Untreated Mantle Cell Lymphoma Research Articles

Polatuzumab Vedotin Combined with Obinutuzumab, Cyclophosphamide, Doxorubicin, and Prednisone (G-CHP) for Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Preliminary Results of a Phase Ib/II Dose-Escalation Study

Introduction: Despite the improved outcomes seen with rituximab-CHOP (R-CHOP) in patients (pts) with newly diagnosed DLBCL, a significant number of pts with high risk disease (defined by IPI) are not cured; thus, new therapies are needed. Obinutuzumab (GA101, G) is a glycoengineered type II anti-CD20 monoclonal antibody with improved direct cell death and antibody-dependent cell-mediated cytotoxicity compared to rituximab. In addition, polatuzumab vedotin (PoV) is an antibody drug conjugate (ADC) designed to deliver the potent microtubule inhibitor MMAE to cells expressing CD79b. Thus, PoV has the potential to replace vincristine with a targeted agent. The incorporation of G and PoV would potentially increase the efficacy of the standard R-CHOP regimen. We report preliminary results from the dose-escalation portion of this Phase Ib/II study of PoV combined with obinutuzumab, cyclophosphamide, doxorubicin, and prednisone (G-CHP) (ClinicalTrials.gov NCT01992653).Methods: This multicenter, open-label study will evaluate the safety, tolerability, and pharmacokinetics of escalating doses of PoV with standard doses of G (1000 mg on days 1, 8, and 15 in cycle 1, and 1000 mg on day 1 of each subsequent cycle) and CHP. Adults, aged 18-80 years, with newly diagnosed or relapsed/refractory B-cell NHL were given PoV intravenously 1.4 or 1.8 mg/kg with G-CHP every 21 days for a total of 6 or 8 cycles. Doses were escalated in a 3+3 design based on dose limiting toxicity assessment during cycle 1. Assessments for anti-tumor activity were performed following 4 cycles of study treatment (tx) and at the end of study tx (EOT).Results: As of Feb. 5, 2016, 12 pts (50% male) enrolled in the G-CHP + PoV dose-escalation (esc). The median age was 69.5 years (range 32-77) for all pts. Pts had untreated DLBCL (n=8), relapsed follicular lymphoma (FL, n=2), and untreated mantle cell lymphoma (MCL, n=2). At baseline, pts had stage I/II (n=5), III/IV (n=7) disease and ECOG status of 0-1 (n=12). Of 8 DLBCL pts, 3 had IPI 0-1, 2 had IPI 2, 2 had IPI 3, and 1 had IPI 4. At the time of this report, 8 pts in the dose escalation phase have completed study tx and all 12 had received interim assessments.The most common adverse events (AEs) in > 30% of pts were alopecia (67%), neutropenia (50%), nausea (42%), anemia (33%), fatigue (33%), cough (33%), and rash (33%). Across both dose levels, 10 pts had 30 Gr 3/4 AEs including neutropenia (58%), anemia (25%), thrombocytopenia (25%), febrile neutropenia (17%), pneumonia (8%), C. difficile (8%), sepsis (8%), device related infection (8%), acute kidney injury (8%), hyponatremia (8%), atrial fibrillation (8%), SVT (8%), tachycardia (8%), syncope (8%) and hypertension (8%).Three pts experienced 10 serious AEs (SAEs). One pt in the 1.4 mg/kg cohort had SAEs of febrile neutropenia (also a DLT), thrombocytopenia, and an atrial fibrillation exacerbation. Two pts in the 1.8 mg/kg cohort experienced a total of 7 SAEs. One pt experienced syncope, C. difficile, and febrile neutropenia while the other pt had sepsis, pneumonia, acute kidney injury, and cardiac complications including SVT and 3 vessel bypass surgery. Four (33%) pts experienced Gr 1 peripheral neuropathy (PN) during tx which did not lead to dose modifications. The reported terms included hypoaesthesia, PN, and paresthesia. There was 1 pt with PN in the 1.4 mg/kg cohort and 3 in the 1.8 mg/kg cohort. 3 pts discontinued study treatment: 1 due to recurrent neutropenic fevers (no subsequent tx), 1 due to pneumonia (followed with R-CVP), and 1 due to physician decision due to lack of treatment response (followed with R-ICE). No deaths were reported.Efficacy: PET/CT response for pts with 1L DLBCL as of February 5, 2016 is reported in Table 1.Of the 2 pts with FL, both achieved CR by PET/CT (1 at 1.4 mg/kg and 1 at 1.8 mg/kg). Of the 2 pts with MCL, both achieved CR by PET/CT (1 at 1.4 mg/kg and 1 at 1.8 mg/kg).Conclusions: Early results show that PoV plus G-CHP has an acceptable safety profile in pts with previously untreated DLBCL and other B cell malignancies. Although the protocol-specified MTD was not formally reached, the recommended phase 2 dose of PoV was established at 1.8 mg/kg based on other studies. The study's Phase 2 PoV+R-CHP expansion and PoV+G-CHP dose expansion are ongoing. [Display omitted] DisclosuresForero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Kolibaba:Pharmcyclics: Research Funding; Novartis: Research Funding; Janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Seattle Genetics: Research Funding; TG Therapeutics: Honoraria, Research Funding. Jones:Genentech, Inc.: Employment. Lee:Genentech, Inc.: Employment. Sharman:Gilead: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; Seattle Genetics: Research Funding.

Antigen Presentation Profiling Reveals T-Cell Recognition of Lymphoma Immunoglobulin Neoantigens

Neoantigens arising through somatic mutations are increasingly recognized as key tumor antigens driving clinical immune responses. We sought to identify human lymphoma neoantigens through a genomic and proteomic characterization of peptide ligands of major histocompatibility complex class I (MHC-I) and class II (MHC-II) of a cohort of patients with untreated mantle cell lymphoma. Peptide identification was performed through analysis of MHC-I and MHC-II peptide ligands using liquid chromatography and tandem mass spectrometry (LC/MS-MS), and augmented by generating patient-specific proteome databases through tumor:normal whole exome sequencing and targeted immunoglobulin gene sequencing in 17 patients. A total of 66 neoantigen peptides from 9 patients were found to be presented by MHC, and surprisingly all neoantigenic peptides were derived from either the lymphoma immunoglobulin heavy or light chain genes. There was no detectable MHC presentation of hundreds of candidate somatic neoantigenic peptides from other genes despite widespread antigen presentation of the proteome including proteins encoded by germline heterozygous single nucleotide polymorphisms. Clonotypic lymphoma immunoglobulin sequences were among the most commonly presented proteins by both MHC-I and MHC-II, yet MHC-I presentation of variable regions was nearly absent and included only a single neoantigen derived from IGVH. In contrast, the variable region was frequently presented by MHC-II and included neoantigen peptides created through somatic hypermutation or VDJ recombination. Autologous circulating T-cells specific for immunoglobulin-derived neoantigens could be detected using MHC-II tetramers and their frequency dynamically changed with vaccination and therapy. These findings suggest that immunoglobulin derived neoantigens are frequently presented by lymphoma, and represent potential targets for CD4, but not CD8, T-cell mediated therapies. [Display omitted] DisclosuresNewman:Roche: Consultancy. Carlton:Adaptive Biotechnologies: Employment, Equity Ownership. Moorhead:Adaptive Biotechnologies: Employment. Faham:Adaptive Biotechnologies Corp: Employment.

