Efficacy Of Lenalidomide Research Articles

Efficacy and Safety of Lenalidomide (LEN) Plus Low-Dose Dexamethasone (DEX; Rd) in Chinese Patients (Pts) With Relapsed/Refractory Multiple Myeloma (RRMM) According to Disease Stage (International Staging System [ISS]): Results From the MM-021 Trial and MM-024 Extended Access Program (EAP)

Efficacy and Safety of Lenalidomide (LEN) Plus Low-Dose Dexamethasone (DEX; Rd) in Chinese Patients (Pts) With Relapsed/Refractory Multiple Myeloma (RRMM) According to Disease Stage (International Staging System [ISS]): Results From the MM-021 Trial and MM-024 Extended Access Program (EAP)

PACE as salvage therapy for relapsed or refractory multiple myeloma

PACE as salvage therapy for relapsed or refractory multiple myeloma

Use of Lenalidomide in 5q-Myelodysplastic Syndrome Provides Novel Treatment Prospects in Management of Pulmonary Sarcoidosis

We present the case of a 71-year-old woman with a long-standing history of refractory pulmonary sarcoidosis, who, upon commencement of treatment with lenalidomide for her newly diagnosed 5q-myelodysplastic syndrome, showed a remarkable, immediate, unexpected response and recovery of her sarcoidosis-related symptoms, improvement of her vital capacity, and complete clearance of her bibasal alveolor infiltrates. To our knowledge, this is the first case to report on the significant and immediate efficacy of lenalidomide in the management of pulmonary sarcoidosis. It provides a potential role for the use of lenalidomide as a novel therapeutic agent in patients with refractory pulmonary sarcoidosis.

Lenalidomide in patients with Relapsed or Refractory HTLV-1 Related Adult T cell Leukemia/Lymphoma (ATLL)

Adult T-cell Leukemia/Lymphoma (ATLL) is resistant to chemotherapy and the acute and lymphomatous subtypes of disease have a dismal prognosis. There is no standard therapy for relapsed or refractory disease in Western countries and new agents are being explored. Lenalidomide is an immunomodulatory agent with promising activity in hematologic malignancies, including non-Hodgkin's lymphoma and represents a novel therapeutic option. We investigated the safety and efficacy of lenalidomide (25 mg once daily) on Days 1 to 21 of every 28-day cycle in a phase two study of patients with relapsed or refractory ATLL. The study was closed early due to limited patient accrual. Of 4 patients enrolled, no response was observed in two patients evaluable for response. No grade 3 or 4 toxicity was noted. In this small single institution experience, lenalidomide showed no clinical activity and manageable toxicity in two evaluable patients with relapsed or refractory ATLL. This experience highlights the need for collaborative studies of this rare disease and enrolling patients on clinical trials promptly.

Lenalidome in combination with rituximab for relapsed or refractory mantel cell lymphoma: Updated analysis of a phase 2 trial.

8542 Background: We previously reported favorable safety and efficacy of lenalidomide plus rituximab in relapsed or refractory (R/R) mantle cell lymphoma (MCL) in a phase 1/2 trial (Wang et al, Lan...

Randomized, phase III trial of the efficacy and safety of lenalidomide plus R-CHOP vs R-CHOP in patients with untreated ABC-type diffuse large B-cell lymphoma.

TPS8600 Background: The activated B-cell like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL) is associated with inferior PFS and OS with R-CHOP-based chemotherapy. Lenalidomide demonstrated...

Lenalidomide in treating patients with castration-resistant prostate cancer.

This analysis was conducted to evaluate the efficacy and safety of lenalidomide based regimen in treating patients with castration-resistant prostate cancer. Clinical studies evaluating the efficacy and safety of lenalidomide based regimens on response and safety for patients with castration-resistant prostate cancer were identified using a predefined search strategy. A pooled response rate (rate of PSA level decline of ≥50%) to treatment was calculated. In lenalidomide based regimen, 3 clinical studies which including 98 patients with castration-resistant prostate cancer were considered eligible for inclusion. These lenalidomide based regimens included cisplatin, doxorubicin, or GM-CSF. Pooled analysis suggested that, in all patients, the pooled PSA level decline of ≥50% was 13.3% (13/98) in lenalidomide based regimens. Fatigue, nausea and vomitting were the main side effects. No grade III or IV renal or liver toxicity were observed. No treatment related death occurred in patients with lenalidomide based regimens. This evidence based analysis suggests that lenalidomide based regimens are associated with mild response rate and acceptable toxicities for treating patients with castration-resistant prostate cancer.

