Ervin‐Haynes, Annette

e19504 Background: Patients with diffuse large-B-cell lymphoma (DLBCL) who are not cured with R-CHOP or high-dose chemotherapy with autologous stem cell rescue have a dismal prognosis. A recent phase II trial (NHL-002) of lenalidomide in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) demonstrated a 19% overall response rate (ORR) with a 7-month median duration of response (DR) in the subset of patients with DLBCL. A supporting international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed or 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: One hundred-three DLBCL patients were enrolled and were evaluable for response assessment. The median age was 66 years (21–87) and 70 patients (68%) were male. Median time from diagnosis was 2 years (0.4–18.6), patients had received a median of 3 prior treatment regimens (1–10) and 46 of the patients (45%) had received a prior stem cell transplant (DLBCL-stem cell). Response rates are shown in the Table . Grade 3 or 4 adverse events occurring in more than 5% of patients were neutropenia (34%), thrombocytopenia (18%), asthenia (9%), anemia (8%), leucopenia (7%), back pain (6%) and dyspnea (6%). Conclusions: This international study demonstrates that lenalidomide is active in heavily pre-treated patients with relapsed or refractory DLBCL and has manageable side effects. [Table: see text] [Table: see text]

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 Background: Patients with diffuse large B-cell lymphoma (DLBCL) not cured by first line R-CHOP chemotherapy or second line high-dose chemotherapy with autologous stem cell rescue have a poor prognosis and represent a clear unmet medical need. Lenalidomide (Revlimid®), an immunomodulatory drug, has activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory DLBCL. Methods: Patients with relapsed/refractory DLBCL with measurable disease 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 for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test was conducted to investigate and characterize associations of prognostic variables with response. Results: Twenty-six patients with DLBCL lymphoma were enrolled. The median age was 66 (45–86) and 13 were female. Median time from diagnosis to lenalidomide was 2.4 (0.5–12) years and median number of prior treatment regimens was 3 (1–6). Three patients (12%) exhibited an objective complete response (1 complete response (CR) and 2 complete responses unconfirmed (CRu)). Two patients had a partial response (PR) for an overall response rate of 19% and 7 had stable disease (SD). Response to lenalidomide was associated with low disease burden (33% for < 50 cm2v 0% for ≥ 50 cm2, P=0.06) and longer time from rituximab to lenalidomide treatment (33% for ≥ 230 days v 0% for < 230 days, P=0.05). Patients with favorable values for both these prognostic factors (N = 10) had a 50% response rate [RR] (30% CR/CRu RR) compared with a 0% RR for patients with unfavorable values (N = 16; P < 0.004) and a progression free survival (ongoing) of 7.4 months v 1.9 months. Although there were no responses in the poor prognosis group, 4 patients exhibited stable disease with an ongoing median PFS of > 4.2 months (> 3.6 - > 6.2). Eight patients (31%) required at least one dose reduction with a median time to first dose reduction of 1.8 months (0.4–2.9). One patient each (4%) had Grade 4 anemia, cauda equinine syndrome, febrile neutropenia, intermittent rash, lymphopenia, neutropenia, pneumonitis and thrombocytopenia. Most common Grade 3 adverse events were neutropenia (19%), thrombocytopenia (15%) and leukopenia (12%). Conclusion: The prognostic factors of tumor burden and time from last dose of rituximab appear to identify relapsed/refractory DLBCL patients with a high likelihood of response to lenalidomide oral monotherapy.

Abstract Background: Mantle cell lymphoma (MCL) is a distinct type of non-Hodgkin’s Lymphoma characterized by being incurable with a low response rate and short progression free survival when treated with conventional chemotherapy agents. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved for the treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a del(q5) cytogenetic abnormality. Lenalidomide has also shown activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide in relapsed/refractory MCL. Methods: Patients with relapsed/refractory MCL and 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 for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fifteen patients with MCL were enrolled. Median age was 67 (45–84) and 7 were female. Median time from diagnosis to lenalidomide was 5.1 (0.7–12.7) years and median number of prior treatment regimens was 4 (2–6). Eight patients (53%) exhibited an objective response (1 complete response (CR), 1 complete response unconfirmed (CRu) and 6 partial responses (PR)), 2 had stable disease (SD) and 5 had progressive disease (PD). All eight responses were in eleven patients having a tumor burden < 50 cm2 and a time since last rituximab therapy of ≥ 230 days. No responses were achieved in four patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of < 230 days. Four of 5 patients (80%) with a prior stem cell transplant responded. Progression free survival [PFS] is 5.7 months and ongoing. Seven patients (47%) required at least one dose reduction with a median time to first dose reduction of 2.3 months (1.2–4.9). Grade 4 adverse events were neutropenia (13%), thrombocytopenia (13%), and thromboembolism (13%). Most common Grade 3 adverse events were neutropenia (33%) and leukopenia (20%). Conclusion: Lenalidomide oral monotherapy produced a 53% response rate in relapsed/refractory MCL with manageable side effects.

