European Mantle Cell Lymphoma Network Research Articles

Conditional survival of younger patients with mantle cell lymphoma: Results from a randomized phase III trial of the European MCL Network.

During a fatal disease, patients often request updated information on their prognosis. After patients have already survived a certain time, conditional survival captures their future survival probability. We investigated conditional overall and failure-free survival in 473 younger mantle cell lymphoma (MCL) patients from a randomized phase III trial comparing immunochemotherapies R-CHOP and alternating R-CHOP/R-DHAP before autologous transplantation. Using conditional Kaplan-Meier method and Cox regression, we estimated subsequent survival of patients who had survived 1-8 years, considering MIPI, Ki-67, and treatment failure status. Starting at a lower level, R-CHOP patients only showed increasing subsequent survival as they survived longer (5-year conditional survival: 72% and 81% after surviving 1 and 7 years), while R-CHOP/R-DHAP patients had stable future survival over time (77% and 78%). The prognostic value of MIPI diminished after 3 years in R-CHOP patients but remained unchanged after R-CHOP/R-DHAP. Patients with treatment failure had markedly inferior survival compared with those in ongoing remission, regardless of the time survived. The longer patients remained in remission, the longer they would stay free of treatment failures. Our results enable personalized counselling for younger MCL patients by offering dynamic prognosis and underscore the importance of highly effective first-line treatment to improve survival.

Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network

Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT. The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m2 on day 1, intravenous doxorubicin 50 mg/m2 on day 1, intravenous vincristine 1·4 mg/m2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258. Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238). Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined. Janssen and Leukemia & Lymphoma Society.

The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma—a randomized, open-label phase III trial of the European mantle cell lymphoma network

The therapy of relapsed or refractory (r/r) mantle cell lymphoma (MCL) patients remains a major clinical challenge to date. We conducted a randomized, open-label, parallel-group phase-III trial hypothesizing superior efficacy of rituximab, high-dose cytarabine and dexamethasone with bortezomib (R-HAD + B) versus without (R-HAD) in r/r MCL ineligible for or relapsed after autologous stem cell transplant (ASCT). Primary endpoint was time to treatment failure (TTF), secondary endpoints included response rates, progression free survival, overall survival, and safety. In total, 128 of 175 planned patients were randomized to R-HAD + B (n = 64) or R-HAD (n = 64). Median TTF was 12 vs. 2.6 months (p = 0.045, MIPI-adjusted HR 0.69; 95%CI 0.47–1.02). Overall and complete response rates were 63 vs. 45% (p = 0.049) and 42 vs. 19% (p = 0.0062). A significant treatment effect was seen in the subgroup of patients >65 years (aHR 0.48, 0.29–0.79) and without previous ASCT (aHR 0.52, 0.28–0.96). Toxicity was mostly hematological and attributable to the chemotherapeutic backbone. Grade ≥3 leukocytopenia and lymphocytopenia were more common in R-HAD + B without differences in severe infections between both arms. Bortezomib in combination with chemotherapy can be effective in r/r MCL and should be evaluated further as a therapeutic option, especially if therapy with BTK inhibitors is not an option. Trial registration: NCT01449344.

Induction and Maintenance Therapy in Elderly Patients with Mantle Cell Lymphoma: Double-Randomized MCL R2 Elderly Clinical Trial By the European Mantle Cell Lymphoma Network

