk groups. 78% and 72% respectively received 4 or more cycles of FCR/FC. At the end of treatment the ORR was 90.6% in the FCR arm and 79.8% in the FC arm (p = 0.01) with CR + CRu rates of 64.7% and 46.9% (p = 0.002) respectively. 5.8% of patients in the FCR arm and 11.9% in the FC arm had PD at the end of treatment. Patients in the FCR arm had longer progression free and overall survival with HRs of 0.56 (95% CI: 0.43–0.73, p < 0.001) and 0.72 (95% CI: 0.54–0.97, p = 0.03) respectively. At a median follow up of 38.8 months the median PFS is 30.6 months in the FCR arm and 16.1 months in the FC arm. The median OS is 45.7 months for FCR and 37 months for FC. The major toxicities were haematological. Significantly more patients in the FCR arm experienced grade 3 or 4 Leucopoenia and Thrombocytopenia however the numbers of grade 4 were not significantly different. Combined grade III/IV toxicity showed 23.3% thrombocytopenia, 45.8% leucopoenia, 12.9% anaemia and 51.4% neutropenia. 11.8% of patients had significant infections. Renal toxicity was modest. 1 patient experienced grade III but there was no grade IV toxicity. Lymphoma was the commonest cause of death, but 29% of patients in the FCR arm and 24% in the FC arm died of other causes, of which almost half were infection related. An additional 11 patients died of a second malignancy, 4 of whom had AML. 14% of patients in the FCR arm and 10% in the FC arm died without evidence of disease progression. Conclusion: The addition of Rituximab to FC chemotherapy leads to a significant improvement in both PFS and OS with an acceptable level of additional toxicity. A significant number of patients treated with FC based chemotherapy die whilst in remission of non lymphoma related causes. Disclosures: Rule: Roche: Consultancy, Research Funding. Off Label Use: Rituximab in mantle cell lymphoma. Follows:Roche: Consultancy, Honoraria. Hillmen:Roche Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKine: Honoraria, Speakers Bureau; Genzyme: Research Funding; MundiPharma: Honoraria, Speakers Bureau. Walewski:Janssen-Cilag: ; Hoffman La Roche: Honoraria, Institutional/personal grants, travel/accommodation expenses; Mundipharma: Honoraria; Celgene: Honoraria.

scholarly journals A Phase II, Open-Label, Single Arm Trial to Assess the Efficacy and Safety of the Combination of Tisagenlecleucel and Ibrutinib in Mantle Cell Lymphoma (TARMAC)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Adrian Minson ◽  
Nada Hamad ◽  
Jason P Butler ◽  
David Alan Westerman ◽  
David Ritchie ◽  
...  
Keyword(s):  
T Cell ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
Complete Response ◽  
Advisory Committees ◽  
Car T ◽  
Mantle Cell

Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.

scholarly journals A Phase II Clinical Trial of Rituximab, Cyclophosphamide, Bortezomib, and Dexamethasone (R-CyBor-D) in Relapsed Low Grade and Mantle Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4410-4410
Author(s):  
Allison C. Rosenthal ◽  
Amylou Constance Dueck ◽  
Katherine Gano ◽  
Craig Nichols ◽  
Daniel Johnson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Combination Therapy ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Sensory Neuropathy ◽  
Low Grade ◽  
Best Response ◽  
Mantle Cell

