High MIPI Research Articles

Frontline treatment with zanubrutinib plus rituximab (ZR) followed by short course R-DHAOx in patients with mantle cell lymphoma (MCL): Results of the phase II CHESS clinical trial.

7062 Background: Combining Bruton’s tyrosine kinase (BTK) inhibitor and rituximab showed favourable efficacy as first-line therapy for mantle cell lymphoma (MCL). Zanubrutinib, a next-generation, highly-selective BTK inhibitor, achieved promising antitumor activity in MCL. In this multicenter phase II trial (CHESS - chemo-less), we aimed to investigate the efficacy and toxicity of zanubrutinib plus rituximab (ZR) combination, followed by short course cytarabine-based chemotherapy, then zanubrutinib maintenance as frontline therapy for MCL (NCT04624958). Methods: Previously untreated MCL patients enrolled and received induction therapy of ZR until complete response (CR) or to a maximum of 12 cycles, and followed by 4 cycles of R-DHAOx regimen (rituximab, dexamethasone, cytarabine and oxaliplatin). Patients achieving CR after chemotherapy would receive maintenance therapy with zanubrutinib for a maximum of 1 year. The primary endpoint was CR rate after induction therapy with ZR regimen. Minimal residual disease (MRD) of bone marrow and peripheral blood were evaluated by flow cytometry. Results: From Oct 2020 to Nov 2023, a total of 42 patients were enrolled and the enrollment was finished. The median age was 57 years (IQR, 51-64). Stage III-IV accounted for 92.8%, and 42.8% were intermediate or high risk simplified MIPI. Thirty-four patients (81.0%) were classic histological subtype. The median cycle of ZR was 4 (range, 2-6). As of Jan 2024, among 37/42 patients with post-treatment PET evaluation, the best CR rate of ZR regimen was 91.9% (34/37), and 94.1% (32/34) obtained CR after 2-4 cycles. The bone marrow MRD negative CR rate was 92.0% (23/25). The other 5/42 patients were still receiving ZR treatment, and PET evaluation would be performed subsequently. Among 27 patients who finished chemotherapy and were evaluable for response, only one patient experienced disease progression. With a median follow up of 11.6 months, the 1-year progression-free survival and overall survival was 90.1% and 96.7%, respectively. Two patients died due to lymphoma (n=1) and COVID-19 (n=1). Grade 3-4 adverse events on ZR regimen were neutropenia (n=3), fatigue (n=2), and aminotransferase (n=1). During chemotherapy, grade 3-4 thrombocytopenia was observed in 75.8% of patients. Conclusions: Induction treatment with ZR followed by short-course R-DHAOx chemotherapy yielded promising antitumor efficacy. This strategy might reduce the toxicity of cytarabine-based chemotherapy without weakening the therapeutic efficacy. Clinical trial information: NCT04624958 . [Table: see text]

Six Years Follow up of Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hyper CVAD/MTX in Patients (age ≤ 65 years) with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-1 Clinical Trial

Background - We reported the efficacy and safety of using a combination of ibrutinib plus rituximab (IR) induction followed by short course (4 cycles) of R-HCVAD/MTX-ara-C as consolidation in previously untreated young (age ≤ 65 years)patients (pts) with mantle cell lymphoma (MCL), Wang M et al Lancet Oncology 2022. Here we report the long term follow up of this study. Methods - We enrolled 131 previously untreated pts in this single institution, single arm, phase II clinical trial - NCT02427620. Pts received IR induction (part-A), until they achieved complete remission (CR) for up to a maximum of 12 cycles, followed by a maximum of 4 cycles of R-HCVAD/R-MTX-ara-C (part-B) as consolidation. The primary objective was to assess overall response rate (ORR), [defined as either a partial response (PR) or a complete response (CR)] after part A. Adverse events were coded as per CTCAE version 4. High risk pts received ibrutinib for 1 year and rituximab once every 2 months for 24 months after completion of part B. Results - Among the 131 pts, the median age was 56 yrs (range - 35-65). High Ki-67 (≥30%) in 58/117 (49.5%) pts, 10 pts (8%) had high risk simplified MIPI score, 15 pts (11%) had aggressive MCL (blastoid/pleomorphic) and 114 pts (87%) had initial bone marrow involvement. Fifty percent of the patients had Ki-67 (≥30%). ORR in part-A was 98% (87% CR). After completion of part A and part B, ORR was 90% (89% CR). After a median follow up of 71 months, 43 patients progressed/died. The median progression free survival (PFS) and overall survival (OS) were not reached. Overall, 30 pts (23%) relapsed after treatment, including 5 who transformed to aggressive MCL. PFS among pts with high and low Ki-67% was 42 months vs not reached (P=0.01) while no difference was observed in OS. PFS was significantly shorter in pts with aggressive histology (p=0.001) but not the OS. PFS was similar in pts who received maintenance vs no maintenance therapy. Overall, 8 pts died (4 with progression, 2 due to disease transformation, one on study due to multiple complications including splenic hematoma, cardio-pulmonary arrest and progression and the last one expired outside and came off study due to encephalitis). 50 pts came off study for various reasons [30 disease progression (including 5 transformation), 10 pt choice, 8 intolerance, 1 second cancer and 1 lost to follow up]. Long term, grade 3-4 toxicities on part A were 6% myelosuppression and 10% each with fatigue, myalgia and rashes and 2% mucositis. Maintenance therapy did not show high toxicities. Conclusions -Long term follow up of chemo-free induction with IR induced durable and deep responses in young MCL pts in the frontline setting. Short course R-HCVAD chemotherapy minimized toxicities and consolidated responses. IR maintenance improved survival outcomes. This combined modality treatment approach may significantly improve young MCL pts outcomes across all risk groups.