Efficacy and Safety of Lenalidomide in the Treatment of Multiple Myeloma

Background:Lenalidomide has emerged as an important treatment for patients with multiple myeloma (MM). However, its role in the management of MM is still controversial and requires further clarification. The aim of this study was to evaluate efficacy and safety of lenalidomide for MM using a meta-analysis.Methods:We searched the electronic databases including: PubMed, EMBASE and the Cochrane Center Register of Controlled Trials. Seven randomized clinical trials were identified, which included a total of 2357 patients with MM who received lenalidomide-containing, noncontaining lenalidomide regimens or placebo as induction therapy or maintenance therapy. The outcomes included overall response (OR) rate, complete response (CR) rate, 3-year progression-free survival (PFS) rate, 3-year overall survival (OS) rate, and different types of treatment-related adverse events. We calculated the risk ratios (RRs) as well as their 95% confidence intervals of these outcomes and pooled the results using RevMan 5.2 software.Results:For patients with previously untreated MM, OR rate and CR rate was significantly higher in lenalidomide-containing group than the control group. For relapsed or refractory MM patients, lenalidomide-containing regimens significantly improved the OR rate, CR rate, 3-year PFS rate and 3-year OS rate. With regard to MM patients after autologous stem cell transplantation, lenalidomide maintenance therapy significantly improved 3-year PFS rate but did not result in improved 3-year OS rate. In terms of toxicities, lenalidomide therapy has a higher rate of Grade 3–4 grade cytopenias, infection, deep-vein thrombosis, and diarrhea. Furthermore, the incidence of second primary malignancies was significantly higher in the lenalidomide group.Conclusions:The lenalidomide-containing regimens as induction therapy clearly increased response rates and improved intervals of survival with acceptable toxicity rates for patients with MM. However, when physicians choose to use the lenalidomide as maintenance therapy, whether the benefits outweigh the risks should be taken into account.

43 A PREDICTIVE MODEL OF RESPONSE TO ERYTHROPOIETIC STIMULATING AGENTS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME

Downregulation of cereblon (CRBN) gene expression is associated with resistance to the immunomodulatory drug (IMiD) lenalidomide and poor survival outcomes in multiple myeloma patients. However, the importance of CRBN gene expression in patients with myelodysplastic syndrome (MDS) and its impact on lenalidomide therapy are not clear. In this study we are following up our earlier investigation (results were published in EJH). We are presenting data from larger sample of patients and in addition bringing the results from lower risk MDS patients without del(5q), marked as non-5q-, treated with lenalidomide. We evaluate cereblon expression in mononuclear cells isolated from peripheral blood (PB) [43 lower risk MDS with isolated 5q deletion (5q-), 53 non-5qand 32 healthy controls] and from bone marrow (BM) [27 lower risk MDS with 5q-, 38 non-5qlower risk MDS and 25 healthy controls] to gain insight into, firstly, the role of cereblon in lower risk MDS patients with or without 5q deletion, and secondly, into the mechanism of lenalidomide action. Patients with 5qlower risk MDS have the highest levels of CRBN mRNA in comparison with both lower risk MDS patients without del(5q) and healthy controls. Five non-5qanemic patients who were treated with lenalidomide showed all lower levels of CRBN mRNA. All these patients did not respond to the treatment. CRBN gene expression level was analyzed by using the reverse transcriptase quantitative “best coverage” TaqMan PCR assay with primers in exon 9 and 10 and probe on exon 9. This assay allowed the detection of the full-length CRBN transcript but not alternative splicing forms without exon 10 (binding site of IMiDs on CRBN). We found that a high level of full-length CRBN mRNA in both bone marrow and peripheral blood mononuclear cells of lower risk MDS with isolated 5q deletion corresponds to the efficacy of lenalidomide in these patients. Moreover, we found that patients who stopped responding to lenalidomide and whose disease progressed showed a sudden decrease of CRBN gene expression. Supported by the research grant NT/13836 from the IGA, Ministry of Health, Czech Republic.

Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial

Patients with metastatic castration-resistant prostate cancer have few treatment options. We investigated the safety and efficacy of lenalidomide, an immunomodulatory agent with anti-angiogenic properties, in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer. In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned chemotherapy-naive patients with progressive metastatic castration-resistant prostate cancer in a 1:1 ratio to receive docetaxel (75 mg/m(2)) on day 1 and prednisone (5 mg twice daily) on days 1-21 and either lenalidomide (25 mg) or placebo once daily on days 1-14 of each 21 day treatment cycle. Permuted block randomisation was done with an interactive voice response system and stratified by Eastern Cooperative Oncology Group performance status, geographic region, and type of disease progression. Clinicians, patients, and investigators were masked to treatment allocation. The primary endpoint was overall survival. Efficacy analysis was by intention to treat. Patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00988208. 1059 patients were enrolled and randomly assigned between Nov 11, 2009, and Nov 23, 2011 (533 to the lenalidomide group and 526 to the control group), and 1046 patients received study treatment (525 in the lenalidomide group and 521 in the placebo group). At data cutoff (Jan 13, 2012) after a median follow-up of 8 months (IQR 5-12), 221 patients had died: 129 in the lenalidomide group and 92 in the placebo group. Median overall survival was 17·7 months (95% CI 14·8-18·8) in the lenalidomide group and not reached in the placebo group (hazard ratio [HR] 1·53, 95% CI 1·17-2·00, p=0·0017). The trial was subsequently closed early due to futility. The number of deaths that occurred during treatment or less than 28 days since the last dose were similar in both groups (18 [3%] of 525 patients in the lenalidomide group vs 13 [2%] of 521 patients). 109 (21%) patients in the lenalidomide group and 78 (15%) in the placebo group died more than 28 days from last dose, mainly due to disease progression. At least one grade 3 or higher adverse event was reported in 381 (73%) of 525 patients receiving lenalidomide and 303 (58%) of 521 patients receiving placebo. Grade 3-4 neutropenia (114 [22%] for lenalidomide vs 85 [16%] for placebo), febrile neutropenia (62 [12%] vs 23 [4%]), diarrhoea (37 [7%] vs 12 [2%]), pneumonia (24 [5%] vs five [1%]), dyspnoea (22 [4%] vs nine [2%]), asthenia (27 [5%] vs 17 [3%]), and pulmonary embolism (32 [6%] vs seven [1%]) occurred more frequently in the lenalidomide group than in the placebo group. Overall survival with the combination of lenalidomide, docetaxel, and prednisone was significantly worse than with docetaxel and prednisone for chemotherapy-naive men with metastatic, castration-resistant prostate cancer. Further research with this treatment combination is not warranted. Celgene Corporation.

