Witzig, Thomas E.

Abstract Intravascular lymphoma is a rare subtype of extranodal DLBCL characterized by the proliferation of malignant B-cells within the lumina of blood vessels. Organ involvement is variable and diffuse. Making the diagnosis can be challenging with symptoms persisting for months prior to definitive diagnosis. Treatment to date with standard anthracycline containing chemotherapy regimens has been disappointing with variable response rates, high relapse rates, and median survival times typically measured in months. We report diagnostic, treatment, and follow-up information regarding a group of patients with intravascular lymphoma evaluated at the Mayo Clinic with special attention to those receiving rituximab and/or high dose chemotherapy with or without peripheral blood autologous stem cell rescue. Methods: The medical records of patients with intravascular lymphoma seen at the Mayo Clinic between January 1970 and May 2005 were reviewed. Patients were included if they had evidence of intravascular lymphoma at the time of diagnosis of lymphoma. Pathologic specimens were reviewed for confirmation of diagnosis. Results: Twenty patients with a diagnosis of intravascular lymphoma were identified. Their median age was 66.5 years. Thirteen (65%) had B symptoms at the time of diagnosis and 13 had a performance status ≥ 3. Nine (45%) had an IPI ≥ 4. The median time to diagnosis from the onset of symptoms was 5.5 months. All had stage IV disease with biopsy proven involvement of at least one organ. The sites of disease involvement were CNS (10), marrow (7), lung (5), adrenal (3), kidney (2), lymph node, seminal vesicle, and skin (1). Two patients had involvement of three organs, six had involvement of two organs, and twelve had involvement of one organ. Nineteen patients received chemotherapy: ProMACE/CytaBOM (3), CHOP (6), RCHOP (6), DHAP (1), high dose methotrexate (1), methylprednisolone, nitrogen mustard, rituximab (1), and hyperCVAD (1). Three patients underwent peripheral blood autologous stem cell rescue after conditioning with BEAM. With a median follow-up of 60 months for all patients, the median overall survival was 8 months. No difference in outcome was seen with regard to site of organ involvement, number of organs involved, presence of B symptoms, or IPI. With a median follow-up for those receiving rituximab of 26 months, the median survival has not yet been reached while the median survival for those receiving non-rituximab containing regimens was 6.5 months. Similarly, with a median follow-up for those receiving high dose chemotherapy (hyperCVAD or BEAM) of 9.3 months, the median survival has not yet been reached while the median survival for those not receiving high dose therapy was 7 months. Conclusion: Intravascular lymphoma is a unique and aggressive subtype of DLBCL. The clinical presentation and sites of organ involvement are variable and the time from onset of symptoms to diagnosis can be prolonged. Standard chemotherapeutic treatment leads to poor outcomes. However, survival may be improved upon with newer strategies such as the use of rituximab and/or high dose chemotherapy with or without peripheral blood autologous stem cell rescue.

Abstract Waldenstrom Macroglobulinemia (WM) is characterized by the presence of lymphoplasmacytic cells in the bone marrow, and often in the lymph nodes. The mechanisms by which cells migrate/home to the bone marrow are poorly understood. The chemokine receptor CXCR4 and its ligand SDF-1 have been implicated in the migration and homing of lymphocytes. The objective of this study was to begin to identify the role of CXCR4 in WM. Paraffin embedded tissues were obtained after informed consent from 10 bone marrow samples of asymptomatic WM/monoclonal gammopathy of undetermined significance (MGUS) (n=5) and symptomatic WM (n=5). Four normal bone marrow samples were obtained for control. CXCR4 expression was determined using anti-CXCR4 antibody (Affinity Bioreagents, Golden, CO) 1:200 dilution for 16hrs, and a scale of 0–3+ was used to determine relative expression in the lymphocytes. Anti-CD20 antibody was used to determine the presence of lymphocytes in the samples. To determine whether the receptor is functional, migration was performed with the WM cell line (WSU-WM, kind gift from Dr. Al-Khatib, Wayne State University) and using a transwell migration assay (Costar, Corning, NY) with serial dilutions of SDF-1 (10-100nM). Comparison between the asymptomatic and symptomatic WM groups was performed by c2 test, and Mann-Whitney