Czuczman, Myron S.

AbstractBackgroundStudies suggest that immune checkpoint inhibitors may represent a promising strategy for boosting immune responses and improving the antitumor activity of standard therapies in patients with relapsed/refractory hematologic malignancies.AimsPhase 1/2 FUSION NHL 001 was designed to determine the safety and efficacy of durvalumab, an anti‐programmed death ligand 1 (PD‐L1) antibody, combined with standard‐of‐care therapies for lymphoma or chronic lymphocytic leukemia (CLL).Methods and ResultsThe primary endpoints were to determine the recommended phase 2 dose of the drugs used in combination with durvalumab (durvalumab was administered at the previously recommended dose of 1500 mg every 4 weeks) and to assess safety and tolerability. Patients were enrolled into one of four arms: durvalumab monotherapy (Arm D) or durvalumab in combination with lenalidomide ± rituximab (Arm A), ibrutinib (Arm B), or rituximab ± bendamustine (Arm C). A total of 106 patients with relapsed/refractory lymphoma were enrolled. All but two patients experienced at least one treatment‐emergent adverse event (TEAE); those not experiencing a TEAE were in Arm C (diffuse large B‐cell lymphoma [DLBCL]) and Arm D (DLBCL during the durvalumab monotherapy treatment period). No new safety signals were identified, and TEAEs were consistent with the respective safety profiles for each study treatment. Across the study, patients with follicular lymphoma (FL; n = 23) had an overall response rate (ORR) of 59%; ORR among DLBCL patients (n = 37) was 18%. Exploratory biomarker analysis showed that response to durvalumab monotherapy or combination therapy was associated with higher interferon‐γ signature scores in patients with FL (p = .02).ConclusionDurvalumab as monotherapy or in combination is tolerable but requires close monitoring. The high rate of TEAEs during this study may reflect on the difficulty in combining durvalumab with full doses of other agents. Durvalumab alone or in combination appeared to add limited benefit to therapy.

PURPOSE Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL. METHODS Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review. RESULTS A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% v 48%), anemia (22% v 14%), thrombocytopenia (17% v 11%), and leukopenia (14% v 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and P = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease. CONCLUSION ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti–CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.

Abstract Radioimmunotherapy (RIT) is a therapeutic modality indicated for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed non-Hodgkin’s lymphoma (NHL), where the mechanism of action involves the intrinsic activity of the monoclonal antibody and the cytotoxic effects of radiation. The primary toxicity is a late-occurring, transient, and reversible myelosuppression. Because of concerns regarding the long-term effects of radiation on the bone marrow, we investigated the incidence of treatment-related myelodysplastic syndrome (t-MDS) and treatment-related acute myelogenous leukemia (t-AML) after ibritumomab tiuxetan RIT. A total of 746 patients with NHL were treated with the ibritumomab tiuxetan regimen in registration and compassionate-use trials between 1996 and 2002. Patients had a median age of 61 years (range, 24–87) and had received a median of 3 prior therapies (range, 0–9+). The crude incidence of t-MDS or t-AML was 2.3% (17/746), with an incidence of 4.7% (10/211) in patients enrolled in registration trials and of only 1.3% (7/535) in patients included in the compassionate-use trial, with a median follow-up of 5.7 and 3.5 years, respectively. These malignancies were documented at a median of 5.6 years (range, 1.2–13.9) after the diagnosis of NHL and 1.5 years (range, 0.1–5.8) after RIT. The annualized rates were 0.3% (95% CI, 0.2%–0.4%) a year after the diagnosis of NHL and 0.7% (95% CI, 0.4%–1.0%) a year after RIT. Cox multivariate regression analysis found that previous treatment with a purine nucleoside analog was a significant risk factor for t-MDS or t-AML (hazard ratio, 3.9 [95% CI, 1.5–10.4]; P = .006). All patients in whom t-MDS or t-AML developed and in whom cytogenetic data were available (n = 15) had multiple cytogenetic aberrations, commonly of chromosomes 5 and 7, suggesting an association with previous exposure to chemotherapy. There were documented bone marrow cytogenetic abnormalities before treatment in 2 patients who developed t-MDS or t-AML. These data suggest that the annualized incidence of t-MDS or t-AML following ibritumomab tiuxetan RIT is consistent with that expected on the basis of the patients’ history of treatment for NHL. Cytogenetic testing before administration of RIT may identify existing chromosomal abnormalities in previously treated patients, particularly in those who have been treated with alkylating agents and/or purine nucleoside analogs and who are thereby at a higher risk for t-MDS or t-AML.