Abstract Background: Indolent non-Hodgkin’s lymphoma (NHL) has a median survival as long as 10 years but is rarely cured. Lenalidomide (Revlimid®), an immunomodulatory drug, is approved in the US for treatment of myelodysplastic syndromes associated with a del[q5] cytogenetic abnormality and is approved both in the US and the EU for the treatment of relapsed/refractory multiple myeloma. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: This study was designed to assess the safety and efficacy of lenalidomide monotherapy in patients with relapsed/refractory indolent NHL. Methods: Patients with relapsed/refractory indolent NHL with measurable disease ≥ 2cm 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 for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Forty-three patients were enrolled in the study and included in this analysis. The median age was 63 (43–89) and 17 were female. Histology was small lymphocytic lymphoma [SLL] (n=18), follicular center lymphoma grades 1, 2 [FCL] (n=22), nodal marginal B-cell lymphoma (n=2) and extranodal marginal zone B-cell lymphoma of MALT type (n=1). Median time from diagnosis to lenalidomide treatment was 4.5 (0.4–24) years and median number of prior treatment regimens was 3 (1–15). Eleven of the 43 patients (26%) exhibited an objective response (2 complete responses (CR), 1 complete response unconfirmed (CRu), 8 partial responses (PR)), 15 had stable disease (SD), 13 had progressive disease (PD) and 4 were not evaluated. Responses included 4/18 SLL (22%) and 7/22 FCL (32%). Median time to response was 3.6 months (range 1.7–4.1). Progression free survival is 4.6 months for all patients, > 7.7 months (range 4.4 - > 13.5) for responding patients and ongoing. Sixteen patients (37%) required at least one dose reduction with a median time to first dose reduction of 2 months (0.5–9.6). The most common Grade 4 adverse event was neutropenia (14%) and the most common Grade 3 adverse events were neutropenia (21%) and thrombocytopenia (12%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory indolent NHL.

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.

Abstract Background: High dose chemotherapy with stem cell transplant is currently employed in relapsed/refractory aggressive Non-Hodgkin’s Lymphoma (NHL). Lenalidomide (Revlimid®), an immunomodulatory drug, has shown activity in hematological malignancies including relapsed/refractory multiple myeloma, chronic lymphocytic leukemia and cutaneous T-cell lymphoma. Aim: To determine the activity and safety of lenalidomide monotherapy in relapsed/refractory aggressive NHL following stem cell transplant (SCT). 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 for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: Fourteen (29%) of the 49 patients enrolled into the study had a prior SCT. Median age was 61 (23–76) and 5 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=5), follicular center lymphoma grade 3 [FL] (n=2), mantle cell lymphoma [MCL] (n=5) and transformed [TSF] (n=2). Median time from diagnosis to lenalidomide was 3.9 (1.1–31.4) years and median time from SCT to study entry was 1.9 (0.5–11.7) years. The median number of prior treatment regimens was 5 (2–8). Seven patients (50%) exhibited an objective response (1 complete response unconfirmed (CRu), and 6 partial responses (PR)), 5 had stable disease (SD) and 2 patients had progressive disease (PD). Six responses were in eight patients having a tumor burden < 50 cm2 and a time since last rituximab therapy of ≥ 230 days. One response was achieved in six patients having a tumor burden ≥ 50 cm2 or a time since last rituximab therapy of < 230 days. Four of 6 (67%) patients who had SCT as their last treatment prior to lenalidomide [median time from SCT to lenalidomide = 0.8 (0.5–4.8) years] responded. Progression free survival [PFS] is 4.5 months and ongoing. Six patients (43%) required at least one dose reduction with a median time to first dose reduction of 1.6 months (0.4–4.9). Two patients each (14%) had Grade 4 adverse events of neutropenia and thrombocytopenia. The most common Grade 3 adverse events were neutropenia (36%), thrombocytopenia (21%), and leukopenia (14%). Conclusion: Lenalidomide produced a 50% response rate with manageable side effects in relapsed/refractory aggressive NHL following stem cell transplant.