test, as appropriate. The baseline patient characteristics are displayed in table 1. CXCR4 expression was present on the surface of scattered lymphocytes in the normal bone marrow (median expression 1+). The expression of CXCR4 was increased in the asymptomatic/MGUS cases of WM (median expression 2+). In contrast, CXCR4 expression was downregulated in 4/5 cases of symptomatic WM specifically all the ones with extensive involvement of the bone marrow with lymphoplasmacytic cells (median expression 0). SDF-1 induced a bell- shaped response of migration in the WM cells with the maximal migration occurring at 1-10nM SDF-1. SDF-1 1-10nM induced 340% increase in migration as compared to untreated cells. However, high doses of SDF-1 100nM did not induce any migration as compared to untreated cells indicating inhibition of migration in response to high doses of SDF-1. In summary, we demonstrate that the CXCR4 receptor is functional and induces migration indicating that it plays a role in the migration of WM cells to the bone marrow. In addition, we demonstrate that CXCR4 expression is downregulated in WM with high infiltration of cells in the bone marrow as compared to those with minimal infiltration. These results may be due to the high level of SDF-1 in the bone marrow that induce downregulation of CXCR4. High levels of SDF-1 may downregulate the receptor and inhibit migration in order to confine the cells within the bone marrow. Supported in part by an ASH scholar award and the RFW. Patient characteristics Asymptomatic WM/MGUS, (range), (N=5) Symptomatic WM, (range) (N=5) Median age at diagnosis 67.6 (55.8–78) 71.5 (61–77) Median IgM level (mg/dL) 997 (904–1490) 5410 (2000–7820) Median Hb (gm/dL) 12.6 (11.1–15.1) 10.8 (9.3–11.6) Organomegaly (liver or spleen) N 20% Lymphadenopathy N 40% Median involvement of tumor cells in the BM in % 5% 30(10–60)

Abstract The proposed immune-mediated mechanisms of action of Rituximab (ADCC or “vaccinal” effect) suggest that the efficacy of rituximab therapy depends on the immunocompetency of the host. Therapies, such as IL-12, that stimulate the immune system may increase the efficacy of rituximab. Recently, we reported that absolute lymphocyte count (ALC), as a surrogate maker of immune recovery, is a survival prognostic factor in autologous stem cell transplantation for non-Hodgkin’s lymphoma (NHL). We hypothesize host immune competence (i.e, normal ALC counts) would predict a superior survival in NHL patients treated with rituximab-based regimens. The primary end-point of the study was to assess whether the ALC count prior to rituximab therapy predicted progression-free survival (PFS) and the second end-point was to identify which lymphocyte subset was responsible for affecting PFS. We studied 41 NHL patients that participated in our Phase I interleukin-12 plus rituximab study. These patients were selected because the Phase I study required baseline ALC count and flow cytometry analysis providing lymphocyte subset data prior to treatment. There were 20 females and 21 males in the study. The median age of the cohort was 53 years (range: 34–84). PFS was assessed from the initial date of treatment. The median follow-up was 42 months (1–84 months). Patients with an ALC ≥ 0.9 × 109/l experienced a superior PFS versus an ALC < 0.9 × 109/l prior to rituximab therapy (31 months vs 4 months, p < 0.0001). The relapse rate in the ALC ≥ 0.9 × 109/l group was 55% (11/20) versus 95 % (20/21) in the ALC < 0.9 × 109/l (p < 0.0016). Patients with a CD4 count ≥ 500 cells/μl also experienced a superior PFS versus a CD4 count < 500 cells/μl (21 months vs 9 months, p < 0.0062). The relapse rate in the CD4 count ≥ 500 cells/μl group was 56% (9/16) versus 88 % (22/25) in the CD4 count < 500 cells/μl (p < 0.0216). No association with PFS was identified for CD3, CD8, CD19, CD16/56, the use of IL-12, or lymphoma type by WHO classification. CD4 count was found to be an independent prognostic factor for PFS. In the subgroup of patients with follicular lymphoma, patients with an ALC ≥ 0.9 × 109/l experienced a superior PFS versus an ALC < 0.9 × 109/l prior to rituximab therapy (35 months vs 9 months, p < 0.0076). The relapse rate in the ALC ≥ 0.9 × 109/l group was 45% (5/11) versus 90 % (9/10) in the ALC < 0.9 × 109/l (p < 0.0243). Patients with a CD4 count ≥ 500 cells/μl also experienced superior PFS versus a CD4 count < 500 cells/μl (not reached vs 9 months, p < 0.0098). The relapse rate in the CD4 count ≥ 500 cells/μl group was 29% (2/7) versus 86 % (12/14) in the group with a CD4 count < 500 cells/μl (p < 0.0216). CD4 count was found to be an independent prognostic factor for PFS when compared to the Follicular Lymphoma International Prognostic Index at the time of treatment. Our data suggest the significance of an immunocompetent host in predicting the efficacy of rituximab therapy. These data support our previous report that patients with higher number of activated CD4+ cells at the lymphoma site have a better prognosis (Ansell et al, JCO2001; 19: 720–6). These findings warrant further studies to understand the role of ALC (i.e, CD4 count) in the mechanism of action of rituximab. Supported in part by CA69912