Background: Mantle cell lymphoma (MCL) formally remains an incurable disease. Recent trials in younger patients have demonstrated the benefit of a cytarabin-containing induction (Hermine, JCO 2022) and a rituximab (Le Gouill, NEJM 2017) as well as a lenalidomide maintenance (Ladetto, Lancet Haematol 2021). The MCL-R2 elderly trial investigated whether an induction with intermediate dose of cytarabine improves long term outcome over R-CHOP alone in elderly patients (>60 yrs). In addition, responders to induction therapy were randomized between a 2 year maintenance with rituximab-lenalidomide (R2) compared to rituximab alone. Here, we present the results of the 2 randomizations. Methods: Patients >60 yrs not eligible for high dose therapy with stage II-IV MCL were included. Initially, patients were randomized between 8 cycles of 3-weekly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or 6 cycles of alternating 3-weekly R-CHOP and 4-weekly R-HAD (rituximab, cytarabine, Dexamethasone). Subsequently, patients in complete or partial remission (CR, CRunconfirmed or PR) underwent a second randomization between rituximab maintenance every 2 months or R2 (lenalidomide 15 mg d2-22 every 4 weeks plus rituximab). Second randomization was stratified for induction regimen, study group, age, MCL international prognostic index (MIPI) and response (CR/CRu vs PR). Both maintenance regimens were continued for 24 months. The primary endpoint was EFS for the maintenance and overall survival for Induction therapy. Results: Out of 624 patients from 7 countries, 620 were randomized for induction, 492 responded (78 % ORR, CR/CRu 41%) and 495 were randomized for maintenance. Median age was 71 yrs, 69% male, 85% stage IV, 47% intermediate and 46% high risk MIPI. Response rate at the end of induction was similar in the 2 groups (OR 88% and 86% in the R-CHOP and R-CHOP/RHAD arm, respectively; CR 33% in both arms). No major safety difference were observed between the 2 induction arms. So far, PFS and OS were not different between the two induction regimen (70.6% vs. 66.8%; p=0.28 and 83% vs. 83% ; p=0.92 respectively: Figure 1A). After a median follow-up of 4.2 years from maintenance randomization, patients in the R2 maintenance arm had a significantly improved PFS in comparison to R alone. The 4-year PFS was 60.9% in the R2 arm vs. 42.9 % in the R arm (p= 0.0002, figure 1B). Adverse events (AEs) were more pronounced in the R2 maintenance arm. Recurrent (> 5%) AEs grade >3 were: neutropenia (50.8% vs 19.2%), respiratory tract infection (6.3% vs. 0.8%), and skin cancer (5.9% vs 3.2%). In 46% of patients in the R2 arm, the dose of lenalidomide had to be reduced at least once. Overall survival (OS) was not different between the two maintenance arms, (R2: 87.6% and R: 85.1% at 2 years). The majority of relapsed/refractory patients were treated with a BTK inhibitor alone or in combination (67.5%; 63% after R-CHOP and 71% after RHOP/RHAD). Conclusions: While no efficacy or toxicity differences were observed between the two induction regimens (8x R-CHOP vs 6x R-CHOP/HAD), the combined R2 maintenance significantly prolonged PFS compared to rituximab alone. However, no difference in OS was observed, and toxicity was increased in the R2 arm. Figure 1: OS(A) stratified by the CHOP and R-CHOP/RHAD arms and PFS (B) stratified by maintenance with rituximab (R) or rituximab-lenalidomide (R2) stratified by the four groups according to induction and maintenance arms.

Rituximab Combined with Chemotherapy and Acalabrutinib Prior to Autologous Stem Cell Transplantation in Mantle Cell Lymphoma: The Rectangle Trial

