Advanced Stage Mantle Cell Lymphoma Research Articles

Intrasinusoidal bone marrow involvement in mantle cell lymphoma: a case series with review of the main differential diagnoses.

Intrasinusoidal bone marrow involvement is an infrequent histological pattern observed in a limited number of B and T cell lymphomas. Mantle cell lymphoma is a biologically and prognostically heterogeneous B cell lymphoma that frequently involves the bone marrow, with interstitial, nodular-paratrabecular, or diffuse patterns. Intrasinusoidal bone marrow involvement has been described only anecdotally in this lymphoma. Here, we describe the clinical, histopathological, and molecular features of four patients diagnosed with advanced-stage mantle cell lymphoma, showing intrasinusoidal bone marrow involvement, and other peculiar immunophenotypical features. As similar cases may represent a relevant issue in bone marrow diagnostic histopathology, we also reviewed the literature to discuss differential diagnoses of B and T cell lymphomas with intrasinusoidal bone marrow involvement.

Concurrent development of advanced-stage mantle cell lymphoma and tuberculous pleural effusion

Concurrent development of advanced-stage mantle cell lymphoma and tuberculous pleural effusion

Overall Survival in Advanced Stage Mantle Cell Lymphoma after Early Autologous Stem Cell Transplantation with Cisplatin, Etoposide, Cytarabine and Melphalan (PEAM) As a Conditioning Regimen

Introduction. Autologous hematopoietic stem cell transplantation (ASCT) currently is the standard of treatment for patients in first remission diagnosed with Mantle cell Lymphoma (MCL). Overall survival (OS) was reported at five-years of 57.2% in a single center retrospective study published in 2011. OS has been improved by using conventional and high intensity induction chemo immunotherapy continuing with maintenance therapy as the GELA study reports a 5 year OS of 75%. LyMa Trial has proved an improvement in the global survival and progression free survival. In this study we aimed to describe the OS patients diagnosed with MCL with PEAM as a conditioning regimen. Methods A retrospective study was conducted on patients diagnosed with MCL and ASCT as consolidation therapy at the Instituto Nacional de Cancerología in Mexico City between 2011 and 2022. Our institutional conditioning regimen PEAM: Cisplatin 100 mg/m2 (-4), etoposide 750 mg/m2 (-4,-3), cytarabine 800 mg/m2 (-4,-3,-2) and melphalan 140 mg/m2( 4).OS results were obtained using the Kaplan-Meier method. Results We analyzed 19 patients with MCL after ASCT as consolidation therapy, a median follow-up of 10 years, the median age at transplantation was 56 years (range 39- 68 y), with male predominance (68.4%). Eleven patients with at least one comorbidity, the most predominant being diabetes mellitus type II (45.5%). Most patients with ECOG score of 1 (58%), 12 patients (63%) with high risk according to Mantle Cell lymphoma International Prognostic Index (MIPI), all patients with clinical stage III-IV, 26% of them with bone marrow infiltration. Eighteen patients (95%) received one line of chemoimmunotherapy, most were treated with R-CHOP plus + R-DHAP( 58%), 3 receive Hiper-CVAD (16%), 4 R-CHOP (21%) and only one R-DHAP . Eighteen patients (79%) with complete response, three (16%) with partial response and one patient (5%) with stable disease before ASCT. Sixteen patients (84%) received PEAM plus rituximab as myeloablative conditioning regimen, Three (16%) PEAM without rituximab. Neutrophil recovery median was 10 days, eleven patients (58%) developed complications being febrile neutropenia the most common (82%). Fifteen patients (79%) received maintenance with rituximab. Fourteen (74%) had complete response at last follow up after ASCT, three (20%) with relapsed disease, two stable disease (10%) Conclusion Conventional chemoimmunotherapy is effective followed by ASCT as consolidation therapy in mantle cell lymphoma with advanced stage disease. We describe higher OS 5-years (81%) as compared with other series (57% and 75%) with similar chemo immunotherapy and conventional conditioning regimen. Three patients relapsed, all died. The OS at 5-years was 81%.

