Long Term Follow-up in Mantle Cell Lymphoma Patients Treated with R-GemOx Followed By Consolidation and Rituximab Maintenance

Abstract Introduction: Six percent of all non-Hodgkin lymphomas (NHL) cases are mantle cell lymphoma (MCL). MCL has a poor prognosis and is considered incurable with current strategies. Intensive approaches are not applicable to most these patients considering the median age at diagnosis (70 years old). Due to the molecular events that drive MCL to be a lymphoma with an aggressive and indolent behavior as well as a tendency to clonal evolution (dysfunction of cell cycle, response to cellular damage and apoptosis), we present a global therapeutic approach which includes an effective induction with a low toxic profile, as well as consolidation and maintenance with the final aim of increasing and maintaining responses. Methods: From December-2008 to January-2018 all MCL patients treated in first line in our center were included. The therapeutic approach was based on an induction with R-GemOx (rituximab, gemcitabine and oxaliplatin) followed by consolidation with autologous stem cell transplant or ibritumomab tiuxetan followed by rituximab maintenance (Rm) (every 2 months for 2-3 years). Since 2016, all patients with less than complete response after induction/consolidation, received Ibrutinib 560 mg daily added to Rm. Standard prognostic variables were collected at diagnosis including MIPI; the response evaluation and follow-up was made considering Cheson criteria; for toxicity assessment, we used OMS grading scales of toxicity criteria. Overall survival (OS) and progression free survival (PFS) were estimated from the beginning of the treatment with the Kaplan-Meier method. Results: Thirteen treatment-naïve MCL patients were included from December-2008 to January-2018. Main characteristics of patients are shown in Table 1. Briefly, this is an old high risk series with a median age at diagnosis of 71 years old and poor prognosis (31% and 69% belong to intermediate and high risk MIPI groups, respectively). Two cases were refractory to R-GemOx induction (a blastic MCL and another case with high MIPI (7.7)). Four cases relapsed between 30 and 66 months after treatment was started. All cases with CR or PR after induction (n=11; 85%), obtained a CR at the end of the maintenance. One of the refractory cases after a second line followed by rituximab and ibrutinib maintenance also reached CR. Only 2 patients died (15%): one disease progression and another non-related pulmonary thromboembolism. The median follow-up was 51 months. Four-years OS was of 83% with a median PFS of 58 months (Figure 1). R-GemOx toxicity profile was manageable: most of them grade 1-2 neutropenia (43%), vomits (100%), diarrhea (30%) and anemia (30%). Grade 3-4 toxicity was scarce (neutropenia 14% and thrombocytopenia 36%). Conclusions: R-GemOx followed by consolidation and Rm should was an effective approach with manageable toxicity and excellent survival considering the median age and the high MIPI risk of the series. We plan to test this global approach in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.

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Prolongation of Progression Free Survival In Mantle Cell Lymphoma After RHCVAD: ASCT Consolidation or Rituximab Maintenance

Blood ◽

10.1182/blood.v116.21.3570.3570 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3570-3570

Author(s):

Jennifer McQuade ◽

Tahamtan Ahmadi ◽

David Porter ◽

Noelle Frey ◽

Alison Wakoff Loren ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Primary Study ◽

Cell Transplant ◽

Data Set ◽

Bulky Disease ◽

Rituximab Maintenance ◽

Mantle Cell

Abstract Abstract 3570 Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. The best initial treatment regimen remains unclear. Although it is generally acknowledged that aggressive approaches using combination chemotherapy and/or high dose chemotherapy can prolong survival, consensus on upfront treatment strategies for advanced MCL is currently lacking without randomized controlled data to guide treatment decisions. We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-HCVAD (N=43) with or without autologous stem cell transplant (ASCT) or Rituximab maintenance. The primary study endpoints were PFS and OS as assessed by chart review and confirmed by SSDI database. Median follow up for all pts was 3 years. The median age was 53.7, and 76.7 % (n=33) were stage IV at diagnosis. 15 patients underwent consolidative ASCT. 11 pts received Rituximab maintenance. Comparing patients treated with R-HCVAD vs R-HCVAD + R maintenance vs. R-HCVAD + ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. Median PFS for all patients was 3.9 years: R-HCVAD alone 2.1 years vs. R-HCVAD+R 3.9 years (P=0.02, HR 3.51, 95%CI: 1.2–10.2) vs R-HCVAD + SCT not reached (p=0.017, HR 3.7, 95%CI: 1.26–10.63). PFS survival rates at 2 years were 50%, 88% and 70%; 33%, 71/% and 63% respectively at 3 years, and 0%, 33% and 33 % at 5 years. 3 year OS for all patients was 84% (95% CI: 65–94) with no significant differences among the three approaches. Notably, only 1/8 patients treated with R-HCVAD + SCT relapsed after 2 years, with a median follow up of 4.8 years for these patients. Our data suggest a further improved PFS when R-HCVAD is consolidated with either Rituximab maintenance or ASCT. While neither of the two consolidative approaches appears superior in our limited data set, both show significant PFS prolongation when compared to R-HCVAD alone. Further prospective investigation of consolidative approaches after RHCVAD in a randomized fashion is warranted. Figure 1: Figure 1:. Disclosures: No relevant conflicts of interest to declare.

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In Vivo Purging with Hyper-CVAD Plus Rituximab Followed by Autologous Stem Cells Transplant and Rituximab Maintenance in Newly Diagnosed Mantle Cell Lymphoma: A Pilot Study for GISL (Italian Cooperative Study Group for Lymphoma).