Abstract Introduction Non-Hodgkin lymphoma responds to single agents such as cyclophosphamide, combination therapy such as CVP and immunotherapy with monoclonal antibodies such as rituximab. There is no consensus on the optimal treatment for relapsed low grade or mantle cell lymphoma. Based on the success and tolerability of combining alkylating agents with proteasome inhibitors in multiple myeloma, a phase II clinical trial of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBor-D) was designed to explore the efficacy and safety of this combination in relapsed low grade and mantle cell lymphoma (MCL). Methods This trial enrolled relapsed patients at Mayo Clinic from October 2008 to March 2014. Eligibility required age≥18; biopsy proven follicular grades 1 or 2 lymphoma (FL), MCL, small lymphocytic lymphoma/chronic lymphocytic leukemia, marginal zone B-cell lymphoma, or Waldenström’s macroglobulinemia (WM); life expectancy >3 months; ECOG PS 0, 1 or 2; measurable disease; Hb ≥8g/dl, ANC ≥1200/uL, platelet ≥75,000/uL, creatinine ≤1.5xULN, total bilirubin ≤1.5xULN, alkaline phosphatase ≤3xULN, AST ≤3xULN; and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Treatment included rituximab 375 mg/m2 IV on day 1 and oral cyclophosphamide 300 mg/m2, IV bortezomib 1.3 mg/m2, and oral dexamethasone 40 mg on days 1, 8, 15, and 22 in a 28-day cycle. Treatment was continued two cycles beyond best response or a maximum of 12 cycles. Allopurinol 300 mg on days 0-14 for the first cycle was strongly recommended. Results 21 patients were enrolled prior to study closure due to slow accrual. Bortezomib was initially given on days 1, 4, 8, and 11 in the first 16 patients, but was subsequently modified to days 1, 8, 15, and 22 due to significant peripheral neuropathy (PN). Median age was 69 years (range 51-80) and 13 (62%) were male. 62% had stage IV disease and 17 (81%) had 2 or more prior treatments with 3 (14%) having prior autologous stem cell transplantation. Histologies included FL-I (n=6), FL-II (n=2), MCL (n=8), and WM (n=5). Patients completed a median of 4 cycles of treatment (range 1-12), discontinuing due to 9 (43%) completion per protocol, 4 (19%) progression, 5 (24%) adverse events, 1 (5%) patient refusal, and 2 (10%) other reasons. Median follow-up is 32.8 months (0.9-54.8). CR or PR as best response was observed in 13 (62%, 95% CI 38-82%; 4 CR [19%], 9 PR [43%]) patients. By histology, CR or PR was observed in 7 (88%) FL patients (4 CR, 3 PR); 2 (25%) MCL patients (both PR), and 4 (80%) WM patients (all PR). CR or PR was observed in 10/16 (62%; 4 CR, 6 PR) before and 3/5 (60%; all PR) after the change in bortezomib schedule. Among 13 patients with CR or PR, median duration of response was 25.9 months (95% CI 8.0-not reached). Median PFS and OS were 11.6 months (95% CI 3.8-not reached) and 54.8 months (95% CI 24.6-54.8), respectively. At least one Gr≥3 adverse event at least possible related was observed in 14 (67%) patients, the most common being leucopenia (7, 33%), neutropenia (7, 33%), thrombocytopenia (6, 29%), anemia (5, 24%), PN (5, 24%), and fatigue (3, 14%). Peripheral sensory neuropathy at least possibly related was Gr1, Gr2, and Gr3 in 5 (24%) patients each, with a lower rate observed for patients after the change in bortezomib schedule (before 13/16 [81%] Gr≥1, after 2/5 [40%] Gr≥1). Among 14 patients who completed a baseline and at least one post-baseline FACT/GOG-NTX additional concerns questionnaire, 10 (71%) reported clinically meaningful (≥3-point) worsening in patient-reported neurotoxicity (8/11 [73%] before and 2/3 [67%] after the change in bortezomib schedule). Conclusions Our results suggest R-CyBor-D is a safe and effective combination in patients with relapsed low grade and mantle cell lymphomas. High response rates were seen in FL and WM. The majority of significant AE’s were hematologic. However, sensory neuropathy was common with twice weekly dosing of bortezomib and lessened with weekly dosing. Determination of optimal treatment regimens in this population remains an unmet need. Additional clinical trials including larger patient numbers are necessary to confirm these observations. This trial was sponsored by Millennium Disclosures Off Label Use: bortezomib was used in combination therapy to treat relapsed low grade lymphomas and Waldenstrom's macroglobulinemia. Bergsagel:Novartis: Research Funding; Constellation Pharmaceutical: Research Funding; OncoEthix: Research Funding; MundiPharma: Research Funding. Tiedemann:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

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