Risk Stratification of Untreated Mantle Cell Lymphoma Patients Using MIPI, Ki67 Proliferative Index and Cytogenetics

Background:There are multiple prognostic markers used to risk stratify pts with mantle cell lymphoma (MCL) including the MCL International Prognostic Index (MIPI) which divides newly diagnosed patients into three groups based on available clinical and laboratory data.Complex karyotype (CK) defined as equal to or greater than 3 chromosomal abnormalities has also been associated with inferior outcomes in MCL although its association with MIPI is lesswell-described. We conducted a multicenter analysis of MCL pts to assess the relative contributions of MIPI, CK and Ki67 as predictors of progression-free (PFS) and overall survival (OS).Methods:Untreated pts atleast18 years of age with MCL from 5 academic centers diagnosed between 1993 and 2015 who had available data describing MIPI, Ki67, and cytogenetics were included. Patients with 3 or more chromosomal abnormalities were defined as having CK. High Ki67 was defined as immunohistochemistry staining >30%. We described the associations between MIPI risk group, CK, Ki67, and other clinical factors of interest as predictors of PFS and OS in univariate and multivariable models.Results:Of 92 eligible MCL patients, 30 (32.6%) had low-risk, 36 pts (39.1%) had intermediate-risk, and 26 pts (28.3%) had high-risk MIPI scores. Ki67 index was >30% in 44.6% of patients, and 17.4% had CK. Neither Ki67 > 30% (p=0.548) norpresence of CK (p=0.409) wereassociated with MIPI risk category. In the low-risk MIPI subgroup, 37% of patients had Ki67 > 30% and 10% had CK. Induction regimens included: R-HyperCVAD (n=15), R-CHOP/R-DHAP (n=7), Nordic regimen (n=13), R-CHOP (n=10), B-R (n=19), and others (n=28). Thirty-two patients (39%) had an autologous stem cell transplant (ASCT) in first remission. Median PFS for the entire cohort was 3.8 years, and median OS has not yet been reached. Median PFS for was 2.2 years, 2.5 years, and 7.9 years for patients with high-, intermediate-, and low- risk MIPI scores, respectively, at diagnosis. Median PFS was 2.4 years for patients with Ki67 > 30% and 7.9 years for patients with Ki67 < 30%. Median PFS was 1.3 years for patients with CK and 4.3 years for patients without CK. High risk MIPI (p=0.042), CK (p=0.002), and Ki67 index > 30% (p=0.002) were all associated with inferior PFS in a univariable analyses (See Figure). In a multivariable analysis (See Table) Ki67 >30% (HR=3.66, p<0.001), and complex karyotype (HR=3.9, p=0.002) were associated with inferior PFS while autologous stem cell transplantation in first CR was associated with improved PFS (HR=0.21, p=0.002). MIPI risk score was not independently associated with PFS.Conclusions:Our findings suggest that Ki67> 30% and CK are independently associated with inferior outcomes in MCL. In this analysis, MIPI risk score was not independently associated with PFS or OS when considering these additional prognostic markers, which needs to be confirmed in other retrospective and prospective cohort studies. Our high-risk MIPI patients, in general, have an improved outcome compared to prior reports. (Hoster2008, 2014;Lex2014), suggesting that alternative markers may play an important role in MCL risk-assessment. Efforts to incorporate additional patients and develop a new prognostic model in MCL are underway. [Display omitted] [Display omitted] DisclosuresDanilov:Pharmacyclics: Consultancy; Astra Zeneca: Research Funding; Takeda: Research Funding; GIlead Sciences: Research Funding; ImmunoGen: Consultancy; Dava Oncology: Honoraria; Prime Oncology: Honoraria. Hamadani:Janssen: Consultancy; Celgene: Honoraria, Research Funding; Takeda Pharmaceuticals: Research Funding. Flowers:TG Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Infinity: Research Funding; Millenium/Takeda: Research Funding; Mayo Clinic: Research Funding; NIH: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; ECOG: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding.

Rituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group

Rituximab Maintenance after Autologous Stem Cell Transplantation Prolongs Survival in Younger Patients with Mantle Cell Lymphoma: Final Results of the Randomized Phase 3 LyMa Trial of the Lysa/Goelams Group

Chemotherapy-Free Induction with Ibrutinib-Rituximab Followed By Shortened Cycles of Chemo-Immunotherapy Consolidation in Young, Newly Diagnosed Mantle Cell Lymphoma Patients: A Phase II Clinical Trial