Blood ◽

10.1182/blood.v106.11.5494.5494 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5494-5494

Author(s):

Edoardo Benedetti ◽

Francesco Caracciolo ◽

Sara Galimberti ◽

Federico Papineschi ◽

Matteo Pelosini ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Dose Intensity ◽

High Dose ◽

Cell Transplant ◽

Rituximab Maintenance ◽

Mantle Cell ◽

High Dose Intensity

Abstract Previously untreated mantle cell lymphoma (MCL) are consistently associated with poor prognosis when treated with CHOP-like regimens. Typically the CR rate is 20–30%, median FFS = 10–16 months and median OS = 3 years. In the attempt to improve outcome we used a high dose intensity regimen such as Hyper-CVAD (HCVAD) with autologous stem cell transplant (ASCT). Twenty patients entered the study but only 10 up to now are valuable. Patients were apheresed after 2nd course of HCVAD and if apheresis (LPH) were PCR positive (Bcl1+/JH+) a second set of LPH were performed after completion of 4th cycle. To perform an in vivo purging Rituximab 375 mg/m2 was added at day +1 and +9 after last dose of ARA-C; GCSF 10μg/kg was commenced on day +5 until LPH was ultimated. Rituximab maintenance (375 mg/m2 once weekly for 4 consecutive weeks) started 2 month post-ASCT and was repeated every 6 months. Ten patients have completed 4 HCVAD and 7 /10 underwent ASCT and were conditioned with BEAM. After 4 HCVAD 7/10 patients were in CR and 3/7 in PR. After ASCT 1 PR obtained a CR, 1 PD obtained a VGPR and 5 CR maintained CR. Only 4CR post ASCT have received Rituximab maintenance and maintain CR. Two patients (1 CR blastic variant and 1 PR) refused ASCT and after 4 HCVAD received Rituximab maintenance and both are in CCR. Overall with a median follow up of 28.6 months (range 12–51) median survival is not reached. At 4 years 77.8% of patients are alive and PFS is 87.9%. Patients were monitored for bone marrow-MRD by PCR. Eight out of 10 were PCR+ at diagnosis and 7/8 were PCR negative after 4 HCVAD. After ASCT one PCR+ converted to PCR- and 1 PCR+ patient after 4 HCVAD converted to PCR- with Rituximab maintenance (refused ASCT). Conclusions: high dose intensity regimen HCVAD + Rituximab as in vivo purging and for maintenance allowed to collect tumor free grafts in 70% of PCR+patients at diagnosis and to reach an ORR of 100%, 7/10 CR and PR 3/10 (included 1 blastic variant). PCR negativity was obtained in 7/8 patients. One patient from PR converted to CR after ASCT and one after Rituximab maintenance (without ASCT); thus we might speculate that both high doses (BEAM) and Rituximab do play a role to increase the probability to obtain a CR and PCR-. Survival and PFS of 77.8% and 87.9% respectively at 4 years are encouraging. Further follow up and a higher enrolment of patients are needed to better define the role of HCVAD + Rituximab and ASCT to increase CR,PCR- PFS and OS in MCL.

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Germline Variation in TNF and NF-Kappa B Pathways and Prognosis In Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v116.21.4127.4127 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4127-4127

Author(s):

Thomas M. Habermann ◽

Matthew J Maurer ◽

Brian Link ◽

William R Macon ◽

Alice H. Wang ◽

...

Keyword(s):