Abstract Two death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), expressed in a wide variety of cancer cell types including lymphoma, enable TRAIL (TNF related apoptosis inducing ligand), a member of the TNF ligand superfamily, to induce apoptosis. HGS-ETR1 (TRM-1, mapatumumab) is a fully human monoclonal antibody agonistic to TRAIL-R1 with preclinical evidence of anti-tumor activity in vitro and in vivo. We conducted a phase 2 multicenter study of HGS-ETR1 in 40 subjects with relapsed or refractory NHL. Patients were included on the study if they had relapsed/refractory NHL of any histologic subtype, irrespective of the number of previous treatment regimens. HGS-ETR1 was administered at 2 dose levels: 3 mg/kg (8 subjects) or 10 mg/kg (32 subjects) every 21 days in the absence of disease progression or prohibitive toxicity for up to 6 cycles. The primary endpoint was tumor response evaluated with the International Working Group Criteria after every third treatment. Responses were confirmed between 4 and 8 weeks after initial documentation of response. Secondary endpoints included safety and tolerability. The median age of subjects was 62 years (range 32–81) (24M:16F) with an ECOG performance status 0–2. Subjects had received up to 12 previous therapeutic regimens (69% received 3 or more prior regimens). Original histologic classification is presently available for 34 subjects (14 follicular, 7 diffuse large B-cell, 6 mantle cell, 1 small lymphocytic, 2 peripheral T-cell, 1 anaplastic large cell, 3 lymphomas not classified). Preliminary response data are available for all 40 subjects. 3 subjects (8%), all with follicular lymphoma, had clinical responses (1CR, 2PR). Additionally, 12/40 subjects (30%) had stable disease, and the remainder had progressive disease at the time of first evaluation. 8 subjects (7 follicular) remain on study without disease progression for >5 to >13 months. One subject with a PR (special permission) has continued to receive HGS-ETR1 (10 cycles to date). Subjects tolerated therapy well with no subjects discontinuing therapy due to toxicity related to drug. There have been 10 reported SAEs, 2 of which were considered possibly/probably related to HGS-ETR1 administration (shingles, fever). In conclusion, HGS-ETR1 can be safely administered to heavily treated NHL patients. Clinical responses were seen in 3/14 follicular lymphoma subjects to date. Final data for all subjects will be reported at the meeting. These data suggest that HGS-ETR1 has activity in heavily pretreated lymphoma patients and further studies in combination with agents active in lymphoma are justified.

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 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.

Abstract Introduction: Mantle-cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma (NHL) that typically responds to initial chemo-immunotherapy, but with a relatively short duration of response (DR) and progression-free survival (PFS) when treated with conventional chemotherapy agents. Although the overall survival (OS) of MCL has improved, most patients are not cured and new agents are needed. A sub-analysis of a recent phase II trial (NHL-002) investigating the efficacy and safety of lenalidomide in patients with relapsed or refractory MCL, demonstrated a promising overall response rate (ORR) of 53% with a median DR of 11.9 months. 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. In this report, we analyze the current results from the MCL patients enrolled in this trial. Methods: Patients with relapsed or refractory MCL and measurable disease ≥2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: This report focuses on the 39 MCL patients that were enrolled and evaluable for response assessment. Median age was 66 (33–82) years and 29 (74%) patients were male. Median time from diagnosis to lenalidomide treatment was 3.4 (0.4–9) years. Patients had received a median of 3 (1–8) prior treatments, and 23% (9/39) of patients had received prior bortezomib treatment. The ORR with lenalidomide was 41% (16/39), including 13% (5/39) complete response (CR)/unconfirmed CR, and 28% (11/39) partial responses. Ten (26%) patients had stable disease. The most common grade 3 or 4 adverse events were neutropenia (51%) and thrombocytopenia (25%), anemia (13%), fatigue (10%) and febrile neutropenia (10%). Conclusion: These results confirm that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects.

