Mantle Cell Lymphoma Pts Research Articles

Complex Karyotype in Mantle Cell Lymphoma (MCL) Is Associated with Inferior Progression-Free Survival in Patients (pts) Receiving R-Hypercvad Followed By Autologous Stem Cell Transplant

Introduction: While cytogenetic assessments are frequently utilized in many hematologic malignancies as prognostic markers, their role in MCL is less well defined. Prior studies have identified a complex karyotype (≥3 chromosomal abnormalities) in 40 - 59.2 % of patients (pts) with MCL, and it has been associated with inferior progression-free survival (PFS) in those series (Cohen et al, 2015; Sarkozy et al, 2014). Our group recently published outcomes for MCL pts at our institution, including 35 pts who received R-HyperCVAD followed by autologous stem cell transplantation (ASCT) who had an overall survival (OS) at 5-years of 74% (Nastoupil et al, 2014). We conducted an analysis of the impact of pretreatment cytogenetics on outcomes for MCL.Methods: We included all pts diagnosed with MCL at Winship Cancer Institute of Emory University between 2002 and 2014 who had available pretreatment conventional cytogenetic and clinical data. Baseline demographic, clinical, laboratory, and therapeutic variables of interest were assessed. Univariate Cox proportional hazards models were fit for each covariate, and hazard ratios are reported. Overall survival (OS) was defined as time to death or last follow-up from diagnosis, and PFS was defined as time to progression, death, or last follow-up from diagnosis. These curves were estimated via the Kaplan-Meier method, and the groups were compared using log-rank tests. We performed a similar analysis for the subset of pts initially treated with HyperCVAD and ASCT. Statistical significance was defined as α=0.05.Results: Among 184 MCL pts, 52 had pretreatment cytogenetics data available. The median age at diagnosis was 64 years (range: 32-81), 36 (69%) were male, and 37 (86%) had stage IV disease. At diagnosis, 36 pts (97%) had ECOG performance status of 0 or 1, 16 (34%) had B-symptoms, 43 (86%) had bone marrow involvement, 8 (16%) had gastrointestinal tract involvement, and 29 (71%) had splenomegaly. Initial induction therapies included R-HyperCVAD (n=27), R-CHOP (n=10), R-bendamustine (n=6), and other/unknown (n=9). Thirty pts (58%) underwent ASCT in first complete or partial remission. Five pts (10%) met criteria for a complex karyotype, 11 (21%) had 1 or 2 detectable chromosomal abnormalities, and 36 (69%) pts had a normal karyotype. Cytogenetics were assessed on nodal samples (n=7) or bone marrow/peripheral blood (n=45). Among all assessed covariates, only elevated WBC count was associated with cytogenetic abnormalities (p=0.04). Overall, there was no significant association of PFS or OS with the presence of a complex karyotype or an abnormal karyotype with < 3 abnormalities when compared to a normal karyotype. Among all assessed variables, only splenomegaly was associated with worsened PFS (p=0.02). We conducted an exploratory analysis of the 24 pts who received R-HyperCVAD followed by ASCT, of which 2 had a complex karyotype. In that subset, median PFS for pts with a complex karyotype was 35.3 months, compared to 77.9 months for those with a non-complex abnormal karyotype or a normal karyotype.Conclusion: Contrary to prior reports, a smaller percentage of pts had complex karyotype (10%) in this cohort, and pretreatment cytogenetics did not impact PFS or OS among the entire heterogeneously treated sample. However, there appears to be inferior PFS for pts with a complex karyotype in the subset who received R-HyperCVAD followed by ASCT, and a larger, multi-center series, may illuminate the impact of a complex karyotype on this subset of aggressively treated patients. DisclosuresNastoupil:AbbVie: Research Funding; Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; Janssen: Research Funding. Flowers:Infinity Pharmaceuticals: Research Funding; Spectrum: Research Funding; Acerta: Research Funding; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy; Gilead Sciences: Research Funding; Millennium/Takeda: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Gilead Sciences: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Onyx Pharmaceuticals: Research Funding; Millennium/Takeda: Research Funding; OptumRx: Consultancy; AbbVie: Research Funding; Seattle Genetics: Consultancy; Genentech: Research Funding; OptumRx: Consultancy; Genentech: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Spectrum: Research Funding. Cohen:Celgene, Pharmacyclics, Millennium, Seattle Genetics: Consultancy; BMS, Janssen: Research Funding.

Long-Term Results of Cytarabine-Containing Induction Followed By Consolidation with Autologous Stem Cell Transplant and Rituximab Maintenance As Primary Treatment for Mantle Cell Lymphoma

Introduction: Mantle cell lymphoma (MCL) often follows an aggressive course and remains incurable with standard therapies. First-line chemotherapy followed by consolidation with high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) has become a standard of care in eligible patients (pts). As relapse remains the main cause of treatment failure, strategies such as intensifying induction therapy with high-dose cytarabine or adding rituximab maintenance (RM) have been tested to reduce the relapse rate (RR) post-ASCT. We evaluated the effect of the addition of cytarabine and RM on the outcome of pts undergoing ASCT.Methods: We conducted a retrospective analysis of consecutive MCL pts who underwent ASCT after first-line chemotherapy at the Princess Margaret Cancer Centre between 2000-2013. Pts received induction with CHOP, RCHOP, or RCHOP alternating with RDHAP (RCHOP/RDHAP), followed by HDT with or without total body irradiation (TBI). All pts had a documented response to induction using Cheson 1999 criteria. After ASCT, pts received maintenance with single-agent rituximab 375 mg/m2 or were simply observed.Results: 98 MCL pts were treated: median age was 56 years (36-66), 15 pts (15%) had blastoid or pleomorphic subtype, 85 pts (87%) had stage IV disease. MIPI was high risk in 18 pts (19%). Induction therapy: CHOP 14 pts (14%), RCHOP 57 (58%), and RCHOP/RDHAP 27 (28%). After induction CR was obtained in 44%, PR in 56% pts. CR rates were: CHOP 7 (50%), RCHOP 25 (44%), RCHOP/RDHAP 12 (44%) (P=ns). 89% pts had collected > 5*106 CD34/kg after RCHOP, and 78% after RCHOP/RDHAP (P=ns). Overall 66/98 pts (67%) had > 5*106 CD34/kg collected with 1 apheresis (Table 1). HDT was melphalan+etoposide for 63% pts, cytarabine+melphalan for 31% pts; 77 (79%) also received TBI. Median time from diagnosis to ASCT was 7.5 months (2.5, 33.4). Post-ASCT responses: CR 92 pts (94%), PR 4 (4%), 2 (2%) PD. Median time to ANC ≥0.5 were 10 days (CHOP), 11 days (RCHOP), and 11 days (RCHOP/RDHAP), while median days to PLT≥20 were 9 (CHOP), 11.5 (RCHOP), and 13 (RCHOP/RDHAP). Post-ASCT, 31% of pts had normal blood counts at 3 months which improved to 52% at 1 year post-ASCT. Maintenance data were available for 95/98 pts. RM was given to 72 pts (74%). Median follow-up from date of transplant for the entire cohort was 3.22 years (range 0.7 - 14.1). The 2-year and 5-year PFS were 85.8% (76.7-91.5) and 52.2% (37.7-64.7), respectively. 32 pts relapsed after ASCT (32.65%). Relapse occurred in 3 (11%) pts after RCHOP/RDHAP, 19 (33%) after RCHOP, and 10 (71%) after CHOP. Median time to relapse was 9 years (95%CI: 4.7-NR). 2-year and 5-year RR were 14.54% and 41.65%, respectively. Median OS was 9.15 years (95%CI: 7.3-NR), 2-year OS was 88.8% (80.2-93.8), and 5-year OS was 74.9% (61.7-84.2%). For patients observed without treatment post-ASCT, median PFS was 2.87 years (1.22-4.63) and median OS 5.19 years (1.66-NR), while for those receiving RM, PFS was 9.06 years (4.97-NR, p<0.001) and median OS has not yet been reached (7.30- NR, p=0.009).Conclusions: Response rate and PFS were similar between different induction regimens. The outcomes of responding pts following ASCT appear superior to previous strategies. Our patients enjoyed a very long PFS and median OS is surprisingly long as well. Within the limits of a retrospective study, our data support the use of rituximab maintenance, showing a significant benefit in both PFS and OS.Table 1ASCT dataStem cell collectionCHOPRCHOPRCHOP/RDHAPP valuePts collecting > 2x106 /Kg CD34+ cells in 1 day4/14 (29%)44/57 (77%)17/27 (67%)0.002Pts collecting 2-5 x106 /Kg CD34+ cellsN/A6/57 (11%)6/27 (22%)Pts collecting >5 x106 /Kg CD34+ cellsN/A51/57 (89%)21/27 (78%)0.153Engraftment median (range)Days to ANC ≥ 0.510 (9,11)11 (9, 12)11 (9, 12)Pts with ANC ≥ 0.5 ≤ 11 days13/13 (100%)45/52 (87%)21/25 (84%)0.33Days to PLT ≥ 209 (7, 15)11.5 (9, 17)13 (9, 26)Pts with PLT ≥ 20 ≤ 12 days12/13 (92%)37/52 (71%)8/25 (32%)0.0001*Days from ASCT to discharge13 (11,26)14 (11,30)13 (11,23)PTs requiring RBC Transfusions11 (79%)43 (75%)22 (81%)0.821Number of RBC Transfusions2 (0, 4)2 (0, 7)3(0, 6)Pts requiring PLT Transfusions12 (86%)52 (93%)25 (93%)0.759Number of PLT Transfusions1 (0, 4)2 (1, 9)3 (1, 5)* comparison CHOP Vs R-CHOP: not significant, p=0.113Legend. ASCT: autologous stem cell transplant; Pts: patients; ANC: absolute neutrophils count;PLTs: platelets; RBC: red blood cells. DisclosuresKuruvilla:Hoffmann LaRoche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy; Janssen: Consultancy, Honoraria; Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Lundbeck: Honoraria; Karyopharm: Honoraria.

Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas

BACKGROUND: Autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) can mediate potent anti-tumor effects in patients (pts) with relapsed or refractory chronic lymphocytic and acute lymphoblastic leukemias. We are conducting a phase IIa clinical trial to evaluate the safety and efficacy of CTL019 cells in pts with relapsed or refractory CD19+ non-Hodgkin lymphomas (NHL).METHODS: Pts with CD19+ diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or mantle cell lymphoma (MCL) with no available curative treatment options, a limited prognosis (<2 years anticipated survival), and responsive or stable disease with most recent therapy are eligible. Pts with DLBCL have residual disease after primary and salvage therapies and are not eligible for autologous stem cell transplant (ASCT) or have relapsed or residual disease after ASCT; FL pts have progression of lymphoma <2 years after second or higher line of therapy (not including single agent monoclonal antibody therapy); MCL pts have relapsed, residual, or progressive disease after rituximab-chemotherapy combination therapy and are not appropriate for transplant or have relapsed after transplant. After steady state apheresis to collect peripheral blood leukocytes, pts receive lymphodepleting chemotherapy based on disease burden, histology, and past therapies. One to 4 days after chemotherapy, pts receive a single dose of CTL019 cells by intravenous infusion. Peripheral blood and marrow samples are collected for immunophenotypic, cytokine, and molecular studies at pre-specified times after T cell infusion. Initial tumor response assessment is performed 3 months after T cell infusion using International Working Group response criteria. Enrollment started in February 2014; data reported here are through July 26, 2015.RESULTS: To date, 38 pts have enrolled (DLBCL 21; FL 14; MCL 3). The median age is 56 years (range: 25-77), male: female ratio is 22:16, median number of prior therapies is 4 (range: 1-10), and number of pts with prior transplant is 12 (32%; 11 ASCT, 1 allotransplant). Ann Arbor stages at enrollment are: Stage IV 23 pts (61%), Stage III 7 pts (18%), Stage II 6 pts (16%), Stage 1E 2 pts (5%); 11 pts (29%) had bone marrow involvement. LDH was increased in 28 pts (74%). ECOG PS was 0 in 16 pts (42%) and 1 in 22 pts (58%). As of July 26, 2015, 24 patients have received the protocol-specified dose of CTL019 cells (13 DLBCL; 9 FL; 2 MCL). Lymphodepleting chemotherapy regimens were bendamustine (6 pts), cyclophosphamide (11 pts), cyclophosphamide-fludarabine (1 pt), modified EPOCH (3 pts), and radiation-cyclophosphamide (3 pts). Median total CTL019 cell dose is 5.00e8 (range: 1.79e8 - 5.00e8); median CTL019 cell dose/kg is 5.84e6 (range: 3.08e6-8.87e6). Median peak CTL019 cell expansion in blood occurred 7 days after infusion (range: 2-14 days); there was no difference in peak expansion between responders and non-responders. Cytokine release syndrome (CRS) occurred in 16 pts (14 grade 2; 1 grade 3; 1 grade 4) and did not predict response. Neurologic toxicity occurred in 3 pts: 2 episodes of delirium (1 grade 2, 1 grade 3) and one possibly related grade 5 encephalitis. 22 pts are evaluable for response (DLBCL 13, FL 7, MCL 2). Overall response rate (ORR) at 3 months is 68% (15/22): DLBCL 54% (7/13); FL 100% (7/7); MCL 50% (1/2). At the median follow-up 11.7 months, progression-free survival (PFS) from CTL019 infusion is 62% (DLBCL 43%; FL 100%). For responders at median follow up, response duration is 83% for DLBCL and 100% for FL.CONCLUSIONS: These results demonstrate that CTL019 cells can be prepared from extensively pretreated pts with active NHL and can induce durable responses with toxicity that is less than reported for chronic lymphocytic and acute lymphoblastic leukemias. [Display omitted] DisclosuresSchuster:Phamacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding. Svoboda:Seattle Genetics: Research Funding; Celgene: Research Funding; Celldex: Research Funding; Immunomedics: Research Funding. Dwivedy Nasta:BMS: Research Funding; Millenium Takeda: Research Funding. Porter:Genentech: Other: Spouse Employment; Novartis: Patents & Royalties, Research Funding. Mato:Celgene Corportation: Consultancy, Research Funding; Genentech: Consultancy; Pharmacylics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Chew:Novartis: Patents & Royalties. Hasskarl:Novartis: Employment, Equity Ownership. Shah:Novartis: Employment, Equity Ownership. Wasik:Janseen and Novartis: Research Funding. Zheng:Novartis: Patents & Royalties. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding.

Efficacy and Safety of Bortezomib Plus Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) Vs R-CHOP in Japanese Patients (Pts) with Newly Diagnosed Mantle Cell Lymphoma (MCL) Not Considered for Transplantation Enrolled in the International, Randomized, Phase 3 LYM-3002 Study (NCT00722137)