INTRODUCTION In the European MCL Network Triangle study (Dreyling, ASH 2022) the addition of ibrutinib to frontline rituximab-containing chemotherapy and subsequent maintenance therapy improved failure-free survival in young, fit patients with mantle cell lymphoma (MCL). Ibrutinib was administered with R-CHOP, but not with R-DHAP, during the induction phase. Continuous, uninterrupted Bruton Tyrosine Kinase (BTK) inhibition could maximize the benefit of front-line therapy given that responses develop over time. Acalabrutinib has less off-target BTK inhibition than ibrutinib. We hypothesize that combining continuous acalabrutinib with R-CHOP may result in a tolerable, outpatient, highly active regimen producing favorable outcomes. METHODS NCT04566887 is a phase II, single-arm, open-label study conducted across 5 academic centres in Canada. Patients ≥ 18 years of age with previously untreated MCL, ECOG performance status 0-2, adequate organ function and considered fit for autologous stem cell transplantation (ASCT) were included. Patients received 6 cycles of R-CHOP at standard doses plus acalabrutinib 100 mg twice per day orally. Responding patients proceeded with ASCT and maintenance rituximab and acalabrutinib for a total of 2 years. The primary endpoint was the complete response (CR) rate after 6 cycles of induction with centrally reviewed PET/CT using the Lugano Criteria (Cheson, 2014). The total sample size was n=54 and the study completed accrual in May 2023. We present the results of the first 43 patients who have completed response assessment according to local investigators after 6 cycles of induction. RESULTS The median age was 62 years (range 38 - 69), 26 (60%) were male, 42 (98%) had performance status 0-1, 33 (78%) Ann Arbor stage IV, 35 (81%) bone marrow involvement, 6 (14%) high risk MIPI, 7 (16%) blastoid/pleomorphic morphology, 11 (26%) Ki67 ≥30%. All patients completed 6 cycles of induction and proceeded to ASCT. The overall response rate was 100%, and 39 (91%) patients achieved a CR. All patients started maintenance acalabrutinib + rituximab, although none have yet completed two years of protocol maintenance therapy. With a median follow up of 11.8 months (range 3.4 - 25.3) by the reverse Kaplan-Meier method, the 12-month PFS was 94% (95% CI 78.1 - 98.5), shown in Figure 1, and OS 95.5% (95% CI 71.9 - 99.3). Three subjects have developed PD so far, all with adverse clinical and biological factors: Baseline high-risk MIPI and Ki67 70%; biopsy at relapse TP53 positive by immunohistochemistry (IHC)Baseline intermediate risk MIPI and Ki67 60%; biopsy at relapse with pleomorphic morphology, TP53 positive by IHC, Ki67 100%Baseline high risk MIPI, Ki67 ≥30%, and blastoid morphology. Table 1 lists common grade 3-4 adverse events (AE) during induction and maintenance. There were no grade 5 AE. Neutropenia was the most common AE during induction and maintenance. Most infections were respiratory. Cardiovascular toxicity was uncommon. CONCLUSIONS Acalabrutinib + R-CHOP is associated with a 91% CR rate with low rates of grade 3-4 AE expected for this combination. All patients have proceeded to ASCT and subsequent maintenance therapy. Maintenance therapy in this setting is associated with additional toxicity, particularly cytopenias and infections.

Combined therapy with ibrutinib and bortezomib followed by ibrutinib maintenance in relapsed or refractory mantle cell lymphoma and high-risk features: a phase 1/2 trial of the European MCL network (SAKK 36/13)

The Bruton's tyrosine kinase inhibitor ibrutinib and the proteasome inhibitor bortezomib have single-agent activity, non-overlapping toxicities, and regulatory approval in mantle cell lymphoma (MCL). Invitro, their combination provides synergistic cytotoxicity. In this investigator-initiated phase 1/2 trial, we established the recommended phase 2 dose of ibrutinib in combination with bortezomib, and assessed its efficacy in patients with relapsed or refractory MCL. In this phase 1/2 study open in 15 sites in Switzerland, Germany and Italy, patients with relapsed or refractory MCL after ≤2 lines of chemotherapy and both ibrutinib-naïve and bortezomib-naïve received six cycles of ibrutinibb and bortezomib, followed by ibrutinib maintenance. For the phase 1 study, a standard 3+3 dose escalation design was used to determine the recommended phase 2 dose of ibrutinib in combination with bortezomib. The primary endpoint in phase 1 was the dose limiting toxicities in cycle 1. The phase 2 study was an open-label, single-arm trial with a Simon's two-stage min-max design, with a primary endpoint of overall response rate (ORR) assessed by CT/MRI. This study was registered with ClinicalTrials.gov, NCT02356458. Between August 2015 and September 2016, nine patients were treated in the phase 1 study, and 49 patients were treated between November 2016 and March 2020 in the phase 2 of the trial. The ORR was 81.8% (90% CI 71.1, 89.8%, CR(u) 21.8%) which increased with continued ibrutinib (median 10.6 months) to 87.3%, (CR(u) 41.8%). 75.6% of patients had at least one high-risk feature (Ki-67>30%, blastoid or pleomorphic variant, p53 overexpression, TP53 mutations and/or deletions). In these patients, ibrutinib and bortezomib were also effective with an ORR of 74%, increasing to 82% during maintenance. With a median follow-up of 25.4 months, the median duration of response was 22.7, and the median PFS was 18.6 months. PFS reached 30.8 and 32.9 months for patients with a CR or Cru, respectively. The combination of ibrutinib and bortezomib shows durable efficacy in patients with relapsed or refractory MCL, also in the presence of high-risk features. SAKK (Hubacher Fund), Swiss State Secretariat for Education, Research and Innovation, Swiss Cancer Research Foundation, and Janssen.

