scholarly journals Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma over 60 Years of Age (PrE0405): A Phase II Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5243-5243 ◽  
Author(s):  
Craig A. Portell ◽  
N. Nora Bennani ◽  
Opeyemi Jegede ◽  
Seema Naik ◽  
Benjamin M Parsons ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Advisory Board ◽  
Dose Titration ◽  
Type I ◽  
Mantle Cell

Background: Mantle Cell Lymphoma (MCL) is an aggressive form of Non Hodgkin Lymphoma (NHL) and typically presents in patients over the age of 60 years. Bendamustine and rituximab (BR) combination is one of the standard treatments for MCL and is given to patients for whom high dose chemotherapy with autologous stem cell rescue is planned in the first remission. Progression free survival (PFS) with BR is approximately 36 months (Rummel M Lancet 2013; Flinn IW Blood 2014) and the regimen is overall well tolerated. Venetoclax (VEN) is an orally available inhibitor of BCL2, an anti-apoptotic protein highly expressed in several NHL. Single agent activity has mostly been studied in a Phase I study (in various NHL histologies) where 28 MCL patients were enrolled. Overall response rate was 75% (21 of 28) but complete response (CR) rate was only 21% (6 of 28). Tumor lysis syndrome (TLS) has been associated with VEN and initial dosing requires a ramp up period (Davids MS JCO 2018). VEN has also been combined with other agents in MCL with promising activity (Tam CS NEJM 2018) VEN has been studied as a chemotherapy sensitizer and has shown pre-clinical synergy with chemotherapy. In Follicular lymphoma, BR+VEN was studied at 800mg PO continuous daily dosing and showed an excessive Grade 3-4 adverse event (AE) rate of 78% compared to historical studies of 46% (Zinzani ASH 2016). We hypothesize that, in MCL, VEN can be safely combined with BR at a lower dose and intermittent dosing with improvements to the response rate based on historical controls and maintain a better safety profile. Study Design: This Phase II single arm, multicenter study evaluates VEN at a max dose of 400mg with BR (Bendamustine 90mg/m2 IV day 1 and 2; rituximab 375mg/m2 IV or SQ equivalent day 1) for six 28-day cycles in untreated patients with MCL over the age of 60 years (NCT03834688). Cycle 1 will include a VEN dose titration over the 4 week course (20mg D1-7, 50mg D8-14, 100mg D15-21, and 200mg D22-28). For Cycles 2-6, VEN will be given at 400mg daily x 10 days starting with day 1. Participants are followed for 6 cycles, though will be followed for progression and survival afterward. Participants may receive maintenance rituximab at investigator's discretion. Eligible participants, age 60 years or older, must have biopsy proven untreated MCL with t(11;14) or cyclin D1 expression, though a short course of steroids is allowed for symptomatic MCL. They must have adequate organ function and not require any prohibited concomitant medications. Primary outcome is CR rate as assessed by the Lugano criteria. We estimate a historical CR rate of BR after induction of about 70%. A 15% increase in this rate, to 85% CR, is considered promising for the combination. To achieve this goal, the study will enroll 56 participants (53 eligible) to achieve a 90% power to detect the difference with a 10% Type I error rate. We will also evaluate PFS and overall survival. TLS is an AE of interest and will be evaluated after 19 participants have been enrolled and treated during cycle 1. Minimal residual disease (MRD) will be assessed throughout the study. MRD from peripheral blood will be compared to bone marrow aspirates in all participants undergoing bone marrow aspirate at the end of treatment. Tumor samples at screening and progression will be collected for future study. This study is conducted through PrECOG and is funded by Genentech, a member of the Roche Group. Venetoclax is co-developed by Genentech and AbbVie. The study is slated to open in Fall of 2019 at 10 US sites. Figure Disclosures Portell: AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board. Naik:Celgene: Other: Advisory board. Parsons:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Kahl:BeiGene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy. OffLabel Disclosure: Venetoclax is not approved for use in MCL.

Phase II Multicenter Study of Single-Agent Lenalidomide in Subjects with Mantle Cell Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib: The MCL-001 “EMERGE” Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 905-905 ◽  
Author(s):  
Andre Goy ◽  
Rajni Sinha ◽  
Michael E. Williams ◽  
Sevgi Kalayoglu Besisik ◽  
Johannes Drach ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Board Member ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Advisory Board ◽  
Safety And Efficacy ◽  
Mantle Cell ◽  
Heavily Pretreated