Mantle Cell Lymphoma in Brazil: First Report from a Real-World Evidence Study of a Third World Country

Introduction: Mantle cell lymphoma (MCL) is an uncommon type of B-cell lymphoma with an heterogeneous clinical presentation and evolution spanning from an indolent leukemic non-nodal disease to an aggressive blastoid or pleomorphic nodal disease. Moreover, MCL has strong prognostic factors such as MIPI, proliferating index by ki-67 and, recently, P53 mutation. The best therapy seems to be an intensive one with rituximab-cytarabine based induction followed by an autologous stem-cell Transplantation with median overal survival (mOS) exceding 10 years. Real world evidence studies (RWE) are important to compare clinical outcomes and population characteristics with the ones from clinical findings. Moreover, the majority of MCL patients are treated in the public system in Brazil without access to important terapies such as rituximab and BTKinhibitors. Objective: We aimed to describe epidemiological characteristics, type of therapy and clinical outcomes of Brazilian patients with MCL diagnosticated between Jan 2010 until Dec 2021. Moreover, the comparison between outcomes according to the place of treatment (public vs private) were analyzed as well. This first report include patients from 5 public and 1 private centers from 3 cities: Rio de Janeiro, Petropolis and Brasilia. Patients and Methods: This RWE study began locally in Rio de Janeiro but is currently being expanded across all Brazilian institutions that fulfilled the compliance and confidentiality forms. Only patients with Cyclin D1 and/or SOX11 positivity are included. All the data is collected locally and typed in an eCRF (Redcap by Einstein Hospital). This analysis were made with patients from 5 included institutions. Ki-67 values were retrieved from the pathological reports as percentages of positive MCL cells. A sample of patients from one public center was tested for P53 by immunohistochemistry(IHC) and results were scored as percentage of positive MCL cells. Statistical tests were done with SPSS 20.0 software. Survival curves were made by the Kaplan-Meier Method and compared with Log Rank test. Results: The study included 75 patients (56 males and 19 females). Median age at diagnosis was 64 years (24y-96y). The ECOG was 0 or 1 in 68 patients. Lymphocytosis was present in 22 patients. MIPI risk-groups could be obtained in 63 patients and it was low in 18, intermediate in 23 and high in 22. The ki-67 was obtained in 43 patients and was ≤ 30% in 28, between 31% and 49% in 11 and ≥ 50% in 12 patients.The citology was reported for 24 patients and it was blastoid or pleomorphic in 8. Fifty-seven patients were treated in public institutions and 26 patients received intensive therapy among 56 patients with less than 70 years at diagnosis. The mOS was 2.1 years (0.3-8.5) for the living patients. Thirty-one patients were alive at the last follow up. The analysis of mOS according to the MIPI was 2.5y for low, 2.7y for intermediary and 2.2y for high-score (P=0.98). The Ki-67 (%) had an adverse prognosis at a cut off of 50% positive cells (3.2y vs 1.6y, P =0.01). Patients with less than 70y had different mOS according to the type of treatment given(mOS for intensive therapy 3.3y vs 1.8y (p=0.04) and there was no difference in mOS between patients treated at public vs private institutions (P=0.34). We did p53 by IHC in 19 patients and there was a trend towards worse mOS for those with > 10% positivice cells (P=0.08). Discussion: We showed the first report from a MLC study collecting RWE from a population of a third world country with low participation in MCL pivotal trials. To the best of our knowledge this is the first attempt to describe epidemiological data and OS for MCL in a multicenter setting. The main finding is that the patients had much worse overall survival than the ones reported in studies from developed countries. Unfortunately, morphology (blastoid/pleomorphic vs others) were not reported in a majority of patients and we should work on that. Our patients had a higher percentage of adverse prognostic factors such as a high MIPI and elevated KI-67. However, the previous was not prognostic and the latter was at a cut off of 50%. P53 seems to be of prognostic importance however our sample was still short. We are looking at more detail on the factors that could explain this poor OS such as the time to diagnosis/therapy and the availability of adequate therapy.

