High TP53 Mutation Load Predicts Primary Refractory Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) is rare B-cell lymphoma subtype with usually aggressive behavior. Mutations of TP53 gene and complex karyotype (CK) were described to be poor prognostic factors (Obr A et al, 2018), but their impact on primary resistance to induction has not been investigated. Methods: We analyzed 115 MCL patients (pts) treated in two Czech university centers from 4/2006 to 10/2016. Both classical cytogenetics and next generation sequencing (NGS, MiSeq, Illumina) for TP53 mutation detection were performed on tumoral tissue (peripheral blood, bone marrow) in all patients. Cut-off for TP53 mutation was 1% variant allele frequency (VAF). CK was defined as 3 and more cytogenetic aberrations in one cell population. Pts with stable or progressive disease (SD/PD) during induction or with relapse within 6 months after induction completion were considered as primary refractory (PrR). Variables were compared by chi-squared test. T-test was used to compare the difference between means of TP53 mutation load in PrR+ and PrR- subgroup. Cut-off for TP53 mutation load (27%) was established as median VAF. Overall and progression free survival (OS, PFS) were calculated from the date of diagnosis. Results: The median age at diagnosis was 66 (40-87) years. Ninety-six percent of pts had advanced disease (III and IV). MIPI score was low, intermediate and high in 19.1%, 27.8% and 53.0% pts, respectively. Induction regimens used were as follows: R-CHOP/R-CHOP-like in 47.8%, intensive R-HDAC-containing in 38.3% and non-anthracycline regimen in 9.6% pts. Complete and partial response was achieved in 53.0% and 27.0% pts, resp. SD/PD was observed in 11.3% pts. Overall, 27 (23.5%) pts were considered as primary refractory. TP53 mutation and CK were present in 37 (32.3%) and 15 (13.0%) pts, respectively. Age, disease stage, ECOG score, MIPI, HDAC therapy and CK did not correlate with PrR status. Significantly higher TP53 mutation load was observed in the PrR+ (42%), compared to PrR- subgroup (25%, p=0.03). After median follow-up of 4.6 years, 3-year overall survival (3-y OS) and 3-year progression free survival (3-y PFS) in all pts was 65.8% and 50.9%, resp. Median OS in PrR+ and PrR- pts was 9.2 months, and 4.5 years, resp. Survival analysis stratified according to the TP53 mutation status/mutation load showed 3-y OS and 3-y PFS for wild type (TP53-WT), low mutation load (TP53-low load), high mutation load (TP53-high load) 74.2%, 47.6%, 33.3% and 56.0%, 37.0%, 27.8%, respectively (p=0.001 both). Conclusions: High TP53 mutation load (>27% VAF), but not CK, has significantly correlated with refractory disease in MCL pts. Pts with high mutation load of TP53 gene should be considered to an innovative treatment. Acknowledgement: Supported by IGA_LF_2019_001, MH CZ - DRO (FNOl, 00098892), AZV16-32339A and AZV16-31092A grants Figure Disclosures Trneny: Morphosys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Gilead sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: a Japanese phase II study

Annals of Oncology ◽

10.1093/annonc/mdf155 ◽

2002 ◽

Vol 13 (6) ◽

pp. 928-943 ◽

Cited By ~ 94

Author(s):

T. Igarashi ◽

Y. Kobayashi ◽

M. Ogura ◽

T. Kinoshita ◽

T. Ohtsu ◽

...

Keyword(s):

B Cell ◽

Mantle Cell Lymphoma ◽

Phase Ii Study ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Free Survival ◽

Factors Affecting ◽

Mantle Cell ◽

Toxicity Response

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High Remission Rates and Prolonged Progression Free Survival in Newly Diagnosed Patients with Mantle Cell Lymphoma Treated with R-MACLOIVAM-T

Blood ◽

10.1182/blood.v112.11.3597.3597 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3597-3597 ◽

Cited By ~ 2

Author(s):

Peter J Hosein ◽

Daniel Morgensztern ◽

Francine Coleman ◽

Gail Walker ◽

Maricer Escalon ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Relapse Rate ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Free Survival ◽