Efficacy and safety of low-dose lenalidomide plus dexamethasone in patients with relapsed or refractory POEMS syndrome.

Although autologous stem cell transplantation or melphalan-based chemotherapy has significantly improved the prognosis of POEMS syndrome, a few patients will relapse or be refractory to primary therapy, and there is a lack of studies regarding these patients. In this study, we used low-dose lenalidomide (10mg daily) and dexamethasone (40mg, once weekly) to treat twelve patients with relapsed (n=8) or refractory (n=4) POEMS syndrome. After a median follow-up time of 20months, the overall hematologic response rate was 77% with 44% having a complete response. Eight (67%) patients had neurological response, and the median overall neuropathy limitation scale score was reduced from 3 (range, 1-9) to 2 (range, 0-6). Serum vascular endothelial growth factor response rate was 91% and 46% of patients had normal serum VEGF levels. One patient had progression of the disease 3months after the end of treatment and subsequently died from the disease. Therefore, the estimated 2year overall survival and progression-free survival were 92%. The low-dose lenalidomide and dexamethasone regimen was well tolerated, with no treatment-related death or any grade 3 or 4 toxicity. In conclusion, low-dose lenalidomide plus dexamethasone therapy is an effective and safe regimen for patients with relapsed or refractory POEMS syndrome.

Dose-adjusted Lenalidomide Combined with Low-dose Dexamethasone Rescues Older Patients with Bortezomib-resistant Multiple Myeloma.

The aim of this study was to assess the safety and efficacy of lenalidomide (Len), with the dose adjusted according to the renal function, plus low-dose dexamethasone (Dex) in older patients with bortezomib (Bor)-resistant multiple myeloma (MM). The study included 68 consecutive patients 70 years of age or older diagnosed with MM at our institute and ineligible for high-dose melphalan therapy plus autologous stem cell transplantation. Fifteen older patients with relapsed or refractory MM (RRMM) previously treated with Bor-containing regimens were treated with the combination of Len plus low-dose Dex. The median treatment duration was 12 months (range, 9 to 43 months), with all patients responding to Len plus low-dose Dex. All patients showed significant renal dysfunction between the beginning and end of treatment; however, the renal function improved in all cases. Treatment with dose-adjusted Len combined with low-dose Dex is an effective and safe therapy for older RRMM patients exhibiting renal impairment after receiving Bor-based therapies.

Efficacy and Safety of Lenalidomide (LEN) Versus Placebo (PBO) in RBC-Transfusion Dependent (TD) Patients (Pts) with IPSS Low/Intermediate (Int-1)-Risk Myelodysplastic Syndromes (MDS) without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs): Results from a Randomized Phase 3 Study (CC-5013-MDS-005)

▪Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs.Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262.Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed.Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. [Display omitted] DisclosuresSantini:Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.

Clinical Impact of TP53 Mutations in Patients with MDS and Isolated Deletion 5(q) Treated with Lenalidomid: Results from the German Prospective Le-Mon-5 Trial

Introduction: MDS with isolated deletion 5(q) accounts for approximately 5% of all MDS cases. A recent retrospective analysis has found a cumulative progression rate of 18% after 5 years in patients with MDS deletion 5(q) without an increased medullary blast count[1]. Retrospective analyses have indicated that mutations in TP53 have an adverse impact on the clinical course of affected patients and their response to Len treatment. Here we report on the results of the German multi-center, prospective Le-Mon-5 trial that investigated the safety and efficacy of lenalidomide (Len) in patients with MDS and isolated deletion 5(q).Methods: Le-Mon-5 is a trial of Len in patients with MDS with isolated 5q abnormality, a blast count of < 5% in the bone marrow, a platelet count > 50.000/µl and absolute neutrophil counts of > 500/µl in the peripheral blood. Patients were treated with the standard dose of 10 mg Len for 21 days q28 days. The primary endpoint was safety. Secondary endpoints included response according to IWG criteria (2000), time to response, duration of transfusion independency and incidence and time to AML-transformation, respectively. All patients gave written informed consent to the trial including additional molecular genetic analyses. Central cytologic, cytogenetic and histologic review was performed. Mutational analysis of TP53 was done by next generation sequencing (NGS). For generation of PCR amplicon libraries TP53 primer plate assays were used and technically validated within the IRON-II (Interlaboratory Robustness Of Next generation sequencing) study network. Amplicon sequencing of TP53 was performed on a Roche 454 GS Junior system. Mean coverage of sequenced exons was about 800-fold allowing an approximate detection sensitivity of 2% mutational burden.Results: A total of 91 patients were enrolled into the trial. Of those, 71 patients (male, n=13) were analyzed for TP53 mutations. Median age was 71 years (range 40-88 years). TP53 mutations prior to treatment initiation with Len were found in 7 patients (10%). There was no difference between the TP53 mutated (TP53mut) versus TP53 wildtype patients (TP53WT) with regard to age, IPSS risk, hemoglobin levels, absolute neutrophil counts and platelet counts at baseline. Transfusion independence was achieved in a significantly lower proportion of patients in the TP53mut group versus TP53WT group (43% vs. 62%, p=0.036). Moreover, median survival was significantly shorter in the TP53mut group as compared to TP53WT group (533 days vs. not reached, p=0.0002). No difference was seen with regard to cytologic and cytogenetic response. Data on evolution into AML are currently being collected. Of 2 patients we had follow-up samples available. Both patients showed no difference with regard to the mutation frequency after a follow-up of 4-17 months on Len treatment (27% and 51%, respectively), although one of the patients achieved a complete cytogenetic response during Len treatment.Conclusions: Using the NGS technique on a routine basis, we achieved high quality runs with a high mean coverage of analyzed exons of TP53. Presence of TP53 mutations adversely affected response to Len with regard to transfusion independence. Moreover, TP53mut patients had a shorter overall survival as compared to TP53WT patients underlining the prognostic relevance of TP53 mutations in this patient cohort. Therefore, mutation analysis of TP53 might guide treatment decisions in the future, e.g. consideration of combination regimens. Since the TP53 clone obviously prevails during Len treatment, careful monitoring for signs of transformation should be performed. DisclosuresPlatzbecker:Celgene Corp.: Honoraria, Research Funding. Götze:Celgene Corp, Novartis Pharma: Honoraria. Schlenk:Celgene Corp.: Research Funding, Speakers Bureau. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bug:Celgene: Honoraria, Research Funding. Germing:Celgene Corp.: Honoraria, Research Funding. Nolte:Celgene Corp., Novartis Pharma: Honoraria, Research Funding.