Introduction: Mantle cell lymphoma (MCL) is a rare and incurable subtype of B-cell lymphoma. Intense chemo-immunotherapy with 8 cycles of Rituximab-HyperCVAD alternating with Rituximab-Methotrexate-Ara C is associated with an overall survival of 10.7 years but the 10-year cumulative incidence of therapy-related myeloid neoplasm was 6.2%. The ibrutinib-rituximab combination has produced durable responses in 88% of patients with relapsed and refractory MCL with acceptable toxicity. This gives rise to a "Window" of opportunity to use chemotherapy-free induction with ibrutinib plus rituximab followed by fewer cycles of chemo-immunotherapy consolidation in young and fit patients with newly-diagnosed, untreated MCL.Methods: Enrolment began in June 2015 for a Phase II single-center clinical trial consisting of an initial chemotherapy-free phase (window) of ibrutinib and rituximab combination treatment in Part 1 until best response, followed by a shortened course of intense chemo-immunotherapy in Part 2 among young newly diagnosed MCL patients of ≤65 years. The primary objective was to evaluate the response rate of ibrutinib plus rituximab. The secondary objectives were to evaluate the progression free survival (PFS) of ibrutinib plus rituximab after consolidation with a shortened number of cycles of intense chemo-immunotherapy, and to further evaluate the toxicity profile. Ibrutinib is dosed at 560 mg orally, daily, continuously. Rituximab is dosed at 375 mg/m2 IV weekly x 4 during cycle 1 (28 days cycle), then day 1 of cycles 3-12. Intense chemo-immunotherapy consists of rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD); alternating every 28 days with rituximab plus high-dose methotrexate-Ara C. If in complete remission (CR) after initial ibrutinib and rituximab treatment, a total of 4 additional treatments of intense chemo-immunotherapy are given. If the patient is in partial response or progression, and if responding to intensive chemo-immunotherapy, a total of 2 cycles of chemo-immunotherapy therapy are administered beyond achievement of CR.Results: As of August 2, 2016, we have completed the target enrolment by accruing 50 out 50 patients with newly-diagnosed untreated MCL. Forty one (n=41) patients have begun treatment and 36 are evaluable for response. Of the 36 evaluable patients, overall response rate (ORR) to Part 1 alone (Ibrutinib plus rituximab) is 100% (n=36) with PR in 28% (n=10) and CR in 72% (n=20). Nineteen 19 patients have completed both Part 1 (ibrutinib and rituximab) and Part 2 (chemo-immunotherapy). The ORR to both Part 1 and Part 2 (n=19) was 100% and was equal to the CR rate (100%, n=19), i.e. all have achieved a CR to Part 1 and Part 2. Toxicities are recorded as the number of patients experiencing a certain adverse event. Regardless of their relation to study drug in Part 1, the most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=40), diarrhea (n=25), rash (n=24), myalgia (n=22), oral mucositis (n=17), peripheral neuropathy (n=15), nausea (n=14), blurred vision (n=14), edema (n=13), constipation (n=12), headache (n=11), dry eyes (n=9), dizziness (n=9) and watery eyes (n=6). Grade 3 non-heme AEs included fatigue (n=3), nausea (n=0), rash (n=1), pleural effusion (n=1), infection (n=2) and dyspnea (n=1). There was no grade 4 or grade 5 non-heme toxicities in Part 1. In part 2, common grade 1-2 hematological (heme) AEs was anemia (n=13). Grade 3-4 haematological AEs included neutropenia (n=2), ALT increase (n=1) and febrile neutropenia (n=1). In Part 2, there was no grade 5 hematologic toxicity. The toxicity after intensive immune-chemotherapy in shortened cycles are much improved compared to historical controls but longer follow-up is needed.Conclusions: Preliminary data indicate that the chemotherapy-free induction with ibrutinib and rituximab in newly diagnosed, young MCL patients was efficacious and well-tolerated. This unprecedented efficacy and safety may provide a window of opportunity for less chemo-immunotherapy needed for consolidation. [Display omitted] DisclosuresWang:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding; BeiGene: Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Research Funding; Asana BioSciences: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding.

The Results of a Phase I Study using Velcade (Bortezomib), Cladribine, and Rituximab (VCR) in treating Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium size B cell lymphoma. There is no standardized treatment for this disease. The conventional chemotherapy results in a high incidence of treatment related toxicity with frequent disease relapse. Cladribine is a hypomethylating agent that indirectly downregulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Velcade (Bortezomib) is a FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this phase 1 study, we evaluated the safety and efficiency of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL.Patients and Methods: This is a single arm, open label, investigator initiated Phase 1 study conducted at PennState Hershey Cancer Institute. This study employed a standard 3+3 dose-escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. The treatment scheme and Cladribine dose escalation levels (1, 2, and 3) are as follows: the therapy consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3-5 mg/m2 (3 mg/m2 for level 1, 4 mg/m2 for level 2, and 5 mg/m2 for level 3) infusion was given on days 1-5 for 6 cycles. If the patient's was older than 70 years old, Cladribine was only given on days 1-3 of each cycle. Velcade 1.6 mg/m2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1-3, then Day 5 and 19 during Cycles 4-6, then once per month as maintenance therapy until toxicity or progression of the disease. The primary endpoint of this study was to investigate the dose-limiting toxicity (DLT), safety, and efficiency of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression-free survival (PFS) and overall survival (OS). The analysis was done by intent to treat. This study is registered with clinicaltrials.gov (NCT01439750).Results: No subject experienced dose limited toxicity (DLT) at either level 1 or 2, one possible DLT (infectious colitis) was observed on a subject during 2nd cycle at level 3. Then no additional DLTs were seen in 3 subjects added to level 3. Overall, this study recruited 13 subjects, with a median age of 64 years old (range from 55 to 83), and a total of 11 male and 2 females. Ten subjects were never previously treated, while 3 either relapsed or failed previous treatments. The majority of subjects tolerated this regimen well. The patient with a history of DLT became the only mortality of this cohort 7 months later as a result of multiple organ failure. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 62% (8/13). In newly diagnosed subject cohort, the RR and OS rates were 100% (9/9), PFR was 89% (8/9), and CR rate was 78% (7/9), of which 2 patients have been followed for more than 3 years and 4 patients for more than 2 years. However, in relapsed/refractory subject cohort, 1 subject achieved CR for 7 months but then relapsed, 2 subjects had no response. There were 2 blastoid subjects, one was newly diagnosed and achieved CR.No severe systemic toxicity was observed in this study. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint.Correlative studies measured cyclin D1 expression levels using mononuclear cells as opposed to formalin-preserved tissue, a technique which allows for monitoring the levels over time. Although limited by a small sample size, the results indicated that the G/G (or A/A) genotype at G870A polymorphism site as well as a rapid decline of cyclin D1 and D1a during treatment may be correlated to a less aggressive disease course. Further studies are needed to explore the underlining mechanism.Conclusions: The VCR combination is a well tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m2 is a tolerable dose with manageable toxicity. A phase II trial to further evaluate the activity and toxicity of VCR regimen is warranted. DisclosuresNo relevant conflicts of interest to declare.