Abstract Abstract 905 Introduction: Though dose-intensive strategies using chemoimmunotherapy have significantly improved mantle cell lymphoma (MCL) outcomes with prolonged progression-free survival (PFS), most patients still relapse over time. In the relapsed setting, MCL patients often develop chemoresistance and have a poor overall prognosis. The immunomodulatory agent lenalidomide has demonstrated tumoricidal and antiproliferative effects in MCL and clinical activity and safety in multiple phase II studies in aggressive non-Hodgkin's lymphoma. The objective of the MCL-001 “EMERGE” study was to examine the safety and efficacy of single-agent lenalidomide in subjects with MCL who relapsed or were refractory to bortezomib. Methods: This phase II, multicenter, single-arm, open-label study examined single-agent lenalidomide administered at 25 mg/d PO on days 1–21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal. The subjects were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (<12 months) after or were refractory to bortezomib. The primary endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), PFS, time to progression (TTP), overall survival (OS) and safety. Efficacy data were measured by investigators and an independent central review committee according to modified International Working Group criteria and analyzed by SAS. Results: 134 subjects with relapsed or refractory MCL who were heavily pretreated (no limitation in number of prior therapies) were enrolled. The median age was 67 y (range, 43–83), two-thirds of them being 65 y or older and 93% with advanced stage disease (stage III-IV). The median number of prior therapies was 4 (range, 2– 10) with 78% of subjects having received ≥ 3 prior lines of treatment. The ORR to single-agent lenalidomide was 28% (CR/CRu 8%; Table 1) by independent central review, with a median DOR of 16.6 mo (95% CI, 7.7–26.7; Figure 1). The ORR was 32% (CR/CRu 16%) by investigator assessment, with a median DOR of 18.5 mo. Median time to response (central review) was 2.2 mo (3.7 mo to achieve CR). The median PFS was 4.0 mo (95% CI, 3.6–5.6); median OS was 19.0 mo (95% CI, 12.5–23.9). Subjects received an average dose of 20 mg/d of lenalidomide. Lenalidomide was dose reduced in 38% of subjects; treatment discontinuation due to an adverse event (AE; primarily myelosuppression) was reported in 19% of subjects. The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%) and fatigue (7%). Other AEs (any grade) included tumor flare reaction (13 subjects, 10%), deep vein thrombosis (5 subjects, 4%), pulmonary embolism (3 subjects, 2%) and invasive second primary malignancies (3 subjects, 2%). Conclusions: The EMERGE study demonstrated rapid and durable efficacy of lenalidomide in MCL subjects who relapsed or progressed after or were refractory to bortezomib. These results in heavily pretreated MCL subjects (median of 4 prior treatments), and with an expected toxicity profile support single-agent lenalidomide in subjects with relapsed or refractory MCL after bortezomib. Disclosures: Goy: Pfizer: Advisory board member, Advisory board member Other; Seattle Genetics: Advisory board member Other; J&J: Advisory board member, Advisory board member Other; Pharmacyclics: Advisory board member, Advisory board member Other; Millenium: Advisory board member, Advisory board member Other, Speakers Bureau; Celgene: Advisory board member Other. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Sinha:Celgene: Research Funding. Williams:Celgene: Clincial Trial Research Support, Advisory Boards, Data Safety Committee Member, Consultant Other, Consultancy. Drach:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Roche: Research Funding. Ramchandren:Seattle Genetics: Speakers Bureau. Herbrecht:Pfizer: Advisory board member Other. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Witzig:Celgene : Research Funding.

scholarly journals Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Final Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Mats Jerkeman ◽  
Martin Hutchings ◽  
Riikka Räty ◽  
Karin Fahl Wader ◽  
Anna Laurell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Molecular Remission ◽  
Mantle Cell ◽  
Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 &gt;30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 &gt;30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

The VcR-CVAD Regimen Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma (MCL): First Analysis of E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for MCL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1661-1661 ◽  
Author(s):  
Brad S Kahl ◽  
Hailun Li ◽  
Mitchell R Smith ◽  
Randy D. Gascoyne ◽  
Elisabeth Paietta ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Complete Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Complete Response ◽  
Mantle Cell ◽  
Grade 3