Phase I Safety and Preliminary Efficacy of Acalabrutinib, Venetoclax, and Obinutuzumab (AVO) in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Introduction: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), even when treated with novel targeted agents, generally have only limited benefit (Rule et al., Leukemia 2018). The triple combination of the first-generation Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, the BCL-2 inhibitor, venetoclax, and anti-CD20 monoclonal antibody, obinutuzumab has demonstrated preliminary safety and efficacy in R/R and treatment naïve (TN) MCL (Le Gouill et al., Blood 2021). We therefore hypothesized that given the favorable toxicity profile of the second-generation BTKi, acalabrutinib, when given in combination with venetoclax and obinutuzumab (AVO), would be effective and well tolerated in both R/R and TN MCL. Here, we report the results of the phase I dose-finding cohort of AVO in patients with R/R MCL. Methods: This is an investigator-initiated, multicenter, multi-cohort phase I/II trial (NCT04855695). The primary endpoints of the phase I portion are the recommended phase II dose (RP2D) and the safety and tolerability of AVO in R/R MCL. The study was designed to evaluate up to 2 dose levels of acalabrutinib, starting with the FDA-approved dose (100 mg po bid, dose level 0 [DL0]) followed by a lower dose (100 mg po daily, DL-1) if dose limiting toxicities (DLTs) occurred in > 1/6 patients in DL0 during the first 4 cycles. Patients were treated in 28-day cycles with acalabrutinib starting with cycle 1, followed by obinutuzumab in cycle 2 (100 mg IV on day 1, 900 mg IV on day 2, 1000 mg IV on days 8 and 15, and on day 1 of cycles 3-7), and venetoclax (weekly dose ramp-up starting in cycle 3 to a target dose of 400 mg daily). Acalabrutinib and venetoclax were continued indefinitely and obinutuzumab maintenance was given every 2 cycles starting with cycle 9 for 12 doses. Patients with progressive disease (PD) or who were unable to receive > 80% of the doses of acalabrutinib and venetoclax during the first 4 cycles were replaced. Key eligibility criteria included R/R MCL after at least one anti-CD20 mAb-based therapy, ECOG PS ≤ 2, and adequate hematologic and organ function. Key exclusion criteria were progression or relapse following prior BTKi or BCL-2 inhibitor and CNS involvement. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy, respectively. Results: As of July 26, 2023, 9 patients in DL0 were evaluable for response as 3 patients were replaced prior to reaching the DLT window. The median age was 67 (range 63-79). 78% were male. Median number of prior treatments was 1 (range 1-2). 33% relapsed after autologous stem cell transplant and 22% had primary refractory disease. All patients had advanced stage MCL, with stage IV disease in 89%. MIPI score was 22% high, 56% intermediate, and 22% low risk. Ki67 index ≥ 30% in 44% and ≥ 50% in 33%. 33% patients had complex karyotype, 22% TP53 mutation, 33% p53 IHC expression > 50%, and 33% blastoid variant. No DLTs were observed and DL0 was determined to be the RP2D. All 9 patients were evaluable for toxicity (Figure 1A). Hematologic toxicity included neutropenia (67%; 33% Gr 3), thrombocytopenia (56%; 22% Gr 3/4), and anemia (22%; all Gr 3). The most common toxicities were headache (77%; all Gr 1/2), bruising (67%; all Gr 1), diarrhea (44%; all Gr 1/2), and upper respiratory infection (22%; 11% Gr 3). There were no serious adverse events. There was no occurrence of febrile neutropenia, atrial fibrillation, bleeding, or laboratory or clinical tumor lysis syndrome. Median follow-up was 6 months (range 1-21). ORR was 78% (7/9) and CR rate was 67% (6/9) after 3 cycles of AVO. Both patients with TP53 mutation and 2/3 patients with blastoid variant achieved CR. Of the 3 patients replaced prior to the DLT window, 2 patients had PD and 1 patient was unable to receive > 80% of the acalabrutinib and venetoclax doses due to grade 4 thrombocytopenia, although achieved CR. 5 patients (56%) remain on treatment and in CR. 1 patient achieved PR after cycle 3 but progressed after cycle 7. Median overall and progression-free survival were not reached. Conclusions: AVO is safe and feasible in patients with R/R MCL with no DLTs observed. RP2D was determined at the full FDA approved dosage of all three drugs. Preliminary efficacy is encouraging in this high-risk R/R MCL population. The phase II TN transplant ineligible or TP53 mutated MCL cohort is now enrolling with minimal residual disease (MRD)-guided time-limited therapy (Figure 1B). The phase I R/R expansion cohort will also open to enrollment.

Predictive Value of Minimal Residual Disease on Efficacy of Rituximab Maintenance in Mantle Cell Lymphoma: Results from the European MCL Elderly Trial

