ALBERT

Description: Recent microarray gene expression profiling studies have identified gene signatures predictive of outcome, so-called “indicator” genes, for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, measurement of these genes in routine practice remains difficult. We applied real-time polymerase chain reaction (PCR) to polyA cDNAs prepared from 106 archived human frozen lymph nodes (63 of FL, 25 of DLBCL, 10 reactive lymph nodes, and cases with paired samples of FL [4] and subsequent DLBCL [4]). Reverse transcription and polyA reverse transcriptase (RT)–PCR was performed, and resultant cDNA was probed by real-time PCR for 36 candidate indicator genes, selected from microarray studies. Nine genes showed statistically significant different expression between FL and DLBCL, including cyclin B, COL3A1, NPM3, H731, PRKCB1, OVGL, ZFPC150, HLA-DQ-a, and XPB. Of these, cyclin B, NPM3, and COL3A1 were higher in DLBCL. Six genes showed statistically significant higher expression in the neoplastic nodes compared with reactive nodes, namely PRKCB1, BCL-6, EAR2, ZFX, cyclin B, YY1. High levels of YY.1 were associated with a shorter survival interval in both FL and DLBCL. The method is simple, sensitive, and robust, facilitating routine use and may be used as a platform for clinical measurement of prognostic gene signatures.

Description: This prospective study aimed to develop reproducible diagnostic criteria for sporadic Burkitt lymphoma (BL), applicable to routine practice, and to evaluate the efficacy of dose-modified (dm) CODOX-M/IVAC in patients diagnosed using these criteria. The study was open to patients with an aggressive B-cell lymphoma with an MKI67 fraction approaching 100%. Immunophenotype and fluorescent in situ hybridization (FISH) were used to separate BL from other aggressive B-cell lymphomas. BL was characterized by the presence of a cMYC rearrangement as a sole cytogenetic abnormality occurring in patients with a germinal center phenotype with absence of BCL-2 expression and abnormal TP53 expression. A total of 128 patients were eligible for the study, of whom 58 were considered to have BL and 70 to have diffuse large B-cell lymphoma (DLBCL). There were 110 clinically fit patients who received dmCODOX-M (methotrexate, dose 3 g/m2) with or without IVAC according to risk group. The 2-year progression-free survival was 64% (95% confidence interval [CI] 51%-77%) for BL, 55% (95% CI 42%-66%) for DLBCL, 85% (95% CI 73%-97%) for low risk, and 49% (95% CI 38%-60%) for high-risk patients. The observed differences in outcome and other clinical features validate the proposed diagnostic criteria. Compared with the previous trial LY06 with full-dose methotrexate (6.7 g/m2), there was a reduction in toxicity with comparable outcomes. This study was registered at www.clinicaltrials.gov as NCT00040690.

Description: Abstract 3955 Background: Patients (pts) with relapsed diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) or relapsing after ASCT have a poor prognosis and limited therapeutic options. New treatment options are needed for these pts. Ofatumumab is a human monoclonal antibody that targets a membrane-proximal epitope comprising both the large loop and small loop of CD20, and has shown effective lysis of chemotherapy-refractory DLBCL cells in vitro (Teeling et al. Blood 2004; Cillessen et al. Blood 2007; abstract 2346). We report the first results from an open-label, single-arm, international Phase II trial that evaluated ofatumumab monotherapy in relapsed or progressive DLBCL. Methods: Pts (age ≥18 years) with relapsed or progressive CD20+ DLBCL ineligible for ASCT or with relapsed or progressive disease after ASCT were enrolled between December 2007 and August 2009 (N=81). Relapsed or progressive disease was defined as relapse after a complete remission (CR) or disease progression after partial remission (PR). Pts received 8 weekly infusions of ofatumumab (dose 1, 300 mg; doses 2–8, 1000 mg). The primary endpoint was overall response rate (ORR) evaluated during the 6 months from the start of treatment, as assessed by an Independent Endpoint Review Committee according to the revised response criteria (Cheson et al. J Clin Oncol 2007). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety. Results: Baseline characteristics are shown in the Table. Pts were heavily pretreated (median 3 prior systemic therapies), and 32% of pts did not respond to their last prior therapy. Nearly all pts (96%) had received prior rituximab-containing treatment; 54% had received 2 or more courses of prior rituximab therapy (Table). Overall, 58% of pts completed all 8 infusions of ofatumumab, 65% received at least 6 infusions, and 81% received at least 4 infusions. The primary reason for treatment discontinuation was disease progression. The ORR (95% CI) was 11% (4–18%), including 3 CRs (4%) and 6 PRs (7%). Of these 9 responding pts, 8 had responded to their last systemic therapy. The median duration of response (95% CI) was 6.9 months (5.3–6.9) and median PFS (95% CI) was 2.5 months (2.3–2.9). Infusion-related events occurred in 59% of pts, primarily occurred during infusion 1 (40% of pts) and infusion 2 (22%), and subsided during subsequent infusions; these events were predominantly grade 1–2 in severity (96% of pts). The most common (〉10% of pts) adverse events (AEs; any grade) were diarrhea (17%), fatigue (15%), peripheral edema (15%), neutropenia (14%), abdominal pain (12%), constipation (12%), nausea (12%), pyrexia (11%), anemia (11%) and leukopenia (11%). Of these, ≥ grade 3 events included neutropenia (10%), leukopenia (6%), anemia (5%) and fatigue (1%). Grade 3 or greater thrombocytopenia and febrile neutropenia were reported in 6% and 4% of pts, respectively. The most common infectious events were upper respiratory tract infections (7% of pts), all of which were grade 1–2 events. In total, 13 pts died during the study; 3 pts died during the treatment period and 10 pts died during post-treatment follow up (until 24 months from study start). Deaths were due to disease progression (n=10), sepsis (n=1), circulatory collapse (no further details; n=1) and multi-organ failure (n=1). Conclusions: Single-agent ofatumumab was well tolerated with an ORR of 11% in heavily pretreated pts with relapsed or progressive DLBCL, nearly all of whom had received prior rituximab therapy. Response to last systemic treatment appeared to influence response to ofatumumab in this pt population. Further studies of ofatumumab in combination with chemotherapy in relapsed DLBCL are currently underway. Disclosures: Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Davies:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Padmanabhan:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:GlaxoSmithKline: Employment. Lin:GlaxoSmithKline: Consultancy, Employment. Davis:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Losic:Genmab A/S: Employment, Equity Ownership. Lisby:Genmab A/S: Employment. Radford:GlaxoSmithKline: Equity Ownership; Genmab: Consultancy, Honoraria.

Description: Introduction: The discovery of 3 distinct molecular subgroups of diffuse large B-cell lymphoma (DLBCL) according to cell-of-origin (COO): germinal centre B-cell (GCB), activated B-cell (ABC) and type III/unclassifiable by gene expression profiling (GEP) (Alizadeh et al, Nature 2000; Rosenwald et al, NEJM 2002) was a key advance in understanding the disease biology. The ABC subtype is associated with inferior survival which has persisted in the rituximab era (Lenz et al, NEJM 2008). Determination of COO by GEP has not been incorporated into routine practice however due to a lack of accessibility and requirement for fresh frozen tissue. Barrans et al (BJH 2012) recently demonstrated that COO could be accurately classified by the Illumina DASL® platform, using RNA extracted