Overall Survival ◽

Genetic Variation ◽

Mantle Cell Lymphoma ◽

Disease Progression ◽

Cell Lymphoma ◽

Age At Diagnosis ◽

Individual Snps ◽

Gene Level ◽

Mantle Cell

Abstract Abstract 4127 Introduction: Mantle cell lymphoma (MCL) is an aggressive lymphoma. NF-κB has been shown to be constitutively activated in MCL cell lines and patient biopsy samples and may play a key role in the growth and survival of MCL cells. We previously reported in a pilot study of 39 MCL patients from the NCI-SEER Survival Study that host genetic variation in candidate TNF and NF-κB genes was associated with overall survival after accounting for clinical variables (Blood 2007;110(11):472a). Here, we attempt to replicate the top 8 genes (NFKB1, IRF4, TNFSF13B, TNFRSF25, NFKBIA, LTA/TNF, TRAF5, RELB) and associated single nucleotide polymorphisms (SNPs) in an independent sample of MCL patients. Methods: We genotyped 71 SNPs from 8 genes in a prospective cohort of newly diagnosed MCL patients with germline DNA enrolled at the Mayo Clinic and University of Iowa from 2002–2008 as part of the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE. All patients were systematically followed through 2009 for overall survival (OS) and event-free survival (EFS, defined as disease progression, retreatment or death due to any cause). Genotyping was performed on an Illumina Golden-Gate platform. Cox regression was used to estimate Hazard Ratios (HRs) and 95% confidence intervals (CI) for individual SNPs with OS and EFS. Each SNP was modeled with the most prevalent homozygous genotype used as the reference group. An ordinal test was used to assess the trend across genotype. A principal components methodology was used for gene-level analyses. All Cox models were adjusted for MIPI and treatment. We compared our results to the previously reported NCI-SEER study that included MCL patients diagnosed from 1998–2000. The NCI-SEER study had a median age at diagnosis of 64 years (range 38–74), 27 deaths (69%), and a median follow-up for living patients of 47 months (23-85 months). Replication was declared based on a p-trend<0.10 in the gene-level test or p-trend<0.10 in the SNP-level ordinal trend test and a HR of similar direction and magnitude to the NCI-SEER study result. Results: The median age at diagnosis of the 101 patients in the SPORE was 64 years (range 42–88), and by simplified MIPI score there were 38% low risk, 37% intermediate risk, and 26% high risk patients. The most common initial therapy was anthracycline-based chemotherapy ± rituximab (59%) with or without stem cell transplantation. Through 2009, there were 61 events (60%) and 31 (31%) deaths, with a median follow-up for living patients of 59 months (range 29–90). At the gene-level, none of the 8 genes replicated at p<0.10. However, at the SNP level, the genes with SNPs that replicated for OS included TRAF5 (rs3738199, rs6684874, rs12569232), TNFRSF25 (rs3138156), and RELB (rs10424046, rs1560725). The strongest TRAF5 SNP was rs3738199 which had a minor allele frequency (MAF) of 0.35. Compared to patients with the AA genotype, those with the AG (HR=2.14, 95% CI 0.91–5.01) or GG (HR=3.72, 95% CI 1.34–10.3) genotypes had inferior survival (p-trend=0.0092). The TNFRSF25 SNP rs3138156 had a MAF of 0.054; compared to patients with the AA genotype, those with the AG or GG genotype (HR=2.46, 95% CI 0.88–6.89) had inferior survival (p=0.087). Finally, the strongest RELB SNP was rs10424046, and had a MAF of 0.54. Compared to patients with the GG genotype, those with the GC (HR=0.57, 95% CI 0.25–1.28) or CC (HR=0.39, 95% CI 0.14–1.12) genotypes had superior survival (p-trend=0.065). Similar results for EFS were observed for the TRAF5 and RELB SNPs. Discussion: Germline genetic variation in the TNF and NF-κB pathway genes TRAF5, RELB, and TNFRSF25 were associated with prognosis in MCL after adjustment for clinical and treatment factors, and this result replicates findings from an independent dataset. TRAF5 is one of the components of a multiple protein complex which binds to TNF receptor cytoplasmic domains and mediates TNF-induced activation; RELB is part of the NF-κB complex; and TNF super family receptor member 25 stimulates NF-κB activity and regulates apoptosis through signal transduction that is mediated by various death domain containing adaptor proteins. In summary, genetic variation in TNF and NF-κB pathway genes may play a role in disease progression and overall survival in MCL, supporting further targeting of this pathway for therapy. Support: Lymphoma Research Foundation, P50 CA97274, R01 CA129539. Disclosures: No relevant conflicts of interest to declare.

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High Complete Response Rates with Dose Dense/Dose Intense Chemotherapy Plus Radioimmunotherapy in High Risk Diffuse Large B Cell and Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.2681.2681 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2681-2681 ◽

Cited By ~ 1

Author(s):

Anne W Beaven ◽

David A. Rizzieri ◽

Zachary Powell ◽

Zhiguo Li ◽

Peggy Alton ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Dose Dense ◽

Large B Cell

Abstract Abstract 2681 Background: Despite recent advances, the 5 year overall survival for patients with high risk diffuse large B cell lymphoma (DLBCL) is approximately 50% and there is still no known cure for patients with mantle cell lymphoma (MCL). This phase II study of multimodal dose dense therapy evaluated 2 courses of dose intense chemotherapy followed by radioimmunotherapy (RIT) consolidation in patients with previously untreated, mantle cell or high/high intermediate (int) risk aggressive B cell lymphoma. Aim: To evaluate the efficacy and safety of dose intense/dose dense, multimodal chemo-immunotherapy combined with RIT. Methods: Patients with untreated MCL or high int/high risk DLBCL were enrolled. Treatment regimen involved 3 phases of therapy: induction 1, induction 2 and consolidation with RIT (Table 1). Induction 2 occurred approximately 5 weeks after induction 1 and RIT was given 12–24 weeks after rituximab was completed. Patients were evaluated after each treatment phase and those with stable disease (SD) or better and blood count recovery could proceed to the next phase of therapy. Results: Thirty nine patients (pts) with high/high int risk DLBCL (n=25) or MCL (n=14) were enrolled. The median age was 60 years (range 21–80). Toxicity: Common, anticipated toxicities in the induction phases were thrombocytopenia, neutropenia, nausea, fatigue, and anemia. During Ind1 (n=39), grade (gr) III mucositis occurred in 13 pts (33%) and febrile neutropenia (FN) in 31 (79%). Three pts did not proceed to Ind2 due to death (1 candidemia, 1 septic knee prosthesis, 1 from complications of colectomy for prolonged diverticulitis after count recovery) and 2 withdrew to pursue less intense chemotherapy. During Ind2 (n=34) gr III mucositis occurred in 12pts (35%) and FN in 24 (67%). Two pts had gr III/IV cerebellar toxicity that was disabling in 1 pt. Of the 34 pts who received the Ind2, 9 did not receive RIT due to progressive disease (PD) (4), prolonged cytopenias (4), or diagnosis of pancreatic cancer (1). Twenty five pts received RIT and 3 (12%) had FN, 20 (80%) had gr III/IV neutropenia, 23 (92%) had gr III/IV thrombocytopenia, 1 pt died from bacteremia. Two pts developed myelodysplasia 21 and 48 months after starting therapy. Response: Pts were evaluated for response after Ind1, Ind2 and RIT. 38/39 pts were evaluable for response, with 1 pt withdrawing prior to assessment. The pts who died prior to response evaluation were counted as non-responders. The best overall response rate (ORR) was 95% (36/38) with a complete response rate (CR) of 84% (32/38). See tables 2 and 3 for more detailed response data by phase of treatment and disease type. After a median follow up of 17.2 months, 30 pts (77%) are alive (see figure). The median overall survival for MCL has not been reached and is 36.5 months for DLBCL. Deaths were from Hodgkin lymphoma (1), infection (3), DLBCL (2), complications of surgery (1), MCL (2). The median progression free survival is 36.5 months with 11/14 (79%) MCL and 14/25 (56%) DLBCL pts alive and in continued CR. Conclusion: The combination of dose dense, dose intense chemotherapy, monoclonal antibody, and RIT demonstrates considerable efficacy, despite expected toxicity, in high risk DLBCL and MCL pts. The response rates seen in this study are higher than expected from standard R-CHOP in this pt population. Further follow up to determine impact on OS and long term complications will be required to confirm these promising outcomes. Disclosures: Beaven: Glaxo Smith Kline: Family Member Employed by GSK. Off Label Use: Tositumomab is approved for use in relapsed/refractory low grade CD20 positive NHL. It is not FDA approved for first line use in diffuse large B cell lymphoma or mantle cell lymphoma. Neither cytarabine nor etoposide are approved for use in non-Hodgkin lymphoma. Rizzieri:Glaxo Smith Kline: Speakers Bureau. Moore:Glaxo Smith Kline: Speakers Bureau.