Abstract Background: Lenalidomide (Revlimid®) has demonstrated activity with manageable side effects in relapsed/refractory aggressive non-Hodgkin’s lymphoma (NHL). In the initial pilot study, response to lenalidomide was associated with low tumor burden, long duration from prior rituximab and high absolute lymphocyte count. Aims: To confirm the activity and safety of lenalidomide monotherapy in patients with relapsed/refractory aggressive NHL in an international setting and Determine whether predictors of response identified in the previous study were valid. Methods: Patients with relapsed/refractory aggressive NHL with measurable disease ≥ 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test were conducted to investigate and characterize associations of prognostic variables with response. Results: Eighteen patients who received lenalidomide were eligible for response assessment as of May 15, 2007. The median age was 66 (43–81) and 17 were male. Histology was diffuse large B-cell lymphoma [DLBCL] (n=11), mantle cell lymphoma [MCL] (n=5) and transformed (n=2). Median time from diagnosis was 2 (0.4–12) years and median number of prior treatment regimens was 3 (1–13). Four patients (22%) exhibited an objective partial response including 2/11(18%) DLBCL and 2/5 (40%) MCL. Five patients had stable disease. Lenalidomide response was associated with low disease burden (29% for < 50 cm2v 0% for ≥ 50 cm2), time from last rituximab to lenalidomide treatment (36% for ≥ 230 days v 0% for < 230 days) and absolute lymphocyte count [ALC] (33% for ≥ 0.6×109/L v 0% < 0.6×109/L). Patients with favorable values for these three prognostic factors (N = 7) had a 57% response rate (compared with a 0% response rate for patients with unfavorable values (N = 11; P = 0.01). Grade 4 adverse events were neutropenia (22%) and thrombocytopenia (11%). Most common Grade 3 adverse events were fatigue (17%), thrombocytopenia (11%) and leukopenia (11%). Conclusion: Lenalidomide has activity in relapsed/refractory aggressive NHL with a favorable safety profile. Initial results from this ongoing study are confirming that patients with low tumor burden, long duration from prior rituximab, and high ALC are more likely to respond.