Interim Results of a Phase I Study of Lenalidomide (CC-5013) Plus Intraventricular/Intravenous Rituximab for Recurrent/Refractory CNS and Intraocular Lymphoma

BACKGROUND: There is an unmet need for effective therapies for relapsed/refractory primary and secondary central nervous system (CNS) and intraocular lymphomas (IOL), complications that are increasing in frequency among patients age >60. Whole brain irradiation, broadly utilized in the relapsed setting, yields insufficient efficacy and considerable morbidity, particularly in older patients. Implementation of new agents that selectively target survival pathways upregulated in refractory CNS lymphoma would have significant impact. Lenalidomide (CC-5013) has established activity as a single agent in aggressive NHL, particularly in ABC-type DLBCL. We recently demonstrated the activity of lenalidomide, at modest doses, in the treatment of recurrent/refractory intraocular and CNS lymphoma (J. Clin Oncol, 2011). We also provided evidence of cereblon-dependent efficacy of lenalidomide in preclinical models of patient-derived CNS DLBCL (ASH, 2013). These observations are the basis for this first trial of IMiD® immunomodulatory compound therapy in CNS NHL, as monotherapy, and in patients with inadequate responses to lenalidomide, in combination with combined intravenous plus intraventricular rituximab. (NCT01542918).METHODS: The primary objective of this phase I study is to evaluate the safety and efficacy of lenalidomide at three dose levels (10, 20, and 30mg) in relapsed/refractory CD20+ CNS NHL, with staging evaluations involving brain, CSF and intraocular compartments. Key secondary endpoints include: (1) determination of extent of CSF penetration by lenalidomide; (2) feasibility and activity of combined intraventricular and intravenous rituximab plus lenalidomide in patients with recurrent CNS lymphoma, not responsive to lenalidomide monotherapy; (3) evaluation of the effects of lenalidomide on the tumor microenvironment, including effects on tumor metabolism and immune cell infiltration and phenotypes.RESULTS: Thus far, seven subjects with relapsed CNS DLBCL (6 PCNSL, 1 SCNSL) have been treated on protocol at UCSF (median age 63, range 46-77). Each had methotrexate-resistant disease and 4 had lymphoma refractory to high-dose chemotherapy. In general, lenalidomide has been well-tolerated in the CNS lymphoma population with one DLT (non-hematologic) noted at the 20 mg dose level: fatigue and memory loss. Clinical benefit has been noted in 3 out of 4 patients with IOL, with 1 PR > 6 months duration and 1 SD > 10 months duration, each to lenalidomide monotherapy. Brain parenchymal responses to lenalidomide monotherapy (20 mg) have been demonstrated at restaging MRI, including 1 CR and 1 PR. There has been 1 CR in the leptomeninges with resolution of B-cell lymphoma in CSF, quantified by serial flow-cytometry. Combined intraventricular (20 mg) plus intravenous infusion of rituximab was well-tolerated in 3/3 patients and, with 10 mg lenalidomide, resulted in 1 PR in highly refractory IOL. Using GC/MS, we demonstrated lenalidomide penetration in ventricular CSF (0.6-7.9 ng/ml) in each of 4 patients, 12-15 hours after dosing at the 20 mg level, but trough lenalidomide concentrations >0.5 ng/ml were detected in only 1 of 3 patients receiving 10 mg lenalidomide. Serial metabolomic profiling revealed that CSF lactate correlated with clinical response to lenalidomide. Finally, we demonstrated that lenalidomide is reproducibly associated with a rapid and reversible effect on peripheral blood macrophage polarization to an M1, iNOS+ phenotype.CONCLUSIONS: These preliminary results provide evidence that lenalidomide is well-tolerated at 10 and 20 mg dose levels in CNS lymphoma. We demonstrate for the first time lenalidomide penetration in ventricular CSF, with higher trough concentrations detected at 20 mg compared to the 10 mg dose level. Encouraging evidence of lenalidomide efficacy in relapsed CNS DLBCL has been demonstrated in intraocular, CSF and brain compartments. Combined intraventricular and intravenous infusion of rituximab is feasible and represents a novel strategy to the potentiation of immunotherapeutic strategies in brain tumors. Studies are in progress to further elucidate the safety, pharmacokinetics and mechanisms involved in this biological approach to the treatment of refractory CNS lymphomas.Supported by NCI, Leukemia and Lymphoma Society, UCSF Helen Diller Comprehensive Cancer Center, Celgene and Genentech DisclosuresOff Label Use: Intrathecal administration of rituximab. Wang:Celgene: Employment. Chen:Celgene: Employment.