from routinely processed FFPE tissue from a population-based cohort of 172 R-CHOP-treated patients, and predicted clinical outcome. The aim of this analysis was to determine GEP-based DLBCL COO using the Illumina DASL® platform, to correlate results with outcome, and to validate this methodology using FFPE tissue samples from patients enrolled in the prospective phase III R-CHOP 14 v 21 trial. Methods: The UK NCRI R-CHOP-14 v 21 trial assessed R-CHOP given 2-weekly versus 3-weekly in 1080 previously untreated DLBCL patients aged ≥18 years and enrolled from 2005-2008. We previously reported that R-CHOP-14 was not superior to R-CHOP-21 for overall survival (OS), progression-free survival (PFS), response rate or safety. COO as determined by the Hans classifier (n=560) was not prognostic for OS (Cunningham et al, Lancet 2013). All patients with sufficient FFPE material remaining were included in this analysis. RNA was extracted and GEP was performed using the Illumina DASL® platform. Cases were classified as ABC, GCB or type III according to the DAC classifier (Care et al, Plos One 2013). Response was assessed using IWG 1999 criteria. PFS and OS were calculated from date of randomisation and analysed using Kaplan-Meier and Cox regression methods. Results: 369 patients had sufficient FFPE material remaining for analysis. COO classification was as follows: ABC 15.2% (n=56), GCB 46.3% (n=171), type III 38.5% (n=142). Baseline characteristics are shown in Table 1. Patients with GCB subtype had a significantly higher incidence of BCL-2 (p1 extranodal site of disease, elevated LDH), sex, bulky disease, B symptoms and trial arm; patients classified as GCB or type III had superior OS versus ABC subtype (HR 0.53, 95% CI: 0.31-0.89; p=0.02) and (HR 0.56, 95% CI: 0.33-0.96; p=0.03) respectively. GCB subtype was also independently associated with superior PFS versus ABC subtype (HR=0.59, 95% CI: 0.37-0.96; p=0.03). The difference in PFS between type III and ABC subtypes did not reach statistical significance, but followed a similar trend (HR=0.65, 95% CI: 0.40-1.07; p=0.09). Results of univariate and multivariate analyses of individual factors and OS are shown in Table 2. Conclusion: Our results demonstrate that the ABC subtype of DLBCL as determined by GEP is independently associated with inferior PFS and OS. Our findings confirm those of Barrans et al (BJH 2012) and serve as a validation cohort for this methodology in the setting of a prospective trial where patients were exclusively R-CHOP-treated. Of note our patient cohort included a high proportion of type III/unclassifiable patients (38.5%) which are being further investigated currently and updated results will be presented at the meeting. Our analysis confirms that GEP-based COO is a significant prognostic biomarker for DLBCL in the rituximab era which can be accurately determined using routinely processed FFPE tissue samples. Table 1 Baseline characteristics Table 1. Baseline characteristics Figure 1. Overall survival by cell-of-origin determined by gene expression profiling group Figure 1. Overall survival by cell-of-origin determined by gene expression profiling group Table 2 Overall survival: univariate and multivariate analyses Table 2. Overall survival: univariate and multivariate analyses Disclosures Cunningham: Medimmune: Research Funding; Merrimack: Research Funding; Celgene: Research Funding; Bayer: Research Funding; Astra-Zeneca: Research Funding; Amgen: Research Funding. Hawkes:Merck Serono: Research Funding; Takeda: Other: travel expenses; BMS: Other: travel expenses, Research Funding. Pocock:Gilead Sciences: Other: Sponsorship to attend the EHA 2016 Meeting; Janssen: Speakers Bureau; Takeda: Honoraria. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Radford:Astra Zeneca: Equity Ownership; GlaxoSmithKline: Equity Ownership; Novartis: Honoraria; Seattle Genetics: Honoraria; Takeda: Honoraria, Research Funding.

