Clinical Trial Of Lenalidomide Research Articles

Phase 1 Results of Anti-PD-Ligand 1 (Durvalumab) & Lenalidomide in Patients with Cutaneous T Cell Lymphoma and Correlation with Programmed Death Ligand 1 Expression and Gene Expression Profile

Background:T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab (NCT03011814) to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/ lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods:Phase 1 portion to evaluate the safety and tolerability of the durvalumab and lenalidomide combination has completed enrollment. Pts were enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results:Thirteen pts. were evaluable for toxicities and 12 patients evaluable for response. 10 males/3 females, median age 36 (29-72 y), with aggressive or refractory/advanced CTCL, clinical stages IB (2), IIA (3), IIB (6), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-8) have been enrolled. Dose level 1 (n=3), dose level 2 (n= 3), dose level 3 (n=4). Median follow up time was 16.1 months (range, 3.7-36.1) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=8), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. One patient discontinued treatment due to fatigue. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Median cycles of treatment were 7 (range, 1-28). Median duration of response was 6 (range, 1- 28+) months. Nine pts achieved PR, 2 pts maintained stable disease and 2 pts developed PD. Five pts remain on treatment. Gene expression levels for several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Gene expression profile highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders; up-regulation of MYC targets, IL2-, JAK-STAT and pro-inflammatory pathways were seen in PD compared to responders. Conclusions:Anti-PD-L1/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to maximum dose of 20 mg lenalidomide daily. Our preliminary results reveal adaptive and innate immune signatures that may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: MiRagen:Consultancy;Stemline:Consultancy;Trillium:Consultancy;Celgene:Research Funding;Kyowa Kirin:Consultancy;Helsinn:Consultancy;Bioniz:Consultancy.Abdulla:Johnson Johnson:Research Funding;Mallinckrodt:Consultancy, Speakers Bureau.Rosen:Seattle Genetics:Consultancy;NeoGenomics:Consultancy;Aileron Therapeutics:Consultancy;Novartis:Consultancy;Pebromene:Consultancy;Celgene:Speakers Bureau;paradigm Medical Communications:Speakers Bureau;Abbvie:Speakers Bureau.Zain:Mundi Pharma:Research Funding;Seattle Genetics:Research Funding;Kyowa Kirin:Research Funding.

Phase 1 Results of Anti-PD-Ligand 1 (Durvalumab) & Lenalidomide in Patients with Cutaneous T Cell Lymphoma and Correlation with Programmed Death Ligand 1 Expression and Gene Expression Profile