Real-World Treatment Outcomes and Toxicities of Outpatient R-CHOP/R-DHAP in Patients with Mantle Cell Lymphoma Eligible for Autologous Stem Cell Transplant

INTRODUCTION: Despite a significant increase in median overall survival (OS) over the past three decades, mantle cell lymphoma (MCL) remains incurable with no standard frontline therapy. The addition of R-DHAP to R-CHOP with autologous stem cell transplant (ASCT) in the European MCL Network - MCL younger trial showed significant improvement in median progression free survival (PFS), although some concerns remain regarding increased toxicity. On this basis, R-CHOP/R-DHAP was approved as first line therapy for MCL at CancerCare Manitoba (CCMB) in 2016. In contrast to the original study, R-DHAP is currently administered in an outpatient setting in Manitoba. OBJECTIVE: To assess the real-world, non-trial PFS, OS, and toxicities of patients with MCL eligible for autologous stem cell transplant receiving R-CHOP/R-DHAP, administered on an outpatient basis, as induction therapy in Manitoba. METHODS: All patients with MCL in Manitoba eligible for R-CHOP/R-DHAP induction between Jan 1, 2016 and Dec 31, 2021 were identified through the CCMB. Individual patient records were obtained and reviewed for baseline demographic data, laboratory data, treatment characteristics including response, and treatment toxicities. SPSS was then used for statistical analysis to calculate PFS and OS using the Kaplan-Meier method. RESULTS: 25 charts were identified. 5 were excluded based on duplicate data for a total of 20 patients (85% male). The mean age at diagnosis was 54.4 (range 42-67). 75% had stage IV disease and 35% had constitutional symptoms. 15% of patients had ECOG ≥2 at diagnosis. 50% had elevated LDH at diagnosis, and the mean β-2-microglobumin was 3.5mg/L (range 1.9-16.1). 10% of patient's largest nodal dimension was >=7.5cm, 20% had disease with Ki67>=40%, and 15% had high risk disease by MIPI. The median number of chemotherapy cycles completed was 6 (range 2-6), with 50% requiring modification to therapy (5% progression, 20% infection, 20% ototoxicity, 20% nephrotoxicity, 5% corneal toxicity, 5% patient preference). 70% received ASCT, with 100% complete response by PET post-ASCT. 75% of all patients received maintenance rituximab, with a median of 8 cycles completed (range 2-8). At the end of follow up, there were 3 progression events, 3 deaths, and 1 death attributed to MCL. At a median follow up of 56.8 months, median PFS and OS were not reached. CONCLUSION: Our real-world data show feasibility of administering R-CHOP/R-DHAP in the outpatient setting with comparable outcome and toxicities to original study where R-DHAP was administered as inpatient. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genotyping and Minimal Residual Disease (MRD) Assessment in cfDNA By the Euroclonality-NGS DNA Capture (EC-NDC) Panel in Mantle Cell Lymphoma (MCL)