Improved Survival of Older Patients with Mantle Cell Lymphoma (MCL) with Front-Line Cytarabine-Based Immunochemotherapy

IntroductionWhile the role of cytarabine-based immunochemotherapy (ICT) and autologous stem cell transplantation (ASCT) in untreated younger patients with MCL is well established, the utility of 'more intense' approaches in older patients is uncertain. Despite a median age at presentation of 60 years or more there are few therapeutic trials focussing on older patients. With the development of targeted agents, the need to define the optimal ICT strategy for comparison is pressing.MethodsThe primary aim of this study was to compare the safety and efficacy of first line ICT based therapy in patients with MCL aged over 60 years. Treatment and outcome data were collected for patients treated between 2000-2015 across a combined health-care network servicing the south-eastern, south-western and central corridor of the Australian state of Victoria (catchment area >2 million patients encompassing four major academic tertiary referral centers). Eligible patients had MCL diagnosed according to WHO 2008 criteria, confirmed by either fluorescence in situ hybridization for t(11;14) translocation or immunohistochemistry for cyclin D1 expression. Only cases with adequate information, including baseline characteristics, treatment regimens and outcome, were included. Overall survival (OS) and progression free survival (PFS) were modelled using Cox regression. For ICT comparison, patients undergoing ASCT were censored at the time of transplant. Differences in hospitalization and transfusion were analyzed using the Mann-Whitney U test.Results52 patients met inclusion criteria with a median age of 69 (range 60-91; M/F >3:1), of which 23 patients were >70 years. Most patients had advanced disease on staging, >1 extra-nodal site and an intermediate-high MIPI score. All received rituximab with initial therapy. Treatment regimens included: R-CHOP-like (31), alternating R-CHOP/R-DHAC (10), R-HyperCVAD/R-MA (7) and other (4). Eleven patients underwent ASCT. The median follow up for surviving patients was 40 months.Type of chemotherapy and up-front ASCT were the only variables influencing PFS and OS. Cytarabine-based ICT was associated with an improved median PFS (not reached vs 35 months, HR 0.27 [0.08-0.93], p=0.018) and OS (not reached vs 54 months, HR 0.28 [0.08-0.94], p=0.039) compared to R-CHOP-like regimens. Patients undergoing ASCT were younger (mostly < 70 years) and demonstrated improved median OS (not reached vs 46 months, HR 0.124 [0.017-0.921], p=0.041). No statistically significant difference in efficacy between R-HyperCVAD/R-MA and R-CHOP/R-DHAC could be determined due to low numbers. Both group of patients receiving cytarabine demonstrated durable response over time. However, those receiving R-HyperCVAD/R-MA experienced greater toxicity with increased hospitalisation: median 54 [31-72] v 20 [6-77] days, p=0.023 and transfusion requirements: median 13 [7-24] v 2 [0-5] red cell units, p=0.001; median 6 [2-15] v. 0 [0-1] platelet pools, p=0.001.ConclusionIn older patients with previously untreated MCL, cytarabine-based ICT resulted in a significant improvement in OS, with a 72% reduction in the risk of death relative to CHOP-like therapy. Cytarabine-based ICT is highly efficacious and well tolerated and should serve as a benchmark with which to compare targeted therapies. ASCT should also be considered in selected older patients. [Display omitted] [Display omitted] DisclosuresQuach:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding.

Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma

AbstractFor elderly patients with mantle cell lymphoma (MCL), there is no defined standard therapy. In this multicenter, open-label phase 1/2 trial, we evaluated the addition of lenalidomide (LEN) to rituximab-bendamustine (R-B) as first-line treatment for elderly patients with MCL. Patients >65 years with untreated MCL, stages II-IV were eligible for inclusion. Primary end points were maximally tolerable dose (MTD) of LEN and progression-free survival (PFS). Patients received 6 cycles every four weeks of L-B-R (L D1-14, B 90 mg/m2 IV, days 1-2 and R 375 mg/m2 IV, day 1) followed by single LEN (days 1-21, every four weeks, cycles 7-13). Fifty-one patients (median age 71 years) were enrolled from 2009 to 2013. In phase 1, the MTD of LEN was defined as 10 mg in cycles 2 through 6, and omitted in cycle 1. After 6 cycles, the complete remission rate (CRR) was 64%, and 36% were MRD negative. At a median follow-up time of 31 months, median PFS was 42 months and 3-year overall survival was 73%. Infection was the most common nonhematologic grade 3 to 5 event and occurred in 21 (42%) patients. Opportunistic infections occurred in 3 patients: 2 Pneumocystis carinii pneumonia and 1 cytomegalovirus retinitis. Second primary malignancies (SPM) were observed in 8 patients (16%). LEN could safely be combined with R-B when added from the second cycle in patients with MCL, and was associated with a high rate of CR and molecular remission. However, we observed a high degree of severe infections and an unexpected high number of SPMs, which may limit its use. This trial is registered at www.Clinicaltrials.gov as #NCT00963534.

Bortezomib Maintenance (BM) Versus Consolidation (BC) Following Aggressive Immunochemotherapy and Autologous Stem Cell Transplant (ASCT) for Untreated Mantle Cell Lymphoma (MCL): CALGB (Alliance) 50403