Background: LYM-3002 was a global study evaluating the efficacy and safety of frontline VR-CAP vs R-CHOP in newly diagnosed MCL pts who were not considered for hematopoietic stem cell transplantation. 487 pts (243 VR-CAP, 244 R-CHOP) were enrolled in 28 countries in the EU, North/South America, and Rest of World. VR-CAP was associated with significantly longer progression-free survival (PFS) by independent radiology review committee (IRC) vs R-CHOP (median 24.7 vs 14.4 mos; hazard ratio [HR] 0.63 [0.50, 0.79]; p Methods: Adults with measurable stage II–IV MCL and ECOG PS 0–2 were randomized 1:1 (stratified by International Prognostic Index [IPI] score and disease stage) to 6–8 × 21-d cycles of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, all IV d 1, and prednisone 100 mg/m2 PO d 1–5, plus bortezomib 1.3 mg/m2 IV d 1, 4, 8, 11 (VR-CAP) or vincristine 1.4 mg/m2 (max 2 mg) IV d 1 (R-CHOP). Response was assessed by IRC and by investigator (INV) per International Lymphoma Workshop Response Criteria. Time-to-event outcomes were estimated by Kaplan-Meier methodology. The Cochran-Mantel-Haenszel Chi-squared test was used for response rate comparisons. Adverse events (AEs) were graded per NCI-CTCAE v3.0. Results: 18 Asian pts with centrally confirmed MCL (7 VR-CAP, 11 R-CHOP) were enrolled in Japan. For VR-CAP vs R-CHOP, pts’ median age was 70 (64–74) and 70 (66–82) yrs; 6 vs 11 pts were aged >65 yrs. 4 vs 8 pts were male, 4/2/1 vs 8/3/0 pts had ECOG PS 0/1/2, 0/2/5 vs 1/1/9 pts had stage II/III/IV disease at diagnosis, and 0/3/3/1 vs 1/3/6/1 pts had IPI score low (0–1)/low–intermediate (2)/high–intermediate (3)/high (4–5). All pts completed ≥6 cycles, except for 1 pt on VR-CAP who discontinued after 2 cycles (grade 2 hypertension). After a median follow-up of ~33 mos, median PFS by IRC with VR-CAP vs R-CHOP was not reached (NR) vs 19.5 mos (1/7 vs 7/11 progression/death events; HR 0.39 [0.04, 3.52]; p=0.384; Figure) and by INV was NR vs 16.2 mos (2/7 vs 9/11 progression/death events; HR 0.46 [0.09, 2.45]; p=0.351). In 17 response-evaluable pts (7 VR-CAP vs 10 R-CHOP), rates of CR/CRu by IRC (bone marrow and LDH-verified) were 71% vs 50% (OR 3.0 [0.15, 59.89]; p=0.495) with median duration of CR/CRu NR vs 16.6 mos, and overall response rates (ORR; CR+CRu+partial response [PR]) were 100% in both arms. Median TFI was NR vs 19.1 mos (HR 0.71 [0.13, 3.89]; p=0.688) and median TTNT was NR vs 24.3 mos (HR 0.71 [0.13, 3.89]; p=0.688), respectively. After only 1 death (R-CHOP arm), median OS for VR-CAP and R-CHOP were not estimable (NE). 3-yr OS rates were 100.0% (NE, NE) vs 80.0% (20.4%, 96.9%). All pts experienced at least one grade ≥3 AE, most commonly neutropenia (100% VR-CAP vs 100% R-CHOP), thrombocytopenia (71% vs 0), febrile neutropenia (43% vs 45%), lymphopenia (43% vs 27%), leukopenia (29% vs 27%), and anemia (0 vs 27%). No grade ≥3 bleeding AEs were reported and grade ≥3 infection AEs occurred in only 1 pt on VR-CAP (herpes zoster infection). Peripheral neuropathy rates were 71% vs 45% (grade ≥3: 14% vs 9%). 1 R-CHOP pt experienced serious AEs (bile duct stone, femur fracture). There were no on-treatment deaths. Conclusions: Results from this cohort of Japanese pts enrolled in LYM-3002, showing improved efficacy in favor of VR-CAP with additional but manageable toxicity, appear consistent with the findings in the overall study population. VR-CAP could be considered as an alternative frontline treatment option for newly diagnosed, transplantation-ineligible MCL pts in Japan. Disclosures Ogura:Janssen: Research Funding; Takeda: Research Funding; Chugai: Research Funding; Celgene: Research Funding; Symbio: Research Funding; Kyowahakko-Kirin: Research Funding; Pfizer: Research Funding; GlaxoSmithKline: Research Funding. Off Label Use: The proteasome inhibitor bortezomib is approved in the US for the treatment of multiple myeloma and for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. In the present study, bortezomib is being investigated in combination with immunochemotherapy for previously untreated patients with mantle cell lymphoma, an indication for which it is currently not approved.. Pei:Janssen: Employment. Rooney:Janssen: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen: Employment; Johnson & Johnson: Equity Ownership. Cavalli:Novartis: Consultancy; Takeda: Consultancy; Roche: Research Funding; Pfizer: Research Funding; Mundipharma: Research Funding.

Observational Study Alternating R-CHOP21 and R-Cytarabine (3+3 Cycles) for Patients with Newly Diagnosed Mantle Cell Lymphoma Not Eligible for High-Dose Therapy: A Czech Lymphoma Study Group Trial Preliminary Results

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin lymphoma characterized by frequent relapses and adverse prognosis. Implementation of high-dose cytarabine (HDAC) and incorporation of anti-CD20 antibody rituximab (R) into induction and maintenance, and consolidation with high-dose therapy and autologous stem cell transplantation (HDT-ASCT) significantly improved pt´s outcome. Therapy of the elderly or comorbid (not eligible for HDT-ASCT) is largely based on R-CHOP or R-bendamustin induction with or without R maintenance. Minimal residual disease (MRD) assessment by quantitative PCR (qPCR) from peripheral blood or bone marrow (BM) has emerged as a powerful molecular marker of outcome. Based on the results of the younger pts some centers adopted the use of HDAC in elderly as well, but no data has been presented yet. Aim: We initiated the observational study as a non-intervention, multi-center trial with the primary objectives to prospectively evaluate efficacy of alternating R-CHOP21 and R-HDAC (1 or 2 g / m2, 2 doses a 24 hours) in newly diagnosed MCL pts not eligible for HDT-ASCT. Methods: Primary endpoints were overall response rate (ORR) by PET-CT, and MRD assessment by qPCR after completion of induction. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. The choice between 1 and 2 g / m2 cytarabine was left at investigator´s discretion, as well as the rituximab maintenance. Patients with known cardiac co-morbidity could be treated with R-COEP (etoposid 50 mg / m2, D1-D3) instead of R-CHOP. Exclusion criteria included eligibility to HDT-ASCT, ECOG≥ 4, and CNS involvement. Results: Altogether 61 pts (38 men and 23 women, ratio 1.7:1) were enrolled into the study between 16-JUN-2011 and 18-MAR-2014. Median age was 70 years both for men and women. 91.5%, and 80% pts presented with stage 3/4 disease, and infiltration of BM, resp. According to the MIPI, 55.7%, 39.4%, and 4.9% pts had high, intermediate and low risk disease, resp. B-symptoms were recorded in 33.3% of pts. 76.8% and 24.2% pts were diagnosed from the lymph node, and trephine biopsy, resp. 62.8%, 27.9%, and 9.3% pts presented with classical, pleomorphic and blastoid variant MCL, resp. Ki67/MIB1 ≥ 30% was observed in 38% of pts. Bulky disease &gt;5cm, and &gt;10cm, was noticed in 31% and 13% pts. Spleen involvement was observed in 53% pts. Extra-nodal involvement other than BM was histologically confirmed in 11.5% pts. R-CHOP was used in 88% pts (12% pts received R-COEP), 86% pts received 2g / m2 cytarabine (14% pts 1g / m2). 86.3% pts with response were treated with R maintenace. Only one patient was excluded from the study due to unacceptable toxicity. 57.7% pts developed grade 3/4 hematologic toxicity (neutropenia, anemia or thrombocytopenia). Grade 3/4 non-hematologic toxicity occurred in 27.3% pts. All pts had PET-CT restaging after completion of induction. Overall response rate (CR+PR) reached 91.7%. CR and PR rate by PET was 76.7%, and 15%, resp. SD, and progression on therapy was noticed in 3.3%, and 5.0%, resp. Samples for MRD assessment were collected from 41 out of 54 pts, who completed induction and achieved response (CR or PR). At the time of abstract submission 21, 7, and 7 (out of 36 so far evaluated pts) were MRD negative, MRD positive-not quantifiable, and MRD positive-quantifiable, resp. With the median follow-up 19.1 month, there were 7 progressions and 6 deaths. 2-year PFS and OS probability were 83.9% and 88.1%. Conclusion: Alternation of R-CHOP and R-HDAC in newly diagnosed elderly or co-morbid MCL pts represents a promising, very effective and well-tolerated treatment approach that induces high ORR, and MRD negativity. Grant Support: IGA-MZ NT/13072-4, PRVOUK-27/LF1/1 Disclosures No relevant conflicts of interest to declare.

Subcutaneous (SQ) Bortezomib (BTZ) in Patients (Pts) with Relapsed Mantle Cell Lymphoma (MCL): Retrospective, Observational Study of Treatment Patterns and Outcomes in US Community Oncology Practices

Subcutaneous (SQ) Bortezomib (BTZ) in Patients (Pts) with Relapsed Mantle Cell Lymphoma (MCL): Retrospective, Observational Study of Treatment Patterns and Outcomes in US Community Oncology Practices

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.