Description: Recent gene expression profiling has identified gene signatures predictive of outcome, Indicator genes, for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). However, measurement of Indicator genes in routine practice remains difficult. We have demonstrated utility of real-time PCR measurement of Indicator genes in globally amplified polyA cDNA as a practical method for their clinical analysis (Sakhinia et al 2005). PolyA PCR enables global mRNA amplification from picogram amounts of RNA and the polyA cDNA pool generated is indefinitely renewable, representing a “molecular block”. Real-time PCR measurement of the expression levels of specific Indicator genes then allows gene signatures to be detected in the polyA cDNA. In this project we applied real-time PCR for 36 Indicator genes, to polyA cDNAs prepared from 122 archived human frozen lymph nodes; specifically 63 cases of FL, 25 of DLBCL and 10 reactive lymph nodes were analysed; the remaining 24 cases were FL with either evidence of focal transformation, of subsequent transformation or (4 cases) paired frozen samples of FL and subsequent DLBCL. PolyA RT-PCR was performed on extracted RNA and resultant cDNA probed for 36 candidate Indicator genes (selected from Husson et al 2002, Shipp et al 2002 and Rosenwald et al 2003), by real-time PCR with quantification against human DNA, and normalisation to the mean of four housekeeping genes. Statistical analysis was performed using the Mann Whitney test and Kruskal-wallis with a p≤ 0.05 for statistical significance; all results detailed below are significant to at least p≤ 0.05. Ten genes showed statistically significant different expression between FL and DLBCL, including Cyclin B, COL3A1, NPM3, H731, PKC.B1, OVGL, ZFPC150, HLA-DQ-a, and XPB. Of these, cyclin b, a cell cycle gene, NPM3, nucleolar phosphoprotein, and COL3A1were higher in DLBCL. Six genes showed statistically significant higher expression in the neoplastic nodes compared to reactive nodes, namely PKCB-1, BCL-6, EAR2, ZFX, Cyclin B, YY.1. Comparison of gene expression levels in cases of FL that either did not or did subsequently transform to DLBCL demonstrated significant upregulation of ACTA, HLA-DQ-a in the latter cases of FL. High levels of YY.1 were associated with a shorter survival interval in both FL and DLBCL by Kaplan-meir survival analysis. This is of particular interest given the reported role of YY.1 in producing resistance to Rituximab due to downregulation of FAS -induced apoptosis (Vega et al, 2005). This was reported for a cell culture study and has not been shown in clinical studies, though the result in this project suggests a possible detrimental role for YY.1 clinically and that it may act as a predictor of Rituximab response. These results :demonstrate the possibility of using polyA PCR for global amplification of clinical samples and real-time PCR to measure diagnostically informative gene expression profiles in the resultant polyA cDNA “molecular block” andidentify novel prognostic markers for FL and DLBCL. The method is simple, sensitive and robust, and amy be used as a platform for clinical measuremen of prognostic gene signatures. Whilst lymphoma represents a relatively small group of cancer patients the generic nature of microarray gene profiles for cancer subtypes will facilitate simple extension of the method to other tumour types.

Description: Zanolimumab (previously referred to as HuMax-CD4) is a fully human monoclonal IgG1k antibody. It is specific for the CD4 antigen expressed on a subset of T cells and has been shown to possess cytotoxic and anti-proliferative effects. We report initial clinical efficacy and safety results following treatment with 980 mg of zanolimumab in 15 patients diagnosed with biopsy-proven, treatment-refractory or relapsed CD4+ systemic PTCL. The following PTCL subtypes were included : enteropathy-type T-cell lymphoma (n=1), anaplastic large T-cell lymphoma (ALCL, n=3, 2 alk-negative, 1 alk-status unknown), angioimmunoblastic T-cell lymphoma (AIL, n=8) and PTCL-unspecified (PTCLu, n=3). The primary endpoint of the study was objective tumor response. Responses were based on CT scan and clinical examination and classified according to the Cheson criteria. Out of 15 patients enrolled, 4 responses have been seen; 2 PR (one patient later achieved a CRu) and 2 CRu verified by CT scan. Further, clinical improvements (marked decrease in the size of peripheral lymph nodes) were recorded in 2 additional patients. So far, a total of 21 SAEs has been reported. Of these, 4 were considered related to the study treatment: febrile neutropenia (n=1), thrombocytopenia (n=1), infusion related reaction (n=1) and hyperthermia (38.8° C) with hypotension (n=1). Eight unrelated deaths have been reported so far, all secondary to disease progression. In conclusion, in this heavily pretreated patient population, zanolimumab demonstrated a good tolerability profile and the present results indicate efficacy in the treatment of CD4-positive PTCL.