Background Modern concepts for the treatment of mantle cell lymphomas (MCL) increasingly integrate clinical and biological variables for risk-adapted treatment strategies. Novel next-generation sequencing (NGS) technologies are highly suited for tumor genotyping as well as disease monitoring by minimal residual disease (MRD) assessment, identifying patients (pts) with a high risk of relapse. Here, we investigated whether the EuroClonality (EC)-NGS DNA Capture (EC-NDC) assay is a) applicable for genotyping of MCL in peripheral blood (PB) and plasma cell-free (cf)DNA and b) suitable for MRD assessment in plasma as compared to the amplicon-based EuroClonality Immunoglobulin-based (IG-)NGS assay. Patients and methods A total of 109 PB samples (55 baseline and 54 interim staging) from a cohort of MCL treated within the TRIANGLE trial by the European MCL network (NCT02858258) were selected according to a PB infiltration ≥10% at diagnosis. From prospectively collected PB samples in national reference labs, DNA from the cellular blood compartment (PBC) and plasma cfDNA was extracted. For targeted capture, the EC-NDC assay (Univ8® Genomics, UK) was used to simultaneously detect immunoglobulin and T cell receptor (IG/TR) rearrangements, structural variants (SV) and single nucleotide variants (SNVs) in 72 genes (Stewart, Blood Adv, 2021). For diagnostic PBC and cfDNA samples, IG clonotypes were called with ≥6 unique reads and ≥5% of annotated IG reads, SV were called with ≥4 unique reads and SNV were called with ≥6 unique reads at ≥4% variant allele frequency (VAF). For amplicon-based MRD analysis the EuroClonality IG-NGS (IG-NGS) assay was used with IG clonotypes called with ≥5% of annotated IG reads and at ≥1 log higher abundance to the polyclonal background. MRD was analyzed by IG-NGS in PBC using 8 µg PBC DNA to reach a sensitivity of 10-6. For MRD analysis in cfDNA, we aimed to use ≥5000 genome equivalents (GE) for both IG-NGS and EC-NDC. Data were analyzed by ARResT/Interrogate (Bystry, Bioinformatics, 2017) with an adapted pipeline for targeted capture in cfDNA. MRD status was defined as positive by detecting a lymphoma-specific IG clonotype and/or SV at ≥1 read, or alternatively by retrieval of ≥1 disease-specific mutation at ≥3 reads. Results Total cfDNA amounts at baseline were high (mean 92.6 ng/mL plasma) and even increasing at interim staging (mean 123.8 ng/mL) while decreasing by 10-fold in 38 samples at end of treatment (EoT)(mean 11.45 ng/mL). At baseline, a tumor-specific IGH-VJ clonotype was detected by IG-NGS in all 55 PBC and cfDNA samples. Genotyping by EC-NDC showed fully concordant results in 55 PBC and cfDNA samples with respect to IG clonotypes, SV and SNV, except for 3 PBC samples with low usable reads covering IGH-VJ regions. The presence of a t(11;14)(q13;q32) translocation was confirmed in 54/55 pts in PBC and cfDNA, while one patient with unknown t(11;14) translocation status by FISH was negative by EC-NDC. EC-NDC identified 106 putative somatic SNVs (VAF 2.7-75%, median 30%) in PBC and cfDNA, and among those were genes described as drivers in MCL (ATM (25/55), TP53 (11/55), KMT2D (9/55), SAMHD1 (5/55), CCND1 (5/55) and 18 other genes (Fig. 1). Six pts with detectable t(11;14) and IG rearrangement did not show additional SNVs. On average, 6 MRD markers/pt were identified (range: 3-10). At interim staging, MRD was analyzed in 54 PBC and 44 cfDNA samples. Twenty-five (47%) pts were MRD+ in PBC by IG-NGS. Twenty (46%) pts were MRD+ in cfDNA by EC-NDC (8 cases with ≥2 markers, 4 with 2 markers, and 8 with 1 marker). From 10/44 (23%) cfDNA samples MRD+ by IG-NGS, 9 were also MRD+ by ED-NDC. From 44 pts with parallel analysis of PBC and cfDNA, 14 (32%) were MRD+ and 18 (41%) were MRD-, while 12 (27%) showed discordant results. Conclusion To the best of our knowledge, this is the first analysis comparing targeted capture and amplicon assays for application in PBC and cfDNA in MCL. The capture-based EC-NDC assay allows a comprehensive liquid biopsy-based genotyping of MCL. In addition, both IG-NGS and EC-NDC assays are suitable for MRD assessment in cfDNA with evidence of more sensitive MRD detection EC-NDC due to multiple MRD targets detected and traced by this assay. Clinical data are still needed to explore the potential prognostic impact of MRD assessment in plasma vs PBC. Updated MRD analysis at EoT and correlation with clinical data will be presented at the meeting. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Ibrutinib improves survival compared with chemotherapy in mantle cell lymphoma with central nervous system relapse