MANTLE CELL LYMPHOMA IN BRAZIL: FIRST REPORT FROM A REAL-WORLD EVIDENCE STUDY OF A THIRD WORLD COUNTRY

Mantle cell lymphoma (MCL) is an uncommon type of B-cell lymphoma with a heterogeneous clinical presentation and evolution spanning from an indolent leukemic non-nodal disease to an aggressive nodal disease. The disease has strong prognostic factors such as MIPI, proliferating index by ki-67 and P53 mutation. The best therapy seems to be with rituximab-cytarabine based induction followed by an autologous stem-cell transplantation with median overall survival (mOS) exceeding 10 years. Real world evidence studies (RWE) compare clinical outcomes and population characteristics with the ones from clinical findings. We aimed to describe epidemiological characteristics, therapy and clinical outcomes of Brazilian patients with MCL diagnosticated between Jan 2010 until Dec 2021 and compare outcomes regarding the place of treatment (public vs private). This first report includes patients from 5 public and 1 private centers from 3 cities. Patients with Cyclin D1 and/or SOX11 positivity were included. All the data is typed in an eCRF (Redcap by Einstein Hospital). Ki-67 values were retrieved from the pathological reports as percentages of positive MCL cells. A sample of patients from one public center was tested for P53 by immunohistochemistry (IHC) and results were scored as percentage of positive MCL cells. Statistical tests were done with SPSS 20.0 software. Survival curves were made by the Kaplan-Meier Method and compared with Log Rank test. The study included 75 patients (56 males). Median age at diagnosis was 64 years (24y-96y). ECOG was 0 or 1 in 68 patients. MIPI risk-groups could be obtained in 63 patients and it was low in 18, intermediate in 23 and high in 22. The ki-67 was obtained in 43 patients and was ≤ 30% in 28, between 31%-49% in 11 and ≥ 50% in 12. The cytology was blastoid or pleomorphic in 8 of 24 patients. Treated in public institutions were 57 patients and 26 received intensive therapy among 56 patients with less than 70y at diagnosis. The mOS was 2.1 years (0.3-8.5) for the living patients, who were 31 at the last follow up. The analysis of mOS according to the MIPI was 2.5y for low, 2.7y for intermediary and 2.2y for high-score (p = 0.98). The Ki-67 (%) had an adverse prognosis at a cut off of 50% positive cells (3.2y vs 1.6y, P =0.01). Patients with less than 70y had different mOS according to the type of treatment given (mOS for intensive therapy 3.3y vs 1.8y (p = 0.04) and there was no difference in mOS between patients treated at public vs private institutions (p = 0.34). We did p53 by IHC in 19 patients and there was a trend towards worse mOS for those with > 10% positive cells (p = 0.08). We showed the first report from a MLC study collecting RWE from a population with low participation in MCL pivotal trials. The main finding is that the patients had worse overall survival than the ones reported in studies from developed countries. Unfortunately, morphology was not reported in a majority of patients and we should work on that. Our patients had a higher percentage of adverse prognostic factors such as a high MIPI and elevated KI-67. However, the previous was not prognostic and the latter was at a cut off of 50%. We will be looking closely on the factors that could explain this poor OS as the time to diagnosis/therapy and the availability of adequate therapy.

P1155: BREXUCABTAGENE AUTOLEUCEL FOR RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA IN ROUTINE PRACTICE: UPDATED REPORT FROM THE US LYMPHOMA CAR T CONSORTIUM

Background: The ZUMA-2 trial and real-world studies showed high efficacy of brexucabtagene autoleucel (brexu-cel) in relapsed/refractory mantle cell lymphoma (MCL). We previously reported an objective response rate (ORR) of 89% in 95 patients receiving standard-of-care brexu-cel in the US Lymphoma CAR T Consortium (Wang et al, ASH 2021). Aims: To update the safety and efficacy results of the Consortium study with more patients and longer follow-up. Methods: Patients who underwent leukapheresis for standard-of-care brexu-cel manufacture at one of the 16 Consortium centers between 8/1/2020 and 12/31/2021 were included. Baseline characteristics, bridging therapy, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and treatment outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined based on characteristics at leukapheresis. Time-to-event data were analyzed using the Kaplan-Meier method. Results: At the data cut-off date of 1/31/2022, 189 patients underwent leukapheresis; 167 (88%) completed infusion and 22 (12%) did not (manufacture failure n=7, death n=6, disease progression n=5, organ dysfunction n=2, complete response [CR] to bridging therapy n=1, patient decline n=1). The median age of the 167 infused patients was 67 years (range 34-89) and 76% were male. 16% had high risk simplified MIPI, 57% had Ki-67 ≥50%, 41% had blastoid or pleomorphic variant, 49% had TP53 alteration, 31% had complex karyotype, 14% had bulky disease (≥10 cm), and 10% had CNS involvement. The median prior lines of therapy was 3 (range 1-10), and 86% were BTKi-exposed (89% of which were refractory). 130 (78%) patients would not have met ZUMA-2 eligibility criteria, and the most common reasons were prior therapies (eg, anthracycline- or bendamustine-naïve [16%], BTKi-naïve [14%], >5 lines of prior therapy [11%]), renal dysfunction (21%), cardiac comorbidities (14%), cytopenias (11%), ECOG PS ≥2 (11%), and CNS involvement (10%). 113 (68%) patients received bridging therapy, which included immunochemotherapy (n=45), BTKi (n=45), venetoclax (n=24), radiotherapy (n=23), corticosteroid (n=18), and lenalidomide (n=6). The median time from leukapheresis to lymphodepletion chemotherapy was 28 days (range 17-140). The rate of CRS was 90% (8% grade ≥3, 1 grade 5), and the rate of ICANS was 61% (32% grade ≥3, 0 grade 5). Medications used to manage CRS and/or ICANS included tocilizumab (76%), corticosteroid (68%), anakinra (16%), and siltuximab (3%). 20% of patients required ICU admission, with a median stay of 3 days (range 1-12); 18% required vasopressors, 3% required mechanical ventilation, and 3% required dialysis. Among 159 evaluable patients, the day 30 ORR was 89%, with 70% CR and 19% partial response (PR). With continued follow-up, the best ORR was 89%, with 80% CR and 9% PR. The best ORR/CR rate were 89%/77% for high Ki-67% (≥50%), 88%/79% for blastoid or pleomorphic variant, 88%/73% for complex karyotype, 90%/72% for TP53 altered, 81%/75% for CNS involved, 89%/79% for BTKi-exposed, 91%/83% for BTKi-naïve, and 89%/78% for ZUMA-2 ineligible. With a median follow-up of 5.6 months (range 0.2-15.3), the 6-month estimates for duration of response, progression-free survival, and overall survival were 67% (95% CI 57-75), 63% (95% CI 54-71) and 85% (95% CI 77-90), respectively. Summary/Conclusion: This updated analysis demonstrated favorable safety and efficacy results of brexu-cel in R/R MCL that are consistent with the initial report. Despite 78% of patients being ineligible for ZUMA-2, the responses, CRS, ICANS and survival outcomes were comparable to ZUMA-2 data.