Description: Radioimmunotherapy is effective in patients with relapsed/refractory and newly diagnosed follicular non-Hodgkin’s lymphoma (FL). This study investigated the efficacy and safety of Zevalin consolidation in patients with advanced stage FL responding to first-line chemotherapy. The concept tested was whether a single infusion of Zevalin would prolong progression free survival (PFS) in patients with (minimal) residual disease. Major inclusion criteria were: CD20-positive grade 1 or 2 FL; stage III or IV at diagnosis; normal peripheral blood cell counts;

Description: Background: Ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK), has demonstrated robust clinical activity in various B-cell malignancies, whose mechanism of action, beside BTK signaling inhibition in B-cells may also depend partially on immune modulation as it also an inhibitor of ITK (interleukin-2-inducible T-cell kinase), a key regulator of T-cell activity. Immune-modulatory cancer therapy, such as check-point inhibitors, may result in different response patterns than traditional cytotoxic therapy, eg, resembling "tumor flare." In a recent study of single-agent ibrutinib for treatment of refractory follicular lymphoma (FL), 7 patients (pts) had documented tumor responses after initial radiological progressive disease (PD), a phenomenon termed "pseudo-progression." We describe these cases that led to a study protocol amendment. Methods: The FLR2002 (DAWN) study was an open-label, multicenter, single-arm, phase 2 study of ibrutinib in pts with chemoimmunotherapy-refractory (ie, ≥ 2 prior lines of therapy & PD within 12 months after last dose of chemotherapy in a chemoimmunotherapy regimen) FL (NCT01779791). All pts received ibrutinib (560 mg QD) until PD or unacceptable toxicity. A protocol amendment was made to address the novel situation of delayed responses that were observed after PD to allow for continuation of ibrutinib in pts with radiological evidence of PD (any new lesion or increase by ≥ 50% of previously involved sites from nadir), but who were clinically stable/improving/exhibiting signs of tumor flare without documented PD by other methods. The primary end point was Independent Review Committee (IRC)-assessed overall response rate (ORR; complete response [CR] + partial response [PR]). T-cell subsets in peripheral blood were monitored by flow cytometry at various timepoints. Results: The sentinel case was a pt diagnosed with grade 1 FL in 2008 and subsequently treated with 3 lines of therapy including autologous stem cell transplant. At time of enrollment, pt had stage III disease, an ECOG score: 0 and FLIPI (Follicular Lymphoma International Prognostic Index) score: 1. At Week 12, the pt was assessed as having PD. Ibrutinib was discontinued, and no other anti-cancer treatment was instituted. However, PET & CT scans performed 4 months later showed CR. Thereafter, 2 other investigators reported similar phenomena, prompting the aforementioned protocol amendment. Investigator assessment of the pt in the sentinel case was confirmed by IRC and ibrutinib treatment was resumed. The pt remains on treatment in CR for 30 months at the time of this report. On the basis of the protocol amendment, approximately 30 pts were approved to continue ibrutinib treatment after radiographic PD. Of these, an additional 6 pts were identified (7 in total) with IRC-confirmed "pseudo-progression" (confirmed by imaging) at a median of 22.0 (range: 11.6-59.6) weeks after starting Ibrutinib. Three of these pts (2 CR, 1 PR) maintained their response for 〉 1 year and 2 continue to respond. Two pts (1 CR, 1 PR) maintained responses for 〉 8 months, but eventually progressed. One pt maintained a PR 〉 1 year, but discontinued ibrutinib therapy due to an adverse event (grade 3 diarrhea). Sufficient sample was available in 2 of these 7 pts and examination of the T-cell profiles showed a strong downregulation of regulatory Tcells (Tregs) at early timepoints after initiation of therapy in both, an effect that was significant also in other responders (CR+ PR, mean decrease 17 to 12.9% CD4, p=0.02) but not in non-responders (SD+PD, 11.5 to 10.4% CD4, ns). Conclusion: Experience from the DAWN study suggests that pts with relapsed or refractory FL treated with ibrutinib may experience initial pseudo-progression followed by robust and durable responses when continued on ibrutinib. This effect may be related to the immune-modulatory effects of ibrutinib as seen by the decrease in Tregs after start of therapy. Biomarker studies are continuing to further understand this phenomenon. Nevertheless, these and other observations have prompted a revision in response criteria that recognize specific response patterns such as these in pts treated with immune modulating agents. Therefore current and future clinical trials should consider the observed phenomenon and physicians should be aware of this pattern of response when utilizing immune-related or targeted therapies to avoid premature discontinuation of therapy. Disclosures Salles: Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria. Cheson:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuster:Pharmacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen Research & Development: 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. Radford:GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Schaffer:Janssen Research & Development: Employment. Damle:Janssen Research & Development: Employment. Gartenberg:Janssen Research & Development: Employment. Vermeulen:Janssen Research & Development: Employment. Balasubramanian:Janssen Research & Development: Employment. Deshpande:Janssen Research & Development: Employment.