Abstract Abstract 1661 Poster Board I-687 Introduction One approach to improving outcomes in Mantle Cell Lymphoma (MCL) is to incorporate newer targeted agents into standard chemotherapy regimens. As the proteasome inhibitor bortezomib (Velcade‘) achieved a 33% response rate in relapsed MCL, we hypothesized that the incorporation of Velcade (Vc) into a modified R-hyperCVAD chemotherapy backbone would result in a high complete response rate (CR). The new regimen, VcR-CVAD, was tested for safety and efficacy in a phase II study within the Wisconsin Oncology Network (UW) and demonstrated a CR rate of 77% (Kahl, ASH 2008). To determine the safety and efficacy of this regimen in a cooperative group setting, we initiated E1405: a phase II study of VcR-CVAD with maintenance rituximab (MR) for untreated MCL. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0-2, and adequate end organ function. The treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1-3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1-2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1-4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients had an option to receive high dose chemotherapy and autologous stem cell transplantation (off protocol) rather than MR. The primary endpoint of the trial was the CR rate, incorporating PET imaging, to VcR-CVAD induction therapy. Results Seventy-six eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40-76), 59M:17F, 91% stage III/IV, and 39% with elevated LDH. Sixty-four patients (84%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), patient preference (2), and other/unknown (5). Response information is available on 74 patients while data is outstanding on 2 patients. The ORR was 96% (73/76; 95% CI, 89%-99%), CR rate 75% (57/76; 95% CI, 64%-84%) and the PR rate 21% (16/76; 95% CI, 13%-32%). Six of the PR patients were coded as such because of protocol violations in which a post-treatment bone marrow biopsy or PET scan was not obtained. The CR rate in the 68 completely restaged patients was 84%. Forty-four patients proceeded to planned MR while 21 patients went off protocol to SCT consolidation. Median follow up is currently too short (9 months) to assess PFS and OS. The major toxicity of the treatment regimen was expected myelosuppression. Grade 3-4 non hematologic toxicities were rare. No patients developed grade 3-4 neuropathy. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall response (96%) and CR rate (75%) in a representative MCL patient population treated on a cooperative group protocol. The CR rate was high and comparable to the UW pilot study (77%). No episodes of severe painful peripheral neuropathy were reported using the reduced vincristine dosage and the overall toxicity profile was very acceptable. Longer follow up is needed to determine if the high CR rate will translate into improved PFS and OS. Disclosures Kahl: Genentech: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as front line treatment in MCL. Smith:Genentech: Research Funding; Millennium: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. Horning:Genentech: Honoraria, Research Funding.

scholarly journals R-BAC Maintains High Response Rate in Mantle Cell Lymphoma Following Relapse on BTK Inhibitor Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3989-3989 ◽  
Author(s):  
Rory McCulloch ◽  
Carlo Visco ◽  
Rebecca Frewin ◽  
Neil Phillips ◽  
Toby A. Eyre ◽  
...  
Keyword(s):  
High Risk ◽  
Mantle Cell Lymphoma ◽  
Treatment Strategy ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Mantle Cell ◽  
Duration Of Response ◽  
Btk Inhibitor