Mantle Cell ◽

Grade 3

Abstract Background: Mantle cell lymphoma (MCL) is an unfavorable subtype of B-cell non-Hodgkin lymphoma characterized by median progression-free survival (PFS) and median overall survival (OS) of only 1.5 and 3–4 years respectively. Although high-dose therapy and an autotransplant may prolong OS, it does not result in a long-term disease free survival. Therefore, there is a need for novel therapeutic approaches for this entity. Methods: We conducted a single-arm phase II study in subjects with newly-diagnosed MCL to assess efficacy and safety of a novel intensive regimen R-MACLO-IVAM-T, a modification of a protocol designed by Magrath et al (JCO1996;14:925). The study size of 22 patients was based on precision of a two-sided 95% confidence interval for the 18-month progression free survival rate. Eligible subjects had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS ≤ 2, adequate organ function and no history of HIV or prior cancer. Lymphoma extent at presentation was assessed by standard staging procedures as well as esophagogastroduodenoscopy and colonoscopy. Prior to initiating thalidomide maintenance, subjects were enrolled in the STEPS® program. Cycle 1 consisted of R-MACLO: rituximab 375 mg/m2 IV on day 1, doxorubicin 45 mg/m2 IV on day 1, cyclophosphamide 800 mg/m2 IV on day 1 and 200 mg/m2/day on days 2–5, vincristine 1.5 mg/m2 on days 1 and 8 capped to 2mg, methotrexate 1.2 g/m2 IV on day 10 over 1 hour followed by 5.52 g/m2 IV over 23 hours followed by leucovorin 36 hours later. G-CSF was begun on day 13. When the ANC was >1.5×109/L, cycle 2 with R-IVAM was begun: rituximab 375 mg/m2 IV day 1, cytarabine 2 g/m2 IV every 12 hours on days 1 and 2, etoposide, 60 mg/m2 on days 1–5 and ifosfamide 1.5 g/m2 on days 1–5 with mesna. Fourteen days after ANC recovery from cycle 2, cycles 3 and 4 were given in identical fashion to 1 and 2. Four weeks after ANC recovery from cycle 4, subjects were re-staged and responses were assessed by standard criteria. Subjects achieving CR at the end of therapy received thalidomide 200 mg/day until MCL relapse or intolerable toxicity. Results: Accrual started in 4/2004 and ended in 3/2008 when the planned 22 subjects were enrolled. All subjects were evaluable for toxicity and 21 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage 3 disease with bone marrow involvement in 19 and gastrointestinal involvement in 10. Distribution according to IPI: 0–1 factor, 3; 2 factors, 8; 3 factors, 8; and 4 factors, 3. Twenty subjects had diffuse variant and 2 had blastic variant. Nineteen subjects completed all 4 cycles of therapy; treatment was stopped in 2 subjects after 2 and 3 cycles respectively, and one subject died during the first cycle. Of the 21 subjects completing 2 cycles of therapy, 20 achieved CR and one PR. Two subjects relapsed at 9 and 33 months respectively, while 19 remain relapse free after median follow-up of 25 months (range 5–51). With a total follow-up of 545 months, the estimated relapse rate is 4.4 per 100 patients per year. There were two deaths: 1 from sepsis on cycle 1 day 8 and the other in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL. Common severe toxicities were grade 3–4 neutropenia, thrombocytopenia and anemia in 33%, 19% and 17% of R-MACLO cycles and in 50%, 88% and 68% of R-IVAM cycles respectively. There were 14 bacteremias in 82 cycles, 12 of which were after R-IVAM therapy. Six episodes of reversible grade 1–2 renal toxicity occurred after methotrexate. The thalidomide maintenance dose was reduced in 6 subjects due to grade 3–4 neutropenia and reduced or stopped in 8 subjects because of grade 3–4 peripheral neuropathy. Patients remain under follow-up for relapse and survival. Conclusions: R-MACLO-IVAM-T results in a high overall response rate of 100% (95% CR and 5% PR) and a low relapse rate. At a median follow-up of 25 months, median PFS and OS were not reached. The 2-year actuarial PFS of 94% compares favorably with previously reported 2-year actuarial PFS of 40% and 67% for CHOP-like regimens without and with upfront bone marrow transplantation (Blood2005;105: 2677). The contribution of thalidomide maintenance to this outcome requires additional study. A multicenter clinical trial is suggested.

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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)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7502 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7502-7502 ◽

Cited By ~ 15

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]

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CXCR4 Expression in Mantle Cell Lymphoma and Mobilization with Plerixafor for ASCT Does Not Negatively Impact Progression-Free Survival

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2014.11.194 ◽

2015 ◽

Vol 21 (2) ◽

pp. S140

Author(s):

Hidong Kim ◽

Patrick B. Johnston ◽

Betsy LaPlant ◽

Stephen Ansell ◽

David J. Inwards ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Progression Free Survival ◽

Cxcr4 Expression ◽

Free Survival ◽

Mantle Cell

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Encouraging Activity of Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma: Results From a Phase II Study (BO20999),

Blood ◽

10.1182/blood.v118.21.3655.3655 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3655-3655 ◽

Cited By ~ 5

Author(s):