Brexucabtagene autoleucel for relapsed/refractory mantle cell lymphoma: Real-world experience from the United States lymphoma CAR T consortium.

e19583 Background: Brexucabtagene autoleucel (BA) is an FDA approved therapy for relapsed/refractory (R/R) mantle cell lymphoma (MCL), based on results from ZUMA-2 study. We report the safety and efficacy of BA in standard of care practice among centers in the US Lymphoma CAR-T Consortium. Methods: 16 centers participated in this retrospective study. Patients (pts) who underwent leukapheresis by 12/31/2021 with an intent to manufacture BA were included. Baseline clinical characteristics, bridging therapy, adverse events after BA infusion, and post-infusion outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined. Survival outcomes were analyzed using the Kaplan-Meier method. Results: At the data cut-off date, 189 pts underwent leukapheresis, among whom 167 (88%) completed BA infusion, 22 (12%) did not receive infusion. The median age was 67 years. 16% had high risk simplified MIPI, 57% had Ki-67≥50%, 41% had aggressive histology, 49% had TP53 alteration, 51% with POD24 and 10% had CNS involvement. The median number of prior lines of therapy was 3 (range 1-10). 86% had prior BTKi treatment (89% refractory). 130 (78%) pts would not have met ZUMA-2 eligibility criteria. 113 (68%) pts received bridging therapy, which included BTKi, venetoclax, chemotherapy. Median time from leukapheresis to lymphodepletion chemotherapy: 28 days (range 17-140). Cytokine release syndrome (CRS) rate was 90% (8% grade ≥3; 1 grade 5), and immune effector cell-associated neurotoxicity syndrome (ICANS) rate was 61% (32% grade ≥3). Grade 5 ICANS (n = 0). Medications used to manage CRS and ICANS were 125 (76%) for tocilizumab, 112 (68%) for corticosteroid, and 27 (16%) for anakinra. 32 (20%) pts required ICU admission, 18 pts required vasopressors, and 5 pts required mechanical ventilation. Day 30 response was evaluable in 155 pts (89% ORR, 70% CR). The best ORR was 89%, with 80% CR, 9% PR. The ORR/CR rates were 88%/79% for aggressive histology, 89%/77% for high Ki-67% (> 50%), 90%/72% for TP53 altered, 81%/75% for CNS involved, 89%/79% for BTKi-exposed, 91%/83% for BTKi-naïve, and 89%/78% for those not meeting ZUMA-2 eligibility criteria. The median duration of response was not reached and at 6-month was 67% (95% CI 57-75). With a median follow-up of 5.6 months (range 0.2-15.3), median PFS was not reached, the 6-month PFS rate was 63% (95% CI 54-71), and median OS was 15.3 months and the 6-month OS rate was 85% (95% CI 77-90). Conclusions: This multicenter retrospective study demonstrated encouraging safety and efficacy data of BA in R/R MCL in the real-world practice. Despite 78% of the pts being ineligible for ZUMA-2, the responses, CRS, ICANS and outcomes were comparable to ZUMA-2 data. Long term safety and efficacy will be reported.

Improvement Diagnosis and Treatment of Mantle Cell Lymphoma in a Middle-Income Country: A Time-Dependent Analysis in Mexico

Introduction: Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma representing 4-9% of all lymphomas. The disease prognosis remains adverse. However, diagnosis and treatment of MCL have undergone a significant improvement in the last years.The World Bank considers Mexico as a Middle-Income Country (MIC). Therefore, MICs experience a delay in accomplishing diagnosis and prognosis strategies and low access to treatment innovation for hematologic malignancies. In Mexico, there is scarce information on the clinical features and treatment patterns of MCL over time. Mainly, the prognosis impact of these strategies is unknown.Methods: We retrospectively evaluated all consecutive patients with a pathological diagnosis of MCL in three referral centers for the uninsured population in Mexico from 2008 to 2020. We followed patients to June 2021 until lost follow-up or death. We made a Time-Dependent-Analysis (TDA) to evaluate the effect of the diagnosis and treatment improvements over time. We divided the population into two groups, from 2008 to 2014 (Group A) and from 2015 to 2020 (Group B). Hematopathologists reviewed all cases at their respective centers. We excluded patients that do not receive treatment and patients without pathological confirmation. Clinical, pathological, and treatment data were collected. Responses were assessed per the Lugano criteria. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method, differences between the groups were evaluated with a log-rank test. Multivariate analysis of factors associated with mortality was assessed with a Cox regression model with a Confidence Interval(CI) of 95%.Results: A total of 139 patients were included in the analysis; 67 patients from Group A; and 72 patients from Group B. The median age was 64 years, 42% were younger than 65 years, 76% were male, 22% had ECOG 2-4, 81% had extra nodal involvement, 28.1% had bulky disease, 94% had stage III/IV disease, 58% had bone marrow involvement, 40.7% had high risk simplified MIPI. Regarding diagnosis approaches between the two groups, only 23% in Group A had an immunohistochemical evaluation of Ki67 compared with an 84% of Group B (p<0.001). The rest of the differences between the groups are in Table 1.In terms of treatment, 84% received an anthracycline-based treatment, 3% bendamustine-based treatment, and 12% a low-intensity treatment, with no difference between the groups. In addition to base treatment, 30% received High-dose Cytarabine (HiDAC), been more frequent in Group B (p<0.001), 59% received rituximab during induction, 37% in Group A, and 80% in Group B, (p<0.001). The main reason to avoid the use of rituximab was the cost and only 20.3% used rituximab maintenance, being more frequent in Group B (p=0.018). The 13.7% received an autologous stem cell transplant, been more frequent in Group B (p= 0.002). Only two patients (1.4%) received treatment in a Clinical Trial setting. In terms of response, in Group A, 58% achieved Complete Response (CR) against 34% of Group B (p=0.006).Median OS on Group A was 38 months (95% CI 25.6 -50.3) against Not Reached in Group B (Log Rank p = 0.037). On the other hand, the median EFS on Group A was 17 months (95% CI 11.6-22.39) against 29 months (95% CI17.6-40.3) in Group B (Log Rank p = 0.005) Figure 2. A multivariate analysis of factors associated with higher mortality found a high-risk MIPI score with an HR of 2.54 (CI 95% 1.5-4.0, p <0.001). Factors associated with lower mortality were the addition of HiDAC in induction HR 0.39 (CI 95% 0.20- 0.75, p= 0.005) and rituximab maintenance HR 0.48 (CI 95% 0.24-0.94, p=0.035)Conclusion: This is the first real-world report of MCL in Mexico. Characteristics of the disease resemble the ones reported by other countries. Despite the limitations of a retrospective analysis, the TDA makes evident the prognosis improvement over time. With progress in EFS of 12 months and an OS impact. Even though the prognosis improvement, to the date, there is a 20% of patients with no rituximab access. Transplant access is low beside that 42% of patients were younger than 65 years, and Clinical Trial access is almost null. Novel therapies for MIC are under development with encouraging results in the first-line and relapsed/refractory setting. However, the high costs of these therapies will limit the access in MIC and would expand the gap of MCL prognosis if a health care strategy that allow access to them is not implemented. [Display omitted] DisclosuresRangel-Patiño: Abbvie: Speakers Bureau; Bristol: Consultancy. Agreda: Roche: Speakers Bureau; Astrofarma: Speakers Bureau; Janssen: Speakers Bureau. Gomez-Almaguer: Bristol-Myers-Squibb: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau. Ramirez-Ibarguen: Takeda: Consultancy, Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Astra Zeneca: Speakers Bureau; Abbvie: Speakers Bureau; MSD: Consultancy; Asofarma: Consultancy.