Background Effective treatment for relapsed, refractory (R/R) mantle cell lymphoma (MCL) post Bruton's Tyrosine Kinase inhibitor (BTKi) therapy represents an unmet clinical need with studies consistently reporting dismal outcome. No treatment strategy demonstrates superiority and there is currently no consensus on management. R-BAC (Rituximab, Bendamustine and Cytarabine) has demonstrated excellent upfront response rates in phase 2 trials (overall response rate (ORR) 100%, 2-year progression free survival (PFS) 95%, Visco et al 2013), but with durable responses also reported with other combination therapies there is a rationale to reserve R-BAC for post-BTKi relapse. Aims There is currently no data available assessing efficacy of R-BAC in the post BTKi setting. We first adopted this treatment strategy within routine clinical practice in 2015 and in this study have collected and analysed clinical outcomes across 20 centers in the United Kingdom and Italy. Methods 35 R/R MCL patients (pts) with prior BTKi therapy started R-BAC between October 2015 and February 2019. Treatment consisted of rituximab (375 mg/m2 or 500 mg) D1, bendamustine 70 mg/m2 D1 and D2 and cytarabine 500 mg/m2 D1 to D3 in a 28 day cycle. 29 pts were treated in the UK and 6 in Italy. Analysis included one pt with previous alloHSCT. Response to therapy was measured using Lugano classification (Cheson et al, 2014), although assessment of CR with bone marrow biopsy was not always undertaken. Baseline data, including response to previous BTKi, was collected retrospectively by the treating physician. The primary outcome was PFS to R-BAC. Results Median age at time of R-BAC was 66.3 years (range 43 to 81) and 82.9% of pts were male. At initial diagnosis MIPI was 34.5% low risk, 17.2% intermediate risk and 48.3% high risk; histology was 20.6% blastoid. Pts received a median 2 prior lines of systemic therapy (range 1 to 6). Frontline therapy included high dose cytarabine containing regimen (61.7%) plus consolidation AutoSCT (40.0%), R-CHOP (26.4%), R-CVP (2.9%), FC (2.9%) and ibrutinib plus rituximab (5.9%). 7 patients received maintenance rituximab (28.6%). 45.7% of patients commenced second line therapy within 2 years of initial diagnosis. Prior BTKi therapy included: ibrutinib (n=30), acalabrutinib (n=2), tirabrutinib (n=2) and M7583 (n=1). ORR to prior BTKi was 67.6% (CR 35.3%) and median PFS was 9.2 months. All patients stopped BTKi therapy due to progressive disease (94.3%) or failure to respond (5.7%). All but 1 patient received R-BAC directly after relapse on BTKi. Patients received a median of 4 cycles of treatment (range 1 to 6). 9 pts received attenuated doses of chemotherapy at clinician's discretion from start of therapy and 13 additional pts received attenuated doses beyond cycle 1 (62.9% of all patients received some form of dose attenuation). ORR to R-BAC was 82.3% (CR/CRu rate 55.9%), median PFS 9.3 months (see fig. 1) and median OS 12.2 months. Importantly, outcome for 11 pts ≥70 yrs was similar to younger pts (median PFS 10.6 months vs 8.6 months, p=0.83). 53.5% of evaluable patients demonstrated longer duration of response compared with preceding BTKi. 25 pts completed the planned treatment course, 2 stopped early due to excess toxicity (prolonged cytopenias and infection) and 8 stopped early due to progressive disease. 9 pts received subsequent consolidation alloSCT, and 1 DLI. Although follow-up is short only 1 patient to receive alloSCT has relapsed. 13 patients overall remain in remission, including 5 beyond 12 months. 18 patients (51.4%) required admission during R-BAC, including 15 with neutropenic fever (42.8%) and 72.7% patients required transfusion support. There were no treatment related mortalities. Conclusion This high risk population with a short PFS to prior BTKi demonstrated an excellent response rate to R-BAC. Favorable outcomes in the cohort consolidated with alloSCT, and the generally short duration of response in other pts, suggests R-BAC can be primarily used as a bridge to alloSCT in suitable pts. Treatment had notable hematological toxicity but with efficacy maintained in older pts R-BAC remains a valid option in those deemed unsuitable for transplant, although judicious dose attenuation is advised. In an area lacking a clear therapeutic path, the results from our study support R-BAC being considered a new standard of care option for R/R MCL in the post BTK inhibitor setting. Disclosures Frewin: AbbVie: Other: Meeting attendance sponsorship ; Novartis: Consultancy, Other: Meeting attendance sponsorship . Eyre:Roche: Honoraria; Abbvie: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Janssen: Honoraria. Lambert:Takeda Pharmaceuticals: Other: Funding to attend a scientific conference in 2018. Crosbie:Janssen: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy.

scholarly journals A Phase 1 Multicenter Open-Label Study of Escalating Doses of the Novel Anti-CD20-Targeting Engineered Toxin Body MT-3724 in Subjects with Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Michael Wang ◽  
Preetesh Jain ◽  
Lei Feng ◽  
Maria Badillo ◽  
Vivian Graham ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Phase 2 ◽  
Open Label ◽  
Mantle Cell ◽  
Cell Kill ◽  
Anti Cd20

Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation by SLT-A of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A, is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. In a Phase 1/1b dose escalation/expansion study of MT-3724 monotherapy in subjects with heavily pretreated (including CD20 monoclonal antibodies) relapsed or refractory B-cell non-Hodgkin lymphoma (r/rNHL) the most common grade ≥3 treatment-related adverse events were myalgia and neutropenia (n=3 each). Dose-limiting toxicities (DLTs) were indicative of innate immune response. In subjects with negative rituximab serum concentrations there was a 38% objective response rate (Hamlin et al. ASH 2019). MT-3724 is currently being studied in five ongoing (three actively recruiting, two in development) Phase 2 studies for r/rNHL. This study will evaluate the safety, tolerability, recommended phase 2 dose (RP2D), efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MT-3724 in two cohorts of subjects with r/r mantle cell lymphoma (r/rMCL). Study Design and Methods: This phase 1, multicenter, open-label, single arm study will include adults ≥18 yrs with histologically confirmed r/rMCL (histology plus expression of Cyclin D1 in association with CD20 and CD5 or evidence of t(11:14)) who have received ≥2 prior systemic therapies (including anti-CD20 antibody alone or in combination with other agents) and have ≥1 measurable lesion (Lugano criteria). Subjects with CNS involvement or recent treatment with rituximab (within 84 days of study initiation; if received within 12-37 weeks of start of treatment, serum rituximab level must be confirmed to be negative [&lt;500 ng/mL]), obinutuzumab (within 184 days), or ofatumumab (within 88 days) will be excluded. The washout period for these anti-CD20 antibodies, based on published half-life data for these agents, is required due to direct binding competition with MT-3724 for the same CD20 epitope. The primary objective is to evaluate safety and determine the RP2D of MT-3724 in subjects with r/rMCL. Secondary objectives include overall response rate based on the Lugano criteria as determined by the investigators, duration of response, disease control rate, progression-free survival, overall survival, PK, PD, and immunogenicity. An exploratory endpoint will assess if responders become eligible for potentially curative therapy (rate of bridge-to-hematopoietic stem cell transplantation or bridge-to-chimeric antigen receptor T-cell therapy). Subjects will receive escalating doses of MT-3724 as a one hr IV infusion in cycle (C) 1 on Days 1, 4, 8, 11, 18, and 25. In C2+, subjects will receive the highest MT-3724 dose on Days 1, 8, 15, and 22 of a 28-day cycle. Two sequential cohorts will be studied. The study will be initiated with Cohort 1 to evaluate DLTs during the first 42 days of therapy. Subjects will have a dose increase only if they do not experience DLTs and dose reductions will be permitted for treatment-related toxicities. If Cohort 1 is deemed tolerable, Cohort 2 (higher doses) will begin; if Cohort 1 dosing is not tolerable, Cohort 0 (lower doses) will begin (Table 1). A Bayesian optimal interval design will be used to identify the RP2D more accurately (target toxicity rate φ=0.3). Enrollment is anticipated to begin in December 2020. Disclosures Wang: Juno:Consultancy, Research Funding;Dava Oncology:Honoraria;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;InnoCare:Consultancy;MoreHealth:Consultancy;Targeted Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Oncternal:Consultancy, Research Funding;Pulse Biosciences:Consultancy;Molecular Templates:Research Funding;OncLive:Honoraria;Verastem:Research Funding;Acerta Pharma:Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;BioInvent:Research Funding;Guidepoint Global:Consultancy;VelosBio:Research Funding;Loxo Oncology:Consultancy, Research Funding;Lu Daopei Medical Group:Honoraria;Nobel Insights:Consultancy;Beijing Medical Award Foundation:Honoraria.Burnett:Molecular Templates, Inc.:Current Employment.Strack:Molecular Templates, Inc.:Current Employment.

Interim Results of the RiPAD+C Regimen Including Velcade in Front Line Therapy for Elderly Patients with Mantle Cell Lymphoma. A Phase II Prospective Study of the GOELAMS Group.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1575-1575
Author(s):  
Remy Gressin ◽  
Sylvie caulet Maugendre ◽  
Steven Le Gouill ◽  
Mario ojeda Uribe ◽  
Magda Alexis Vigier ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Therapeutic Option ◽  
Front Line ◽  
Good Efficacy ◽  
Line Therapy ◽  
Mantle Cell

Abstract Elderly patients with mantle cell lymphoma (MCL) do not take benefit from dose-intensive chemotherapy such as HyperCVAD because of its high toxicity (Romaguera JCO 2005). Prior Goelams clinical trials using the VAD plus Chlorambucil regimen with or without Rituximab have demonstrated a good efficacy/toxicity ratio in front line therapy (EHA 2008, a0259). Proteasome inhibitors are among the most promising new agents for relapsing patients (Fisher, JCO 2006). Therefore, the GOELAMS conducted a phase II clinical trial including Velcade plus R-AD and Chlorambucil (RiPAD + Chlorambucil) for elderly MCL patients upfront. Aims: To evaluate toxicity and overall response rate after 4 cycles of RiPAD + Chlorambucil regimen. Protocol: RiPAD + C: Rituximab 375 mg/sqm, D1 (and D8 for cycle 1); PS 341, Velcade 1.3 mg/sqm D1, 4, 8 and 11; Adriblastine 9mg/sqm/D in a 4 days continuous infusion; Dexamethasone 20 mgx2/D for D1 to D4; Chlorambucil 12 mg/D, D20 to D29. One cycles every 35 D. The patients received a maximum of 6 cycles. Inclusion criteria: Untreated MCL patients (from 65 to 80 years) with a stage II to IV disease, and good PS (Ecog &lt; 3). Response criteria is evaluated according to the 1999 Cheson’s criteria, all patients were also evaluated by FDG-PETscan. Results: since June 2007, 27 patients have been included. Thirteen have been evaluable after 4 cycles. Median age is 71 years (66–80 y). After 4 cycles, disease Status was: 10 patients in response (3 in CR with negative FDG-PETscan and 7 in PR including 3 with a negative PETscan) and 3 patients progressed on therapy. The 3 non responding patients had the highest Ki67 value over 30%. Toxicity evaluation has been evaluated based on 59 cycles. Grade 3–4 toxicities have been reported in 5 cases (2 neurologic, 1 hepatic, 1 cardiac and 1 pulmonary). Only 3 cycles were delayed because of toxic reasons. Conclusion: this intermediaire analysis shows an ORR of 77% (10/13) including 6 patients with a negative FDG-PET after only 4 cycles. Our study demonstrates that the RiPAD+C regimen has a good efficacy/toxicity ratio and is a promising therapeutic option for MCL elderly patients. The study is ongoing and additional results on response rate and toxicity will be updated for presentation in the ASH meeting.