Introduction: Aggressive chemo-immunotherapy followed by peripheral blood stem cell autografting (ASCT) in CALGB 59909 achieved a median progression-free survival (PFS) in MCL of 5 years (Damon et al JCO, 2009), but late recurrences occurred. Bortezomib has a 33% response rate in relapsed/refractory MCL. Using the CALGB 59909 treatment backbone, we evaluated tolerability and efÞcacy of adding post-transplant BC or BM in a randomized phase II trial.Methods: The primary endpoint was PFS estimated from study entry for each treatment arm. Induction therapy was with 2-3 cycles of augmented R-CHOP (2000 mg/m2 cyclophosphamide) and methotrexate (300 mg/m2) followed by high-dose cytarabine/etoposide/rituximab(R)/Þlgrastim (EAR) stem cell mobilization and cyclophosphamide/carmustine/etoposide (CBV) ASCT. After 2 doses of post-transplant R, patients were randomized to BC (1.3 mg/ m2 days 1, 4, 8, 11 of a 3 week cycle for 4 cycles) or BM (1.6 mg/m2 weekly 4 of 8 weeks for 18 months) beginning at approximately day 90. Minimal residual disease (MRD) was analyzed using patient-specific PCR probes for the bcl-1 / IgH junction or the IgH CDR3 region.Results: 151 patients were enrolled at 14 sites and 147 received treatment. Median age was 59 (29-69); stage II (2.7%), III (12%), IV (86%); MIPI low (52.4%), int. (30.6%), high (17%); blastoid histology (14%); bone marrow involvement (81%). 118 (88%) underwent ASCT and 102 (68%) were randomized. Most withdrawals (45) were for progression (10) or adverse events (AEs) (19) including 4 treatment-related deaths. Following randomization, 34 (65%) completed BM and 33 (66%) completed BC. Withdrawal for AEs occurred in 14 (28%) of BC and 7 (13%) of BM patients (p = 0.088), most for cytopenias or peripheral neuropathy. Median follow-up was 5.5 years from registration. Median PFS was significantly greater than the null hypothesis (4 years) for both BM and BC (1-sided test of exponential parameter p < 0.001). The 5-year PFS estimates from study entry in the BM and BC arms were 70% (55-81%) and 69% (54-80%), respectively. Progression occurred in 17 BM (12 post-treatment) and 19 BC patients (all post-treatment). Five-year PFS from time of transplantation in CALGB studies 50403 (n=118) and 59909 (n=66) was 72.7% (63-80%) and 51.5% (36.7-62%), respectively (log rank p=0 0006) favoring the 50403 trial which differed from 59909 only by the addition of post-transplant bortezomib. MRD results were available in 47 patients. Five-year PFS from study entry was 93% if MRD-negative (n=15) and 51% if MRD-positive (n=32) following induction chemo-immunotherapy (log rank p=.003) (See figure).Conclusions: Induction chemotherapy followed by ASCT and either BC or BM was efficacious and tolerable, although BC was associated with more withdrawals for toxicity. The comparison between studies 50403 and 59909 suggests a PFS benefit from the addition of BC or BM. MRD-negativity following induction chemo-immunotherapy is highly associated with improved PFS and could provide an important tool for designing future trials. [Display omitted] DisclosuresOff Label Use: Post-autotransplant use of bortezomib . Bartlett:Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy; Janssen: Research Funding; Pharmacyclics: Research Funding; Astra Zeneca: Research Funding; ImaginAB: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Millenium: Research Funding; Celgene: Research Funding. Byrd:Acerta Pharma BV: Research Funding. Blum:cephalon: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding. Hurd:Procter and Gamble: Equity Ownership; Medtronic: Equity Ownership; Pfizer: Equity Ownership; Merck: Equity Ownership; Bristol Myers Squib: Equity Ownership. Czuczman:MorphoSys: Consultancy; Cellgene: Employment; Immunogen: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Cheson:AstraZeneca: Consultancy; Astellas: Consultancy; Ascenta: Research Funding; Spectrum: Consultancy; Teva: Research Funding; MedImmune: Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Predictive Power of FDG-PET Parameters at Diagnosis and after Induction in Patients with Mantle Cell Lymphoma, Interim Results from the LyMa-PET Project, Conducted on Behalf of the Lysa Group

INTRODUCTION. FGD-PET has emerged as an important predictor of clinical outcome in lymphomas. However, its utility in everyday clinical practice in mantle cell lymphoma (MCL) remains uncertain because there is a lack of large prospective trials including FDG-PET results. To address this question, we conducted the LyMa-MRD project as an ancillary study in a prospective phase III trial in MCL (NCI NCT00921414; LyMa Trial). From Sept 2008 to Aug 2012, 299 previously untreated MCL patients (<66yrs) were enrolled in the LyMa trial (a phase III international prospective trial, NCT00921414). Briefly, all patients received 4 courses of R-DHAP followed by ASCT using an R-BEAM conditioning regimen (n=257). After ASCT, patients were randomized between observation (obs) (n=120) versus Rituximab maintenance (RM) (n=119). The first planned interim-analysis, with a median follow-up of 40.6 months was presented at ASH 2014 and indicated superior progression-free survival (PFS) in the RM versus Obs arms (Le Gouill et al. ASH 2014). Sequential FDG-PET monitoring was optional and a predefined secondary objective and was performed throughout. Treatment strategy was not modified by FDG-PET results. Indeed, the population of the LyMa trial is the ideal population to investigate the predictive power of FDG-PET parameters at diagnosis and after induction in MCL. Herein, we present the first results performed from the database of first planed interim-analysis.METHOD. FDG-PET of 94 MCL patients have been independently and centrally reviewed by 2 lymphoma expert nuclear physicians. Quantitative metrics including SUVmax, SUVmean, SUVpeak, total lesion glycolysis (TLG) were extracted from the area with the highest uptake, at diagnosis and before ASCT (iPET). Visual analysis by the Deauville scale was also performed at iPET. The best cut-off values were determined for each metric using X-tile® analysis. Prognostic value was assessed using univariate analysis by Kaplan-Meier estimates of PFS.RESULTS. The studied population did not differ from the whole population of the LyMa trial (baseline characteristics, demographic data, staging, balance between observation vs maintenance and outcome). At diagnosis, univariate analysis showed a prognostic value on PFS of 4 metrics: SUVmax (p<0.001), SUVmean (p< 0.001), SUVpeak (p<0.001), TLG (p=0.03). The best cut off for these 4 indices, were 11.4, 7.7, 8.7, and 65 respectively. Indeed, median PFS was not reach (NR) for patients with low SUVmax (n=63) as compared to only 26.3 months for patients with high SUVmax (p<0.0001) (n=31). Results were similar for SUVpeak, SUVmean and TLG. The prognostic value of SUVmax was reinforced when combined with MIPI. Indeed, patients can be separated in 3 prognostic groups including a group of patients with a very good outcome (low SUVmax plus MIPI inter/low). Results of iTEP showed that ΔSUV before ASCT (defined as a decrease of SUVmax values from diagnosis to end of induction > 29.65%) was predictive of PFS: median NR vs 42.3m (p=0.0051). In contrast FGD-PET before ASCT according to Deauville scale was only predictive for score 5 vs 1/2/3/4.Conclusion. The LyMa-PET project is the largest study addressing the question of FDG-PET in a homogeneously treated population of MCL. It shows for the first time that SUVmax (</>11.4) at diagnosis and ΔSUV (</>29.65%) provide predictive parameters for outcome in MCL. Update results and patients' outcome according to randomization arms will be updated for the time of the meeting. DisclosuresNo relevant conflicts of interest to declare.