Abstract Background: Abnormally increased tumor associated neovasculature plays an important role in tumor progression in solid tumors and hematological malignancies. In multiple myeloma (MM) bone marrow angiogenesis, measured in terms of microvessel density (MVD), has prognostic value, and appear to increase with disease progression from monoclonal gammopathy of undetermined significance to relapsed MM. We have shown that MVD has prognostic value in patients with newly diagnosed MM including patients undergoing upfront high dose therapy and stem cell transplantation, but comparison with other known prognostic factors has been limited by sample size. It is also not known whether the MVD adds prognostic value once the recently described International Staging System (ISS) is applied. The goal of this study was to determine the prognostic effect of bone marrow MVD in newly diagnosed MM relative to the ISS and other known prognostic factors. Methods: We studied 400 patients with newly diagnosed MM seen at the Mayo Clinic between March of 1988 and December 2001. Sections from bone marrow biopsy blocks from the time of initial diagnosis were studied by immunohistochemistry using antibodies against CD34 antigen to high light the endothelial cells. Under low power (100X); three areas with maximum number of microvessels (hotspots) were identified. Each of these areas was further studied at 400X magnification and the number of microvessels per high power field counted. The average of the three readings was taken as the MVD for the sample. In addition, the samples were graded as low, intermediate or high by using a visual estimate as previously described. Additional clinical data was extracted from medical records. Some of the patients have been included in previous studies related to angiogenesis. Results: A total of 400 patients in whom a bone marrow biopsy from within 30 days of diagnosis was available were studied. The pts were followed for a median of 37 months (Range: 1 month to 16.5 years) and 318 pts (80%) had died at the time of this analysis. The median MVD for the entire group was 14.7 (Range 0–168). The median overall survival for the three groups according to the MVD grade was lower for the high grade group (31.9 months) compared to the intermediate grade group (37.2 months) and the low grade group (not reached); P <0.029, log rank test. We examined this group of patients for other factors prognostic for overall survival. Factors significant on univariate analysis included ISS stage, platelet count (<150 vs. >= 150 X 106/L), and plasma cell labeling index (<1 vs >=1). In a multivariate analysis using these variables and MVD as a continuous variable, high MVD and the ISS staging system were significantly associated with poorer survival (Table). Conclusion: In this large group of pts with newly diagnosed MM, we confirm the prognostic value of increased bone marrow angiogenesis. We examined the MVD as a continuous variable in the multivariate analysis for a closer evaluation of this measure in this comparison. More importantly, the prognostic value appears to be independent of the ISS and other major prognostic factors. The resultsof this study reinforces the biological relevance of this finding in MM. HR 95% CI P value MVD 1.006 (1.001, 1.011) 0.0279 ISS Stage I 0.37 (0.25, 0.56) <0.001 ISS Stage II 0.58 (0.41, 0.83) 0.0025