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

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1622-1622
Author(s):  
Jose D Sandoval-Sus ◽  
Peter J Hosein ◽  
Deborah Goodman ◽  
Alexandra Stefanovic ◽  
Joseph D Rosenblatt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Maintenance Phase ◽  
Induction Phase ◽  
Rituximab Maintenance ◽  
Mantle Cell

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

scholarly journals Ofatumumab-Bendamustine As First Line Treatment for Elderly Patients with Mantle Cell Lymphoma: A Phase II Risk Adapted Design with Comprehensive Geriatric Assessment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1751-1751
Author(s):  
Carla Casulo ◽  
Augustine Iannotta ◽  
Jannelle Walkley ◽  
Craig H. Moskowitz ◽  
Alison J Moskowitz ◽  
...  
Keyword(s):  
High Risk ◽  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Line Treatment ◽  
First Line ◽  
Mantle Cell ◽  
First Line Treatment

Abstract Introduction: Mantle cell lymphoma (MCL) is a heterogeneous disease and risk-stratification of patients (pts) for treatment is not performed routinely. For older pts ineligible for aggressive treatments, comprehensive geriatric assessments (CGA) are recommended but not routinely implemented into practice. Commonly used chemo-immunotherapeutic options result in low rates of complete remission (CR) (40%-50% bendamustine-rituximab; Rummel et al Lancet 2013; Flinn et al Blood 2014), with frequent relapses. Risk-stratification of older MCL pts through biological and clinical characteristics may improve treatment outcomes and reduce toxicity. Ofatumumab may have an advantage over rituximab given more efficient complement activation and complement dependent cytotoxicity. To test this we designed a phase II risk-stratified study of ofatumumab alone or in combination with bendamustine as first line treatment for elderly MCL with the goal of improved remission rates and extended survival. Methods: This was a single-institution phase II study. The primary objective was response. Eligible pts were 65 years of age or older with untreated MCL and/or ineligible for aggressive treatments such as high dose chemotherapy/autologous stem cell transplant. Patients were risk-stratified for therapy. Low risk pts with no GELF/NCCN criteria, low/intermediate risk MIPI, Ki-67 index < 30% and no blastic morphology received single agent ofatumumab weekly for 4 doses. High risk pts with GELF/NCCN criteria present, high risk MIPI, Ki-67 index > 30% or blastic morphology received ofatumumab and bendamustine (O-B) every 28 days for 6 cycles. A simon-two stage design was implemented requiring 6 of 12 pts to have a CR in the O-B arm to proceed. Pts receiving ofatumumab only were permitted to cross over to O-B for less than a partial response (PR) at restaging. Survival probability was estimated by the Kaplan-Meier method. CGA was performed prior to each cycle, and correlation to treatment toxicity was evaluated as a secondary endpoint. Results: Twenty pts in total were enrolled. Median age was 73 (range: 44-83). Seven pts (35%) were classified as low risk and received single agent ofatumumab. Thirteen pts (65%) were classified as high risk and received O-B. All patients in the O-B arm completed 6 cycles of treatment, all met GELF/NCCN criteria. Of these, 54% had high risk MIPI, 54% had Ki67 ≥30%. Among pts receiving single agent ofatumumab, 71% (5 pts) had < PR (stable disease), 1 had CR (14%), and 1 pt was not evaluable. Three pts with < PR crossed over to the O-B arm. Among 12/16 evaluable pts (3 too early, 1 withdrew) in the O-B arm; overall response rate was 92%; CR rate was 67%, PR rate 25%. One patient had stable disease (8%). After median follow-up of 1.8 years (range 0.1-2.6 years), overall survival in the entire group is 100%. Progression free survival at 2 yrs for the O-B arm is estimated at 68%. Both regimens were safe and well tolerated. Incidence of grade 3/4 serious adverse effects was 15% (3 of 22 patients), all in the O-B group. Baseline CGA identified patients as low (n=15) and medium risk (n=3) for grade 3/4 toxicity, with all three SAE (pneumonia, UTI, SVT) occurring in medium risk patients (p=0.001). Baseline timed-up and go showed a trend for anticipated toxicity for patients in the worst quartile (p=0.11). Conclusions: The combination of ofatumumab and bendamustine has promising activity in elderly pts with high risk MCL, with superior CR rates compared to historical chemo-immunotherapeutic regimens. Single agent ofatumumab had modest activity, but was safe in low risk pts and did not impact responses to chemoimmunotherapy. CGA assessment may help predict toxicity. Ofatumumab-bendamustine is effective as first line treatment for older pts with MCL and holds promise as a platform for combination with novel agents in prospective trials of untreated MCL. Figure 1 Figure 1. Disclosures Off Label Use: Ofatumumab is an anti CD20 monocloncal antibody not approved for use in mantle cell lymphoma. Moskowitz:Genentech: Research Funding; Merck: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding. Zelenetz:Foundation Medicine, Inc: Consultancy. Hamlin:Seattle Genetics, Inc.: Consultancy, Research Funding.