On behalf of the European MCL Network Introduction: Rituximab (R) maintenance after immunochemotherapy represents standard of care in older mantle cell lymphoma (MCL) patients. The European MCL Elderly trial has shown the efficacy of R maintenance after R-CHOP in terms of PFS and OS (Kluin-Nelemans et al., JCO 2020). Induction with R-FC showed similar response rates and failure-free survival but inferior OS as compared to R-CHOP. The assessment of minimal residual disease (MRD) represents a promising tool for individualized treatment decisions. Within the European MCL Elderly trial, we investigated whether MRD status predicts the efficacy of maintenance and aimed to identify MRD-based trigger time points for targeted intervention. Patients and methods: The MCL Elderly trial included patients with previously untreated, advanced stage MCL aged 60 years or older and not suitable for autologous stem cell transplantation. MRD assessment was done at predefined time points during and after treatment until clinical progression for patients recruited in France or Germany with baseline samples and at least one follow-up sample. Three central MRD labs performed marker screening (BCL1-JH t(11;14) translocation or IGH rearrangement) and real-time quantitative PCR (qPCR) following standardized ESG guidelines, as previously reported (Pott et al., Blood 2010). MRD status was pooled from bone marrow and peripheral blood results by classifying a patient as MRD negative if all available samples at the respective time point were negative. Predictive value of MRD status at end of induction for efficacy of maintenance was analysed with Cox regression for PFS including the interaction term of MRD status and treatment group. To assess the prognostic value of MRD status for clinical progression, landmarks were defined at midterm induction (MI), end of induction (EOI), and during four 6-months periods following EOI. Results: A molecular marker for MRD assessment was generated in 85% of 288 screened patients and in 80% a qPCR assay fulfilling standardized criteria could be established. Patients in whom a molecular marker could be identified had more frequently generalized disease compared with those without molecular marker (85% vs. 51% stage IV, 78% vs. 37% with bone marrow involvement, median LDH/ULN quotient: 0.93 vs. 0.81). Among patients without clinical progression during induction, MRD-negativity was achieved more frequently and earlier with R-FC (MI: 63% of 82 patients; EOI: 80% of 82) than with R-CHOP (MI: 26% of 84, p<0.0001; EOI: 53% of 89, p=0.0002). The efficacy of maintenance was clearly seen in patients MRD negative at EOI (PFS-HR 0.38, 95% CI 0.21-0.63, Figure 1A) and was slightly less pronounced in MRD positive patients (HR 0.51, 95% CI 0.26-1.02; interaction p=0.48, Figure 1B). Especially after R-CHOP, the efficacy of R-maintenance was higher among MRD-negative patients (HR 0.23, 95% CI 0.10-0.52) than among MRD-positive patients (HR 0.59, 95% 0.28-1.26, interaction p=0.097). Landmark analyses confirmed the prognostic value of MRD status during and after R-FC and during maintenance/follow-up after R-CHOP. Median time from MRD-positivity 6/12/18/24 months from EOI to clinical progression was consistently short with 2.2/1.2/1.6/1.4 years after R-CHOP and 1.0/1.0/0.7/0.7 years after R-FC. Conclusions: The results confirm the strong efficacy of R-maintenance in MRD-negative patients after induction. Omitting or stopping maintenance based on MRD-negativity is thus discouraged. Considering the short time to progression, more effective treatment strategies should be explored in MRD-positive patients to improve the long-term prognosis of patients with MCL. Figure 1: Progression-free survival (PFS) from end of induction (EOI) by maintenance randomization (R vs. no R) in patients MRD-negative (A) or MRD-positive (B) at EOIFigure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Spontaneous tumor lysis syndrome in hyperaggressive mantle cell lymphoma.

An otherwise well 61-year-old male presented to his primary care practitioner with drenching sweats, weight loss, massive splenomegaly (30 cm as measured by computed tomography [CT], Figure 1A) and a lymphocytosis (white blood cell [WBC] at diagnosis 150 × 109/L). The peripheral smear was notable for the presence of pleomorphic abnormal lymphocytes, with clumped chromatin, high nuclear:cytoplasm ratio and irregular nuclei (Figure 1B). Peripheral blood flow cytometry revealed a kappa light chain restricted population of mature B-cells which co-expressed CD20 and CD5 (Figure 1C). CD23 and CD10 were negative. Fluorescent in situ hybridization revealed a CCND1/IGH rearrangement, consistent with a diagnosis of advanced stage mantle cell lymphoma (MCL). Approximately 3 weeks after diagnosis, he was admitted electively for chemotherapy. On admission to the unit he was well, with normal vital signs and a normal baseline tumor lysis profile (K, Phos, Ca, urate and creatinine all within institution limits). His WBC was noted to have increased modestly to 264 × 109/L. Unfortunately, over the course of the next 12 h, prior to the administration of any systemic anti–cancer therapy (including steroids), he developed spontaneous tumor lysis syndrome and died of catastrophic metabolic derangement, despite aggressive supportive care. He developed severe, refractory hyperkalemia (7.5 mmol/L), severe hyperphosphatemia (3.83 mmol/L) and profound metabolic acidosis (pH <6.9, HCO3– 3 mmol/L, lactate 17 mmol/L). His WBC had also climbed explosively to 695 × 109/L (Figure 1D), putting him at significant risk of leukostasis. I postulate that, via clonal evolution, his disease acquired a hyperproliferative phenotype, resulting in fulminant, spontaneous tumor lysis syndrome. There are limited reports of secondary translocations involving the MYC proto-oncogene in patients with MCL. This is associated with aggressive clinical course and short overall survival; however there are no reports of MCL behaving this aggressively in the literature. Practitioners should be aware of this rare but potentially devastating complication of MCL. James Wilson wrote the manuscript and took pictures. The author declares they have no conflicts of interest. The author received no specific funding for this work. No research on human was performed on this study. Data sharing not applicable—no new data generated.