Franck Morschhauser ◽

Guillaume Cartron ◽

Catherine Thieblemont ◽

Philippe Solal-Celigny ◽

Corinne Haioun ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Response Duration ◽

Free Survival ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Anti Cd20 ◽

Large B Cell

Abstract Abstract 3655 Obinutuzumab (GA101) is a type II glycoengineered, humanized anti-CD20 monoclonal antibody that has increased antibody-dependent cellular cytotoxicity and direct cell death activity but lower complement-dependent cytotoxicity compared with type I anti-CD20 antibodies such as rituximab and ofatumumab. GA101 is in clinical development for the treatment of lymphoma and chronic lymphocytic leukemia. The Phase I/II study BO20999 has evaluated the efficacy and safety of GA101 monotherapy in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (aNHL). Here, we report updated Phase II results including progression-free survival (PFS) and best overall response (BOR). Patients (n = 40) were randomized to receive GA101 (D1, D8 and D22, then 3-weekly for total of 9 infusions) at either a high dose (1,600 mg on D1 and D8, then 800 mg thereafter; 1,600/800 mg cohort; n = 19), or a flat low dose of 400 mg (400/400 mg cohort; n = 21). Baseline patient characteristics were similar for both cohorts (Table 1). The median observation time for all patients was 9.5 months (0.3–26.1 months). BOR rates are given in Table 2, with 8/25 diffuse large B-cell lymphoma (DLBCL) patients (32%) and 4/15 mantle cell lymphoma (MCL) patients (27%) responding to GA101. Among the patients with rituximab-refractory disease, a response was observed in 1/13 patients (7.7%) and 4/12 patients (33.3%) treated in the 400/400 mg and 1,600/800 mg cohorts, respectively. Of these, 4 patients (1,600/800 mg cohort) had a response duration > 6 months, with 2 patients having an ongoing response (response duration: 9.8, 16.5+, 19.5 and 20.0+ months). Median PFS for patients with DLBCL (Figure 1) was 1.9 months (range: 0.3–15.7 months) for the 400/400 mg cohort and 2.7 months (range: 0.2–22.3) months) for the 1,600/800 mg cohort (hazard ratio: 0.70; 95% CI: 0.30–1.66). For the DLBCL subgroup, response duration was 3.1, 3.1+, 5.8, 16.5+ and 19.5 months for the 5 responders in the 1,600/800 mg cohort, compared with 6.3, 8.6 and 9.8 months for the 3 responders in the 400/400 mg cohort. Individual response data indicated that 2 MCL patients had an ongoing response for ≥ 20 months (20.0 and 20.4 months). GA101 was well tolerated in both cohorts. Infusion-related reactions (IRRs; all grades) were the most common adverse event (AE), occurring in 81% of patients in the 400/400 mg cohort and 68% of patients in the 1600/800 mg cohort. Grade 3/4 AEs occurring in >5% of patients across both cohorts included IRRs (10%), tumor lysis syndrome (10%), cardiac failure (not treatment-related; 10%), anemia (14%) and thrombocytopenia (14%) in the 400/400 mg cohort and IRRs (5%) and anemia (5%) in the 1,600/800 mg cohort.Table 1.Baseline patient characteristicsCharacteristic400/400 mg (n = 21)1,600/800 mg (n = 19)All (n = 40)Median age, years (range)70 (43–80)72 (22–85)71 (22–85)Histology, nDLBCL101525MCL11415Median number of prior treatments, n (range)4 (1–17)3 (1–6)3 (1–17)Previous rituximab, n211940Rituximab refractory*, n131225Prior stem cell transplant, n268DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.*Rituximab refractory defined as patients who had a response of < 6 months or who failed to respond to a rituximab-containing regimen (rituximab monotherapy or in combination with chemotherapy) at any point during their treatment history.Table 2.Best overall response according to diagnosis and cohortDLBCLMCLResponse, n (%)400/400 mg (n = 10)1,600/800 mg (n = 15)400/400 mg (n = 11)1,600/800 mg (n = 4)Complete response (CR)0 (0.0)3 (20.0)2 (18.2)0 (0.0)CR unconfirmed1 (10.0)0 (0.0)0 (0.0)0 (0.0)Partial response2 (20.0)2 (13.3)0 (0.0)2 (50.0)Stable disease1 (10.0)1 (6.7)3 (27.3)0 (0.0)Progressive disease5 (50.0)9 (60.0)6 (54.5)2 (50.0)No response assessment1 (10.0)0 (0.0)0 (0.0)0 (0.0)DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma.Figure 1.Progression-free survival for patients with diffuse large B-cell lymphomaFigure 1. Progression-free survival for patients with diffuse large B-cell lymphoma In conclusion, GA101 shows encouraging single-agent efficacy in these heavily pretreated patients with relapsed/refractory aNHL (DLBCL or MCL). A Phase III trial of rituximab plus CHOP vs GA101 plus CHOP in first-line DLBCL has recently started. Disclosures: Morschhauser: Roche: Honoraria; Celgene: Consultancy, Honoraria. Cartron:Roche: Consultancy, Honoraria; GSK: Honoraria; LFB: Honoraria. Milpied:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wenger:Roche: Employment. Wassner-Fritsch:Roche: Employment. Asikanius:Roche: Employment. Salles:Roche: Consultancy, Honoraria.