scholarly journals Triangle: Autologous Transplantation after a Rituximab/Ibrutinib/ara-c Containing Induction in Generalized Mantle Cell Lymphoma - a Randomized European MCL Network Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2816-2816 ◽  
Author(s):  
Martin Dreyling ◽  
Marco Ladetto ◽  
Jeanette K. Doorduijn ◽  
Eva Gine ◽  
Mats Jerkeman ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Advisory Board ◽  
High Dose ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Mantle Cell ◽  
Scientific Advisory

Background: Mantle cell lymphoma (MCL) is a distinct subtype of lymphoma with a wide variation of clinical course. Based on randomized trials of our network, current standard of care is a cytarabine-containing immunochemotherapy induction (Hermine, Lancet 2016) followed by autologous stem cell transplantation (SCT; Zöllner, ICML 2019) and rituximab maintenance for 3 years (Le Gouill, NEJM 2018). In relapsed MCL the BTK inhibitor ibrutinib achieves high response rates and ongoing remissions (Wang, NEJM 2013; Dreyling, Lancet 2016). This approach achieved especially longer remission durations in earlier treatment lines (Rule, Hamatologica 2019). We aim to clarify whether ibrutinib added to induction and as maintenance with or without autologous stem cell transplantation might improve outcome. Study design and methods: In this international, randomized three-arm phase III trial (EudraCT-no. 2014-001363-12) young, fit patients ( up to 65 years) with histologically confirmed, untreated mantle cell lymphoma advanced stage II-IV qualify for 1:1:1 randomization after written informed consent according to ICH/EU GCP. In the control arm A, patients receive an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (either BEAM or THAM: TBI, high dose Ara-C and melphalan). In arm A+I Ibrutinib is added to the R-CHOP cycles (560 mg day 1-19) and applied as maintenance (continuous dosing) for 2 years. In arm I the same induction and maintenance is applied but high dose consolidation and autologous SCT is skipped. A rituximab maintenance (single doses every 2 months up to 3 years) may be added in all study arms according to national clinical routine. The primary study aim is to show superiority of one of three study arms as future standard of care based on the comparison of the investigator-assessed failure-free survival (FFS), i.e. to investigate if the addition of ibrutinib improves the efficacy of standard 1st line treatment, and can even challenge the use of high-dose chemotherapy with autologous SCT. Secondary study aims include the efficacy of the three treatment arms and the safety and tolerability of ibrutinib during induction immuno-chemotherapy and maintenance. Accordingly, overall and complete response rates, progression-free and overall survival will be determined as well as adverse events during induction immuno-chemotherapy and follow-up including the cumulative incidence rates of SPMs. In addition, minimal residual disease is regularly determined based on patient-specific PCR assay according to the standardized Biomed-2 procedure. Results: As of July 30th, 511 of up to 870 patients have been randomized from 12 different European countries. In a meanwhile completed safety run-in of the initial 50 patients, feasibility of the two experimental arms was confirmed with no major differences in hematological and other toxicities and no major delays during induction. Disclosures Dreyling: Acerta: Other: Scientific advisory board; Novartis: Other: Scientific advisory board; Mundipharma: Other: Scientific advisory board, Research Funding; Janssen: Other: Scientific advisory board, Research Funding, Speakers Bureau; Gilead: Other: Scientific advisory board, Speakers Bureau; Celgene: Other: Scientific advisory board, Research Funding, Speakers Bureau; Bayer: Other: Scientific advisory board, Speakers Bureau; Sandoz: Other: Scientific advisory board; Roche: Other: Scientific advisory board, Research Funding, Speakers Bureau. Ladetto:Roche: Honoraria; AbbVie: Honoraria; J&J: Honoraria; Celgene: Honoraria; Pfizer: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria. Doorduijn:Roche: Honoraria, Research Funding. Gine:Janssen: Other: Travel expenses, Research Funding; Gilead: Other: Travel expenses, Research Funding; Roche: Other: Travel expenses, Research Funding. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Mey:Janssen-Cilag: Consultancy; Roche: Consultancy, Research Funding. Hutchings:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding. Kolstad:Merck: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Trneny:Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Gilead sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria. Gomes da Silva:AbbVie: Consultancy, Other: Travel support; Roche: Consultancy, Other: Travel support; Janssen-Cilag: Consultancy, Other: Travel support; Celgene: Consultancy; Gilead Siences: Other: Travel support, Research Funding. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding. Unterhalt:F. Hoffmann-La Roche: Research Funding. Hoster:Janssen: Research Funding; Roche Pharma AG: Other: Travel Support.