Efficacy of Standard Dose R-CHOP Alternating with R-HiDAC Followed By ASCT As Initial Therapy of Mantle Cell Lymphoma: Cleveland Clinic Experience

Abstract Introduction: A common approach to initial treatment for young, fit patients (pts) with mantle cell lymphoma (MCL) is induction chemoimmunotherapy followed by high dose chemotherapy with autologous stem cell support (ASCT). Induction regimens with modifications of R-CHOP (rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone) and/or incorporation of high dose cytarabine (HiDAC) appear more effective than RCHOP alone, as in R-HyperCVAD/MA (cyclophosphamide-vincristine-doxorubicin-dexamethasone alternating with methotrexate-cytarabine, MDACC), R-CHOP alternating with R-DHAP (rituximab-dexamethasone-cytarabine-cisplatin, European MCL Network) and dose intensified R-CHOP alternating with HiDAC followed by ASCT (Nordic Lymphoma Group). At the Cleveland Clinic, in 2010 we adopted as our standard induction regimen a modification of the Nordic protocol, using standard dose R-CHOP alternating with R-HiDAC for 3 cycles each or, for pts who had already been treated with R-CHOP x 6 cycles prior to referral for ASCT, an additional 2 R-HiDAC. Here we report analysis of our institutional experience with this regimen. We use as historical comparison pts with MCL who underwent ASCT at our institution following R-HyperCVAD/MA or R-CHOP. Method: We retrospectively analyzed the outcome of 87 MCL pts who received first line therapy including ASCT at Cleveland Clinic from Aug 1999 - Apr 2014. Pt characteristics, treatment regimens and biological markers were evaluated with regard to overall survival (OS) and relapse free survival (RFS). Pts were grouped according to induction chemotherapy: Group A (HyperCVAD/MA x4 cycles), Group B (R-CHOP x 6 cycles), and Group C (R-CHOP alternating with R-HiDAC for 6 total cycles or R-CHOP x 6 cycles followed by HiDAC x 2 cycles). All pts received ASCT consolidation therapy with high dose busulfan, cyclophosphamide, and etoposide. OS and RFS were estimated using the Kaplan-Meier method and compared among groups using the log-rank test. Cox proportional hazards analysis was used to identify univariable prognostic factors for OS and RFS. Results: The median age of the entire cohort was 59 years (range: 41-73), with male predominance (74%). All pts had ECOG performance score ≤1, MIPI low/intermediate/high scores were 57%/30%/13%. Complete remission prior to ASCT was achieved in 76% of pts. Pt characteristics, including MIPI scores, were evenly distributed among three treatment groups except for: (1) age (median age at diagnosis Group A=53 yr, Group B=62 yr, and Group C=57 yr, P&lt;0.001) (2) more blastoid subtype in Group A (19%) while Group C had no blastoid subtypes of MCL (0%, P=0.03); and (3) higher proportion of patients in Group C with comorbidities (85.7%, p=0.003). With a median follow-up of 26.6 months, 2 year OS rate (Fig. 1) was 95.2%, 94.7% and 100% in groups A, B and C respectively; 2 year RFS rate (Fig. 2) of 85.7%, 73.7% and 93.3% respectively. In univariate analysis, blastoid subtype (HR=5.37, 95% CI 1.97-14.6), and high risk MIPI score (HR=14, 95% CI 3.38-57.6) were predictive of OS as well as of RFS (HR = 2.76, 95% 1.14-6.69 and HR 6.45, 95% CI 2.41-17.2). Post-ASCT treatment was required for 41% of pts, 8 pts (42.1%) in group A, 38 pts (58.3%) in group B and 5 pts (17.9%) in group C, although pts in group C had shortest follow up to date. In conclusion, our outcomes for pts with newly diagnosed MCL demonstrated no statistically significant difference in OS and RFS among the 3 treatment groups. While longer followup is needed, these data suggest that our less toxic approach of using standard dose and schedule R-CHOP alternating with R-HiDAC, without dose-intense R-CHOP or addition of methotrexate or cisplatin, is highly effective pre-ASCT first line therapy for MCL. Fig 1. Fig 1. Fig. 2 Fig. 2. Disclosures No relevant conflicts of interest to declare.

Efficacy and Safety of Frontline Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) Vs R-CHOP in a Subset of Newly Diagnosed Mantle Cell Lymphoma (MCL) Patients (Pts) Medically Eligible for Transplantation in the Randomized Phase 3 LYM-3002 Study (NCT00722137)

Efficacy and Safety of Frontline Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP) Vs R-CHOP in a Subset of Newly Diagnosed Mantle Cell Lymphoma (MCL) Patients (Pts) Medically Eligible for Transplantation in the Randomized Phase 3 LYM-3002 Study (NCT00722137)

Abstract 4139: Healthcare resource utilization (HRU) in treated mantle cell lymphoma (MCL) patients

Abstract Background: MCL, a subtype of non-Hodgkin's lymphoma, has an aggressive clinical course &amp; poor prognosis. Few studies have described treatment patterns &amp; HRU in treated MCL patients (pts). Methods: U.S. healthcare claims data (Truven Health) was used to identify adult pts with a new episode of MCL therapy (tx) (defined as no MCL tx claim in prior ≥ 12 months) occurring within 90 days of an MCL diagnosis, &amp; ≥ 12 months enrollment before &amp; after the first MCL tx claim (index date). Pts with claims for pregnancy or non-MCL txs were excluded. The identification period was from 2007 - 2011. MCL txs included bendamustine, bortezomib, busulfan, carboplatin, carmustine, cisplatin, cladribine, cyclophosphamide, cytarabine, doxorubicin, etoposide, fludarabine, ifosfamide, melphalan, MESNA, methotrexate, mitoxantrone, lenalidomide, pentostatin, procarbazine, rituximab, temsirolimus, vincristine, or combinations. Demographics, MCL treatment patterns &amp; HRU were summarized using descriptive statistics. HRU patterns during the 12 months before &amp; after initiating MCL tx were analyzed. Results: This analysis identified 381 pts. Mean age was 65 (SD 12) years; 73% were male. Prior to 2010, more than 70% of initial txs consisted of one of the following regimens: 1) cyclophosphamide-doxorubicin-rituximab-vincristine, 2) rituximab monotherapy, 3) vincristine monotherapy or 4) cyclophosphamide-rituximab-vincristine. After 2010, more than 70% of initial txs consisted of 1) cyclophosphamide-doxorubicin-rituximab-vincristine, 2) bendamustine-rituximab, &amp; 3) rituximab monotherapy. MCL tx claims were reported for a mean of 4.0 (SD 2.0) months per pt in the 12 months following the index date. The table reports HRU in the 12 months before &amp; after initial MCL tx. Conclusions: This observational study of 381 treated MCL pts reported significant HRU in the 12 months following initiation of MCL tx. These results provide an indicator of MCL disease burden &amp; provide stakeholders an estimate of HRU upon which standardized costs may be imputed. TableHRU Category12 monthspre-index12 months post-index% with ≥1 hospitalization45% (171/381)57% (219/381)Hospital days per patient* Mean (SD)5.2 (10.3)13.5 (20.4)% with ≥ 1 Emergency room (ER) visit32% (123/381)43% (163/381)ER visits per patient*Mean (SD)0.5 (1.3)0.8 (1.4)Number of outpatient encounters per patient, mean (SD)31 (20)63 (35)% with ≥ 1 claim for colony stimulating factor use21% (80/381)69% (261/381)% with ≥1 claim for red blood cell growth factor use2% (9/381)17% (65/381)% with ≥1 red blood cell transfusion3% (11/381)15% (59/381)*Includes patients with zero resource use in the category Citation Format: Chris M. Kozma, Terra Slaton, Lorie Ellis, R S. McKenzie. Healthcare resource utilization (HRU) in treated mantle cell lymphoma (MCL) patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4139. doi:10.1158/1538-7445.AM2014-4139

Comparison Of Deep Sequencing and Allele-Specific Oligonucleotide PCR Methods For MRD Quantitation In Acute Lymphoblastic Leukemia and Mantle Cell Lymphoma: CALGB 10403 and CALGB 59909 (Alliance)