IBRORS-MCL study: a Spanish retrospective and observational study of relapsed/refractory mantle-cell lymphoma treated with ibrutinib in routine clinical practice

This retrospective study evaluated 66 patients diagnosed with relapsed and/or refractory mantle cell lymphoma (R/R MCL) treated with ibrutinib in Spain in routine clinical practice. At diagnosis, patients had a median age of 64.5 years, 63.6% presented with intermediate/high sMIPI (simplified prognostic index for advanced-stage mantle cell lymphoma), 24.5% had the blastoid variant, and 55.6% had a Ki67 > 30%. Patients had received a median of 2 prior lines of therapy (range 1–2; min–max 1–7). Overall response rate was 63.5%, with 38.1% of patients achieving complete response (CR). With a median duration of ibrutinib exposure of 10.7 months (range 5.2–19.6; min–max 0.3–36), the median progression-free survival (PFS) and overall survival (OS) were 20 months [95% confidence interval (CI) 8.8–31.1] and 32 months (95% CI 22.6–41.3), respectively, and were not reached in patients achieving CR. No grade ≥ 3 cardiovascular toxicity or bleeding was reported. This study supports that treatment with ibrutinib leads to high response rates and favorable survival outcomes in patients with R/R MCL.

Mantle cell lymphoma involving tonsils: a clinicopathologic study of 83 cases

We report 83 cases of mantle cell lymphoma (MCL) involving the tonsil as initial manifestation (IM). The median age at the time of tonsillar involvement was 58 years (range, 35-79 years). Most (85%) patients presented similar to acute tonsillitis. Lymphadenopathy (84%) and advanced stage of disease (81%) were frequent. With a median follow-up of 6.1 years (range, 0.5-18.4 years), the median overall survival (OS) was 11.3 years for all patients. Cases with classic MCL morphology demonstrated a superior OS (median OS: 11.7 years versus 7.8 years for aggressive morphology, P=0.0361). Approximately 20% of patients had limited stage of disease, and they had excellent outcomes (median OS: not reached versus 11.3 years for advanced-stage MCL, P=0.0479). All the patients were alive after a median follow-up of 6.6 years (range, 1-16.2 years). There were no differences in relapse-free survival in morphology and stage (P>0.05). When tonsils were involved by relapsed MCL, patients less commonly had acute tonsillitis-like symptoms, lymphadenopathy, and advanced stage of disease compared to MCL as IM. Patients in the relapse group had poorer OS than patients in the IM group from the time of tonsillar involvement by MCL to the date of death or last follow-up (7.8 versus 11.7 years, P=0.003). Compared with a group of 93 patients whose initial biopsy specimen was a lymph node, patients whose initial biopsy specimen was tonsil had similar OS (11.7 versus 8.8 years, P=0.1764). However, patients with tonsillar MCL more commonly had limited stage disease (19% versus 8%, P=0.0385) and a low-risk Mantle Cell Lymphoma International Prognostic Index score (71% versus 47%, P=0.0025).

Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial

Autologous haematopoietic stem-cell transplantation (HSCT) in first remission is the current standard treatment in fit patients with mantle cell lymphoma. In this long-term follow-up study, we aimed to evaluate the efficacy of autologous HSCT versus interferon alfa maintenance after chemotherapy without or with rituximab in patients with primary advanced-stage mantle cell lymphoma. We did a post-hoc, long-term analysis of an open-label, multicentre, randomised, phase 3 trial done in 121 participating hospitals or practices across six European countries. Patients who were aged 18-65 years with previously untreated stage III-IV mantle cell lymphoma and an ECOG performance score of 0-2 were eligible for participation. Patients were randomly assigned (1:1) to receive either myeloablative radiochemotherapy (fractionated total body irradiation with 12 Gy/day 6-4 days before autologous HSCT and cyclophosphamide 60 mg/kg per day intravenously 3-2 days before autologous HSCT) followed by autologous HSCT (the autologous HSCT group) or interferon alfa maintenance (the interferon alfa maintenance group; 6 × 106 IU three times a week subcutaneously until progression) after completion of CHOP-like induction therapy (cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, vincristine 1·4 mg/m2 [maximum 2 mg] intravenously on day 1, and prednisone 100 mg/m2 orally on days 1-5; repeated every 21 days for up to 6 cycles) without or with rituximab (375 mg/m2 intravenously on day 0 or 1 of each cycle; R-CHOP). The primary outcome was progression-free survival from end of induction until progression or death among patients who had a remission and the secondary outcome was overall survival from the end of induction until death from any cause. We did comparisons of progression-free survival and overall survival according to the intention-to-treat principle between both groups among responding patients and explored efficacy in subgroups according to induction treatment without or with rituximab. Hazard ratios (HRs) were adjusted for the mantle cell lymphoma international prognostic index (MIPI) numerical score, and in the total group also for rituximab use (adjusted HR [aHR]). This trial was started before preregistration was implemented and is therefore not registered, recruitment is closed, and this is the final evaluation. Between Sept 30, 1996, and July 1, 2004, 269 patients were randomly assigned to receive either autologous HSCT or interferon alfa maintenance therapy. The median follow-up was 14 years (IQR 10-16), with the intention-to-treat population consisting of 174 patients (93 [53%] in the autologous HSCT group and 81 [47%] in the interferon alfa maintenance group) who responded to induction therapy. The median age was 55 years (IQR 47-60), and R-CHOP was used in 68 (39%) of 174 patients. The median progression-free survival was 3·3 years (95% CI 2·5-4·3) in the autologous HSCT group versus 1·5 years (1·2-2·0) in the interferon alfa maintenance group (log-rank p<0·0001; aHR 0·50 [95% CI 0·36-0·69]). The median overall survival was 7·5 years (95% CI 5·7-12·0) in the autologous HSCT group versus 4·8 years (4·0-6·6) in the interferon alfa maintenance group (log-rank p=0·019; aHR 0·66 [95% CI 0·46-0·95]). For patients treated without rituximab, the progression-free survival adjusted HR for autologous HSCT versus interferon alfa was 0·40 (0·26-0·61), in comparison to 0·72 (0·42-1·24) for patients treated with rituximab. For overall survival, the adjusted hazard ratio for HSCT versus interferon alfa was 0·52 (0·33-0·82) without rituximab and 1·05 (0·55-1·99) for patients who received rituximab. Our results confirm the long-term efficacy of autologous HSCT to treat mantle cell lymphoma established in the pre-rituximab era. The suggested reduced efficacy after immunochemotherapy supports the need for its re-evaluation now that antibody maintenance, high-dose cytarabine, and targeted treatments have changed the standard of care for patients with mantle cell lymphoma. Deutsche Krebshilfe, the European Community, and the Bundesministerium für Bildung und Forschung, Kompetenznetz Maligne Lymphome.

Survival Trends in Patients Under Age 65 Years With Mantle Cell Lymphoma, 1995-2016: A SEER-Based Analysis.

Purpose: The treatment paradigm for mantle cell lymphoma (MCL), a B-cell malignancy, has shifted considerably during the past decades. This study aimed to evaluate time trends in overall survival (OS) and disease-specific mortality (DSM) of younger (age ≤ 65 years) patients with MCL from 1995 to 2016.Methods: We used the Surveillance, Epidemiology, and End Results database. Year of diagnosis was divided into three eras: the chemotherapy-alone era (1995–2000), intensified-immunochemotherapy era (2001–2012), and targeted-therapy era (2013–2016). We used the Kaplan–Meier method, log-rank test, and subdistribution proportional hazard regression in the analysis.Results: A total 4,892 patients were identified. Median OS increased from 67 months in the chemotherapy-alone era to 107 months in the intensified-immunochemotherapy era (P < 0.001). The DSM rate decreased significantly from 1995 to 2016 (P < 0.001); the adjusted hazard ratios of MCL-specific death were 0.589 (P < 0.001) for the intensified-immunochemotherapy era and 0.459 (P < 0.001) for targeted-therapy era, as compared with the chemotherapy-alone era. Patients with advanced-stage MCL exhibited lowering risk of death across the three eras (P < 0.001).Conclusions: During 1995–2016, survival in younger patients with MCL increased significantly, especially those with advanced-stage disease, potentially reflecting the impact of advancement in treatment modalities on MCL outcome.