scholarly journals Long-Term Clinical and Molecular Remissions in Patients with Mantle Cell Lymphoma (MCL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2819-2819
Author(s):  
Bernd Metzner ◽  
Jochen Casper ◽  
Koehne Claus-Henning ◽  
Andrea Renzelmann ◽  
Thomas H. Mueller ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Advisory Board ◽  
Scientific Advisory Board ◽  
Mantle Cell ◽  
Scientific Advisory

Background:Long-term clinical and molecular remissions in patients with MCL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for remission duration over 5 years. So the curability of this disease remains an open question. Patients and methods:Altogether 61 patients with MCL were treated in our institution with ASCT from 1998 to April 2019 (50 1st-line ASCT, ten 2nd-line ASCT, one 3rd-line ASCT). The data were collected retrospectively in 29 and prospectively in 32 patients who participated in two clinical trials: the 1st-line therapy trials of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Dreyling M, Blood 2005] and the European Mantle Cell Lymphoma Network [Hermine O, Lancet 2016], respectively. The diagnosis was regularly approved by the reference pathology of the GLSG (W.K.). The induction therapy before 1st-line ASCT consisted of 6 courses CHOP (n=11), mostly combined with rituximab and followed by Dexa-BEAM, and 6 alternating courses of R-CHOP and R-DHAP (n=39), respectively. For the salvage treatment patients usually received three to four courses of the DHAP protocol or the ESHAP protocol, since 2001 also combined with rituximab.Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols in remission. High-dose protocols: 1) total body irradiation with cyclophosphamide or melphalan and cytarabin (n=32) or 2) BEAM (n=29). Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible (n=4). Since 09/2016 patients received a maintenance therapy with rituximab after ASCT (every 2 months, planned for 3 years, n=14). Further details are described in an earlier publication of our first 36 patients (Metzner B, Ann Hematol 2013). Response assessment was performed by careful clinical examination and by ultrasound, chest x-ray and partly CT at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 5 years; n = 18), peripheral blood was regularly tested twice a year for minimal residual disease (MRD) by quantitative t(11;14) or allel specific IGH RQ-PCR and/or IGH-consensus PCR.Calculations were done using IBM SPSS Statistics Version 25. Data were analysed as of 01 July 2019. Results:With a median follow-up of 5 years (range 0.1-20) 10-year overall survival, progression-free survival (PFS) and freedom from progression (FFP) after 1st-line ASCT were 54%, 46% and 52%, respectively, after 2nd-line ASCT 42%, 20%and 20%, with a significant difference for PFS (p=0.045) and FFP (p=0.014) between 1st-line and 2nd-line cohort.Further prognostic factors (like sex, age, MIPI, bone marrow involvement, remission grade at ASCT: CR vs. PR, type of HDT: TBI vs. BEAM…) seemed to be without relevance (considering the small subgroups). Only one clinical relapse occurred after 5 years following ASCT in 1stor 2ndremission, respectively (one patient 6 years after 1st-line ASCT and another patient 7 years after 2nd-line ASCT and subsequent radiotherapy). So far, 18 patients experienced long-term remissions of at least 5 years (median 9 years, from 5 to 16 years). Fifteen of 17 tested patients were MRD negative at last follow-up, the two MRD positive patients (positive at a low level below the quantitative measuring range) had no clinical signs of relapse at last follow-up. None of these 18 patients had received rituximab maintenance therapy. None showed clinical criteria of "smoldering mantle cell lymphoma" at induction therapy. Treatment-related mortality at 100 days after ASCT was 1.6% (pneumonitis following TBI). One patient developed a secondary invasive malignancy in remission after ASCT (acute myeloid leukemia 4 years following TBI). Conclusion: Sustained long-term clinical and molecular remissions up to 16 years can be achieved following ASCT (without rituximab maintenance therapy), indicating the potential curative impact of 1st-line ASCT in MCL. The 2nd-line ASCT was obviously less effective. Disclosures Dreyling: Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Acerta: Other: scientific advisory board; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board. Klapper:Roche, Takeda, Amgen, Regeneron: Honoraria, Research Funding.

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