Abstract Rationale Escalation of the Zevalin dose is limited by hematologic toxicity associated with marrow B-cells ± tumor cells. Rituxan treatment before Zevalin may reverse marrow infiltration with malignant and normal B-cells allowing an increase in the dosage of Zevalin with enhanced radiation delivery to lymphoma tumor sites. Since NHL is radiation sensitive, a substantial increase in radiation dose delivered should increase the ORR and CR rates. Design Low-grade follicular/transformed NHL patients receive 4 weekly dose of Rituxan (375mg/m2) before the corresponding Zevalin dose. Bilateral bone marrow biopsies/aspirates as well as biodistribution and dosimetry studies using 111In-2B8 were obtained before and after Rituxan. The trial was schedule to escalate the Zevalin dose (from 0.4 to 0.7 mCi/Kg). After completion of the 0.4 mCi/kg cohort an additional cohort of Rituxan sensitive patients using 0.3 mCi/kg was completed. Safety, pharmacokinetics, dosimetry and preliminary responses are presented. Results 5 pts were enrolled in the 0.4mCi/kg cohort and 6 pts in the 0.3 mCi/kg cohort. In the 10 Rituxan sensitive patients the plasma T ½ and the AUC of 111In-2B8 increased after the administration of Rituxan, with a reduction in the plasma clearance (T½ from 45 ± 4.5 hours to 54 ± 1.9 hours, AUC from 60 ± 10 hrs/μCi/ml to 85 ± 14 hrs/μCi/ml, and the clearance from 1.4 ± 0.3 ml/hrs/kg to 0.9 ± 0.2 ml/hrs/kg). Dosimetry showed no differences in the radiation-absorbed dose for major normal organs (whole body, liver, kidneys) except for the spleen in which a reduction was observed in 7 out of 10 patients. The radiation-absorbed dose to the marrow increased after Rituxan; from 3.6 rads/mCi to 4.28 rads/mCi. In the 0.4 mCi/kg cohort 3 out of 4 evaluable patients for response had a complete response, and 1 patient had progression documented at initial evaluation six weeks post-Zevalin (patient refractory to previous Rituxan). No non-hematological toxicity was observed. One patient had a grade 4 thrombocytopenia, 3 patients had grade 3 thrombocytopenia, and 4 patients had grade 4 WBC and ANC. All patients recovered within two weeks after the nadir. Two out of 6 patients treated in the 0.3 mCi/kg cohort had complete response by physical evaluation, and 4 had partial response; no early progressions were seen in this cohort. No non-hematological toxicity was observed. Only one patient had a grade 4 WBC and ANC, and 2 patients had a grade 3; 3 patients had grade 3 thrombocytopenia; all patients recovered. Conclusions The administration of high doses of Rituxan before Zevalin prolongs the circulation time of the radiolabeled antibody and increases the bone marrow exposure to the radioisotope. Additionally, the increased amount of the radiolabeled antibody available after Rituxan therapy with the prolonged circulation time may explain the unusual high complete response rate observed in this small number of patients despite extensive chemotherapy failures. Although this is very provocative data, the number of patients is very limited to generate a strong conclusion. The trial continues at this time.

Abstract Background: The presence of circulating myeloma cells (CMC) detected by flow cytometry at the time of diagnosis of multiple myeloma is associated with a shortened response to therapy and reduced overall survival (OS). We hypothesized that the presence of CMC at the time of stem cell collection prior to high dose therapy (HDT) and autologous stem cell transplantation (ASCT) would identifies a cohort of patients with a high risk of rapid progression. Methods: The Mayo Clinic myeloma transplant database was queried for patients who were mobilized using cyclophosphamide and hematopoietic growth factors. CMC was determined using flow cytometry by gating on a population of CD38 bright and CD45 negative cells. The impact of CMC on OS and time to progression (TTP) and its role in the context of established prognostic parameters was evaluated. Results: Of 246 patients with MM undergoing ASCT, 95 had CMC. Patients with CMC had significantly higher plasma cell labeling index, adverse cytogenetics, B2-M and resistant disease. Complete response (CR) rates post transplant were 32% and 36% for patients with and without CMC (p=0.5034). OS was 33.2 and 58.6 months (p=0.0052) while TTP was 14.1 and 22 months respectively (p=0.0005). Figure Figure On multivariate analysis, CMC remained an independent prognostic factor in a model that included cytogenetics and disease status at time of transplant (p=0.0314). A prognostic system based on the presence or absence of CMC and karyotype abnormalities was developed. Patients with neither, one or both parameters had a median, OS of 55, 48 and 21.5 months respectively (p<0.0001) while TTP was 22, 15.4 and 6.5 months for the same groups (p<0.0001). Conclusion: The presence of CMC at the time of HDT and ASCT is an independent prognostic factor. The combination of CMC and cytogenetics provides a simple yet powerful scoring system that stratifies patients and guides their management.