1558 Diffuse Primary Gastrointestinal Mantle Cell Lymphoma: A Rare Cause of Hematochezia

INTRODUCTION: Mantle cell lymphoma (MCL) is non-Hodgkin lymphoma that classically does not involve the gastrointestinal (GI) tract. Although in some cases MCL has been shown to spread to the GI tract, primary gastrointestinal MCL is exceedingly rare and has only been described anecdotally. Often, the diagnosis of MCL is made once the disease is metastatic given its largely nonspecific symptom profile. We present a case of diffuse MCL of the GI tract presenting as hematochezia, in a patient with ulcerative colitis. CASE DESCRIPTION/METHODS: An 80-year-old male with history of newly diagnosed ulcerative colitis (UC) presented with four weeks of worsening diarrhea and hematochezia associated with a 30-pound weight loss over five months. He had been on mesalamine for UC, but had not experienced symptomatic relief. On admission, the patient was anemic to a hemoglobin of 9.3 g/dL, white blood cell count of 21.6 × 103/L with 13% bands and 48% atypical lymphocytes, and an albumin of 1.7 g/dL with normal platelets and INR. Abdominal imaging showed diffuse mesenteric lymphadenopathy concerning for a lymphoproliferative process and circumferential gastric, rectal and sigmoid wall thickening and edema. Clostridium Difficile (C. Diff) stool PCR was positive, and he was started on oral vancomycin therapy. Colonoscopy showed diffuse inflammation and edema of the colon with poor mucosal integrity and a hypertrophic mass in the ascending colon. Upper endoscopy showed diffuse, hypertrophied, thickened folds within the stomach and duodenum along with ulcerations. Endoscopic ultrasound was performed to biopsy para-aortic and celiac lymph nodes. Given high suspicion for lymphoma, a bone marrow biopsy was also obtained. Histopathology from the multiple biopsies were all consistent with Stage 4 pleomorphic Mantle Cell Lymphoma. DISCUSSION: This case describes a rare presentation of MCL, complicated by C. Diff colitis in addition to UC. There has been little data to show that these unique clinical entities are significantly correlated. Although hematochezia is a rare presentation of MCL, clinicians should maintain a high index of suspicion for malignancy and pursue additional imaging and/or procedures, even in a patient that has other reasons to present with hematochezia. This case of advanced stage MCL of the GI tract adds to a small body of literature regarding primary gastrointestinal MCL and warrants further research in to this rare gastrointestinal malignancy.

The Signal Transducer and Activator of Transcription 5B (STAT5B) Gene Promotes Proliferation and Drug Resistance of Human Mantle Cell Lymphoma Cells by Activating the Akt Signaling Pathway.

BackgroundMantle cell lymphoma (MCL) is a high-grade B-cell lymphoma with poor prognosis. Fludarabine is used alone or in combination for relapsed and advanced-stage MCL. The expression of the signal transducer and activator of transcription 5B (STAT5B) gene is associated with tumorigenesis in solid tumors, but its role in MCL remains unknown. The aims of this study were to investigate the role of STAT5B in GRANTA-519 human mantle cell lymphoma cells and drug resistance.Material/MethodsGRANTA-519 human mantle cell lymphoma cells were cultured with and without 10 μM fludarabine dephosphorylated 9-β-D-arabinofuranosyl-2-fluoroadenine, (2-F-araA) or 10 μM 4-hydroperoxycyclophosphamide (4-HC). The MTT assay assessed cell proliferation. Flow cytometry was used to investigate the cell cycle in MCL cells treated with the specific inhibitor of the Akt pathway, LY294002, and assessed cell cycle and cell apoptosis. Western blot was used to detect the expression levels of p-Akt/Akt and STAT5B/p-STAT5B. The gene expression profiles of lymph node (LN)-derived MCL cells were compared with peripheral blood (PB)-derived lymphocytes using bioinformatics and hierarchical cluster analysis. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to determine the expression of the marker of proliferation Ki-67 (MKI67) gene.ResultsSTAT5B was significantly upregulated in LN-derived MCL cells compared with PB lymphocytes. Increased expression of STAT5B was associated with increased MCL cell proliferation and reduced cell apoptosis and was associated with drug resistance and activation of Akt.ConclusionsSTAT5B promoted cell proliferation and drug resistance in human MCL cells by activating the Akt signaling pathway.

Lenalidomide Maintenance after Autologous Transplantation Prolongs PFS in Young MCL Patients: Results of the Randomized Phase III MCL 0208 Trial from Fondazione Italiana Linfomi (FIL)

Lenalidomide Maintenance after Autologous Transplantation Prolongs PFS in Young MCL Patients: Results of the Randomized Phase III MCL 0208 Trial from Fondazione Italiana Linfomi (FIL)

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Identification of DNA Copy Number Variations Associated with the Clinical Outcome in Young Mantle Cell Lymphoma Patients Treated with Cytarabine-Based High Dose Sequential Chemotherapy and Autologous Stem Cell Transplantation in the Prospective from the MCL0208 Phase III Trial from Fondazione Italiana Linfomi (FIL)