BackgroundThe assessment of minimal residual disease (MRD) is a key component of prognosis and monitoring in acute lymphoblastic leukemia (ALL) and mantle cell lymphoma (MCL). Allele-specific oligonucleotide (ASO)-PCR can be used to assess MRD; however, this technique requires preparation of clonotype-specific primers for each patient, which is laborious and time-consuming. We demonstrated the utility of sequencing-based MRD assessment in ALL (Faham et al., Blood 2012). This quantitative approach relies on amplification and sequencing of immunoglobulin and T-cell receptor gene segments using consensus primers and can address some of the limitations associated with traditional MRD detection. Here we compared the ability of the sequencing and ASO-PCR methods to identify clonal cancer gene rearrangements at diagnosis and evaluated the concordance of MRD detection in bone marrow (BM) or blood samples from 37 patients (pts) with ALL and 22 pts with MCL entered onto prospective CALGB treatment trials, 10403 and 59909 (Alliance), respectively . MethodsUsing the quantitative ASO-PCR and sequencing assays, we analyzed diagnostic blood and BM samples from ALL pts for clonal rearrangements of immunoglobulin (IGH-VDJ, IGH-DJ, IGK) and T cell receptor (TRB, TRD, TRG) genes. We then assessed MRD at the IGH and/or TRG locus in 84 follow-up samples from ALL pts. Similarly, we analyzed samples from 22 MCL pts for immunoglobulin (IGH-VDJ, IGH-DJ, IGK) clonal gene rearrangements and measured MRD at the IGH and/or IGK locus in 114 follow-up samples. Sensitivity of the ASO-PCR vs sequencing was 1 X 10 4-5 vs 1 X 106, respectively. Concordance between sequencing and ASO-PCR MRD assessment on serial samples collected during and post-treatment was evaluated across all pts and within disease groups using concordance correlation coefficients for repeated measures (CCC-RM). Concordance in identification of detectable vs. undetectable MRD by both methods was also evaluated using Kappa statistics. ResultsUsing the sequencing platform, high frequency clonal rearrangements were observed in at least two receptors in 97% and 95% of pts with ALL and MCL, respectively. Selected ALL samples were known to have IGH-VDJ or TRG clonal rearrangements by ASO-PCR; however, sequencing revealed additional clonal rearrangements in 36/37 (97%) pts with ALL. Good concordance was observed with identification of MRD positive vs. negative between the methods (K=0.62; p<0.0001), where better agreement was observed within the ALL (K=0.63) than within the MCL (K=0.59) cohorts. Across both diseases, the sequencing method proved a more sensitive measure and CCC-RM was 0.82, reflecting the fact that 28 pts with undetectable MRD by ASO-PCR methods had low detectable MRD measures by the sequencing approach. The sequencing platform also provided new insights into kinetics of relapse. In one ALL case (Fig 1), we observed three high frequency IGH-VDJ clones, two of which are related based on VDJ replacement model. Dramatic reduction in frequency of one clone (clone 3, Fig 1) was observed following initial induction chemotherapy in both BM and blood. Only this single clone was monitored using ASO-PCR, and the patient appeared to be in molecular remission. However, the other two high frequency clones were chemo-resistant, and sequencing MRD monitoring revealed no reduction in clone frequency in either the BM or blood. The patient experienced early relapse at day 56, which may have resulted from the expansion of a clone carrying one or both of the clonal sequences that was not monitored by ASO-PCR. Thus, the sequencing method can be used to monitor response to treatment at the individual clone level. [Display omitted] ConclusionsThis study demonstrates concordance between identification of detectable MRD in ALL and MCL by sequencing and ASO-PCR Methods. The sequencing approach offers improvements over ASO-PCR including the ability to monitor multiple clonal sequences, faster turnaround time (results in 1 week), and greater sensitivity. The clinical significance of this greater sensitivity remains to be tested prospectively and must be correlated with clinical results. Nevertheless, the sequencing method represents an alternative approach for clinical MRD monitoring which could fundamentally improve the ability to monitor disease progression and recurrence in patients with lymphoid malignancies. Disclosures:Carlton:Sequenta, Inc.: Employment, Equity Ownership. Weng:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

A Phase II Trial of Myeloablative I-131-Tositumomab, Etoposide and Cyclophosphamide Followed by Autologous Transplantation for B-Cell Non-Hodgkin's Lymphoma

AbstractAbstract ▪811▪This icon denotes a clinically relevant abstract Background:High-dose therapy and autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for many patients (pts) with high-risk or relapsed B-cell non-Hodgkin lymphoma (B-NHL). Despite the use of transplant, relapse is likely for most with indolent or mantle cell lymphoma (MCL) as well as for aggressive B-NHL recurring after rituximab (R)-based chemotherapy. Total body irradiation (TBI) has been incorporated into ASCT regimens to overcome chemotherapy resistance and improve outcomes, but studies to date indicate that escalation of TBI is not feasible due to toxicity in non-target organs. We hypothesized that radioimmunotherapy (RIT) could supplant TBI and identified the maximally tolerated dose (MTD) of high-dose RIT using I-131-tositumomab that could be safely combined with high-dose etoposide (VP-16) and cyclophosphamide (CY) prior to ASCT (Press, Blood 2000). We now present the mature data of a large prospective phase II trial at the MTD of high-dose I-131-tositumomab, VP-16, and CY. Methods:Pts were eligible if they were <60 years of age, had MCL in first remission or any relapsed/refractory B-NHL, an ECOG PS of 0–1, acceptable organ function, >2×106 autologous CD34+ peripheral blood stem cells/kg collected, <20 Gy prior radiation to critical organs, and no human-anti-mouse-antibodies. All pts underwent outpatient biodistribution studies using tositumomab (1.7 mg/kg, n= 64 or 485mg flat dose, n= 43) labeled with ∼10mCi I-131 followed by serial quantitative gamma camera imaging to calculate individualized organ-specific absorbed dose estimates. Pts then received therapeutic infusions of I-131-tositumomab to deliver 25Gy to the critical normal organ receiving the highest radiation absorbed dose. When residual radiation was <7mR/hr at 1m (median 10 days) pts received 60mg/kg VP-16 followed 48 hours later by 100mg/kg CY. ASCT occurred when residual radiation was <2mR/hr at 1m. Toxicity was scored on the Bearman transplant scale and CTCAE 2.0. Response followed standard criteria. Results:Between June 1999 and April 2011 107 pts were transplanted on this protocol. Baseline characteristics included: median age 52 yrs (range 32–60), stage III/IV = 104 (97%), median number of prior regimens = 3 (range 1–11), prior R = 98 (92%), R refractory = 35 (33%), chemoresistant disease (defined as < a partial response [PR] to the most recent regimen) = 41 (40%), >1 extranodal site = 36 (33%), elevated LDH = 46 (42%). Histological strata: Indolent 43% (45 follicular lymphoma [FL], 1 lymphoplasmacytic lymphoma), MCL = 31%, Aggressive 27% (27 diffuse large B-cell including 12 with transformed disease, 2 Burkitt’s). Dose limiting critical normal organs receiving up to 25Gy included lung (71), liver (29), kidney (6), and heart (1) from a median administered I-131 activity of 557 mCi (range 231–1353) resulting in a median whole body dose of 4.4Gy. ASCT occurred an average of 14 days after the I-131-tositumomab infusion with a median of 5.9×106 CD34/kg (range 2–20×106 CD34/kg). An unsupported ANC>500/μL and platelets >20K/μL occurred at a median of day 12 and day 13, respectively. Bearman toxicity of grade III/IV was observed in 6 pts (5.6%) with 3 (3%) non-relapse deaths (all cardiopulmonary toxicity) by day 100. Pulmonary toxicity of ≥ grade 4 CTCAE occurred in 10 (9%) pts. Responses to therapy included: CR/CRu = 87 (81%), PR = 8 (7%), SD = 11 (10%), and PD = 1 (1%). Currently, 76 (71%) pts are alive with 59 (55%) progression-free. The estimated 5-year overall survival (OS), progression-free survival (PFS) and relapse were 72%, 56%, and 36%, respectively (figure, median follow up of 5.2 years). Five-year OS/PFS estimates for the 3 histological groups included indolent (81%/61%), aggressive (69%/51%), and MCL (57%/52%). MCL pts with relapsed/refractory disease had a 5-year OS/PFS of 55%/42%. Multivariable analysis only identified chemoresistant disease as associated with death (HR 3.07 (1.46–6.44, p=.003) and relapse or death (HR 2.12 (1.17–3.86, p=.01). Secondary AML/MDS occurred in 1 patient to-date. Conclusions:This largest prospective trial of myeloablative RIT demonstrates that I-131-tositumomab delivering 225Gy to critical organs along with high-dose VP-16 and CY prior to ASCT is feasible and effective with toxicities comparable to TBI-based regimens. These data provide the foundation for future approaches incorporating RIT into transplant conditioning regimens for lymphoma. [Display omitted] Disclosures:Gopal:GSK: Research Funding; Spectrum: Research Funding. Off Label Use: high-dose use of I-131-tositumomab. Rajendran:GSK: Research Funding. Pagel:GSK: Research Funding. Maloney:GSK: Research Funding. Press:GSK: Research Funding.