Phase II Randomized, Multicenter Study of Lenalidomide Vs Best Investigator’s Choice in Relapsed/Refractory Mantle Cell Lymphoma: Results of the MCL-002 (SPRINT) Study

Introduction: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with poor outcome, especially after failure of first-line treatment. Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, has shown activity in single-arm phase II studies of patients with relapsed/refractory (R/R) MCL. The present controlled randomized study compared the efficacy and safety of lenalidomide vs investigator’s choice (IC) in patients with R/R MCL.Methods: MCL-002 (SPRINT), a European multicenter, open-label, phase II study enrolled patients with up to 3 relapses or who failed prior therapy and were ineligible for intensified treatment or stem cell transplantation (NCT00875667). Oral lenalidomide was given at 25 mg/day on days 1-21 of each 28-day cycle until progressive disease (PD) or intolerability. The IC treatment consisted of single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil. Patients who progressed on IC per investigator judgment were allowed to crossover to lenalidomide. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), time to first response, duration of response (DOR), overall survival (OS), and safety. Response assessments were centrally reviewed using the modified IWG criteria.Results: 254 patients with R/R MCL were randomized 2:1 to lenalidomide (n=170) or IC (n=84). Patients had median age 68.5 years, were predominantly male (73%), and had received a median of 2 prior therapies. 91% had stage III/IV disease at diagnosis, with 34% high-risk MIPI, 43% high tumor burden, and 20% bulky disease at baseline. Overall, patients on the lenalidomide arm had a worse prognostic profile than the IC arm due to higher tumor burden and disease risk (>5 percentage points for a number of parameters). After a median time of 2.9 months, 39 patients (46%) from the IC arm crossed over to lenalidomide due to PD. Overall, 84 patients remain on lenalidomide (15 having crossed over from IC) and 11 patients on IC without PD.At a median follow-up time on study of 15.9 months, the risk reduction for PFS was 39% (HR=0.61 [95% CI, 0.44-0.84]; P=0.004; Table) in favor of lenalidomide (median PFS: 8.7 months lenalidomide vs 5.2 months IC). ORR was significantly improved for lenalidomide vs IC (40% vs 11%; CR/CRu 5% vs 0%). Median time to first response was 4.3 months for lenalidomide (not reached for IC). Median DOR (16.1 vs 10.4 months) and OS on mature data (27.9 vs 21.2 months) were longer for lenalidomide vs IC. Efficacy results were consistent among subgroups. Safety data in 250 patients receiving ≥1 dose showed more dose reductions in lenalidomide-treated patients (41%) vs IC (17%), due in part to a longer median duration of lenalidomide treatment vs IC, and to strict dose modification rules for lenalidomide. The most common grade 3/4 adverse events (AEs) were neutropenia (lenalidomide 44% vs IC 34% [without increased risk of infection]), thrombocytopenia (18% vs 28%), and leukopenia (8% vs 11%). Tumor flare reaction occurred in lenalidomide patients only (10%; 2% grade ≥3); 1 patient in each arm experienced tumor lysis syndrome. Invasive second primary malignancies were identified in 4% and 5% of lenalidomide and IC treated patients, respectively.Conclusions: The MCL-002 study demonstrated a statistically significant and clinically meaningful improvement in PFS for lenalidomide over best IC monotherapy in patients with advanced R/R MCL despite a worse prognostic profile in the lenalidomide arm at baseline. In addition, ORR and CR rates, TTR, DOR, and OS were improved for lenalidomide over IC. The DOR has been remarkably consistent in various studies with lenalidomide in MCL patients. The safety profile for lenalidomide was as expected and no new safety signals were identified. The results of this first randomized, controlled study of lenalidomide showed superior efficacy compared to IC in patients with R/R MCL with a manageable toxicity profile.TableEfficacy of lenalidomide vs IC in R/R MCLEfficacyLenalidomide (n=170)IC (n=84)PPFS (Lenalidomide vs IC)Median PFS, mo (95% CI)8.7 (5.54-12.14)5.2 (3.67-6.95)Sequential HR (95% CI)0.61 (0.44-0.84)Sequential log-rank test p-value0.004ORR, n (%)68 (40)9 (11)<0.001CR/CRu, n (%)8 (5)0 (0)0.043Median DOR, mo16.110.40.421Median OS, mo27.921.20.52 DisclosuresTrneny:Celgene, Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Research Funding. Walewski:Celgene: Consultancy, Other, Research Funding; Janssen-Cilag: Consultancy; Mundipharma : Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other, Research Funding. Jurczak:Celgene, Eisai, Gilead, Janssen, Pharmacyclics, Pfizer, Roche, Novartis, Spectrum, Takeda, Teva: Research Funding. Belada:Celgene: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Biyukov:Celgene: Employment. Patturajan:Celgene: Employment. Casadebaig Bravo:Celgene: Employment. Arcaini:Celgene, Roche, Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees.