AbstractCentral nervous system (CNS) relapse of mantle cell lymphoma (MCL) is a rare phenomenon with dismal prognosis, where no standard therapy exists. Since the covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is effective in relapsed/refractory MCL and penetrates the blood–brain barrier (BBB), on behalf of Fondazione Italiana Linfomi and European Mantle Cell Lymphoma Network we performed a multicenter retrospective international study to investigate the outcomes of patients treated with ibrutinib or chemoimmunotherapy. In this observational study, we recruited patients with MCL with CNS involvement at relapse who received CNS-directed therapy between 2000 and 2019. The primary objective was to compare the overall survival (OS) of patients treated with ibrutinib or BBB crossing chemotherapy. A propensity score based on a multivariable binary regression model was applied to balance treatment cohorts. Eighty-eight patients were included. The median age at study entry was 65 years (range, 39-87), 76% were males, and the median time from lymphoma diagnosis to CNS relapse was 16 months (range, 1-122). Patients were treated with ibrutinib (n = 29, ibrutinib cohort), BBB crossing chemotherapy (ie, high-dose methotrexate ± cytarabine; n = 29, BBB cohort), or miscellaneous treatments (n = 30, other therapy cohort). Both median OS (16.8 vs 4.4 months; P = .007) and median progression-free survival (PFS) (13.1 vs 3.0 months; P = .009) were superior in the ibrutinib cohort compared with the BBB cohort. Multivariable Cox regression model revealed that ibrutinib therapeutic choice was the strongest independent favorable predictive factor for both OS (hazard ratio [HR], 6.8; 95% confidence interval [CI], 2.2-21.3; P < .001) and PFS (HR, 4.6; 95% CI, 1.7-12.5; P = .002), followed by CNS progression of disease (POD) >24 months from first MCL diagnosis (HR for death, 2.4; 95% CI, 1.1-5.3; P = .026; HR for death or progression, 2.3; 95% CI, 1.1-4.6; P = .023). The addition of intrathecal (IT) chemotherapy to systemic CNS-directed therapy was not associated with superior OS (P = .502) as the morphological variant (classical vs others, P = .118). Ibrutinib was associated with superior survival compared with BBB-penetrating chemotherapy in patients with CNS relapse of MCL and should be considered as a therapeutic option.

P1245: CLINICAL IMPACT OF IMMUNOGLOBULIN HEAVY CHAIN REPERTOIRE IN MANTLE CELL LYMPHOMA: A STUDY FROM THE FONDAZIONE ITALIANA LINFOMI (FIL) PHASE III MCL0208 TRIAL.

Background: Mantle cell lymphoma (MCL) is characterized by a highly restricted immunoglobulin heavy chain (IGH) gene repertoire with stereotyped IGHV CDR3s, strongly implying a role for antigen-driven selection. Nonetheless, differently from chronic lymphocytic leukemia, where the prognostic role of IGH parameters is known since decades, published data are less consistent in MCL. Recently, LRPAP1 autoantibodies were detected in 13% of patients from the European MCL Network trials and were associated with superior outcome, while the autoreactivity of IGHV 4-34 antibodies is largely known. Aims: We aimed at characterizing the IGH VDJ repertoire and its putative clinical relevance in a large, prospective, trial of the Fondazione Italiana Linfomi (FIL) enrolling younger MCL patients. Methods: IGH clonal rearrangements detection was performed by Sanger sequencing on bone marrow or peripheral blood samples collected for minimal residual disease purposes in FIL MCL0208 trial (NCT02354313). This is a prospective, randomized phase III trial comparing lenalidomide maintenance vs observation after an intensive cytarabine containing chemo-immunotherapy followed by autologous transplantation in frontline <66 year-old MCL patients. IMGT/V-QUEST tool was used to annotate IGHV-D-J and mutational status (cut-off 98%) according to ERIC guidelines. Finally, these biological data were integrated with published clinical, pathological, and mutational data from the trial (current median follow-up 38 months). Results: A clonal IGH productive rearrangement was detected in 209/300 patients (70%), resulting in 159 (76%) unmutated (UM) and in 50 (24%) mutated (M) cases, as expected. Overall, VDJ usage included 29 IGHV families, with IGHV 3-21 (#45, 22%), 4-34 (#33, 16%), 3-7 (#15, 7%), 3-23 and 5-51 (#12 each, 6%), 4-39 and 4-59 (#10 each, 5%) as the most frequent groups, together representing the 66% of the analyzed series (Figure 1A). Interestingly, patients carrying IGHV 3-21 were often characterized by low Ki-67 index (Ki-67 <30%: 86% vs 64% of other cases, p<0.01) and low risk MIPI score (73% vs 43%, p=0.001), while no case of blastoid morphology was registered among the IGHV 4-34 patients (vs 89%, p<0.05). Moreover, by grouping together these two rearrangements, statistically significant associations were found with several biomarkers of favorable prognosis (low Ki-67, p<0.01; non-blastoid, p<0.05; absence of TP53 aberrations, p<0.05, or KMT2D mutations, p<0.05, and low-risk MIPI, p<0.0001). Accordingly, both IGHV 3-21 and 4-34 patients showed better long-term outcomes, with longer PFS and OS if compared with all the other cases, both singularly and when grouped together (3 years PFS: 75% vs 53%, p<0.05; 3 years OS: 91% vs 76%, p<0.01, Figure 1B, C). Finally, these results were independent from IGHV mutational status (p=0.09) and lenalidomide maintenance (p=0.46). Image:Summary/Conclusion: This is the first study assessing the clinical impact of VDJ IGH repertoire in a large prospective trial in MCL. As expected, 76% of patients resulted UM, with 3-21 and 4-34 representing more than one third of all the IGHV rearrangements. Notably, in our series, no significant correlation between mutational status and outcome was recorded. On the other hand, patients carrying either IGHV 3-21 or 4-34 rearrangements were characterized by favorable clinical and biological known prognosticators and were associated with both PFS and OS improvement, if compared to other patients. Deeper translational insights are needed to clarify the biological (autoreactive?) basis of this observation.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