Background: DLBCL has traditionally been classified by cell of origin (COO) subcategories based on tumor gene expression profiles which include Activated B-Cell (ABC) and Germinal Center B-Cell (GCB). Recently, using tumor samples from patients treated with RCHOP, new classification models have focused on DNA alterations. However, a comprehensive integrative approach using a large transcriptomic data set across both newly diagnosed (nd) and relapsed/refractory (r/r) DLBCL is yet to be accomplished. A robust clustering of this type will allow for identification of biologically driven DLBCL patient subgroups and may predict patient outcome and inform treatment approaches. Methods: RNAseq was performed on a total of 882 DLBCL tumor FFPE biopsies from 2 ndDLBCL cohorts (cohort 1 and 2) and 2 r/r DLBCL cohorts (cohorts 3 and 4). Cohort 1 (N=267) was commercially sourced and served as the discovery cohort. Cohort 2 (N=340) was from the Mayo/Iowa Lymphoma SPORE Molecular Epidemiology Resource (MER) and served as the replication cohort. Cohort 3 (N=189) was from the CC-122-ST-001 and CC-122-DLBCL-001 clinical trials (NCT01421524 and NCT02031419), and cohort 4 (N=86) was from r/r patients from the MER. Clustering input consisted of gene expression data, gene set variation analysis (GSVA) scores computed from the hallmark gene sets of MSigDB gene sets, as well as immune cell abundance estimates from a DLBCL-specific deconvolution method. An integrative clustering method iClusterPlus was applied to the input data to identify patient subgroups. A multinomial generalized linear model classifier was trained on the discovery dataset and applied to cohorts 2, 3, and 4 to assess patterns of gene expression and clinical features among the subgroups. Results: Integrative clustering identified 8 subgroups of ndDLBCL patients (DLBCL1-8; D1-D8) in cohort 1. Classifiers trained on cohort 1 were applied to cohort 2 and the same 8 clusters were identified. Among RCHOP treated patients in cohort 2, subgroups D4 (p<0.01) and D8 (p<0.0001) had significantly worse survival outcomes than the rest of the population. D4 comprised 21% of the MER ndDLBCL replication cohort (cohort 2) with a median event-free survival (mEFS) of 38.2 months and a median overall survival (mOS) of 80.3 months. D8 comprised 5% of the cohort with a mEFS of 7.5 months and a mOS of 12.1 months. The remaining 6 subgroups were standard risk, with mEFS ranging from 82.1 months to not reached, and none reaching mOS. The subgroups were not uniquely defined by previously known molecular classification methods such as COO or double hit signature (DHITsig), nor by clinical risk factors such as age or international prognostic index (IPI). Within D4, 92% of patients were ABC, representing a high risk subset of ABC patients. The mEFS in D4 ABCs was 38.2 months, while mEFS of non-D4 ABCs was not reached (p<0.005). Transcriptomic analysis revealed a lower abundance of immune infiltration. D4 was associated with high IPI, with 49% of D4 having IPI>2, compared to 33% of non-D4 with IPI>2 (p<0.05). D8 represented a high-risk subset which was 73% GCB. The mEFS of D8 GCBs was 5.4 months, while mEFS of non-D8 GCBs was not reached (p<0.0001). Transcriptomic analysis revealed low expression of immune response and cytokine signaling pathways, consistent with the low abundance of immune cells in D8. This subgroup consisted of 63% DHITsig positive patients. Although only 20% of all DHITsig positive patients were in D8, these D8 DHITsig patients showed significantly worse survival than non-D8 DHITsig patients (mEFS 11.3 months vs. not reached, p<0.0001). In the r/r DLBCL setting, D1-D8 were all present, with an increased prevalence of D4 and D8 in Cohort 3 (30% and 17%, respectively) and Cohort 4 (30% and 14%) compared to the newly diagnosed setting. Mutational data for these cohorts has been collected and is being interpreted in the context of the discovered subgroups. Conclusion: A novel integrative clustering of transformed gene expression data revealed 8 biologically homogeneous groups, two of which had inferior outcomes when treated with RCHOP therapy. Furthermore, these two subgroups were more prevalent in r/r DLBCL. This classification allows for the transcriptomic identification of high-risk patients underserved by RCHOP therapy. *Ortiz, Wenzl and Stokes contributed equally **Gandhi and Novak contributed equally Disclosures Ortiz: Celgene Corporation: Employment, Equity Ownership. Stokes:Celgene Corporation: Employment, Equity Ownership. Huang:Celgene Corporation: Employment, Equity Ownership. Maurer:Celgene: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Towfic:Celgene Corporation: Employment, Equity Ownership. Hagner:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Ratushny:Celgene Corporation: Employment, Equity Ownership. McConnell:Celgene Corporation: Employment, Equity Ownership. Danziger:Celgene Corporation: Employment, Equity Ownership. Stong:Celgene Corporation: Employment, Equity Ownership. Lata:Celgene Corporation: Employment, Equity Ownership. Kamalakaran:Celgene Corporation: Employment, Equity Ownership. Mavrommatis:Celgene Corporation: Employment, Equity Ownership. Trotter:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Ansell:Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding. Cerhan:NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Nowakowski:Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Gandhi:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Novak:Celgene Coorperation: Research Funding.