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Efficacy of Chemotherapeutic Regimens for Mantle Cell Lymphoma: A Systematic Review of Phase III Trials

Blood ◽

10.1182/blood-2020-141181 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 6-7

Author(s):

Ali Jaan ◽

Muhammad Tayyeb ◽

Farhan Khalid ◽

Muhammad Khawar Sana ◽

Zahoor Ahmed ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Interferon Alfa ◽

Phase Iii ◽

Cell Transplant ◽

Mantle Cell ◽

Combination Regimens

Background: The mainstay treatment for mantle cell lymphoma (MCL) is chemotherapy ± immunotherapy. The standard chemotherapeutic regimens have limited efficacy in MCL when used alone. In this systematic review, we have assessed the efficacy and safety of various combination regimens for the treatment of MCL evaluated in phase III clinical trials. Methods: We performed a comprehensive systematic literature search on PubMed, Embase, clinicaltrials.gov, and Web of Science databases with the date of inception to May 2020. We used MeSH (Medical Subject Headings) terms for "mantle cell lymphoma", "treatment outcome" along with their keywords, and combined their results. Our search generated a total of 3572 articles. After excluding case reports, case series, observational studies, review articles, meta-analysis, phase I/II clinical trials, and pre-clinical studies, we included five phase III randomized clinical trials (RCTs) reporting the efficacy of combination regimens for MCL treatment. Results Data from five phase III RCTs was pooled with total N=1683 (newly diagnosed (ND), n=1242, relapsed/refractory (RR), n=441). 1610 patients were evaluable. Kluin-Nelemans et al. 2020 (n=560) studied induction with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) vs R-FC (rituximab, fludarabine, and cyclophosphamide) for ND-MCL with follow-up on maintenance with rituximab (R) -vs interferon alfa. At a median follow up of 7.6 years (y), median overall survival (mOS) was 6.4 vs 3.9 y (p=0.0054) in R-CHOP vs R-FC group, respectively. The median progression-free survival (mPFS) and mOS in the R-CHOP cohort on R maintenance were significantly better when compared to those on interferon alfa maintenance (mPFS, 5.4 y vs 1.9 y, p<0.001) (mOS, 9.8 y vs 7.1 y, p=0.0026). Robak et al. (2015) (n=487) assessed bortezomib in ND-MCL by substituting it for vincristine in the standard R-CHOP therapy. A cohort of MCL ineligible for stem cell transplant (SCT) was randomly assigned to either R-CHOP or VR-CAP (bortezomib replacing vincristine). At a median follow-up of 40 months (mo), mPFS was 24.7 mo vs 14.4 mo in VR-CAP vs R-CHOP (HR 0.63, p<0.001), respectively. Similar, relative improvements were reported in complete response (CR) (53% vs 42%, p=0.007) and 4-year OS was (64% [95% CI 56-71] vs 54% [95% CI 45-62]). Jin et al. (2018) (n=121) assessed R-CHOP vs VR-CAP in ND-MCL patients ineligible for SCT. After a median follow-up of 42.4 mo, mPFS for VR-CAP was better than R-CHOP (28.6 mo vs 13.9 mo, HR=0.7, p=0.157). The overall response rate (ORR) was almost similar in VR-CAP (97%) and R-CHOP (98%). The 4-year OS was 62% vs 61% in VR-CAP vs R-CHOP, respectively. Flinn et al. (2014) (n=74) studied the efficacy of bendamustine in combination with rituximab (BR) vs R-CHOP or R-CVP (R-CHOP minus doxorubicin) as induction regimens in ND-MCL. 36 patients received BR and 38 patients received R-CHOP/R-CVP. ORR was 94% vs 85% with BR vs R-CHOP/R-CVP, respectively. Hess et al. (2009) (n=162) evaluated temsirolimus in RR-MCL. The study population was randomized to either 175/75mg temsirolimus (arm A), 175/25mg temsirolimus (arm B), and the investigator's choice of chemotherapy (arm C). The mPFS was significantly better in arm A compared to arm C (4.8 mo vs 1.9 mo, HR 0.44 [97.5% CI 0.25-0.7], p=0.0009). Arm B had slight improvement but insignificant. Similarly, mOS was 12.8 mo in arm A (HR 0.8 [95% CI 0.5-1.28], p=0.35), and 8.8 in arm B (HR 0.96 [95% CI 0.60-1.54], p=0.87), when compared to 9.5 mo in arm C. Drelying et al. (2016) (n=280), studied temsirolimus in comparison with ibrutinib, RR-MCL with mPFS of 14.6 mo (95% CI 10.4-not estimable) vs 6.2 mo (95% CI 4.2-7.9), respectively. Toxicities were typically manageable. VR-CAP was associated with a higher incidence of toxicity (100%) vs R-CHOP (94%) majority of which was hematological. Thrombocytopenia was particularly more prominent with temsirolimus. Granulocytopenia was persistent in 30-40% in the R-FC cohort after 5 y. Conclusion: The chemo-immunotherapy combination is favorable compared to chemotherapy alone for the treatment of MCL. R-CHOP induction followed by rituximab maintenance in MCL shows favorable long-term safety and efficacy profile. Bortezomib substituting for vincristine in R-CHOP improves the efficacy outcomes. Ibrutinib-based regimens are superior to temsirolimus-based regimens. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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Clinical Characteristics, Treatment and Outcome of Patients with Mantle Cell Lymphoma: A Large, Multicenter Retrospective Analysis in China