The EHA Research Roadmap: Malignant Lymphoid Diseases.

Frontline chemotherapy-free induction for mantle cell lymphoma.

Standard treatment for young patients with mantle cell lymphoma involves intensive regimens (rituximab–anthracycline–cytarabine-based) with or without autologous haematopoietic stem cell transplantation (HSCT) and rituximab maintenance and yields high complete response rates (61–89%). 1 Romaguera JE Fayad L Rodriguez MA et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005; 23: 7013-7023 Crossref PubMed Scopus (459) Google Scholar , 2 Geisler CH Kolstad A Laurell A et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008; 112: 2687-2693 Crossref PubMed Scopus (487) Google Scholar , 3 Eskelund CW Kolstad A Jerkeman M et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016; 175: 410-418 Crossref PubMed Scopus (112) Google Scholar , 4 Hermine O Hoster E Walewski J et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016; 388: 565-575 Summary Full Text Full Text PDF PubMed Scopus (229) Google Scholar , 5 Le Gouill S Thieblemont C Oberic L et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017; 377: 1250-1260 Crossref PubMed Scopus (185) Google Scholar However, relapses still occur, with 3-year progression-free survival rates of 60–85%, and such treatment regimens are also associated with non-negligible adverse events. 1 Romaguera JE Fayad L Rodriguez MA et al. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005; 23: 7013-7023 Crossref PubMed Scopus (459) Google Scholar , 2 Geisler CH Kolstad A Laurell A et al. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008; 112: 2687-2693 Crossref PubMed Scopus (487) Google Scholar , 3 Eskelund CW Kolstad A Jerkeman M et al. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016; 175: 410-418 Crossref PubMed Scopus (112) Google Scholar , 4 Hermine O Hoster E Walewski J et al. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016; 388: 565-575 Summary Full Text Full Text PDF PubMed Scopus (229) Google Scholar , 5 Le Gouill S Thieblemont C Oberic L et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017; 377: 1250-1260 Crossref PubMed Scopus (185) Google Scholar Ibrutinib–rituximab followed by R-HCVAD as frontline treatment for young patients (≤65 years) with mantle cell lymphoma (WINDOW-1): a single-arm, phase 2 trialInduction with ibrutinib–rituximab in the frontline treatment of young patients with mantle cell lymphoma is active and safe. This approach allowed minimisation of the number of chemotherapy cycles, thereby reducing the adverse events associated with chemotherapy. Newer trials bringing the next-generation Bruton's tyrosine kinase inhibitors into the frontline setting might obviate the need for chemotherapy altogether in patients with mantle cell lymphoma. Full-Text PDF

A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial.

Simple SummaryThe interest in using Machine-Learning (ML) techniques in clinical research is growing. We applied ML to build up a novel prognostic model from patients affected with Mantle Cell Lymphoma (MCL) enrolled in a phase III open-labeled, randomized clinical trial from the Fondazione Italiana Linfomi (FIL)—MCL0208. This is the first application of ML in a prospective clinical trial on MCL lymphoma. We applied a novel ML pipeline to a large cohort of patients for which several clinical variables have been collected at baseline, and assessed their prognostic value based on overall survival. We validated it on two independent data series provided by European MCL Network. Due to its flexibility, we believe that ML would be of tremendous help in the development of a novel MCL prognostic score aimed at re-defining risk stratification.Background: Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313). Methods: We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0–9.6; High→Int, HR: 2.3, 95% CI: 1.5–4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential.