Background. Mantle Cell Lymphoma (MCL)represents an aggressive lymphoma for which an effective treatment has still to be determined. The FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25) is exploring R-CHOP followed byi) high-dose cytarabine, autologous stem cell transplantation, and ii) randomization between lenalidomide maintenance vs observation (Cortelazzo et al, EHA 2015). We performed genome-wide DNA profiling to identify unbalanced copy number variations (CNVs) with a clinical significance in patients enrolled in the FIL-MCL0208 phase III trial.Patients and Methods. The study included untreated, advanced stage MCL patients (<65 years) enrolled into the MCL0208 trial. Clinical results of the first interim analysis (without random unblinding) have been already reported and are the basis of the present analysis: median follow-up of alive patients was 26 months, and at 2-years, 79% of patients were progression free and 91% alive (Cortelazzo et al EHA 2015). DNA profiling with the Illumina HumanOmni2.5 arrays was performed on 174 DNA samples derived from baseline bone marrow CD19+ purified tumor cells. Genomic profiles were segmented with the Fast First-derivative Segmentation Algorithm (Rinaldi et al, BJH 2013; Kwee et al, bioRxiv 2016). Recurrent CNVs were defined applying both the minimal common regions and the GISTIC algorithms (Lenz et al, PNAS 2008; Mermel et al, Genome Biol 2011). CNVs were integrated with somatic mutational data obtained for 8 genes recurrently affected in MCL (ATM, BIRC3, CCND1, KMT2D, TP53, TRAF2, WHSC1, NOTCH1) (Rossi et al, ASH 2015). Progression free survival (PFS) was the primary endpoint of the analysis.Results. 161 patients were currently evaluable for CNVs and clinical outcome. Patients had an intermediate/high-risk MIPI and a Ki67 ³ 30% in 43% and 42% of the cases, respectively. Twenty-five recurrent unbalanced CNVs were defined (Table 1). By multiple test corrected univariate analysis, seven CNVs had a negative impact on PFS: +3, 7p gain, 9p loss (CDKN2A), 17p loss (TP53), 8p loss, and 2 losses at 22q (Table 1). MIPI (intermediate/high vs low risk), Ki67+ and the TP53/KMT2D model (Rossi et al, ASH 2015) were also statistically significant. Combining CNVs and mutations, TP53 was inactivated in 27/147 cases (18%): mutated/deleted in 7/147 (5%), deleted but not mutated in 14/147 (10%), and mutated but not deleted in 6/147 (4%). The negative prognostic impact was equal for all the 3 inactivation modalities, which were then considered as a single group for further analyses. ATM was inactive in 69/147 (47%): mutated/deleted in 24/147 (16.3%), deleted in 12/147 (8%), and mutated in 33/147 (22.4%). KMT2D (MLL2) was inactive in 18/147 (12%): mutated/deleted in 1/147 (<1%), deleted in 1/147 (<1%), and mutated in 16/147 (11%).The lesions with a significant impact at univariate were included in a multivariate analysis alongside MIPI, KMT2D inactivation and Ki67+ as continuous variable. Only TP53 inactivation by deletion and/or mutation, 7p22.2-p12.1 gain and KMT2D inactivation maintained their independent prognostic significance.Conclusions. Genome wide DNA profiling in the FIL-MCL0208 phase III trial identified lesions, namely TP53 and KMT2D inactivation and gains at 7p, which maintain a poor outcome significance in young MCL patients even following high-dose cytarabine and autologous stem cell transplantation. [Display omitted] DisclosuresRossi:Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Stelitano:Azienda Ospedaliera: Employment. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria.

3219 90Y-ibritumomab-tiuxetan consolidation for advanced stage mantle cell lymphoma after first line autologous stem cell transplantation: Is it time for a step forward?

3219 90Y-ibritumomab-tiuxetan consolidation for advanced stage mantle cell lymphoma after first line autologous stem cell transplantation: Is it time for a step forward?

CD34+ selected versus unselected autologous stem cell transplantation in patients with advanced-stage mantle cell and diffuse large B-cell lymphoma

Novel strategies aiming to increase survival rates in patients with advanced-stage mantle cell lymphoma (MCL) and relapsing diffuse large B-cell lymphoma (DLBCL) are a clinical need. High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) has improved progression-free (PFS) and overall survival (OS) in MCL and relapsed DLBCL. However, the role of CD34+ cell selection before ASCT in MCL and DLBCL is unclear. We retrospectively analyzed the outcome of 62 consecutive patients with advanced-stage MCL or relapsed DLBCL undergoing ASCT with (n=31) or without (n=31) prior CD34+ selection. All patients had stage III or IV disease, with 47% having DLBCL and 53% MCL. The median duration for neutrophil and platelet recovery was 12 and 16 days in CD34+ selected patients, and 11 (P<.001) and 14 days (P=.012) in the group without selection, respectively. No differences in toxicities were observed. The 5-year PFS for CD34+ selected versus not selected patients was 67% and 39% (P=.016), and the 5-year OS was 86% and 54% (P=.007). Our data suggest that using CD34+ selected autografts for ASCT in advanced stage MCL and DLBCL is associated with longer PFS and OS without increased toxicity.