Consolidation with High Dose Therapy and Autologous Stem Cell Transplant Improves Survival for Patients with Mantle Cell Lymphoma

Abstract 2006 Background:Mantle cell lymphoma (MCL) comprises 5–7% of all non-Hodgkin lymphomaand remains incurable with conventional chemotherapeutic approaches. Some clinical series and trials suggest that outcomes are improved with intensive induction containing cytarabine (Ara-C) and/or the use of high dose therapy (HDT) and autologous stem-cell transplantation (ASCT) once patients (pts) achieve remission. What is not apparent are the contributions of each and which prognostic factors influence outcomes. We examined our single center experience with initial management strategies for pts diagnosed with MCL between 1995 and 2011 and compared outcomes of CHOP±R (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone), an intensive induction regimen HCVAD±R (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate/cytarabine) in patients who subsequently underwent observation or HDT/ASCT. Methods:To examine the effectiveness of CHOP±R, HCVAD±R and HDT/ASCT, and the contributions of each to overall survival (OS), we conducted an IRB-approved retrospective review of consecutive cases of MCL identified from our database. Responsesfollowing the first management strategy were retrospectively assessed using International Working Group Criteria (JCO 1999). Descriptive statistics for the baseline characteristics of pts who received CHOP±R and HCVAD±R were compared using Chi-square tests. Kaplan–Meier estimation was used to evaluate OS and the treatment regimens were compared with the log-rank test. Toevaluate prognostic factors and the effects of treatment on OS, Cox proportional hazards models were used controlling for sex, race, stage, presence of B-symptoms, MIPI score, and those who underwent consolidation with HDT/ASCT. Results:103 ptswere identified with a median age of 58 (range 32–79 years), 27% were ≥65 years of age, 80% were male, 77% were white, 96% had an ECOG PS ≤1, 93% were advanced stage (III/IV), and the majority had a low risk MIPI score (53%). 43% (N=44) received CHOP±R (mean # of cycles 5.3, median 6, range 1–8) and the remaining 57% received HCVAD±R (N=59, mean # of cycles 4.5, median 4, range 1–12). 65% of HCVAD pts and 27% of CHOP pts received R. No significant differenceswere observed in the baseline characteristics of the two groups: age (59 years CHOP±R vs. 57 HCVAD±R, p=0.06), presence of B symptoms (32% vs. 31%, p=0.77), stage (III/IV, 91% vs. 95%, p=0.69), or MIPI score (low 50% vs. 56%, p=0.97). Of the pts who were consolidated with a transplant (N=47), median age was 58, 85% were male, 32% had B-symptoms, all had an ECOG PS ≤1, 26% had an LDH>ULN, 51% had a low MIPI, and 81% received HCVAD±R as induction. In comparison to those observed, the only significant differences were ECOG PS (8% ≥2, p=0.05) and induction regimen (63% CHOP±R, p<0.001). There were no significant differences in 5-year OS for CHOP±R: 64% (95% CI 44–79%) and HCVAD±R:68% (52–80%). There was a significant difference in 5-year OS for patients who underwent HDT/ASCT vs. those who did not consolidate with transplant (74% vs. 59%, p=0.03). 5-year OS for those treated with HCVAD±R + HDT/ASCT was not significantly different from the rest of the pts74% vs. 61% (p=0.19). After controlling for clinical confounders including sex, race, stage, presence of B-symptoms, consolidation with HDT/ASCT was associated with superior OS (HR 0.46 95% CI 0.22–0.93) while having a high MIPI score was associated with inferior OS (HR 3.79, 95% 1.59–9.01). Conclusions:Our single institution experience for untreated MCL pts demonstrates favorable 5-year OS independent of induction chemotherapy. Patients who underwent consolidation with HDT/ASCT had superior OS compared to those who did not. Disclosures:Flowers:Genentech/Roche (unpaid): Consultancy; Millennium (unpaid): Consultancy; Celgene: Consultancy; Celgene: Research Funding; Spectrum: Research Funding; Millennium: Research Funding; Gilead: Research Funding; Janssen: Research Funding.

The Pre-Transplant Mantle Cell Lymphoma International Prognostic Index Predicts Overall and Progression-Free Survival Following High-Dose Therapy and Autologus Stem Cell Transplant for Mantle Cell Lymphoma

Abstract 2026 Background:High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) is frequently employed to improve outcomes in patients with mantle cell lymphoma (MCL), yet results after transplant vary widely. We and others have shown that the Mantle Cell International Prognostic Index (MIPI) measured at diagnosis can predict overall survival (OS) after HDT and ASCT (Geisler, Blood 2010; Budde JCO 2011). Unfortunately, this approach is often limited at the time of transplant by the lack of available MIPI data from the time of diagnosis. Furthermore, the MIPI at diagnosis does not take into account other disease-related data that may be present at transplant. We hypothesized that the MIPI measured immediately before initiation of HDT could be attainable and predictive of outcomes after ASCT and explored the contribution of this measure along with other clinical factors to OS and progression-free survival (PFS). Methods:Records of consecutive MCL patients undergoing HDT and ASCT at our centers were reviewed under an IRB approved minimal risk protocol. Patients undergoing planned tandem autologus-allogenic transplants were excluded. MIPI elements, simplified MIPI score, and other clinical data were collected from the period immediately prior to initiation of conditioning and evaluated for their independent association with OS and PFS. Results:Between November 1995 and May 2011 190 MCL pts meeting the above criteria underwent HDT and ASCT at our centers, of these 186 (98%) had all available pretransplant MIPI data and were included in the analysis. Pretransplant MIPI scores of 0–1, 2, 3, 4, and 5–7 were seen in 27 (15%), 61 (33%), 60 (32%), 21 (11%), and 17 (9%) patients, respectively. Other baseline pretransplant characteristics included: median age 57 years (range 35–71years), elevated LDH = 48 (26%), median WBC = 4.51/μL (range 0.7 –42.43/μL), performance score 0 = 103 (55%), median prior regimens = 2 (range 1–9), blastoid variant = 16 (8%), leukemic variant = 6 (3%), chemosensitive disease = 157 (86%), and administration of rituximab (R) within 3 months prior to transplant = 139 (75%). The 8-year estimates of OS and PFS for the entire cohort were 43% (95% CI 27 – 57%) and 31% (95% CI 16 – 48%), respectively with 3 years median follow up for survivors. The pretransplant MIPI was highly associated with OS when modeled as a continuous (p=0.008) or categorical variable (p=0.002). Survival at 2 years was 88% (95% CI 78 – 93%) for MIPI 0–2, 73% (61 – 82%) for MIPI 3 or 4, and 65% (34 – 84%) for MIPI 5 or greater (Figure). Of the MIPI elements, age (hazard ratio [HR] for death 1.5 for every 10 yrs, p=0.03) and performance score (HR 1.6 for score >1, p=0.08) had the greatest independent impact on OS. In addition, chemosensitive disease (HR 0.3, p<0.001), number of prior regimens (p<0.001), and R within 3 months prior to transplant (HR 0.6, p=0.05) were all independently associated with OS after adjusting for the pretransplant MIPI.The pretranplant MIPI score was also predictive of PFS, but less so than with OS (global and categorical p=0.02) with age providing the greatest independent association (HR for death or progression 1.3 for every 10 years, p=0.08). Again, non-MIPI factors including number of prior regimens (p<0.001), blastoid variant (HR=2.1, p=.05), chemosensitive disease (HR 0.3, p<0.001), and R within 3 months prior to transplant (HR=0.4, p=0.001) independently added to predictive ability of the MIPI for PFS. Conclusions:Our data suggest that the simplified MIPI score measured immediately prior to HDT and ASCT is a readily available and robust predictive tool for OS and PFS in MCL pts undergoing transplant. This score along with other clinical factors can be utilized to counsel patients and to compare results between various treatment options. The independent association of pretransplant R with improved outcomes supports its use in this setting. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

12-Year Experience with High-Dose Rituximab-Containing Autologous Stem Cell Transplantation for SOX11-Positive Mantle Cell Lymphoma Patients in First Remission: Emerging Lymphoma-Free Survival Plateau After 3 Years,