Blood ◽

10.1182/blood-2021-149042 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4522-4522

Author(s):

Ping Yang ◽

Shuozi Liu ◽

Jing Wang ◽

Wei Zhang ◽

Hui Liu ◽

...

Keyword(s):

High Risk ◽

Mantle Cell Lymphoma ◽

Maintenance Treatment ◽

Cell Lymphoma ◽

Risk Group ◽

High Risk Group ◽

High Dose ◽

Mantle Cell ◽

High Dose Cytarabine

Abstract Background Mantle cell lymphoma (MCL) is an uncommon heterogeneous subtype of B cell non-Hodgkin lymphoma, most MCL cases have a rapid evolution and an aggressive behavior with an unfavorable outcome. Clinical features in mantle cell lymphoma appeared regional characteristics and the epidemiology of MCL in Asia is not accurate documented. MCL treatment opinions are not uniform between country/region within Asia and China. At present, the large-scale Asian patient-specific data for the treatment of MCL are lacking. Aims To obtain 'real world' clinical characteristics,treatment patterns and prognosis factors of MCL patients in China and to address the knowledge gap in Chinese MCL patients. Methods Patients diagnosed with MCL between April 1999 and December 2019 at 19 comprehensive hospitals in China were included in this retrospective analysis. The median follow-up times was 36.0 months. The data of total 805 patients with mantle cell lymphoma were collected, 112 patients with incomplete clinical data, no chemotherapy and missing follow-up data were excluded. Finally, 693 patients with complete clinical data, treatment information and survival follow-up data were included in this study.Fully detailed information of patients, disease characteristics, treatments and outcomes were collected. Fisher's exact test or Pearson's Chi-squared test were used to compare categorical variables.Survival analysis was performed by Kaplan-Meier. Results The median age of the cohort was 60.0 years with a male-to-female ratio of 3.36:1. 477 patients (68.8%) were younger than 65 years at diagnosis.Advanced stage of diseases were 90.0%. Extranodal organ involvement was 83.4% and the most frequently involved extranodal organs were bone marrow(46.2%), spleen(36.1%), gastrointestinal tract(24.8) and oropharynx(17.7%). Blastic/pleomorphic mantle cell lymphoma accounted for 12.8%, and non-nodular mantle cell lymphoma accounted for 3.3%. Ki-67 more than 30% was 57.7% and Ki-67 ≥ 50% was 26.1%. The intermediate /high risk group was 49.8% according to MIPI score. The first-line therapeutic schedule is not completely unified, the most frequently regimen was CHOP/CHOP-like±R (n=312,45.0%) ,then high-dose cytarabine (n=222,32.0%), VR-CAP(n=44,6.3%), BR(n=30,4.3%), R-EPOCH (n = 17, 2.5%), FC / FCM±R regimen (n = 13,1.9%),and 55 patients(7.9%) uesd chemo-free regimen including IR / R2 / IR2 .Only 80 patients (11.5%) received autologous hematopoietic stem cell transplantation as consolidation therapy after chemotherapy remission. The ORR rate was 85.0%with 46.6% CR and 38.4% PR in the initial treatment.During the follow-up to June 2021(2-204months), 222 patients(32.0%) had died. The 5-year PFS and OS was 30.9% and 65.0%respectively.In the multivariate Cox regression model, ki67 ≥ 50% (HR 1.27, 95%CI 1.01-1.60, p = 0.038) ,stageⅢ/Ⅳ (HR1.56, 95%CI 1.05-2.33, p = 0.029),high- intermediate/high risk group accouding to MIPI-c (HR1.56, 95%CI 1.05-2.33, p = 0.008),spleen involvment (HR1.35, 95%CI 1.08-1.69, p = 0.009),without maintenance treatment (HR0.71, 95%CI 0.56-0.88, p = 0.003) ,SD/PD in inital treatment (HR6.20, 95%CI4.71-8.14, p < 0.001) were independently associated with poorer PFS while ki67 ≥50% (HR 1.74, 95%CI 1.31-2.31, p< 0.001),B symtom (HR 1.52, 95%CI 1.15-2.00, p = 0.003), high-intermediate/high risk group accouding to MIPI-c (HR1.43, 95%CI 1.24-1.64, p < 0.001),without high-dose cytarabine (HR0.47, 95%CI 0.31-0.70 ,p < 0.001) ,without maintenance treatment (HR0.40, 95%CI 0.28-0.58,p < 0.001)and relapse/refractory state (HR 4.04, 95%CI 2.21-7.39, p < 0.001) were independently associated with poorer OS. Conclusions This study describes the characteristics of mantle cell lymphoma in Chinese population with younger onset age and a higher tumor proliferation index. High dose cytarabine treatment and maintenance treatment have shown survival benefits in real-world.Recurrence and refractory is an important factor affecting survival,the strategy of combining molecular biological characteristics with novel strategies may improve outcome in these patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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B-Cell Depletion for Two Years after Autologous Stem Cell Transplant Reduces Lymphoma Relapse but Induces Prolonged Hypogammaglobulinemia beyond the Rituxan Maintenance Period.