A Phase I/II Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin’s Lymphoma (HL)

Introduction: Phase 2 single agent trials with lenalidomide and panobinostat in patients with relapsed or refractory HL have demonstrated overall response rates (ORR) of 19% (Fehniger et al., Blood 118:5119-5125, 2011) and 27% (Younes et al., JCO 30:2197-2203, 2012), respectively. We conducted a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with combined lenalidomide and panobinostat in patients with relapsed HL.Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy were eligible. Measurable disease > 1 cm, ejection fraction ≥ 45%, ECOG PS 0-2, QTc ≤ 450 msec, ANC ≥ 1200/mm3, platelets ≥ 100,000/mm3, AST/ALT ≤ 2.5 x the upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN, and creatinine clearance 60 ≥ ml/min were also required. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly were combined with lenalidomide 25 mg days 1-21 utilizing a 3+3 standard dose escalation design. DLT was defined during cycle 1 as grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, or other grade 3-4 non-hematologic toxicity. Twenty-eight days defined a cycle and patients could remain on therapy until disease progression. Response was assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 25:579-586, 2007).Results: From Feb 2012 through June 2014, 22 patients (16 males) with cHL (n=21) and LP HL (n=1) and a median age of 45 (range 22-72) have been enrolled. Patients had received a median of 4 prior therapies (range 2-13), 9 patients were refractory to their most recent therapy, and 91% had stage III-IV disease at study entry. Ten patients had a prior autologous SCT, 1 patient had received prior allogeneic EBV-directed cytotoxic T-cells, 1 patient had a prior syngeneic transplant, and 1 patient had both prior autologous and allogeneic transplants. Eleven patients were enrolled in the phase 1 study at dose level (DL) 1 (25 mg lenalidomide + 15 mg panobinostat, n=6) and at DL 2 (25 mg lenalidomide + 20 mg panobinostat, n=5). Although there were no DLTs observed in cycle 1, 2 patients treated at DL 2 experienced grade 4 neutropenia and thrombocytopenia for > 14 days in cycle 2 and 3 of 5 patients were dose reduced to DL 1 in cycles 2 or 3. Therefore, DL 1 was expanded to 6 patients to ensure patient safety at this dose level and the phase 2 study was conducted at DL 1. Eleven patients have been treated in the phase 2 study. In all 22 patients, the median number of cycles completed on study was 4 (range 1-22). Grade 3-4 toxicities in all patients included neutropenia (59%), thrombocytopenia (41%), lymphopenia (27%), febrile neutropenia (27%), hypophosphatemia (9%), hypocalcemia (5%), QTc prolongation (5%), fatigue (5%), nausea/vomiting (5%), erythema nodosum (5%), transaminitis (5%), and unexplained altered mental status after administration of study medications (5%). Dose reductions were required in 10 patients (45%, 5 in the phase 2 study and 3 patients with multiple dose reductions) for febrile neutropenia, grade 3-4 neutropenia/thrombocytopenia, erythema nodosum, and transaminitis. Twenty-one patients have discontinued protocol therapy for PD (n=15), adverse events (n=5, including grade 4 neutropenia/thrombocytopenia or unexplained altered mental status after drug dosing), and to undergo elective CABG (n=1). ORR is 14% (2 CR and 1 PR) in 21 evaluable patients with complete responses in 1 patient with cHL and 1 patient with LP HL of 6 and 25 months duration, respectively.Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL. Due to myelosuppression at higher doses, the recommended phase 2 dose of the combination is 25 mg lenalidomide days 1-21 with 15 mg panobinostat days 1, 3, and 5 weekly on a 28-day cycle. Accrual continues to the two-stage phase 2 trial, but based on preliminary data in the first 22 patients, the efficacy of combined lenalidomide and panobinostat appears similar to that previously reported with these drugs as single agents. DisclosuresChristian:Celgene: Research Funding. Fehniger:Celgene: Research Funding. Wagner-Johnston:Celgene: Research Funding. Bartlett:Celgene: Research Funding; Novartis: Research Funding. Blum:Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of Hodgkin’s lymphoma.

A Detailed Analysis of Myelodysplastic Syndrome Complicated By Autoimmune or Inflammatory Disorders: A Possible Efficacy of Low-Dose Lenalidomide

[Background] Approximately 10-20 % of the patients with myelodysplastic syndrome (MDS) are known to be complicated by autoimmune or inflammatory disorders (ADs) such as vasculitis. However, most of the reports on such MDS were published before 2000, in which the diagnosis of MDS was made with previous criteria; about 20% (range 9-43%) of the patients in these reports may not be diagnosed as MDS with the present criteria. In addition, many of these reports do not offer sufficient information on cytogenetic analysis, a presently known critical factor that affect pathophysiology of MDS. These facts could make difficult to discuss its characteristics, prognosis and treatment options. Therefore, we made a detailed retrospective analysis on clinical features and treatment outcomes of MDS complicated by ADs based on more recent knowledge.[Results] A total of 102 Japanese patients with MDS (70 males and 32 females, median age of 73), diagnosed between June 2007 and June 2014, were evaluated. The diagnosis was made with WHO (2008) classification. Bone marrow G-band chromosome analysis was available in 95 % of the patients. "Very High" risk category of IPSS-R criteria comprised 29% of the patients. As summarized in Table 1, 14 episodes of AD were observed in 13 (13%) patients; 4 with Sweet syndrome, 2 each with Bechet like symptoms, interstitial pneumonia, large vessel vasculitis and myelitis, and 1 each with HPS and seronegative arthritis. As in the previous reports, the patients who developed ADs (AD group) were characterized by younger age and higher frequency of complex cytogenetics compared with those who did not (non-AD group). In addition, patients of AD group showed lower neutrophil count and higher frequency of trisomy 8 (p=.034 and <.01, respectively). Of note, despite no significant difference in median IPSS-R score, the progression rate to AML in AD group was more than two-times higher compared with non-AD group (p=.01). Survival rates were not significantly different between two groups.Corticosteroids were given to 8 patients of AD group and 6 of them (75 %) showed a certain degree of responses. Six patients with relapsed or refractory AD after the steroid therapy were treated with low-dose Lenalidomide (LEN) (10mg/day for 21 days). Interestingly, 5 of them responded to LEN with 3 achieving complete remission. Furthermore, the patients of AD group received LEN showed better survival compared with those treated without LEN (1.2y vs. 3.1y, p=.017) (Figure 1).[Conclusion] The present observation indicated that MDS with AD may be associated with cytogenetic abnormalities including trisomy 8 and higher progression rate to AML. Of note, LEN might be a possible treatment option for those resistant to steroid therapy. [Display omitted] [Display omitted] DisclosuresNakamae:Novartis: Honoraria, Research Funding, Speakers Bureau, Travel/accomidations/meeting expenses Other. Hino:Nippon Shinyaku CO.,LTD: Research Funding; astellas CO.,LTD: Research Funding.