Abstract 4138 Background:The addition of high-dose rituximab to conditioning regimens has been shown to improve outcomes of autologous stem cell transplantation (ASCT) for mantle cell lymphoma (MCL) patients (pts) in first partial (PR) or complete remission (CR)(Tam C et al. Blood 2009,113:4144). It has been suggested that absence of SOX11 expression can identify a subtype of indolent MCL with excellent outcomes that might be managed more conservatively than conventional MCL. We now report updated results of ASCT for 40 MCL pts treated at our center between 05/99 and 10/10. We also report on SOX-11 expression in a subset of these pts. Methods and Patients:Pts had a median age of 54 years (range, 38–72), and 30% were older than 60 years. At diagnosis, 60% had IPI>1, 30% had intermediate/high MIPI, 88% had stage IV disease, and 78% had bone marrow involvement. 28% had blastic features and Ki-67 was ≥30% in 11/23 (52%) pts who were tested. Pts were treated with R-CHOP or R-hyper-CVAD × 4 cycles induction in 30% and 45% respectively (Group A). Since 2001, pts were referred to ASCT only if they failed to achieve CR with >4 cycles of R-hyper-CVAD induction (n= 10, 25%) (Group B). Prior to transplant, CR (or CR unconfirmed-CRu) was present in 62% pts; 38% were in PR, and 18% were PET+. Conditioning was R-BEAM and R-Cy-TBI conditioning in 77% and 23% respectively. Pts received R during stem cell collection with R administered at 375 mg/m2 on the day before initiating chemotherapy for stem cell mobilization, and again at 1000 mg/m2, 7 days later. Pts then received additional R at 1000 mg/m2 on days +1 and +8 after ASCT, as previously described. Pts were staged with CT, PET (whenever indicated) scans, bone marrow biopsy, and colonoscopy (if history of GI involvement) every 3 months for the first year, every 6 months for 5 years, then yearly thereafter. Results: a.SOX11: Formalin-fixed, paraffin-embedded tissue biopsy sections were assessed by immunohistochemistry (IHC) using anti-Sox-11 rabbit polyclonal antibody (Abcam, Cambridge, MA; 1:1500). For IHC controls we used a tissue microarray including 13 cases of MCL in addition to one complete section of MCL serving as positive controls, and sections from two cases of small lymphocytic lymphoma involving lymph node serving as negative controls. The 11 cases consisted of five GI biopsies, three lymph node biopsies, two bone marrows and one testis. 10/11 showed positive staining for SOX11. The case with negative staining, a GI biopsy, had scattered positive cells. b.Clinical outcome : Following transplantation, CR/CRu was achieved in 100% pts. With a median follow-up of 37 months (range, 6–145), 10 pts experienced recurrent disease. All progressions occurred within 3 years, with a clear plateau emerging subsequently (Figure). The projected lymphoma-free-survival at 10-year, was 65% (95%CI, 44–80). A tendency for a higher risk of relapse was observed in R-hyper-CVAD resistant pts (Group B) pts [4/10 pts (40%) vs 6/30 (20%) in Group A; HR 2.5 (95%CI, 0.7–9.2), p=0.2)], and in pts with ki-67 ≥30% [HR 2.2 (95%CI, 0.4–11), p=0.3). MIPI, blastic histology, age (> 60 years), disease status at transplant (CR/PR) and conditioning were not found to be of prognostic value in our study. 2 pts (5%) developed myelodysplasia, one of which was concurrent with progression. [Display omitted] Conclusions:ASCT with high-dose rituximab has the potential to cure a proportion of pts with MCL after response to induction chemotherapy. Our results are favorable despite the inclusion of pts who were resistant to R-hyper-CVAD. Randomized studies comparing this strategy to conventional chemo-immunotherapy are warranted. The prognostic significance of Ki-67 level needs to be assessed in a larger cohort of patients. Disclosures:No relevant conflicts of interest to declare.

Efficacy and safety of bendamustine (BDM) in patients (pts) with mantle cell lymphoma (MCL).

e18562 Background: BDM is approved in the United States for relapsed indolent lymphoma. However, the prospective study establishing the BDM monotherapy indication did not include any MCL pts (Friedberg, JCO 2008). Another study of rituximab plus BDM for relapsed indolent lymphomas included only 12 MCL pts (Robinson, JCO 2008). Herein we report our experience with BDM specifically in MCL pts. Methods: We retrospectively reviewed the records of all MCL pts who were treated with BDM at 3 centers. Demographic, clinical, toxicity, response and survival data were collected. The primary endpoint was overall response rate (ORR) and secondary endpoints were overall survival (OS), event-free survival (EFS) and safety. Results: Between 11/2008 and 12/2010, 21 MCL pts received BDM, 4 as frontline treatment and 16 for relapsed disease. The median age was 57 years (range 42-86) and 95% had stage IV disease. The most common regimen was rituximab 375mg/m2 on day 1 and BDM 100mg/m2 on days 1 and 2, every 28 days. A median of 5 cycles were given per patient (range 1-6). There were 10 complete responses (CR) and 6 partial responses (PR) with an ORR of 76% (95%CI 58-94%). After a median follow-up of 5.7 months (range 0.3 – 24 months), the median EFS and OS were not reached. The Kaplan-Meier estimated 2-year EFS and OS was 63% (95%CI 48-77%) and 72% (95%CI 60-85%) respectively. Grade 3 or 4 neutropenia, anemia, thrombocytopenia and neutropenic fever occurred in 29%, 5%, 24% and 10% respectively. Severe non-hematological toxicities included one case of herpes zoster during therapy and one case of progressive multifocal leukoencephalopathy (PML) occurring 10 months after completion of therapy. Conclusions: BDM in combination with rituximab had a high response rate, with 48% CR’s, in this study of predominantly relapsed/refractory MCL pts. The hematological toxicities were expected and manageable. There was one case of PML, which has not previously been described with BDM, but this patient was also treated with rituximab which is associated with PML. BDM appears to be a good salvage agent for MCL.

Final 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.

AbstractAbstract 2791 Introduction:Elderly mantle cell lymphoma (MCL) patients (pts) do not benefit from dose-intensive chemotherapy upfront.1 The GOELAMS group recently demonstrated that a regimen comprising Vincristine/Adriamycine/Dexamethasone plus Chlorambucil (VAD+C) was well tolerated, had a good efficacy/toxicity profile and induced similar PFS than R-CHOP (median PFS between 16 to 18 months2,3,4). Additionally, it has been shown that bortezomib (Velcade®), with or without Rituximab has efficacy in relapsed/refractory MCL patients5,6. These data prompted, our group to conducte a phase II prospective non randomized clinical trial evaluating the combination of Velcade plus Rituximab/Adriblastine/Dexamethasone/Chlorambucil (RiPAD+C) as a first line therapy for elderly MCL patients. Aims:To evaluate the overall response rate (ORR) and toxicity after 4 cycles of RiPAD+C regimen (main objective) and to evaluate prognostic factors for survival (secondary objective). Protocol:RiPAD+C : Rituximab 375 mg/m2 on d1 (and d8 for cycle 1); PS 341, Velcade® 1.3 mg/m2 on d1, 4, 8 and 11; Adriblastine 9mg/m2/d as a continuous infusion for 4 days; Dexamethasone 20 mgx2/d from d1 to d4; Chlorambucil 12 mg/d, d20 to d29. Repeat cycles every 35d. After 4 cycles, responding pts (Cheson 1999 criteria) received 2 additional cycles for a maximum of 6. Patients and methods:Inclusion criteria: All untreated elderly (65 to 80 years old) MCL patients (including blastoid forms) presenting with a stage II to IV disease with a good PS (ECOG<3) were eligible. Histologic samples were centrally reviewed and Ki67 expression was evaluated for each sample according to the European guidelines7. Results:Population: from June 2007 to December 2009, 39 pts were enrolled in the study with a majority of males (n=30). Median age at diagnosis was 72 years [65-80]. All patients had stage III/IV disease and PS was ≥2 in 5 cases (15%). Elevated serum LDH were observed in 47% of cases. According to the MIPI, 28 patients (80%) had an intermediate or high score. Eleven (30%) patients presented with a blastoid variant and Ki67 staining was superior to 30% in 12 cases (37%). Toxicity: A total of 195 courses have been performed. Fourteen hospitalization (median duration = 7 days [1 and 55]) due to toxicity were necessary involving 12 pts (34%). Seven pts (18%) experienced grade 3 peripheral neuropathy. ten (25%) pts required blood transfusions for a total of 8 red blood cells and 14 platelets transfusions. Response after 4 cycles: ORR was 80% (n=31) including 51% of CRs. Eight pts discontinued the treatment before reaching cycle 4, two of them for toxicity reasons. Six patients (15%) were refractory or in progression. Response after 6 cycles (n=25; 64%): ORR was 74% including 20 pts in CRs (59%). Survival: With a median follow-up of 24 months, 27 pts are still alive. Two pts died of toxicity (severe sepsis) and 10 pts progressed. The median PFS is 26 months and the median OS has not been reached yet. According to the MIPI score, no differences in PFS were between pts with low and int/high scores. Conversely, the recently described Goelams index2 stratified pts with a low score (normal LDH, Ki67≤26%, PS≤1, and no B symptoms) from patients with an int/high score (p=.055). Conclusion:The results of the current phase II trial indicate that the RiPAD+C regimen, integrating bortezomib, is feasible and well tolerated as a first line therapy in elderly MCL pts. Historical comparisons suggest that this regimen compares favourably to the classical R-CHOP regimen in terms of response rates and duration. Bibliography:1 Romaguera JE et al, JCO 2005; 2 Gressin R et al., Haematological 2010; 3 Howard OM et al., JCO 2002; 4 Lenz G et al., Blood 2005; 5 Fisher RI et al., JCO 2006; 6 Goy A et al., JCO 2009; 7 Klapper W et al., Haematopathol 2009. Disclosures:Off Label Use: velcade is of label in France for the treatment of mantle cell lymphoma.