Initial Therapy for Mantle Cell Lymphoma with Abbreviated R-CHOP Followed By Y90-Ibritumomab Tiuxetan: Ten Year Follow-up of the Phase 2 ECOG-ACRIN Study E1499

There is no single accepted treatment approach for mantle cell lymphoma (MCL), varying from intensive therapy in young, fit patients (pts) to less intensive for the more common older or less fit pts. R-CHOP remains a commonly used initial therapy for MCL, yielding high response rates but with limited durability, and still serves as a comparator in recently published studies. E1499 was designed to test the hypothesis that 1 dose of radioimmunotherapy (RIT) consolidation with 90Y-ibritumomab tiuxetan after only 4 cycles of R-CHOP-21 as initial therapy for MCL would be safe, well-tolerated and improve time-to-treatment failure (TTF) compared with historical R-CHOP data. E1499 met its primary endpoint with TTF at 1.5 years of 69% (95% CI 58-78%) (Smith et al JCO 2012) and treatment was well-tolerated. Here we report 10 year follow-up data on this uniformly-treated cohort of pts with MCL.56 eligible pts with previously untreated MCL and adequate organ function were enrolled between 11/03-2/05. Median age at enrollment was 60 (range 33-83) yrs, 73% were male and MIPI was low in 50%, intermediate in 27% and high in 21%. All cases were centrally reviewed. Therapy was standard dose R-CHOP given every 3 weeks for only 4 cycles, followed in pts whose disease did not progress with a single standard administration of 90Y-ibritumomab tiuxetan. All planned therapy was administered to 91% (5 did not receive RIT: 3 PD, 1 death from MI, 1 pt preference). The overall response rate after all treatment was 82% (55% CR/CRu). Median follow-up is now 9.8 years (May 2015 data cut-off). Median TTF is 34 months (mos). By MIPI, TTF was 36 mos for low, 25 mos for intermediate and 10 mos for the 12 pts with high MIPI. Pts who achieved CR had median TTF of 38 mos vs 15 mos for PR (p = 0.01).Median overall survival (OS) for the 56 eligible pts is 7.9 yrs. For pts < 65 median OS has not been reached at 10 yrs, compared with 7 yrs for those ≥ 65 (p = 0.07). OS for low MIPI pts also has not been reached at 10 yr, is 8 yr for intermediate and 5.5 yrs for high MIPI. Although TTF was longer for pts with CR/CRu, OS did not differ. There has been no additional therapy-related myeloid neoplasia (t-MN) other than 1 previously reported t-MN which occurred after additional therapy. Other malignancies include 2 non-small cell lung cancers, 1 bladder cancer, 1 ampullary adenocarcinoma and 2 resected localized non-melanoma skin cancers.Long-term follow-up of this cohort of pts treated with a simple 4 month outpatient regimen continues to suggest a benefit for RIT consolidation in prolonging TTF, with median TTF of almost 3 yrs. Though in somewhat older populations, median PFS was 14 mos for 6xR-CHOP alone and 25 mos for 6xVR-CAP (Robak T NEJM 2015), and 22 mos for 6xR-CHOP in StiL trial (Rummel M Lancet 2013). Ongoing rituximab maintenance after 8xR-CHOP is also effective (Kluin-Nelemans NEJM 2015) with 57% of pts progression-free at 4 yrs. For OS, age is the single most important prognostic factor in this cohort. Pts with high MIPI had short TTF, but their OS suggests that additional therapies were effective. As novel agents rapidly move into first-line regimens, often based on early assessments of efficacy, these long-term data inform benchmark expectations of PFS and OS in MCL. OS in our cohort is comparable to contemporaneous studies using either intense or non-intense initial therapy, raising questions regarding the value of intensive treatment strategies in MCL. [Display omitted] DisclosuresSmith:celegene, spectrum, genentech: Honoraria. Off Label Use: Y90-ibritumomab tiuxetan is not approved for use in mantle cell lymphoma. Gordon:Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending; Northwestern University: Employment. Horning:Genentech: Employment.

Rituximab-Bendamustine Cytarabine (R-BAC) As Frontline Therapy in Mantle Cell Lymphoma: A Single-Center Experience

Background and objectives. Bendamustine in combination with rituximab has demonstrated a relevant clinical activity and a good toxicity profile in patients with mantle cell lymphoma (MCL). Cytosine arabinoside (Ara-C) is a key drug in induction chemotherapy regimens of young patients with MCL. In vitro studies have shown that bendamustine increases the cytotoxic effect of Ara‐C in leukemic blasts and lymphoma cells, and the two drugs display high synergistic activity when used in consecutive combinations. Clinically, it has recently been demonstrated that rituximab + bendamustine + Ara‐C (R-BAC) combination has a remarkable activity and is well tolerated both in untreated and in relapsed/refractory patients with MCL (Visco C et al. J Clin Oncol 2013 31:1442-1449). In the present study, we report data from an Italian single-center experience evaluating the efficacy and tolerability of R-BAC association in previously untreated MCL patients both eligible and ineligible for transplantation.Design and methods. From January 2009 to November 2014, 25 newly diagnosed patients with MCL (median 67 years; range 57-83 years) were treated with immunochemotherapy according to R-BAC schedule (Rituximab 375 mg/mq day 1; Bendamustine 70 mg/mq days 2, 3; Ara-C 500 mg/mq days 2-4) x 4 or 6 28-day cycles. All patients received G-CSF prophylaxis. Ninety-six percent of patients had stage III/IV disease; MIPI score was high in 24%, intermediate in 60% and low in 12%; in one patient it was not evaluable.Results. Twenty-two patients (88%) completed the scheduled treatment (4 or 6 cycles). The ORR was 88%: CR 84% (21 patients); PR 4% (1 patient); 1 patient was in SD, but he received only 1 cycle due to toxicity and died still in SD about three years later. Seven patients (28%) underwent autologous stem cell transplantation (ASCT); seven patients (28%) received rituximab maintenance for two years. Two patients (8%) experienced disease progression during first line therapy, both had intermediate MIPI score. After a median follow up of 33 months (range 4-65 months), the OS was 80% (one patient died for unrelated causes) and the PFS was 80%. At this time point, 19 (76%) and 1 (4%) patient were in CR and in PD, respectively. The latter patient is currently undergoing salvage chemotherapy. Patients who received either maintenance immunotherapy with rituximab or consolidation with ASCT after R-BAC (overall 56%) seemed to experience longer PFS and OS. In the ASCT group the OS was 100% at a median follow up of 23 months; in the rituximab maintenance group the OS was 71% at a median follow up of 41 months. In the group of patients that received R-BAC induction therapy only, the OS was 61% at a median follow up of 26 months (p=0.14, likely due to the low number). The most common adverse events (AEs) during R-BAC were hematological: grade 3-4 neutropenia (88%), grade 3-4 thrombocytopenia (64%) and grade 3-4 anemia (36%). The numbers of common grade 3/4 non hematological AEs in the study included: febrile neutropenia (28%), acute coronary syndrome (4%), lung infection (4%) and hyperglycemia (4%). No treatment-related mortality was observed, one patient died of secondary acute myeloid leukemia four years later from induction therapy.Conclusions. The present retrospective study confirms that R-BAC as frontline regimen in MCL is well tolerated and highly effective in ASCT ineligible patients and that it can be administered also in ASCT eligible patients as induction therapy. Moreover, our data suggest that a consolidation therapy (ASCT or maintenance immunotherapy) after R-BAC induction could improve the outcome. DisclosuresNo relevant conflicts of interest to declare.