Ibrutinib Plus Rituximab and Venetoclax (IRV) Followed By Risk-Stratified Observation or Short Course R-Hypercvad/MTX in Young Patients with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-2 Clinical Trial

Ibrutinib Plus Rituximab and Venetoclax (IRV) Followed By Risk-Stratified Observation or Short Course R-Hypercvad/MTX in Young Patients with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-2 Clinical Trial

Brexucabtagene Autoleucel for Relapsed/Refractory Mantle Cell Lymphoma: Real World Experience from the US Lymphoma CAR T Consortium

Brexucabtagene Autoleucel for Relapsed/Refractory Mantle Cell Lymphoma: Real World Experience from the US Lymphoma CAR T Consortium

Impact of p53 Disruption on Mantle Cell Lymphoma (MCL) Treatment out-Come, Multi-Centre Retrospective Study

Background: MCL is a rare type of non-Hodgkin lymphoma (NHL) with an aggressive clinical course. MCL is associated with poor prognosis and incurable disease in the majority of patients. However, a minority of patients will not require any treatment for many years. TP53 mutations continue to confer a dismal prognosis in MCL with a median survival of 1.3 years. However, targeted therapy and, more recently, promising CAR-T treatment have revolutionised the outcome.Methods: Patients were identified through our pathology database, and informed consent was obtained. The patient's demographic characteristics, clinical features, laboratory findings, MIPI score, initial / subsequent treatment and survival were analysed. p53 expression percentage and its concordance with the mutational status were evaluated in a subset of patients.Results: One hundred and one patients were included in this study, with a male predominance (80%), median age 67 years (Range 37-89 years) and majority with advanced disease. Fifty-one patients (50%) presented with extra-nodal disease. Most of the patients presented with Classical MCL ( 75%) histological sub-type, 20 patients (20%) with blastoid variant and 6 patients (6%) with indolent disease. Seventy-four patients (73%) had a high MIPI risk score, while intermediate and low scores were noted in 17 patients (17%) and 10 patients (10%), respectively. Chemo-immunotherapy (CIT) was the main initial treatment modality in our cohort (79 patients / 78%). Watch and wait approach was applied in 6 patients with the indolent disease, 4 patients (4%) were not fit for any form of therapy. Forty-four patients (44%) had Rituximab maintenance and autologous stem cell transplant (Auto-SCT ) consolidation was used in 12 patients (12%). Five patients (5%) had allogeneic SCT (Allo-SCT) post-remission.Initially, 29 patient samples were used to validate immunohistochemistry (IHC) p53 expression percentage and its correlation with TP53 mutational data from genomic sequencing (SS and NGS). p53 expression of > 30% had 100% concordance with TP53 mutational status.A total of 128 patient samples, including 27 samples with relapsed disease, were screened for TP53 alterations using IHC p53 expression as a surrogate marker. Twenty samples (16%) showed p53 overexpression (15/12% diagnostic & 5/19% relapsed samples).At the final data compilation (31/01/2021), 44 patients were still alive, and 57 patients had died. The OS and PFS for the whole cohort were 69 and 47 months, respectively. (Figure 1)The prognostic impact of age (<65 years), MIPI score & disease sub-type were confirmed in this cohort with a P-value of P.00046, P.0.036 and P.0.0192, respectively. In the treated cohort, p53 disruption revealed a dismal prognosis and poor treatment outcome, with a median OS and PFS in the p53 wild-type cohort of 95 months and 50 months. In contrast, in patients harbouring p53 disruption, the median OS & PFS were 38months (P.0323) and 25 months (P.0383 ), respectively. (Figure 2)ConclusionThis study reflects real-life MCL experience and the potential use of p53 expression using IHC in routine practice in assessing MCL disease prognosis. It also confirms the dismal outcome of MCL patients with TP53 mutations. Participation in clinical trials based on genetic risk stratification is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Paired-Box 5 Positivity Related to High MIPI Score Predicts Shorter Overall Survival in Mantle Cell Lymphoma Patients