Abstract INTRODUCTION: Adult mature T- and NK-cell neoplasms are a heterogeneous group of aggressive lymphomas comprising approximately 10% to 20% of all non-Hodgkin lymphomas (NHL) with an estimated 5-year overall survival of 40%. Staging and treatment strategies are guided by malignant involvement on PET/CT scan and bone marrow (BM) biopsy. The Lugano Criteria, established in 2014, suggested that focal FDG uptake within the bone marrow was highly sensitive for both Hodgkin (HL) and diffuse large B-cell lymphoma (DLBCL) potentially obviating the need for a bone marrow biopsy if no lesions were seen. Limited data exist regarding the sensitivity of PET for BM involvement in T-cell lymphoma. This study compares PET/CT scans and repeat BM biopsy in patients who have undergone treatment for peripheral T-cell lymphomas (PTCL) by evaluating BM avidity on PET scans. METHODS: This is a single institution study using the Mayo Clinic Lymphoma Database between January 1, 2001 and January 1, 2015. We retrospectively identified all patients with a diagnosis of PTCL, biopsy proven BM involvement at diagnosis, and a concomitant PET for staging. Patients were then reviewed to assess completion of induction therapy and availability of both PET/CT and bone marrow results post-therapy. Evaluation for concordance and discordant BM involvement were then determined using BM biopsy as the gold standard. RESULTS: Sixteen patients had both PET/CT and BM biopsy after completing induction therapy. Median age at diagnosis was 63 years (range 34-72) and 69% were male. PTCL subtype was peripheral T-cell lymphoma, not otherwise specified in seven patients; ALK negative anaplastic large cell lymphoma in one patient; and angioimmunoblastic in 8 patients. Pre-treatment PET/CT scans demonstrated eight patients (50%) with false negative scans. Post-treatment biopsy results demonstrated that ten (62.5%) had biopsy proven residual bone marrow involvement after induction. Eight patients (50%) were found to have BM biopsy proven disease with a negative PET scan. Two patients (12.5%) had both positive BM biopsy and PET scans; 5 patients (31.3%) had negative BM biopsies and PET scans. One patient (6.25%) had a negative BM biopsy, but had a PET scan that revealed positive disease. This patient was considered to have had a false positive PET scan and indeed has remained in remission since April 2009 without any further relapse or treatment. Sensitivity of PET for BM involvement was very poor at 20% (2/10) with a specificity of 50% (2/4) (Table 1 and 2). CONCLUSIONS: This study in PTCL indicates that PET scans at the completion of therapy have a 50% false negative rate. These patients should not be assumed to have negative bone marrow involvement based solely on PET/CT scans. A bone marrow biopsy at the end of therapy is necessary in PTCL patients to confirm complete response. Table 1. Bone Marrow Involvement Pre-Therapy PET Scan Imaging PET Negative PET Positive Total Patients Bone Marrow Negative NA NA NA Bone Marrow Positive 8 8 16 Total Patients 8 (50%) 8 (50%) 16 Abbreviations: NA, not applicable. The study defined that all patients had to have a positive bone marrow at baseline to be eligible for the study. Table 2. Bone Marrow Involvement PET Negative PET Positive Total Patients Bone Marrow Negative 4 2 6 (37.5%) Bone Marrow Positive 8 2 10 (62.5%) Total Patients 12 (75%) 4 (25%) 16 Table 1 and 2. Involvement of bone marrow with peripheral T-cell lymphoma based on evaluation by PET scans versus bone marrow biopsy. Disclosures Maurer: Kite Pharma: Research Funding.

Abstract Introduction: Diffuse large-B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas (NHL). Patients with DLBCL who are not cured by treatment with R-CHOP chemotherapy or high-dose chemotherapy with autologous stem cell rescue have a poor prognosis. These patients reflect a clear unmet need in the treatment of DLBCL. A previous sub-analysis of a phase II trial (NHL-002) of lenalidomide in patients with relapsed or refractory DLBCL, demonstrated a 19% overall response rate (ORR) with a 7-month median duration of response (DR). A confirmatory international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed/refractory aggressive NHL that had received at least one prior treatment and had measurable disease. Herein, we report the data from the DLBCL patients enrolled in this trial. Methods: Patients received 25 mg oral lenalidomide once daily on days 1–21 of every 28-day cycle and continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: This report focuses on the 73 DLBCL patients that were enrolled and evaluable for response assessment. The median age was 67 (21–87) years and 49 (67%) patients were male. Median time from diagnosis to lenalidomide treatment was 2 (0–18.6) years, and patients had received a median of 3 (1–6) prior treatment regimens. The ORR to lenalidomide was 29% (21/73), with 4% complete response (3/73) and 25% partial response (18/73). Eleven patients (15%) had stable disease. The most common grade 3 or 4 adverse events were neutropenia (32%), thrombocytopenia (15%), asthenia (8%) and anemia (7%). Conclusion: These results of this international study confirm that lenalidomide is active in heavily pre-treated patients with relapsed or refractory DLBCL with manageable side effects.