Abstract Background: Lenalidomide (Revlimid®) has been reported to show activity in non-Hodgkin’s Lymphoma (NHL). However, prognostic factors predicting an individual patient’s response were unavailable. Aim: To investigate prognostic factors for lenalidomide response in patients with relapsed/refractory aggressive NHL. 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 for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Univariate analyses using Fisher’s exact test and multivariate analyses using logistic regression were conducted to investigate associations of prognostic variables with response. Results: Forty-nine patients received lenalidomide oral monotherapy. The median age was 65 (23-86) and 24 were female. Histology was diffuse large B-cell lymphoma (n=26), follicular center lymphoma grade 3 (n=5), mantle cell lymphoma (n=15) and transformed (n=3). Median time from diagnosis was 2.7 (0.4-32) years and median number of prior treatment regimens was 4 (1-8). Forty-five (92%) of the patients had received prior rituximab and 63% were rituximab-refractory. Seventeen patients (35%) exhibited an objective response (2 complete responses, 4 complete responses unconfirmed and 11 partial responses). Response to lenalidomide was the same for patients who were refractory to rituximab (30%) and those who were not (31%). Three of 4 patients who were rituximab naive responded. Multivariate analysis including IPI, ECOG PS, stage, LDH, # of extranodal sites, age, sex, # of prior regimens and time from diagnosis identified only time since last rituximab and tumor burden as correlated with response. Response to lenalidomide was associated with low tumor burden (52% for <50 cm2v 0% for ≥50 cm2, P=0.033, odds ratio=10.9) and longer time from rituximab to lenalidomide treatment (52% for ≥ 230 days v 6% for <230 days, P=0.031, odds ratio=6.6). Rituximab depletes normal host B-cells and the kinetics for their loss and recovery are consistent with the timing of lenalidomide activity following rituximab. This may be a basis for this effect. However other tumor/host biological factors may also play a role. Patients with favorable values for both prognostic factors (N=24) had a 67% response rate [RR] compared to a 4% RR for patients with unfavorable values (N=25; P< 0.001) and a progression free survival (ongoing) of 7.5 months v 1.9 months. Although absolute lymphocyte count was not selected as a prognostic indicator of response in the multivariate setting, a trend was evident in the univariate analysis (42% for > 0.6 × 109/L v 9% for ≤0.6 × 109/L, P=0.071). Conclusion: Tumor burden and host immune competence may determine the response of relapsed/refractory aggressive NHL to lenalidomide monotherapy.

8066 Background: Lenalidomide, an immunomodulatory drug, is approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. This study was designed to assess the safety and efficacy of lenalidomide monotherapy in patients with relapsed/refractory indolent non-Hodgkin's lymphoma (NHL). Methods: Patients with relapsed/refractory indolent NHL with measurable disease 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 for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: As of enrollment cut-off, 43 patients received drug and 27 were evaluable for response. The median age was 63 (43–82) and 12 were female. Histology was small lymphocytic lymphoma [SLL] (n=12), follicular center lymphoma grades 1,2 [FCL] (n=12) and nodal marginal B-cell lymphoma [NML] (n=3). Median time from diagnosis to lenalidomide was 4.3 (0.4- 24) years and median number of prior treatment regimens was 3 (1–17). Seven patients (26%) exhibited an objective response (2 complete responses (CR), 1 complete response unconfirmed (CRu) and 4 partial responses (PR)), 9 had stable disease (SD) for a tumor control rate (TCR) of 59% and 11 progressive disease (PD). Responses were produced in each of the indolent histologic subtypes studied: SLL (3/12), FCL (3/12) and NML (1/3). Since most responses develop at ≥ 4 months, additional responses may be seen in early SD patients with longer follow-up. Five patients (12%) exhibited Grade 4 neutropenia, and Grade 3 adverse events were neutropenia (16%) and thrombocytopenia (14%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory indolent NHL. [Table: see text]