Novel agents in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma, comprising approximately 6-8% of all non-Hodgkin lymphomas. MCL is biologically and clinically heterogeneous, and there is no standard treatment for MCL. Although untreated MCL often responds well to frontline combination chemotherapy, relapsed, refractory MCL can be challenging to treat and traditional cytotoxic chemotherapy is typically not highly effective. In recent years, increased insight into the molecular and genomic diversity of MCL and the pathogenesis of the disease has given rise to the development of many new biologically targeted therapies. Ibrutinib was recently FDA approved for relapsed, refractory MCL and will likely have a significant impact on treatment paradigms for MCL. In addition to ibrutinib, there are many classes of novel agents that are currently in development. This review focuses on recent developments in the management of relapsed, refractory MCL, describing the growing armamentarium of novel agents available to combat this disease.

Bortezomib: A Review in Mantle Cell Lymphoma in Previously Untreated Patients Unsuitable for Stem-Cell Transplantation.

Bortezomib (Velcade(®)) is a proteasome inhibitor that is approved for the treatment of multiple myeloma and mantle cell lymphoma (MCL). This article reviews the efficacy and tolerability of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in the treatment of previously untreated MCL unsuitable for stem-cell transplantation, and overviews the pharmacology of bortezomib. In the large, randomized, assessor-blinded, multinational LYM-3002 trial, induction therapy with VR-CAP improved progression-free survival significantly more than R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) after a median follow-up of 40 months in patients with newly diagnosed MCL ineligible or not considered for stem-cell transplantation. Complete response and certain other secondary endpoints were improved significantly more with VR-CAP than R-CHOP. Overall survival data were not mature at the time of assessment. The improved efficacy with VR-CAP was accompanied by an increased incidence of grade 3 or higher adverse events, particularly haematological adverse events.

Phase II study of rituximab plus high-dose ara-C (HDAC)-containing chemotherapy (CTX) followed by ASCT in untreated mantle cell lymphoma (MCL): Japan Clinical Oncology Group study (JCOG0406).

8565 Background: Although HDAC-containing CTX with rituximab (R) followed by high-dose CTX (HDC) with autologous stem cell transplantation (ASCT) has been recommended in younger untreated MCL patie...

Molecular imaging of infectious and inflammatory diseases: a terra incognita.

659 Objectives The objective of the study was to analyse whether quantitative indices derived from pre-treatment 18F-FDG PET/CT can provide prognostic value for untreated mantle cell lymphoma (MCL) patients. Our work is an ancillary study of the prospective phase III Lyma trial (Le Gouill et al. ASH 2014) (NCT00921414). Methods Pre-treatment FDG-PET of 53 untreated MCL patients were centrally reviewed by 2 lymphoma expert nuclear physicians .Quantitative metrics including SUVmax, SUVmean, SUVpeak, total lesion glycolysis (TLG) and 15 textural features (TF) were extracted from the area with the highest uptake. Whole-body metabolic tumor volume (MTVwb) and whole-body TLG (TLGwb) were also derived considering all detected lesions . The best cut-off values were determined for each metric using X-tile® analysis. Prognostic value was assessed using univariate analysis by Kaplan-Meier estimates of progression-free survival (PFS). Results Clinical characteristics and PFS of the 53 patients were similar to these of the entire Lyma cohort (n=299). Univariate analysis showed a prognostic value on PFS of 4 metrics: SUVmax (p Conclusions The present preliminary results show a strong prognostic value on PFS of SUVmax, SUVmean, SUVpeak and one TF determined on pre-treatment FDG PET in MCL untreated patients. The study is ongoing and supplementary data including more patients of the LyMa trial will be presented at the congress.

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

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 &lt; 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 &gt; 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 &lt; PR (stable disease), 1 had CR (14%), and 1 pt was not evaluable. Three pts with &lt; 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.

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

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

Rituximab Maintenance Bimonthly for Two Years after Prolonged Immunochemotherapy in Elderly Patients with Mantle Cell Lymphoma (MCL) Results in Long Remissions: Update with Six-Year Follow-up of a Prospective Study By the Finnish Lymphoma Group