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

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

Role Of High-Dose Cytarabine and Total Body Irradiation Conditioning before Autologous Stem Cell Transplantation In Mantle Cell Lymphoma - A Comparison Of Nordic MCL2, HOVON 45, and European MCL Younger Trials

IntroductionHigh-dose cytarabine containing immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) has been established as standard first-line treatment in younger mantle cell lymphoma (MCL) patients (ESMO guideline, Ann Oncol 2013). However, the role of total body irradiation (TBI) as conditioning regimen for ASCT has not been clarified so far. A retrospective EBMT survey of 418 MCL patients suggested a benefit of TBI with respect to the rate of relapse in patients who achieved a partial remission before ASCT (Rubio et al., ASH 2010). We combined the individual patient data of the Nordic MCL2 trial (Geisler et al., Blood 2008), the HOVON 45 trial (van't Veer et al., BJH 2008, both without TBI), and the high-dose cytarabine containing study arm of the European MCL Younger trial (Hermine et al., ASH 2012, with TBI) to evaluate potential differences in long term outcome. MethodsAll trials included patients with advanced stage MCL up to 66 years and a central review of histology. Induction treatment of Nordic MCL2 consisted of 6 alternating courses of Maxi-CHOP or high-dose cytarabine (12g/m2 per cycle, 8g/m2 in patients > 60 years, total cumulative dose 24-36g/m2) combined with 4-6 cycles rituximab, in HOVON 45 three courses R-CHOP were followed by one cycle of high-dose cytarabine (16g/m2), and in MCL Younger patients received 6 alternating courses of R-CHOP or R-DHAP (4g/m2 cytarabine per cycle, total cumulative dose 12g/m2). Conditioning before ASCT consisted of BEAM or BEAC in Nordic MCL2, and BEAM in HOVON 45, whereas a TBI-containing regimen (TAM: 10 Gray TBI, 6g/m2 cytarabine, 140mg/m2 melphalan) was applied in MCL Younger. We compared baseline characteristics, progression free survival (PFS) overall survival (OS) after ASCT from the three patient cohorts with adjustment for MIPI (Hoster et al., Blood 2008) and quality of remission before ASCT. ResultsIn Nordic MCL2, HOVON 45, and MCL Younger 145, 61, and 171 patients were transplanted in complete (CR) or partial (PR) remission (median age 57, 55, and 56 years, p=0.24). According to MIPI, 46%, 56%, and 67% were low risk, whereas 22%, 13%, and 11% were high risk patients (p=0.006). Five-year PFS after ASCT was 61%, 50%, and 78%, respectively (p<0.001) after a median observation time of 6.6, 6.5, and 4.2 years). After adjustment for MIPI score and quality of response (CR/unconfirmed CR vs. PR) before ASCT, the hazard ratio for PFS after ASCT of MCL Younger vs. Nordic MCL2 was 0.75 (p=0.17). Among the patients with CR or unconfirmed CR before ASCT, the adjusted hazard ratio was 0.91 (p=0.76) in comparison to 0.66 (p=0.17) among the PR patients. On the other hand, the hazard ratio of MCL Younger in comparison to HOVON 45 was 0.45 (p=0.001) after adjustment for MIPI score. OS after ASCT was not different between the three cohorts with 5-year OS rates of 75%, 71%, and 80%, respectively (p=0.61). ConclusionThe longer PFS after ASCT of MCL Younger compared to HOVON 45 patients may be due to the different time schedule of cytarabine during induction or to a higher efficacy of TBI vs. BEAM, as the total chemotherapy doses were comparable and we adjusted for MIPI. We could not see an improved PFS after ASCT of MCL Younger compared to Nordic MCL2 patients transplanted in CR or unconfirmed CR and, after adjustment for the different risk profiles, this was also not clearly seen for patients transplanted in PR. Taking into account the substantially higher cytarabine dose in Nordic MCL2 during induction one might speculate that this fact at least partially compensated for a higher efficacy of TBI. Multivariable analyses incorporating additional prognostic factors (Ki-67 and MRD) will help to clarify the impact of the individual parts of the current multimodal approach in younger MCL patients.On behalf of the European Mantle Cell Lymphoma Network Disclosures:No relevant conflicts of interest to declare.

Guidelines for the investigation and management of mantle cell lymphoma.

The guideline group was selected to be representative of UK-based medical experts and patients representatives. Ovid MEDLINE, EMBASE and NCBI Pubmed were searched systematically for publications in English from 1980 to 2011 using the MeSH subheading 'lymphoma, mantle cell' and 'lymphoma, mantle cell' as a keyword, as well as all subheadings. In addition, all references to mantle cell lymphoma in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue (Swerdlow et al, 2008) and the British Committee for Standards in Haematology (BCSH) Guideline: Best Practice in Lymphoma Diagnosis and Reporting (Parker et al, 2010) have been included. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology Task Force of the BCSH. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of patients with mantle cell lymphoma. The guidance may not be appropriate to patients with other lymphoma sub-types and in all cases individual patient circumstances may dictate an alternative approach.