Introduction: Mantle cell lymphoma (MCL) is a sub-type of B-cell non-Hodgkin Lymphomas (NHL) that characterized by a heterogenous clinical course and poor prognosis. The transcription factor paired-box 5 (PAX5) is associated with B cell normal differentiation and development. Herein, we aim to explore both the prognostic factors and the role of PAX5 expression in MCL patients from single-center, which can provide theoretical guidance for clinical practice.Methods: The data of 80 MCL patients admitted to Shandong Provincial Hospital from October 2006 to April 2020 were collected to be analyzed. Kaplan-Meier method and univariate and multivariate cox analysis was used to analyze the correlation between overall survival and prognostic factors. Chi-square test, Pearson and Fisher correlation analysis were performed for statistical analysis of clinical features and experimental indicators. *p value<0.05 indicated that the difference was statistically significant. Immunohistochemistry (IHC) was used to label the protein expression. Gene expression profiles were applied to analyze the discrepancy of PAX5 mRNA expression in some lymphoma types.Results: Clinical characteristics of all MCL patients were analyzed. PAX5 expression was identified by IHC in this study: the positive expression rate of PAX5 in all MCL patients was 60% (Figure 1A). The mRNA expression level of PAX5 was obviously elevated in MCL specimens than in normal group compared with other groups (p= 0.034) (Figure 1B). Besides, CD5, CD19, CD22, CD38, CD79α, CD79β and SOX11 were shown co-expressed with PAX5 by string database analysis (Figure 1C). PAX5-related genes were found mainly enriched in lymphocyte activation, B cell proliferation and NOTCH1 signaling pathway (Figure 1D). As is shown in Figure 1E-I, MIPI score (≥6), median to high risk group, high β2-MG level (≥2.65 mg/L), ECOG score (≥2), and splenomegaly were associated with adverse survival (p= 0.006, 0.030, 0.001, 0.019 and 0.001 respectively). The positive expression of PAX5 indicated a shorter overall survival in MCL patients (p= 0.024, Figure 1G). Positive PAX5 expression was associated with international prognostic index (MIPI) score (p= 0.038), high risk stratification (p= 0.006), WBC count (p= 0.024), and increased β2-microglobulin level (p= 0.008). MCL patients with PAX5-positive expression, high level of β2-MG level (≥2.65 mg/L), splenomegaly correlated with a poorer OS (p=0.002, and 0.004 respectively, Figure 1K, L). In patients with PAX5-negative expression, splenomegaly also indicated poor prognosis (p= 0.030, Figure 1M). Furthermore, among patients with high MIPI scores, PAX5-positive MCL patients had a shorter overall survival than PAX5-negative patients (p= 0.016, Figure N, O). Multivariate analysis showed that positive PAX was an independent prognostic factor for poor survival of MCL (p= 0.035).Conclusions: The positive expression of PAX5 in immunohistochemistry may be a factor contributing to the poor prognosis of MCL patients, which is correlated with clinical characteristics and laboratory indicators to a certain extent. Our results the role of PAX5 positivity in MCL and provide clinical guidance for clinical prognostic risk assessment and treatment strategy selection.Keywords: Mantle cell lymphoma; Paired-box 5; Prognosis; Immunohistochemistry [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Survival of Mantle Cell Lymphoma in the Era of Bruton Tyrosine Kinase Inhibitors: A Population-Based Analysis

Survival of Mantle Cell Lymphoma in the Era of Bruton Tyrosine Kinase Inhibitors: A Population-Based Analysis

Bortezomib enhances the anti-cancer effect of the novel Bruton's tyrosine kinase inhibitor (BGB-3111) in mantle cell lymphoma expressing BTK.

BGB-3111, a novel Bruton’s tyrosine kinase (BTK) inhibitor, shows promising anti-cancer effects in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia (WM). This study aimed to investigate the anti-cancer effects of BGB-3111 combined with bortezomib (BTZ) against the BTK-expressing MCL. We found that BTK, which was overexpressed in 59.4% of patients with MCL, was mainly characterized by high Ki67 and elevated MIPI scores. BGB-3111 strongly inhibited cell proliferation, induced cell cycle arrest in the G1/G0-phase, and promoted cell apoptosis in the MCL cells expressing BTK. BGB-3111 provides better safety than another BTK inhibitor, ibrutinib as ibrutinib inhibits the inducible T-cell kinase (ITK) as an off-target effect but BGB-3111 does not inhibit ITK. Low doses of BTZ enhanced the anti-cancer effect induced by the low dose of BGB-3111 by downregulating the expression levels of PARP and Bcl-2 and increasing the expression levels of cleaved PARP and cleaved caspase-9. In addition, low doses of BGB-3111, but not of BTZ, inhibited BTK phosphorylation. However, low-doses of BTZ strengthened the anti-cancer effect induced by the low-doses of BGB-3111 via synergistically suppressing the IκBα and P65 phosphorylation. Taken together, our findings validate that BGB-3111 is a novel and effective BTK inhibitor for MCL-expressing BTK. Hence, it can be harnessed as a potential therapeutic strategy through a combinatorial treatment comprising low-dose BGB-3111 and low-dose BTZ to gain strong anti-cancer effects and better safety for MCL patients.