Use of radioimmunotherapy for consolidation for chemosensitive mantle cell lymphoma (MCL): Summary of International Radioimmunotherapy Registry data.

e18519 Background: Mantle cell lymphoma (MCL) is a rare subtype (3-9%) of non-Hodgkin lymphoma (NHL) with a relatively poor prognosis (5-year survival < 40%). Consolidation with autologous stem cell transplantation (ASCT) but only less than one-fourth of the patients may be subjected to this intensive treatment due to advanced age and co- morbidities. Standard-dose non-myeloablative radioimmunotherapy (RIT) was proved to be an efficient approach for treatment of certain NHL, however, there are almost no data available on the efficacy and safety of RIT in MCL. Methods: In the RIT-Network, a web-based international registry collecting real observational data from RIT-treated patients, 115 MCL patients treated with ibritumomab tiuxetan were recorded. Most of the patients were elderly males with advanced stage of the disease: median age – 61 (range 31-78); males – 70.4%, stage III/IV – 91%. RIT was a part of the first line therapy in 53 pts. (46%). Further 27 pts. (24%) received ibritumomab tiuxetan after two previous chemotherapy regimens, and 35 pts. (30%) after completing 3-6 lines. In 75 cases RIT was applied as a consolidation of chemotherapy induced response. Results: After RIT the patients achieved high response rate: CR 64.2%, PR 22.1%, and SD 2,1%. Only 11,5% of the patients progressed. The projected 3-year overall survival after radioimmunotherapy was 72% (41% for progression free survival). In 75 patients RIT was a consolidation of chemosensitive patients (49 pts – after the first and 26 after previous 2-6 lines of chemotherapy). The 3 year OS is 79 and 60% respectively. RIT was feasible for almost all patients; only 3 procedure-related deaths were reported in the whole group. The main adverse event was hematological toxicity (grade III/ IV cytopenias) showing a median time of recovery of Hb, WBC and Plt of 65, 52 and 60 days respectively. Conclusions: Standard-dose non-myeloablative RIT is a feasible and safe treatment modality, even for elderly MCL pts. Consolidation radioimmunotherapy with ibritumomab tiuxetan may pro-long survival of patients who achieved clinical response after chemotherapy. No significant financial relationships to disclose.

Validation of the Mantle Cell Lymphoma Prognostic Index (MIPI): A Valuable Tool for Risk Stratification in Mantle Cell Lymphoma.

Abstract 2703Poster Board II-679 Introduction:Mantle cell lymphoma (MCL) is an incurable disease with a highly variable course. Improvements in therapy have been impeded by the lack of a universal prognostic model, making risk stratification and comparisons across clinical trials difficult. The International Prognostic Index (IPI) and Follicular Lymphoma International Prognostic Index (FLIPI) have been applied but show limitations in MCL, especially in distinguishing low and intermediate-risk patients (pts).The MIPI (Mantle Cell International Prognostic Index) was developed to overcome these limitations, and is based on WBC, age, and LDH (analyzed as continuous variables) and ECOG performance status.1 However, the MIPI has yet to be independently validated, and failed to predict outcome of MCL pts treated with Hyper-CVAD.2 To examine the prognostic capacity of the MIPI, we reviewed outcomes of pts diagnosed with MCL from 1998–2008 at the Cleveland Clinic Taussig Cancer Institute (CCTCI). Methods:Cases of MCL diagnosed at CCTCI were identified from our pathology database, yielding 85 unique pts. These subjects were retrospectively analyzed with approval of our Institutional Review Board. A total of 48 pts with advanced stage disease who underwent immediate treatment (within 90 days of diagnosis), and for whom adequate data for assignment of both MIPI and IPI existed, were the subject of review. Survival was identified from medical records and confirmed using a public social security database. Outcomes were compared using log-rank analysis of Kaplan-Meier survival analyses, and MIPI was calculated in accordance with the initial publication.1 Results:Pt characteristics at diagnosis were: median age 62 (range 39–85), 73% male, 75% ECOG performance status of 0-1, 96% stage IV disease, 52% elevated LDH, and 40% had extranodal involvement other than bone marrow (23% with GI involvement). Six pts had the blastoid variant of MCL. IPI scores at diagnosis were as follows: low (17%)/ low-intermediate (31%)/ high-int (25%)/ high (27%). MIPI scores at diagnosis were: low (33%) / int (25%)/ high(42%).Initial treatment included an anthracycline in 71% and rituximab in 60%. HyperCVAD was given 33%, and 23% underwent upfront (CR1/PR1) autologous transplantation.Median follow-up of survivors is 5.7 years. Median OS and RFS for all pts is 3.9 and 2.5 years, respectively. The IPI distinguished low and high-risk groups, but low-int and high-int groups were closely approximated (Figure 1). On the other hand, the MIPI distinguished 3 separate groups (Figure 2), including a high risk group with a 5-year survival of 11%. The MIPI maintained its prognostic capacity even in HyperCVAD-treated pts (log rank p=.01 for low/int/high MIPI among 16 pts, figure not shown.) The use of regimens including rituximab was not associated with improved OS (log rank p=0.21, comparing rituximab at any time vs none, figure not shown). [Display omitted] [Display omitted] Conclusions:Based on long-term follow-up of 48 pts diagnosed with MCL at CCTCI from 1998–2008, we verified the accuracy and ease of application of the MIPI for determining prognosis in MCL. On further analysis, rituximab did not impact OS of MCL pts. Clinical trials in MCL should employ the MIPI as a risk-stratification tool, and novel approaches are urgently needed for pts in the high-risk group. Disclosures:No relevant conflicts of interest to declare.

Overall Survival (OS) Benefit of Rituximab Based Immunochemotherapy Followed by Post-Induction Treatment in Mantle Cell Lymphoma (MCL): a Retrospective Analysis of 279 Patients Treated by Polish Lymphoma Research Group (PLRG) Centers.

Abstract 1702Poster Board I-728 BackgroundASCT consolidation in the first remission is the treatment of choice in MCL patients. However lack of adequate response to the first line therapy, elderly age and co-existing co-morbidities makes it feasible for less than a third of patients. MethodsRetrospective analysis of 279 MCL cases treated at 10 PLRG centers was performed: 52% of them (144 pts) received Rituximab in induction therapy; 35% (97 pts) were subjected to post-induction therapy (ASTC – 16%, radioimmunotherapy consolidation – 13% and Rituximab maintenance – 6%). There were no significant differences in risk factor distribution among analyzed subgroups. Results1) At 5 years OS was 40% in the whole group: 77% for those subjected to post-induction therapy vs 25% for those who were not; 5 year PFS is 20%, 48% and 5% respectively (p<0,0001, in both comparisons).2) Pts with initial good response, whose treatment was NOT continued after induction, had inferior results (5 year OS and PFS – 30 and 10 % respectively) to those subjected to post-induction therapy (p<0,0001).3) Rituximab included in the first line regimens increased RR, increasing % of pts that could be subjected to post-induction therapy: progression/ death during the first line therapy were 5,5% (8/144 Rituximab treated pts) as compared to 15,5% (21/135 treated without Rituximab). ConclusionsWith all limitations of retrospective analysis, it strongly supports the necessity of Rituximab immunochemotherapy followed by post induction treatment in MCL pts. The role of ASCT is established in younger patients, radioimmunotherapy consolidation or Rituximab maintenance should be considered in elderly and unfit ones. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.