Background: T cells in CTCL are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, targeting exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug (IMiD) and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Associations between immune checkpoints, gene expression profile and the clinical efficacy of durvalumab/lenalidomide combination were evaluated. The primary objectives were to determine the recommended phase 2 dose of lenalidomide in combination with durvalumab and safety with primary endpoint of toxicity (using CTCAE 4.03). Secondary end points included objective response rate (ORR) and median duration. Relationships between gene expression profile (GEP), PD-L1 expression, and antitumor activity were exploratory end points. Methods: A Phase 1 portion (NCT03011814) is ongoing to evaluate the safety and tolerability of the durvalumab and lenalidomide combination. Pts are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (dose level 1 = 10 mg for all cycles; dose level 2 = 10 mg for cycle 1, 15 mg for all subsequent cycles; dose level 3 =10 mg for cycle 1, 15 mg for cycle 2, and 20 mg for all subsequent cycles) to characterize safety, efficacy and antitumor activity. Serial skin samples were collected to assess the impact on the tumor microenvironment and anti-tumor activity. Results: Ten pts. were evaluable for toxicities. Nine patients were evaluable for response with three patients at each dose level. 8 males/2 females, age 29-59 y, with refractory/advanced CTCL, clinical stages IB (1), IIA (3), IIB (4), IIIA (1), and aggressive epidermotropic CD8+ CTCL (1) and a median of prior systemic treatments of 3 (range, 2-4) have been enrolled. Median follow up time was 12 (range, 3-24+) months. No serious AEs or DLTs were observed during the DLT evaluation period (cycles 1-3). The most frequently reported AEs were fatigue (n=7), skin pain (n=4), chills (n=3), anemia (n=3), and leukopenia (4). One grade 3 maculopapular rash (possibly due to lenalidomide) was observed, all other treatment-related AEs were grade 1/2 in severity. Median cycles of treatment were 7 (range, 3-20+) months. Median duration of response was 4 (range, 1- 21+) months. Six pts achieved PR, while 3 pts maintained stable disease. Three pts remain on treatment. Expression panels of several checkpoints (PD1, PD-L1 & ICOS) (Cycle1 Day1 vs Cycle 2 Day15) were analyzed. Detectable levels of PD-L1 but low levels of ICOS are observed in responding pts vs. high PD-L1 and ICOS levels in non-responders. GEP highlights downregulation of TNF-alpha signaling via NFkB, IFN-gamma, and PI3-AKT-mTOR signaling pathways among other pathways. Conclusions: Durvalumab/lenalidomide has significant clinical activity in refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion. Responses were durable and ongoing, and treatment was well tolerated. Dose escalation is up to lenalidomide 20 mg daily. Our preliminary results from pts on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. Disclosures Querfeld: Bioniz: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Soligenix: Other: Investigator; Celgene: Other: Investigator, Research Funding; City of Hope Cancer Center and Beckman Research Institute: Employment; Medivir: Consultancy; Trillium: Consultancy, Other: Investigator, Research Funding; miRagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Kyowa: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Eisai: Other: Investigator; Elorac: Other: Investigator, Research Funding; Helsinn: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Investigator. Palmer:Gilead Sciences: Consultancy. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy.

Phase 1/2 Trial of Durvalumab and Lenalidomide in Patients with Cutaneous T Cell Lymphoma (CTCL): Preliminary Results of Phase I Results and Correlative Studies

Background: In CTCL, intratumoral T cells are functionally exhausted and are characterized by the expression of immune inhibitory molecules such as PD1 and PD-L1 (Cancer Immunol Res 6; 2018). These findings justify the evaluation of immune checkpoint inhibition to reverse T cell exhaustion in CTCL. To this end, we initiated a phase 1/2 clinical trial of lenalidomide and durvalumab to determine the safety and efficacy of this regimen. Durvalumab is a human monoclonal antibody with high affinity and selectivity for PD-L1, with mechanisms of action that target the exhausted T cells and distinct cells within their environment. Lenalidomide, an oral immunomodulatory drug and analog of thalidomide, has previously shown activity in CTCL (Blood 123; 2014). Durvalumab may restore an anti-tumor immune response, and the combination of durvalumab and lenalidomide may enhance immune checkpoint blockade-induced immune responses. Methods: A Phase 1 portion is ongoing to characterize the safety and tolerability of durvalumab and lenalidomide combination. Patients (pts) are enrolled in sequential cohorts to receive durvalumab (fixed dose at 1500 mg) and dose escalation of lenalidomide (cohort 1 = 10 mg; cohort 2 = 15 mg; subsequent planned dose increments of 5 mg) to evaluate safety, efficacy and antitumor activity. Serial skin and blood samples were collected to assess the impact on the tumor micro-environment. We examined the correlation between clinical response and resistance and the following biological factors: PD1 clustering at the single molecule level using super-resolution microscopy, and expression of PD-L1 and ICOS at the tissue level by means of multiplex immunohistochemistry on pre-treatment primary cells (migrated from skin explants), and skin tissue (formalin-fixed and paraffin-embedded) from clinical trial subjects. Results: Six patients (5 males/1female, age 32-57 years) with refractory/advanced CTCL (mycosis fungoides/Sezary syndrome subtype), clinical stage IB (1), IIA (1), IIB (3), IIIA (1) have been enrolled as of July 2018. Duration time on treatment was 4 to 13+ months. Four patients showed improvement of skin disease with 2 patients achieved partial response with > 90% improvement of skin disease by mSWAT. Two patients developed progressive disease. No serious adverse events (AEs) were observed. The most frequently reported AEs were fatigue (n=6), skin pain (n=4), anemia (n=3) chills (n=4), and decreased appetite (n=3). All treatment-related AEs were Grade 1 or 2 in severity. One grade 3 fatigue occurred in one patient. No dose limiting toxicity has been observed to date. Using multispectral microscopy, we analyzed expression panels of several checkpoints: PD1, PD-L1, and ICOS on lesional skin biopsies at baseline. Strong PD-L1 and ICOS expression is observed from non-responders. Detectable levels of PD-L1, but low levels of ICOS is observed in responding patients. Quantitative super-resolution microscopy detected nanoscale clusters of PD1 in T cells from responders and no PD1 clustering was observed in T cells from non-responders. Conclusions: Durvalumab/lenalidomide has significant clinical activity in patients with refractory/advanced CTCL, which will be formally evaluated in the Phase 2 portion of this trial. Responses were durable and ongoing, and treatment was well tolerated with a low toxicity profile. Dose escalation is planned up to lenalidomide 20 mg daily. Our preliminary results from patients on trial demonstrated that immune signatures on skin biopsies at baseline may be predictive of response to checkpoint blockade and yield insights into mechanisms of therapeutic resistance. DisclosuresQuerfeld:Acelion: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees; Bioniz: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Phase I/II Clinical Trial of Lenalidomide in Combination with AT101 for the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia (B-CLL)