Abstract Background Rituximab (R) maintenance therapy bimonthly until progression has been shown in a recent randomized study to prolong duration of remission (with median follow-up of 37 months) and overall survival in elderly patients (pts) with MCL after R-CHOP, but not after R-FC, induction therapy (Kluin-Nelemans et al, N Engl J Med 2012; 367:520-31). We have previously reported initial results of 60 elderly pts with MCL treated with induction therapy consisting of 10 cycles of alternating standard CHOP and intermediate-dose AraC (combining fludarabine in 3 cycles) with 8 doses of R, followed by bimonthly R maintenance for 2 years (yrs) (Räty et al. Leuk Lymphoma 2012; 53:1920-8). High response rate to induction therapy with ORR of 95% (CR/CRu 87%) was seen. PFS was 70% and OS 72% at 4 yrs with the median follow-up of 40 months. Herein, we update our results of this prospective study with completed maintenance therapy in all pts with a median follow-up time of 6 yrs for surviving pts. Methods The pts were recruited at 10 Finnish centres during Dec 2004 and Aug 2010. Eligible pts were &gt; 65 yrs old with histologically confirmed newly diagnosed (WHO criteria, CD5+, CD19/20+, Cyclin D1+) and previously untreated stage II-IV MCL with adequate organ functions and performance status (WHO) &lt;4. Induction: standard dose R-CHOP (cycles 1, 3, 5), R-AraC (R 375 mg/m2 x1, AraC 1 g/ m2 4 doses with 12 hrs intervals; cycles 2, 4), R-AraC with fludarabine (F) (F 25 mg/m2 2 doses, cycles 6-8), CHOP (cycles 9, 10). Maintenance for pts in CR/PR: R 375 mg/m2 bimonthly x 12. Response was evaluated according to Cheson’s criteria after 5th, 8th and 10th cycle, every 6 months during maintenance and 1 year follow-up, and clinically for later follow-up every 6 months. Median follow-up time at the time of this analysis was 70 months (range 41 – 113 months) for living pts. Results At the time of diagnosis the median age of 60 recruited pts was 74 yrs (range 65-83), 62% were males, 97% had advanced disease (stage III-IV), 77% had good performance status (PS 0-1). Most (87%) had a history of some other notable illness, most typically cardiovascular disease. Another cancer had been diagnosed earlier in 9 pts (prostate n=3, breast n=3, other n=3). The MIPI risk was low in 2%, intermediate in 45% and high in 53% of the pts, respectively. ORR was 95% (CR/CRu n= 52, PR n=5, PD n=2). One patient could not be evaluated for response due to withdrawal of consent after the first cycle. Seven pts did not receive R maintenance (died/progressed/relapsed during induction n=5, withdrawal of consents n= 2). All 12 doses were given to 34 of 53 pts (64%, CR/CRu n=32, PR n=2). Four pts discontinued maintenance due to recurrent infections / neutropenia,10 pts due to relapse and 5 due to other reasons (secondary MDS n=1, general fatigue n=2, unknown n=2). A transient grade 4 neutropenia was seen in 20 pts during maintenance with no serious infections. HZV or VZV infections were recorded in 9 pts. Altogether 22 of responding pts have progressed/relapsed (during induction n=2, during maintenance n=10, during follow-up n=10), 6 of them with isolated CNS relapse. Twenty-one pts have died (sudden cardiac death during induction n=1, progressive MCL n=17, secondary MDS/AML n=1, unknown n=2). At 6 yrs (intention to treat) PFS was 64% (median 97 months, 95% CI 75 – 120 months), EFS 59% (median 95 months, 95% CI 75 – 114 months) and OS 62% (median not reached), respectively. DFS was 72% at 6 yrs (median 91 months, 95% CI 89 – 93 months) for 52 pts in CR/CRu. Two pts have developed secondary MDS (at 27 and 67 months). Eight new cancers (prostate n=3, breast n=1 and skin n=4) have been recorded in 6 patients during maintenance or follow-up. Conclusions Long PFS and OS over 60% at 6 yrs with median DFS of more than 7 yrs can be achieved with prolonged cytarabine-containing immunochemotherapy followed by 2 yrs R maintenance in elderly pts with MCL. Maintenance therapy was well tolerated in general. Transient neutropenia during maintenance was not uncommon, but serious infections were not seen and only 4 pts discontinued maintenance therapy because of recurrent neutropenia or infections. Attention for second malignancies is requested as 9 pts had cancer before MCL diagnosis, MDS/AML was developed in 2 pts and 6 pts showed carcinomas during follow-up in this elderly patient population. Disclosures Räty: Roche Ltd: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline Ltd: Honoraria; Mundipharma: Honoraria. Mikkola:Roche Ltd: Honoraria. Poikonen:Celgene: Speakers Bureau; Amgen: Speakers Bureau; Baxter: Speakers Bureau; Novartis: Speakers Bureau; GlaxoSmithKline: Consultancy; Mundipharma: Honoraria; Novartis: Honoraria. Räsänen:Novartis: Honoraria; Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria.

Phase II Trial of R-CHOP Plus Bortezomib Induction Therapy Followed By Bortezomib Maintenance for Previously Untreated Mantle Cell Lymphoma: SWOG 0601

BackgroundMantle cell lymphoma (MCL) is incurable with current standard therapies, and there is no consensus for the optimal induction regimen. Bortezomib, a 26S proteasome inhibitor, is active as a single agent in this disease, and preclinical data suggest that combination with chemotherapy may be synergistic. A recent randomized trial found that maintenance rituximab after R-CHOP led to a survival benefit, suggesting maintenance strategies are worth investigating in MCL. The SWOG cancer research cooperative group conducted a phase II study (S0601) to evaluate the safety and efficacy of combining bortezomib with R-CHOP for induction, followed by bortezomib maintenance for 2 years.MethodsPatients were eligible if they had previously untreated stage III, IV, or bulky stage II evaluable mantle cell lymphoma. Induction therapy consisted of six cycles of R-CHOP (375 mg/m2 rituximab, 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine, and 100 mg prednisone daily for 5 days) plus bortezomib 1.3 mg/m2 on days 1 and 4 of every 21 day cycle. Patients achieving at least stable disease after induction were eligible for bortezomib maintenance therapy 1.3 mg/m2 days 1, 4, 8, and 11 every 3 months for 8 cycles (one cycle was defined as 3 months for the maintenance phase). The study was designed to estimate the 2 year PFS rate to within 13% (95% CI).ResultsOf the 68 enrolled patients, 65 were eligible and evaluable for toxicities. The patient population had a median age of 61 (range 36-85), with 80% male sex, 15% bulky disease, 98% stage III-IV, 37% elevated LDH, and MIPI scores of: 45% low-risk, 43% intermediate risk, and 12% high-risk. In general, the treatment was well-tolerated, with 48% of patients experiencing grade 4 hematologic toxicities during induction therapy, and 38.5% grade 3 non-hematologic and 6% grade 4 non-hematologic toxicities. During maintenance therapy, 13% of patients experienced grade 3 non-hematologic toxicities. Grade 3 peripheral neuropathy was experienced by 8% of patients during induction and 2% of patients during maintenance bortezomib, and there was no grade 4 neuropathy. One patient died of toxicities possibly related to therapy: complete heart block in the setting of pneumonia and acute respiratory distress syndrome. With a median follow-up time among surviving patients of 5.9 years, 52 patients have progressed or died. The estimate of 2-year progression-free survival (PFS) was 62%, and 2-year overall survival (OS) was 85%. At 5 years, the PFS was 28% and OS was 66%. Based on prior studies, the historical 2 year PFS rate for R-CHOP alone in this population is 30%. MIPI scores were significantly associated with outcome, with 2-year PFS of 72%, 61%, and 25% for low, intermediate, and high risk MIPI groups, respectively. However, in a regression analysis to identify prognostic factors associated with a ≥ 5 year PFS, the only significant factor found was absence of splenic involvement. Additional correlative studies are planned to identify predictive biological markers associated with long-term remissions.ConclusionsCombination R-CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared with historical data of R-CHOP alone, doubling the historical 2 year PFS rate, with nearly one third of patients achieving a PFS of 5 years or longer. These results suggest that the addition of bortezomib to induction chemotherapy and/or maintenance is promising and warrants further exploration.Support: CA32102, CA38926, and in part by Millennium Pharmaceuticals, Inc. DisclosuresOff Label Use: The use of bortezomib in the induction and maintenance setting for mantle cell lymphoma will be discussed.. Fisher:Johnson & Johnson: Consultancy; MorphoSys AG: Consultancy.