Description: The success of monoclonal antibodies in the treatment of certain cancers demonstrates that immune based therapies can work and are particularly effective in B cell malignancies. However, tumours can still avoid antibody mediate mechanisms of attack and there is currently no estalbished method of effectively recruiting T cells to harness their potential anti-tumour effects. We are exploring gene therapy approaches to endow T cells with antibody type specificity in order to more efficiently target and lyse tumours and thereby improve the overall immune therapy of cancer T cells grafted with a CD19 specific receptor consisting of a CD19 scFv linked to human CD3zeta (CD19z) were tested for their potency against B cell lymphoma lines in vivo. T cells were engineered using retroviral vestors to possess a CD19 specific receptor which endows the T cells with specificity for B cell lymphoma. The vector incorporates a truncated hCD34 gene as a marker to facilitate assessment of transduced cells using as clinically applicable, non-immunogenic marker gene. Mice bearing B cell lymphoma were treated with a systemic infusion of targeted T cells with or without non-myeloablative chemotherapy. Human T cells targeting CD19 cured 40% of SCID/beige mice with 6 day established metastatic tumour but only in conjunction with a single dose of cyclophosphamide. Murine T cells expressing the CD19z receptor were also effective with cure of 24hr established s.c human CD19+ tumour in SCID/beige and immunocompetent mice. Pretreatment with cyclophosphamide did not affect T cell engraftment or efficacy in immuno-compromised animals but was necessary for T cell engraftment in immuno-competent animals. These results which parallel the approach successfully used with tumour infiltrating lymhocytes in melanoma patients conclusively demonstrate that the combination of engineered T cells with “pre-conditioning” chemotherapy significantly impacts upon tumour growth in vivo and this evidence supports the development of phase I clinical trials targeting B cell lymphoma.

Description: Background: Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have limited treatment options, especially those receiving multiple prior therapies. Patients with MCL are mostly an elderly population with various comorbidities who receive multiple medications that may lead to an increased risk of toxicity from underlying disease, as well as drug interactions. These multiple, concomitant conditions introduce complexity into the evaluation of the risk-benefit ratio of available therapies. In the relapsed setting, there is increasing use of new treatment options, such as lenalidomide, which is an immunomodulatory agent with direct and immune-mediated mechanisms of action. Lenalidomide has shown efficacy and a tolerable safety profile in multiple studies of R/R MCL, including the randomized MCL-002 (SPRINT) study comparing lenalidomide vs. investigator's choice (IC) of monotherapy. The objective of this post hoc subgroup analysis from the MCL-002 study was to examine the effect and safety of lenalidomide in patients who are at risk of bleeding events because of multiple comorbidities or treatments (i.e., polymedication) denoted as LEN-CM compared with those not at risk (LEN), LEN-CM being a population with a limited choice of treatment options. Methods: The multicenter MCL-002 study randomized patients 2:1 to lenalidomide vs. single-agent IC of monotherapy (rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine; NCT00875667). Patients had 1-3 relapses or had failed prior therapy, and were ineligible for intensified chemotherapy or stem cell transplantation. Oral lenalidomide was initiated at 25 mg/day on days 1-21 of 28-day cycles until disease progression or as tolerated. Progression-free survival (PFS) was the primary endpoint (per modified 1999 IWG criteria); secondary endpoints