Blood ◽

10.1182/blood.v110.11.4480.4480 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4480-4480

Author(s):

Seah H. Lim ◽

William V. Esler ◽

Yana Zhang ◽

Jian Zhang ◽

Phillip O. Periman ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large Cell ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Maintenance Period ◽

Mantle Cell

Abstract Although autologous stem cell transplant (ASCT) may benefit patients with relapsed or high risk non-Hodgkin’s lymphoma (NHL), many patients still relapse and die of their disease. Most relapses occur during the first three years after transplant. In an attempt to reduce disease relapses, we have applied a maintenance regimen to patients after ASCT for B-cell NHL. In this regimen, all patients received low dose rituximab infusion (375 mg/m2 for one day only) every three months starting D+100 for a total of 2 years or until disease relapse. We reasoned that rituxan infusion given for only one day every three months may be sufficient to prevent disease relapse during this post-transplant period when any residual tumor bulk is likely low. Fifteen patients (eight men, seven women) with high-risk B-cell lymphoma have been treated. Their diagnoses: advanced mantle cell lymphoma in first complete remission (CR1) (8), refractory advanced marginal zone lymphoma (2), refractory follicular large cell lymphoma (1), high risk T-cell rich B-cell NHL in CR1 (1), Stage IV diffuse large cell lymphoma in CR1 (1) and relapsed B-cell NHL in CR2 (2). The median age was 59 years (range 38–72 years). CR was achieved using R-CHOP (10) or R-DHAP/R-ICE (5) and autologous hematopoietic stem cells were harvested during hematopoietic recovery from the last course of chemo-immunotherapy. With a median follow-up of 46 months (range 12–66) for the group and 47 months (range 16–66) for patients with advanced mantle cell lymphoma, the projected 5.5 years relapse-free survival for the group is 100% and the overall survival 80%. Two patients with mantle cell lymphoma died, one due to metastatic breast cancer and another a stroke at 40 and 41 months respectively. Unlike patients who underwent ASCT without rituximab, in whom B-cell recovery occurred between 3–6 months, we observed severe delays in the immunoglobulin recoveries in these patients (Figure 1). With a median immunoglobulin follow-up of 28 months (range 6–64), none of the fifteen patients showed normalization of total IgG. Two patients achieved a normalized total IgA and two a normalized total IgM. This hypogammaglobulinemia persists beyond the rituxan maintenance period. The median time to attainment of 75% normal level of immunoglobulin is 36 months for IgG, 48 months for IgA and not reached for IgM. The severe immunoglobulin deficiencies may be clinically relevant. Six of fifteen patients developed recurrent upper respiratory tract infection. No fatal infection was observed among any of the patients. Our results, therefore, suggest that low dose rituximab administration every three months after ASCT for high-risk B-cell lymphoma may prevent lymphoma relapse. However, this is associated with severe and prolonged delays in immunoglobulin recovery beyond the rituxan maintenance period. Careful monitoring of the immunoglobulin recovery and intervention as appropriate should be done routinely in these patients. Figure Figure

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Phase II Study of Modified Hyper-CVAD with Rituximab Maintenance for Previously Untreated Mantle Cell Lymphoma: A Wisconsin Oncology Network Study.

Blood ◽

10.1182/blood.v104.11.1388.1388 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1388-1388 ◽

Cited By ~ 5

Author(s):

Brad S. Kahl ◽

James McGovern ◽

Jules Blank ◽

Anthony Jaslowski ◽

Gerald Bayer ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Progressive Disease ◽