Lenalidomide Promotes Degradation of Casein Kinase 1a (CK1a) through Cereblon: Implications for the Efficacy of Lenalidomide in MDS and AML

Background: Lenalidomide has broad clinical activity in hematologic malignancies, including lymphoid malignancies (multiple myeloma (MM), non-Hodgkin’s lymphomas, B cell chronic lymphocytic leukemia) and myeloid malignancies (myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)). Lenalidomide’s molecular mechanism involves modulation of the cullin 4 RING E3 ubiquitin ligase complex (CRL4-CRBN), with downstream effects on protein homeostasis. The binding of lenalidomide to CRL4-CRBN promotes ubiquitination and degradation of Aiolos and Ikaros in B cell lineages (MM, lymphoma), and regulation of Ikaros has been shown to be a key effector of lenalidomide’s anti-myeloma tumoricidal and T cell immunomodulatory activities. Multiple mechanisms of clinical efficacy have been hypothesized for lenalidomide activity in del(5q) MDS; however, lenalidomide-regulated substrates of therapeutic relevance to myeloid malignancies have not been defined. We undertook a proteomics approach to identify such substrates.Methods: Changes in global cellular protein levels were measured by tandem-mass-tagged proteomics in a del(5q) MDS cell line (MDS-L) and an AML cell line (HNT-34), following treatment with vehicle or 10 uM lenalidomide for 8, 24 and 72 hours. Western blot analysis was used to subsequently validate proteins that were differentially regulated in these lenalidomide-sensitive cell lines. Sensitivity to lenalidomide treatment in a panel of myeloid cancer cell lines was evaluated by tritiated thymidine and/or BrdU assays.Results: Across a panel of myeloid cancer cell lines evaluated for sensitivity to lenalidomide, HNT-34 and MDS-L cells were the most sensitive to lenalidomide, with EC50’s of 0.6 and 1.5 µM, respectively, while other cell lines were predominantly insensitive (EC50 > 10 µM). Proteomic analysis of lenalidomide-regulated proteins in MDS-L cells revealed Ikaros as the most down-regulated protein at 72 hrs (5.3 fold), and CK1α was the second most down-regulated protein (2.8 fold). The decrease of Ikaros and CK1α proteins by lenalidomide was confirmed by Western blot analysis in MDS-L and HNT-34 cells. Ikaros protein levels were reduced by lenalidomide in cell lines that were sensitive or insensitive to lenalidomide, suggesting that modulation of other proteins may be responsible for lenalidomide sensitivity of myeloid cancer cells. Ikaros levels were also decreased by a CRBN-binding glutarimide analog in HNT-34 cells, which were insensitive to the analog, further suggesting that Ikaros was not a substrate of consequence to sensitivity. In contrast, an initial study of five cell lines showed that lenalidomide promoted the greatest degradation of CK1a in the most sensitive lines (HNT-34, MDS-L), but did not degrade CK1a in the most insensitive line (MOLM-13). Mechanistic studies addressing CK1α regulation in HNT-34 cells revealed that CK1α protein levels were reduced by lenalidomide treatment in a time- and dose-dependent manner, with maximal reduction of 3.3 fold observed at 4 hrs using 10 µM lenalidomide, and CK1α degradation observed with lenalidomide at a dose as low as 0.1 µM. Pre-treating HNT-34 cells with the proteasome inhibitor MG-132 stabilized CK1α protein levels in the presence of lenalidomide, demonstrating proteasome-dependent degradation. A competition experiment performed by pre-treating HNT-34 cells with the glutarimide analog that binds CRBN, but does not result in the degradation of CK1a, resulted in CK1α protein stabilization in the presence of lenalidomide, demonstrating CRBN-dependence of the lenalidomide-induced degradation. Degradation of CK1α was also observed in primary peripheral blood mononuclear cells of AML patients treated with lenalidomide.Conclusions: CK1α is a lenalidomide-induced substrate of CRL4-CRBN, with initial links to myeloid cancer cell line sensitivity to lenalidomide. As the CSNK1A1 gene is located at 5q32, a commonly deleted region in MDS, further reduction of haplo-insufficient expression of CK1α is a potential mechanism of sensitivity to lenalidomide in del(5q) MDS. The therapeutic relevance of CK1α regulation by lenalidomide in AML requires further exploration. CK1α gene silencing and additional correlative studies of lenalidomide-induced degradation of CK1α are ongoing to define mechanistic links to myeloid cancer cell sensitivity to lenalidomide. DisclosuresHollenbach:Celgene: Employment, Equity Ownership. Lu:Celgene Corp: Employment. Gandhi:Celgene Corp: Employment, Equity Ownership. Chopra:Celgene Corp: Employment, Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership.