Consolidation with Autologous Hematopoietic Cell Transplant in First Remission Improves Overall Survival in Younger Patients with Mantle Cell Lymphoma in the Rituximab Era

Abstract Introduction: Mantle cell lymphoma (MCL) is a CD5+ B-cell lymphoma characterized by cyclin D1 expression. The disease has heterogeneous clinical outcomes: in a subset of patients, it is indolent but many others have an aggressive course with poor outcome. Consolidative autologous hematopoietic cell transplant (HCT) in 1st remission is often employed for fit patients ≤65; however the benefit of this approach remains uncertain without prospective validation in the rituximab era. Herein we retrospectively assessed the impact of HCT consolidation following induction therapy on survival in a large multicenter cohort of transplant eligible patients aged ≤65. Methods: We retrospectively studied adults with newly diagnosed MCL, aged ≤65, transplant eligible at diagnosis, and treated with induction chemotherapy from 2000-2015. Eligibility for transplant was determined by the institutional chart reviewer. 22 US and Canadian academic medical centers contributed. Information on prognostic markers, treatment, response to induction, and survival was collected. The primary objective was to assess for an overall survival (OS) benefit of HCT consolidation in first remission. A landmark survival analysis was restricted to patients surviving >6 months who achieved ≥partial response (PR) after induction, with OS and progression-free survival (PFS) defined as time from diagnosis to event (death or relapse). Cox multivariate regressions were performed to evaluate the effect of HCT consolidation on OS and PFS after adjusting for confounders (age, sex, MIPI, stage, induction regimen, blastoid/pleomorphic phenotype, response to induction (complete response (CR) vs. PR), and maintenance therapy. Due to the differential times of HCT, this was included in the model as a time-varying covariate. Ki67 was excluded from regression models as it was available in Results: Data was collected for 1113 patients, and 921 patients met inclusion criteria. HCT was performed in 595 patients (64%). The two most common reasons for not performing HCT were physician (46%) or patient preference (23%). Three centers, who contributed a combined 135 patients, performed HCT in Conclusion: In this large cohort of younger transplant eligible patients with MCL, HCT consolidation in first remission was associated with significantly improved OS and PFS after adjusting for prognostic factors and differences in initial treatment. Within the limitations of retrospective analysis and inherent selection bias, our findings support the benefit of HCT consolidation following induction therapy for fit patients ≤65 in the rituximab era. Download : Download high-res image (148KB) Download : Download full-size image Disclosures Barta: Janssen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Merck: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding. Villa: Roche: Consultancy, Honoraria, Other: Travel, Research Funding; Lundbeck: Consultancy, Honoraria, Other: Travel; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria; Abbvie: Other: Travel. Gerrie: Roche: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lundbeck: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Fenske: Celgene: Consultancy; Sanofi: Consultancy; Pharmacyclics: Consultancy. Maddocks: Merck: Research Funding; Pharmacylics: Research Funding; BMS: Research Funding; Novartis: Research Funding. Lansigan: Spectrum Pharmaceuticals: Consultancy, Research Funding; Seattle Genetics: Consultancy. Reddy: Abbvie: Consultancy; BMS: Consultancy; Celgene: Consultancy; Gilead: Speakers Bureau. Landsburg: Curis: Consultancy, Research Funding; Takeda: Research Funding. Karmali: Celgene: Speakers Bureau. Kaplan: Takeda: Research Funding; Millennium: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding. Caimi: Celgene: Speakers Bureau; Abbvie: Equity Ownership; Seattle Genetics: Equity Ownership; Incyte: Equity Ownership. Cohen: Takada: Research Funding; Bristol Myers Squibb: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; LAM Therapeutics, Inc: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees. Calzada: Seattle Genetics: Research Funding. Handorf: Pfizer: Research Funding. Bachanova: Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Comprehensive Analysis of Factors Predictive for Time to Transformation and Risk of Transformation in Patients (pts) with Mantle Cell Lymphoma

Comprehensive Analysis of Factors Predictive for Time to Transformation and Risk of Transformation in Patients (pts) with Mantle Cell Lymphoma

Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX in Patients (age ≤ 65 years) with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-1 Clinical Trial

Ibrutinib Plus Rituximab (IR) Followed By Short Course R-Hypercvad/MTX in Patients (age ≤ 65 years) with Previously Untreated Mantle Cell Lymphoma - Phase-II Window-1 Clinical Trial

Clinical Outcome of Mantle Cell Lymphoma Patients with High Risk Biology (high Ki-67, blastic MCL, or high p53 expression)