Abstract The objective of this study was to analyze protein changes that occur a the molecular level with novel therapeutic agents used in MM in order to identify potential combinations for clinical trials. We employed antibody protein microarrays (BD Clonetech, CA) to measure changes in the patterns of protein expression in Kas 6/1 MM cell line after treatment with bortezomib, dexamethasone, CC-5013, and 17-AAG. The antibody array is a new technique that assays protein differences directly by hybridizing fluorescently labeled protein mixtures from cell extracts onto glass slides spotted with 512 different monoclonal antibodies specific for human proteins. Induction of apoptosis was assessed by Annexin/Propidium iodide FACS analysis at 24 and 48 hours using different concentrations of the inhibitors. Protein arrays were performed at concentrations and treatment times that did not induce more than 25% apoptosis to ensure adequate analysis of early changes in signaling pathways. Bortezomib 5nM at 10 hours, dexamethasone 100mM, CC-5013 250nM, and 17-AAG 1mM at 24 hours were used. Control cells were treated with vehicles ETOH or DMSO at the same concentrations as the inhibitors. To assess differential protein expression, the mean of the Cy5/Cy3 ratios for each sample and its control were analyzed using the Clontech software and an internally normalized ratio (INR) was calculated. INR values >1.3 or <0.77 were considered as valid changes in protein abundance for this study. All inhibitors induced the upregulation of apoptosis proteins including BAK, BIK, SMAC/DIABLO, and caspase 14. Several proteins were inhibited by all 4 inhibitors indicating common pathways affected by these agents. These included members of the PI3K pathway (PI3K-p85a, p70S6kinase, and cyclin dependent kinases), MAPKinases (ERK1 and 2), antiapoptotic protein Bclx, heat shock proteins Hsp70 and HSP60, and ubiqutin/NFkB pathway (Ubch6, IKKalpha, and IKBe). These results indicate that inhibitors of the PI3K pathway such as mTOR inhibitors, IKK inhibitors or MAPkinase inhibitors may be used in the future in combination with bortezomib, dexamethasone, CC-5013 or 17-AAG. Fatty acid synthetase was downregulated by bortezomib and dexamethasone indicating potential use of fatty acid synthase inhibitors in combination with bortezomib or dexamethasone in future clinical trials. These results suggest that antibody protein arrays may be used in the rational design of combinations of targeted therapies in MM.

Abstract Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma that if not cured with aggressive chemoimmunotherapy and stem cell transplant is usually fatal. The intravenous proteasome inhibitor bortezomib produces an overall response rate (ORR) of 33% in patients with relapsed MCL (J Clin Oncol2006;24(30):4867–74). Unfortunately, most patients eventually relapse and new agents are needed for this disease. Two recently conducted phase II trials (NHL-002 and NHL-003) tested single-agent lenalidomide for patients with relapsed MCL. Fifty-four patients with MCL were enrolled into the two studies; 26% (14/54) had received prior bortezomib and they are the subject of this report. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least one prior treatment regimen including prior bortezomib were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Therapy was continued as tolerated or until disease progression. The 1999 IWLRC methodology was used to assess response and progression. Results: The 14 patients in this study were heavily pretreated with a median of 4 (2–6) prior treatments (including bortezomib) and 50% were bortezomib-refractory. Median age was 66 (45–84) years and 6 (43%) patients were female. Median time from diagnosis to lenalidomide treatment was 3.3 (0.7–7.6) years. The ORR with lenalidomide was 57% (8/14), including 21% (3/14) complete response (CR)/unconfirmed CR and 36% (5/14) partial responses. One (7%) patient had stable disease. The most common grade 3 or 4 adverse events were neutropenia (50%), thrombocytopenia (43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenic fever occurred in 7% of patients. Conclusion: These results demonstrate that lenalidomide oral monotherapy is very effective with manageable side effects in patients with relapsed or refractory MCL who had received prior treatment with bortezomib.