A Phase II Study of the Combination of FCR-Lite and Lenalidomide Followed By Lenalidomide Maintenance in Front-Line CLL: The FCR2 Regimen

Introduction: Fludarabine, cyclophosphamide, rituximab (FCR) remains the standard of care for the treatment of newly diagnosed, fit CLL pts requiring therapy. However, the FCR side effects profile is non-trivial and CLL pts with poor risk features have inferior outcomes. Strategies aimed at minimizing toxicity without compromising efficacy have been reported including modifications of the optimal dosing and duration of FCR using a dose-reduced approach (Foon et al, “FCR lite”) or reduction in number of FCR cycles based on MRD status (Strati et al). In the era of biological agents, both preclinical and clinical data have shown the efficacy of lenalidomide (Len) in CLL likely through its role as an immunomodulator and interference with interactions between CLL and its microenvironment. In CLL, Len presents a clinical opportunity both in combination with chemotherapy and as maintenance strategy. This was the rationale for our trial using Len in combination with FCR and as maintenance to improve outcomes and shorten therapy.Methods: We conducted a phase 2 cohort study examining the combination of dose-reduced FCR and Len (“FCR2”) followed by Len maintenance for treatment naïve, CLL pts requiring therapy (NCIWG criteria). Eligible pts (age ≥18 yr, ECOG 0-2, CrCl ≥30 ml/min, absence of AIHA) were treated with 4-6 cycles of FCR2 (D1-3 fludarabine 20 mg/m2, D1-3 cyclophosphamide 150 mg/m2, D1&15 rituximab 500 mg/m2 every 28 days). Len was administered on D 8-28 of each cycle (starting dose of 5 mg increasing to 10 mg and 15 mg in cycle ≥ 2 based on toxicity algorithm). Pts who were MRD (-) in PB and BM (multicolor flow cytometry) initiated Len maintenance after cycle 4 FCR2 (otherwise proceeded to 6 cycles). Supportive care included asa 81 mg, pegfilgrastim, and antimicrobial prophylaxis (ciprofloxacin, bactrim, fluconazole, acyclovir). Daily Len maintenance started two months after FCR2 completion in responding pts for a total of 12 months (5-15 mg based on toxicity algorithm). The primary study endpoint was the proportion of CR pts after cycle 4 of FCR2 with ≥ 8/19 (≥ 40%) CR+CRi considered a positive result and worthy of further study (α 0.05, β 90%). Secondary endpoints included MRD status, ORR, OS, PFS and toxicity (CTCAE V. 4.0). We report the primary endpoint and preliminary data on non-survival secondary endpoints.Results: 25 pts met inclusion criteria for enrollment of which 22 pts enrolled and 19 were evaluable (consent was withdrawn on 3 pts after ≤ 4 FCR2 cycles due to pt preference n=1, physician preference n=2, one additional pt withdrew consent after cycle 5 to proceed with Allo SCT.) Baseline characteristics expressed as median (range) were as follows: age 62.5 yr (42-75 yr), ECOG PS 1 (0-2), WBC 115.4 x 109/L (8.7-301.7), Hb 12.2 g/dL (7.8-15.3), Plt 131 x 109/L (60-178), IgG 602 mg/dL (294-1018), β2mg 2.8 μg/mL (1.74-6.69), LDH u/L 471 (132-1022), BM % lymphs 75 (25-100%), baseline SPD 23.4 (2.9-63.5). In addition 30% pts had Rai stage III-IV, 53% unmutated-CLL, 5% del17p and 30% del11q. After 4 cycles of FCR2 (n=19) response rates were as follows CR 47%, CRi 5%, PR 42%, SD 5% (pts were MRD neg in 29% BM and 56% PB samples, 3 pts (16%) were MRD neg in both PB and BM). After 6 cycles of FCR2 (n=16), response rates improved and were as follows: 63% CR, 13% CRi, 19% PR, 5% PD (pts were MRD neg in 50% BM and 72% PB samples). Table 1 shows MRD status following 4 and 6 cycles of FCR2. During induction, 12 pts required a treatment interruption or dose reduction of Len per protocol (median dose of len was 10 mg). The most common grade 3-4 toxicities were as follows (% events): neutropenia (51%), leukopenia (20%), hyperglycemia (5%), NTP fever (5%). Grade 3-4 TLS and tumor flare were not noted. The med follow up for the entire cohort is 13.1 months (7.3-22.5 months). One progression has occurred in a pt who withdrew from study after 2 cycle of FCR2. One death has occurred in a pt with del17p who died on D+255 following allogeneic SCT in CR from the complications of cGVHD. 10 pts have gone on to initiate Len maintenance.Conclusions: FCR-lite in combination with Len is feasible and demonstrates encouraging clinical activity in a high-risk, CLL pt population with an acceptable toxicity profile. A significant proportion of pts are MRD neg in PB and/or BM following FCR2. Addition of Len to FCR may minimize chemotherapy exposure without compromising outcome. Table 1:MRD StatusFollowing Cycle 4 FCR2Following Cycle 6 FCR2Bone Marrow29%50%Peripheral Blood56%72% DisclosuresMato:Celgene : Honoraria, Research Funding, Speakers Bureau.