Addition of High-Dose Cytarabine to Immunochemotherapy before Autologous Stem-Cell Transplantation in Patients Aged 65 Years or Younger with Mantle Cell Lymphoma (MCL Younger): A Long-Term Follow-up of the Randomized, Open-Label, Phase 3 Trial of the European Mantle Cell Lymphoma Network

Addition of High-Dose Cytarabine to Immunochemotherapy before Autologous Stem-Cell Transplantation in Patients Aged 65 Years or Younger with Mantle Cell Lymphoma (MCL Younger): A Long-Term Follow-up of the Randomized, Open-Label, Phase 3 Trial of the European Mantle Cell Lymphoma Network

Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial

Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial

Rituximab Maintenance after First-Line Immunochemotherapy in Mantle Cell Lymphoma: Long-Term Follow-up of the Randomized European MCL Elderly Trial

Rituximab Maintenance after First-Line Immunochemotherapy in Mantle Cell Lymphoma: Long-Term Follow-up of the Randomized European MCL Elderly Trial

LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome

Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain–restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P = .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index–adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P = .0083) and for OS of 0.47 (95% CI 0.24-0.94, P = .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients.

Droplet Digital PCR Quantification of Mantle Cell Lymphoma Follow-up Samples From Four Prospective Trials of the European MCL Network.

Minimal residual disease (MRD) has been increasingly investigated in mantle cell lymphoma (MCL), including for individual therapeutic stratification and pre-emptive treatment in clinical trials. Although patient/allele specific real-time quantitative polymerase chain reaction (qPCR) of IGH or BCL1-IGH clonal markers is the gold-standard method, its reliance on a standard curve for relative quantification limits quantification of low-level positivity within the 1E-4 to 1E-5 range; over half of positive MRD samples after treatment fall below the quantitative range (BQR) of the standard curve. Droplet digital PCR (ddPCR), in contrast, allows absolute quantification, including for samples with no baseline determination of tumor infiltration by multicolor flow cytometry (MFC), avoiding the need for a reference standard curve. Using updated, optimized, ddPCR criteria we compared it with qPCR in 416 MRD samples (and with MFC in 63), with over-representation (61%) of BQR results by qPCR, from a total of 166 patients from four prospective MCL clinical trials. ddPCR, qPCR and MFC gave comparable results in MRD samples with at least 0.01% (1E-4) positivity. ddPCR was preferable to qPCR since it provided more robust quantification at positivity between 1E-4 and 1E-5. Amongst 240 BQR samples with duplicate or triplicate analysis, 39% were positive by ddPCR, 49% negative and only 12% remained positive below quantifiable ddPCR limits. The prognostic relevance of ddPCR is currently under assessment in the context of prospective trials within the European MCL Network.

Reproducibility of histologic prognostic parameters for mantle cell lymphoma: cytology, Ki67, p53 and SOX11.

Mantle cell lymphoma (MCL) shows a clinical aggressiveness that varies from patient to patient. Despite major advances in outcomes with current immunochemotherapy, the future development of therapies requires risk stratification to tailor therapy intensity. Within the group of reference pathologists for the ongoing trials of the European MCL Network, we performed a round robin test on a tissue microarray to evaluate the reproducibility in assessing the biomarkers of outcome in MCL. Cytological subtype, Ki67-index and expression of p53 and SOX11 were evaluated on 20 diagnostic tumour samples by eight participating labs independently. We demonstrate that the assessment of the proliferation index by counting the Ki67 positive cells as well as assessment of SOX11 and p53 expression status is reproducible between labs. For the most established prognostic biomarker, Ki67, the intra-class correlation coefficient was very good when assessed as a continuous parameter (0.87). The agreement was lower when the values were analysed in a dichotomized way applying the commonly used cutoff of 30% (kappa = 0.65, complete concordance of all labs in 13/20 (65%)). Cases with discrepant results between labs in the dichotomized analysis showed mean values close to the cutoff of 30%. Centralised scoring and digital image analysis revealed results in line with the scores from individual labs. All cases in our cohort were additionally assessed for gene expression signatures and of TP53 gene alterations. Given the good reproducibility when guidelines of assessment are applied, the biomarker studied in this inter-laboratory test presents potential candidates to be enhanced for risk-stratification in the future clinical trials.