INTRODUCTION: Mantle cell lymphoma (MCL) is a distinct lymphoma subtype with a wide variation of clinical course. Previously a clinically defined risk score (MIPI) was established which partly reflects the heterogeneity of clinical outcome in this disease (Hoster, JCO 2004). Based on prospective trials, cytology (classical type vs. blastoid variant; Hoster, JCO 2016), cell proliferation as determined by Ki-67expression (Hoster, JCO 2016), and p53 alterations (Eskelund, Blood 2017; Aukema, Blood 2018) all have been identified as major drivers of a rapidly progressing disease, independent of MIPI. Aim of this study was to assess the clinical outcome of patients with at least one of these 3 different biological risk factors in a large uniformly treated patient population. METHODS: All patients were treated in the MCL Younger (Hermine, Lancet 2016) and MCL Elderly trials (Kluin-Nelemans, NEJM 2012) of the European MCL Network. Formalin fixed paraffin embedded (FFPE) diagnostic patients' material was classified as classical or blastic/pleomorphic variant and analyzed by Ki-67 or p53 immunohistochemistry on either tissue microarrays or whole tissue sections. Patients were classified as having high risk biology if they displayed blastoid cytomorphology, Ki-67 ≥30% according to the published guidelines, or high p53 staining indicating a mutated gene status expression. As control, standard risk disease patients had classical MCL with low Ki-67 &lt;30%, and p53 IHC expression ≤50%. RESULTS: In 365 MCL (MCL younger: n=192, MCL elderly: n=173) out of 1229 study patients, at least one of the biological parameters indicated a high risk biology, or high risk biology was excluded by determination of all 3 parameters. No major survival difference was observed for patients with and without IHC data available, excluding a major selection bias. 65 of 319 analysed cases displayed a blastoid cytomorphology (20%), 175 of 345 cases had an increased Ki-67&gt;30% (51%), and 54 of 254 cases displayed a mutated p53 status (21%). Based on the selection procedure of the cases, a total of 224 cased displayed a high risk biology (63%) vs 130 cases with confirmed standard risk disease(37%). Median failure-free (6.3 years vs, 2.2 years; p&lt; 0.0001) and overall survival (median not reached vs. 4 years; p&lt;0.0001) was significantly prolonged in the standard risk cohort compared with the high risk biology group. These significant differences were detected in both, patients treated with conventionally dosed chemotherapy (median PFS: 3.8 vs. 1.3 years, p=0.0001; OS: median not reached vs 2.5 years, p&lt;0.0001) as well as patients receiving a cytarabine containing induction and autologous transplantation (median PFS: 7.5 vs. 3.7 years, p=0.0011; OS: median not reached vs 6.5 years, p&lt;0.0001). Interestingly, MIPI remained a prognostic factor in the groups of patients without and with high-risk biology (FFS low risk disease: p=0.0223); PFS high risk disease: p&lt;0.0001), and distribution of risk groups differed only slightly in these subsets of patients (biological low risk: 51% low/32%intermediate/17% high MIPI; biological high risk: 31% low/35% intermediate/34% high MIPI). Similar results were observed for overall survival. CONCLUSIONS: Although our enrichment strategy does not allow the estimation of the frequency of high risk biology and the patient group with standard risk disease is underrepresented in this evaluation, the patients with high risk biology as defined by blastoid variant, Ki-67 &gt;30%, or high p53 expression had a significantly shorter failure-free and overall survival even without consideration of the clinical features of the disease (MIPI). As these biological factors seems to dictate the sometimes dismal clinical course of the disease, we recommend to incorporate these factors in routine diagnostic practice. Future studies should investigate the differential impact of targeted therapies in this biologically defined subset of patients. Disclosures Dreyling: Sandoz: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau; Novartis: Other: Scientific advisory board; Mundipharma: Other: Scientific advisory board, Research Funding; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: Scientific advisory board; Bayer: Other: Scientific advisory board, Speakers Bureau. Hoster:Roche Pharma AG: Other: Travel support; Janssen: Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hermine:AB science: Consultancy, Equity Ownership, Honoraria, Research Funding; Celgene: Research Funding; Novartis: Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding.

Use of Lenalidomide Plus Rituximab in TP53-Mutated Mantle Cell Lymphoma (MCL) Outside of Clinic Trial: The Moffitt Experience

Introduction MCL is an incurable B-cell lymphoma, accounting for 3-8% of Non-Hodgkin Lymphoma (NHL). Efforts to increase frontline treatment intensity with cytarabine (AraC), autologous transplant, and prolonged Rituximab maintenance have improved outcomes for many. However, those with TP53 mutations do not show similar benefit, highlighting a need for novel approaches in this setting. Lenalidomide plus Rituximab (R2) has been shown to have activity in MCL, but little data exist in the context of TP53 alterations. Methods We retrospectively reviewed 145 patients diagnosed with MCL between 2005 and 2019. Cases were selected by diagnosis of MCL and clinical evaluation from July 2018 to June 2019. A total of 145 unique cases were identified, of which 63 had insufficient testing for TP53, 50 were negative, and 32 were mutation positive by cytogenetics, NGS, or FISH. Patients with mutated TP53 were further assessed for the primary outcome of event-free survival (EFS) and a secondary outcome of overall survival (OS). All statistical analyses were performed using SPSS software. Results Of 32 analyzed patients, 72% were male, with median age 67 years (46-87) and median WBC 15 (3-283). All but one patient presented with ECOG PS 0-1. LDH was elevated in 44%, with high MIPI in 56% of patients. Ki67 was available in 8 cases (median 30%), with 2 additional cases noted only as "blastoid." Frontline therapy consisted of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (RCHOP) or Bendamustine plus Rituximab (BR) with maintenance Rituximab (6 patients), AraC, and/or transplant (8), R2 (8), BTK+Rituximab (2), or palliation (XRT 1, Rituximab 2, watchful waiting 5). Seven patients received R2 in the relapsed setting. With median followup of 44 months, the median OS was not reached (83%), and median EFS among all treated patients was 36 months. Among those who received frontline R2, 63% were male, with median age 68 (55-75), median WBC 74 (11-283), with elevated LDH in 50% and high MIPI in 88%. Ki67 was available for 2 patients, and measured 10% and 80%. The Median OS and EFS were 100% with median followup on therapy of 15 months. Conclusions Survival was surprisingly robust across this cohort of high risk MCL. Treatment with Lenalidomide plus Rituximab may provide an alternative regimen for TP53-mutated MCL in the first-line setting. Further analysis of long-term data will be beneficial to monitor durability of remission. Figure Disclosures Chavez: Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Bello:Celgene: Speakers Bureau. Sokol:EUSA: Consultancy. Pinilla Ibarz:Novartis: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau. Shah:Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria.

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

Frontline Treatment with Ibrutinib with Rituximab (IR) Combination Is Highly Effective in Elderly (≥65 years) Patients with Mantle Cell Lymphoma (MCL) - Results from a Phase II Trial

Frontline Treatment with Ibrutinib with Rituximab (IR) Combination Is Highly Effective in Elderly (≥65 years) Patients with Mantle Cell Lymphoma (MCL) - Results from a Phase II Trial