Cell Lymphoma ◽

Response Rates ◽

High Response ◽

High Dose ◽

Hematologic Toxicity ◽

Rituximab Maintenance ◽

Mantle Cell

Abstract Introduction: Mantle cell lymphoma has the poorest 5-year survival of all the non-Hodgkin’s lymphoma subtypes and appears incurable with standard therapies. High response rates are seen with CHOP plus rituximab (R), but the progression free survival (PFS) is disappointingly short (median 16–20 months). Favorable results have been reported for hyper-CVAD + R with midcycle high dose methotrexate and cytarabine, but this regimen can be prohibitively toxic for some patients. We hypothesized that eliminating methotrexate and cytarabine while adding R to the induction hyper-CVAD would produce high response rates with acceptable toxicity. We further hypothesized that adding R maintenance would prolong the PFS. Methods: Eligible patients had histologically confirmed CD20+ mantle cell lymphoma and could not have received more than 1 cycle of CHOP-like therapy for their disease prior to study entry. PS 0-2 was allowed. The treatment plan included rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 2 mg IV day 3, dexamethasone 40 mg po days 1–4, and G-CSF 5mg/kg/day starting after therapy until ANC ≥ 4000/mm3. Cycles were repeated every 28 days, up to 6 cycles. Patients achieving at least a PR received R maintenance therapy (375 mg/m2 IV weekly X 4 doses) every 6 months for 2 years. The accrual goal was 20 patients evaluable for response. Results: Enrollment is completed. All 22 patients are evaluable for toxicity, PFS, and OS and 20 patients evaluable for response rate (2 patients died before any restaging). Patient characteristics include 20/22 male, median age 63 (40–81), median IPI 3 (1–5), and 19/22 stage IV. All patients have completed the induction chemotherapy. Six patients have completed the R maintenance, 10 remain on R maintenance, and 6 patients came off study due to progressive disease (4) or death (2). The ORR is 85% (17/20) with 3 PR, 14 CR/CRu. With a median follow up of 22.5 months (range 4–45), the median PFS and OS have not been reached. The 2-year PFS is 73% (95% CI 50–89%) and the 2-year OS is 82% (95% CI 60–95%). Responses are ongoing in 16 patients, with response duration ranging from 2+ to 39+ months. The most common grade 3–4 toxicities in the 22 patients included neutropenia (10), anemia (5), thrombocytopenia (5), and infection (4). To date, five patients who participated in this study have died (1 treatment-related neutropenic fever, 1 post-surgical infection, 3 progressive disease). The major toxicity of this treatment regimen is expected hematologic toxicity. Conclusion: Modified hyper-CVAD with rituximab maintenance demonstrates ORR comparable to conventional hyper-CVAD (85% vs. 93%) and is less toxic, especially in patients over 60. Compared with published reports for R-CHOP, we observed higher CR rates (70% vs 34–48%) and considerably longer median PFS (not yet reached vs. 16–20 months). Longer follow up will better define the effectiveness of this regimen, but the encouraging results of this pilot study provide the basis for additional study in a larger setting.

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Should Intensive Chemotherapy Be Required for All Mantle Cell Lymphoma Patients

Blood ◽

10.1182/blood.v118.21.5188.5188 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5188-5188

Author(s):

Zhen Tang Lao ◽

Kathleen Khoo ◽

Jasmine Koh ◽

Whee Sze Ong ◽

Tiffany Tang ◽

...

Keyword(s):

High Risk ◽

Mantle Cell Lymphoma ◽

Combination Chemotherapy ◽

Cell Lymphoma ◽

P53 Mutation ◽

Disease Stage ◽

Cell Transplant ◽

Intensive Chemotherapy ◽

Mantle Cell ◽

Sox11 Expression

Abstract Abstract 5188 Background: Mantle cell lymphoma (MCL) has been found to be a heterogenous disease and this has been further validated based on gene expression profiling studies. Due to this heterogeneity, the treatment of MCL is not standardized, with some groups advocating intensive chemotherapy on initial presentation, and those who adopt a wait and see approach initially. In an effort to better prognosticate MCL, several tools or factors such as MIPI score, blastoid subtype, Ki67 and P53 expression have also been used in clinical practice. As such, our study serves to describe the clinicohistopathological and molecular characteristics of MCL patients and elucidate any correlation between mutation status and prognosis. Methods: We studied 25 newly diagnosed MCL patients with adequate clinical, immunohistochemical and cytogenetic data treated at our institution between Jan 1998 and June 2010. The histological diagnosis in all cases was centrally reviewed by our hematopathologists. In addition, all patients had fluorescence in situ hybridization (FISH) performed; using breakapart FISH probes targeting CCND1, BCL2, BCL6, MYC, MALT1 and IgH genes. Results: The median age of patients was 59 years (43 to 84), with a male preponderance (ratio of 4:1) and nearly all patients presenting with advanced disease (Stage III or IV) except for one patient. Correspondingly, 7 out of 25 patients had high risk disease based on the simplified mantle cell lymphoma international prognostic index (MIPI). The blastoid morphology was exhibited in 4 of the 25 patients (16%). 21 out of 24 patients (88%) were also found to express SOX11, while none of our patients in the study expressed P21. FISH analysis revealed that P53 mutation was found in 4 (19%) of 21 patients, ATM deletion detected in 10 (42%) out of 24 patients, and BCL 6 amplification was detected in 5 (20%) out of 25 patients. Notably, only one patient with double translocation involving c-myc and cyclin D1 was found, the patient also had ATM deletion. The presence of ATM deletion, however, was not significantly associated with p53 mutation or BCL6 amplification in our series. All except for 2 patients received combination chemotherapy, with 18 patients (78%) receiving rituximab based chemotherapy. 8 patients were treated with the intensive combination chemotherapy of HyperCVAD ± rituximab. Of which, 3 patients were treated with HyperCVAD without rituximab followed by autologous stem cell transplant in 2 of the patients. Only the presence of a blastoid morphology (15.6 months vs. 98.7 months; P= 0.004) and high risk MIPI (81.3 months vs. 154.6 months; P = 0.007) score predicted for a worse outcome. Aside from those 2 factors, the presence of P53 mutation, ATM deletion, SOX11 expression, high Ki67, BCL 6 amplification, patients treated with rituximab based chemotherapy and patients who received HyperCVAD chemotherapy did not confer any difference in survival. Interestingly, the survival outcomes in our MCL patients were longer than the reported median survival of 3–4 years in the literature. The median overall survival (OS) of our MCL patients was 98.7 months and a progression free survival (PFS) of 48.9 months, with a median follow-up of 37.3 months. Conclusion: The MCL patients in our study appear to have a favourable outcome, with a median OS of 98.7 months. Only the blastoid subtype and high risk MIPI score conferred a worse prognosis. The presence of P53 mutation, high Ki67, SOX11 expression, BCL6 amplification and the use of intensive chemotherapy such as HyperCVAD did not appear to influence survival. In view of the excellent survival, a period of initial observation or the use of less intensive chemotherapy regimen instead of HyperCVAD may be a reasonable approach for MCL patients with non-blastoid subtype or low risk MIPI score. Disclosures: No relevant conflicts of interest to declare.