included response rates, duration of response (DOR), overall survival (OS), and safety. The current analyses were based on investigator's assessment. Specific patient groups with or without increased bleeding risk due to comorbidities and/or treatment were identified for the subgroup analysis based on pre-existing characteristics at study initiation. Patients in the LEN-CM group included those with hemorrhages (or predispositions to such), concomitant anticoagulant therapy with vitamin K antagonists or nonsteroidal anti-inflammatory drugs, and/or current or preexisting atrial fibrillation requiring anticoagulants. Results: Of 170 patients originally randomized to lenalidomide treatment, there were 60 (35%) LEN-CM vs. 110 (65%) LEN patients included in this subanalysis. At baseline, patients in both groups generally had a similar baseline patient profile and prior treatment history, although there were some differences between groups: more patients in the LEN-CM group (vs. LEN) were 〉=65 years of age (78% vs. 62%) and had more high-risk MIPI score at baseline (47% vs. 29%), whereas fewer had positive bone marrow (7% vs. 15%), high tumor burden (37% vs. 54%), or bulky disease (15% vs. 25%). Median PFS by investigator assessment was 10.7 months (95% CI, 4.3-14.0) for LEN-CM and 7.0 months (95% CI, 5.3-14.6) for LEN (Table 1). Overall response rates (ORR) in the LEN-CM vs. LEN patients were 29/60 (48%) and 49/110 (45%) with complete response (CR)/CR unconfirmed (CRu) rates of 6/60 (10%) and 13/110 (12%), respectively. Median DOR and OS were also similar in both groups of lenalidomide-treated patients. The safety profiles were similar for these subgroups, with similar rates of AEs leading to discontinuations and dose reductions/interruptions. Most common any grade treatment-emergent AEs (〉=20%) for LEN-CM vs. LEN groups respectively were 48% vs. 52% neutropenia, 33% vs. 38% thrombocytopenia, 32% vs. 27% anemia, 25% vs. 19% fatigue, 23% vs. 22% diarrhea, and 5% vs. 23% pyrexia. Conclusions: For patients with R/R MCL, there is a high, unmet medical need for effectivetherapy with acceptable toxicity. Overall, the LEN-CM and LEN subgroups showed similar efficacy and safety outcomes. Results from this subgroup analysis of the MCL-002 study show that lenalidomide leads to clinically meaningful PFS and other efficacy outcomes irrespective of the presence or absence of bleeding risk due to comorbidities and/or treatment. Disclosures Walewski: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Novartis: Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Belada:Seattle Genetics: Research Funding. Radford:Novartis: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; GSK: Equity Ownership; Astra-Zeneca: Equity Ownership; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jurczak:Morphosys: Consultancy, Research Funding, Speakers Bureau; Acerta: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Celtron: Research Funding; Bayer: Research Funding; Takeda: Research Funding; Servier: Research Funding; Teva: Research Funding; Roche: Research Funding, Speakers Bureau; Sandoz-Novartis: Speakers Bureau. Morschhauser:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Servier: Consultancy, Honoraria. Kaplanov:State Budgetary Healthcare Institution "Volgograd Regional Clinical Oncology Dispensary #1: Employment. Thyss:Takeda: Research Funding; Millennium: Research Funding. Kuzmin:Republican Clinical Oncology Dispensary: Employment. Stelitano:Azienda Ospedaliera: Employment. Marks:Pfizer: Honoraria. Trümper:Roche: Research Funding; Mundipharma: Research Funding; Hexal: Membership on an entity's Board of Directors or advisory committees. Biyukov:Celgene: Employment, Equity Ownership. Barnett:Celgene Corporation: Employment, Equity Ownership. Casadebaig Bravo:Celgene: Employment, Equity Ownership. Arcaini:Sandoz: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.