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Elevated Soluble IL-2Ra Levels Are Associated With Inferior Outcome and Is Independent Of MIPI Score in Patients With Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v122.21.4256.4256 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4256-4256

Author(s):

Mohamad Bassam ◽

Matthew J Maurer ◽

Mary Stenson ◽

Linda E Wellik ◽

Christine Allmer ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Newly Diagnosed ◽

Event Free Survival ◽

Free Survival ◽

Cytokine Levels ◽

Mantle Cell ◽

Pre Treatment ◽

Normal Controls

Abstract Blood cytokine elevations have been associated with non-Hodgkin's lymphoma (NHL) such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Although other types of NHL have been studied, to our knowledge, cytokine deregulation in mantle cell lymphoma (MCL) has not been comprehensively studied. In this study, we studied cytokine levels in untreated and relapsed MCL patients using a multiplex assay to determine the role of dysregulated cytokines in these patients and study any prognostic relevance that could be drawn from their effect on relapse and survival. Samples from two data sets of MCL patients were used for this study. The first dataset was pre-treatment serum samples from newly-diagnosed patients with MCL (n=88) from the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource. The second dataset included pre-treatment plasma samples from relapsed MCL patients (n=20) treated on the MC0048G clinical trial studying the effect of everolimus in lymphoma patients. In addition, unrelated controls from a case-control study of lymphoma were included (n=15 serum, n=24 plasma). Thirty cytokines were assessed using a multiplex ELISA. Differences between cytokines in cases and controls were assessed using Wilcoxon rank-sum tests; associations between cytokines and event-free survival were assessed using Kaplan-Meier curves and Cox proportional hazards models. In the newly diagnosed MCL patients, IL-10 (p<0.0001), IL-1RA (p=0.001), IL-6 (p= 0.04), sIL-2Rα (p=0.005), and MIG (p=0.002) were elevated compared to normal controls. The only significantly elevated cytokine in the recurrent MCL cases compared to controls was sIL-2Rα (p= 0.0006). High levels (above median) of sIL-2Rα levels were associated with inferior event-free-survival (EFS) in both newly diagnosed (HR=2.61 (95% CI: 1.41-4.81, p= 0.0022) and relapsed MCL (HR=2.90, 95% CI: 1.08-7.80, p=0.035) patients; this remained significant after adjusting for MIPI (p=0.01 and 0.03, respectively). Moreover, in the relapsed MCL group eotaxin (p< 0.0001), IL-12 (p< 0.0001), and MCP-1 (p= 0.0002) were suppressed compared to normal controls. We hypothesized that STAT3 (pSTAT3) in MCL cells might be the possible cause behind IL-12 suppression. Indeed, 12/13 MCL samples from IL-12-suppressed relapsed MCL patients were pSTAT3+. When studying the association between cytokine levels and clinical characteristics in both untreated and relapsed MCL groups, sIL-2R was significantly associated with the MIPI score in both untreated (p<0.0001) and relapsed (p=0.007) MCL groups; and with performance status (p=0.005), lymphoma stage (p=0.004), and B symptoms (p=0.006) in the newly diagnosed MCL group.Figure 1Event-free survival of patients with untreated and relapsed MCL by sIL-2R levels.Figure 1. Event-free survival of patients with untreated and relapsed MCL by sIL-2R levels. Our study shows that cytokines are deregulated in both untreated and relapsed MCL patients. It emphasizes on the importance of sIL-2R in its association with negative clinical parameters and worse prognosis in MCL. These findings gives the rational for using sIL-2R along with MIPI and other parameters in predicting prognosis and further to monitor response in MCL. Furthermore, we showed that IL-12 is suppressed in relapsed MCL group and that pSTAT3 expression is a possible mechanism behind this suppression. Further studies are needed to investigate the effect of drugs that suppress pSTAT3 expression in IL-12 suppressed MCLs and disease progression in relapsed MCL patients. Disclosures: No relevant conflicts of interest to declare.

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