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Updated Analysis of a Prospective Phase II Trial of R-MACLO-IVAM Followed by Maintenance for Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.1622.1622 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1622-1622

Author(s):

Jose D Sandoval-Sus ◽

Peter J Hosein ◽

Deborah Goodman ◽

Alexandra Stefanovic ◽

Joseph D Rosenblatt ◽

...

Keyword(s):

Bone Marrow ◽

Mantle Cell Lymphoma ◽

Phase Ii ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Maintenance Phase ◽

Induction Phase ◽

Rituximab Maintenance ◽

Mantle Cell

Abstract Abstract 1622 Background: Contemporary therapy for mantle cell lymphoma (MCL) in fit patients usually consists of an induction phase followed by autologous stem cell transplantation (SCT). We previously reported a phase II trial of intensive chemotherapy induction with R-MACLO-IVAM followed by thalidomide maintenance and demonstrated promising progression-free survival (PFS) and overall survival (OS) rates without SCT (Lossos et al, Leuk Lymph 2010). We subsequently modified the protocol to utilize rituximab maintenance instead of thalidomide. Herein we present updated results and follow-up for the patients treated on this trial. Methods: This was a prospective single-arm phase II trial conducted at the University of Miami with IRB approval. Eligible patients were chemotherapy-naïve and had a confirmed diagnosis of MCL using WHO criteria, age 18–75 years, ECOG PS 0–2, adequate organ function and no history of HIV or prior cancer. Pretreatment staging include CT and PET scans, endoscopy, colonoscopy and bone marrow biopsy. Cycle 1 consisted of R-MACLO (rituximab, methotrexate, doxorubicin, cyclophosphamide and vincristine) followed by G-CSF. When the ANC was >1.5×109/L, cycle 2 with R-IVAM (rituximab, ifosfamide, mesna, etoposide and cytarabine) was begun, followed by G-CSF, as previously reported. 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, patients were re-staged and responses were assessed by standard criteria. Patients who achieved complete responses (both radiologically and pathologically) were eligible for the maintenance phase. The first 22 patients were treated with thalidomide maintenance (target daily dose of 200mg); the protocol was subsequently modified to utilize rituximab maintenance at a dose of 375 mg/m2 IV weekly × 4 weeks, repeated every 6 months. Maintenance therapy was continued until MCL relapse or intolerable toxicity. OS was calculated from the date of diagnosis to the date of death or last follow up. PFS was calculated from date of diagnosis until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics and survival was analyzed using the Kaplan-Meier method. Results: Between June 2004 and June 2012, 32 patients were enrolled, 22 on the first phase and 10 after the amendment to rituximab maintenance. All patients were evaluable for toxicity and 31 were evaluable for response. Median age was 56.5 years (range 39–73). All subjects had at least stage III disease with bone marrow involvement in 84% and gastrointestinal involvement in 38%. Distribution according to MIPI: low 28%; intermediate 38%; high 34%. All patients had diffuse variant except 2 with blastic variant. Twenty-eight patients completed all 4 cycles of therapy; treatment was stopped in 2 after 3 cycles, and in one after 2 cycles, and 1 died during cycle 1. Of the 31 patients completing 2 cycles of chemotherapy, 29 (94%) achieved a complete response (CR) and 2 had a partial response (PR). After a median follow-up of 54.9 months, the 5-year PFS was 69% (95% CI 51% – 82%) and the 5-year OS was 88% (95% CI 72% – 95%) [Fig 1 & 2]. Lower MIPI group (low vs intermediate vs high) was associated with longer PFS (log rank p = 0.007) and longer OS (log rank p = 0.036) [Fig 3 & 4]. Nine patients relapsed and 5 died; 1 died from sepsis on cycle 1; 1 died in CR at 38 months from non-small cell lung cancer diagnosed 19 months after MCL and the other 3 died from relapsed MCL after 22, 24 and 60 months respectively. Seven of the 9 patients who relapsed were treated with rituximab and bendamustine and one underwent an allogeneic SCT. Toxicities during the chemotherapy phase for the last 10 patients were similar to what was previously published for the first 22 patients, with the exception of lower renal toxicity since the dose of methotrexate was reduced to a total of 4.2 g/m2 instead of 6.7 g/m2 prior to the amendment. The toxicities during the thalidomide maintenance phase were similar to what was previously reported. For the 10 patients who received rituximab maintenance, there were no unexpected toxicities during the maintenance phase. Conclusions: R-MACLO-IVAM results in a high overall response rate (94% CR and 6% PR) and a low relapse rate after over 4.5 years of median follow-up. The median PFS and OS still have not been reached. These results compare favorably with regimens that include upfront SCT. Disclosures: No relevant conflicts of interest to declare.

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