Background: Lenalidomide (Len) is clinically active in CLL patients (pts). Robust anti-leukemic immune response from Len is truncated by dysfunctional immune system in CLL and anti-apoptotic bcl-2 protein. We hypothesized that therapeutic downregulation of Bcl-2 may help enhance the killing potential of immune effector cells that are activated by Len. AT-101 is a novel, orally active BH3-mimetic that binds to antiapoptotic Bcl-2 family proteins (Bcl-2, Mcl-1 and Bcl-xL) and induces CLL cell death ex vivo (Masood et al British Journal of Haematology 2012). Encouraging efficacy and safety results of AT-101 alone or in combination with rituximab in CLL have been reported in Phase I/II studies. We have previously demonstrated that bcl-2 downregulation in CLL cells enhanced the killing potential of Len-activated immune cells. Conversely, pretreatment of CLL cells with Len enhanced AT-101 cytotoxicity in an immune cell independent manner (Masood et al British Journal of Haematology 2012). These preclinical findings formed the basis of a phase I/II clinical trial testing the combination of AT-101 and lenalidomide in relapsed B-CLL patients.Methods: The phase I portion of this study (NCT 01003769) utilizes a standard cohort of three design to determine the maximum tolerated dose (MTD) of the combination regimen. The MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients. Following the MTD determination, the phase 2 portion will assess the efficacy of this combination using a one-stage design with an interim analysis. Key inclusion criteria include adult CLL pts with relapsed disease who have received 1-4 prior lines of treatment (Rx) (phase I) or 1-2 lines of Rx (phase II), last dose > 4 weeks from enrollment, ECOG performance status 0-2, good renal/liver function, acceptable blood counts. Patients with known hypersensitivity to thalidomide/Len or prior use of gossypol/AT-101 were excluded. Cycle 1 Rx includes Len alone and cycles 2-12 includes Len and AT-101. Starting doses of Len and AT-101 are 5mg oral daily on days 1-21 and 40 mg oral twice daily (b.i.d) on days 1-3 of a 28-day cycle. Planned dose escalation is shown in Table 1. Three pts will be treated at each dose level and observed during the first cycle of the combination Rx. Dose limiting toxicity is defined as grade 4 anemia unrelated to disease, thrombocytopenia-grade 4 or grade 3 with bleeding/requiring platelets, ANC <500 for >14 days, febrile neutropenia , Grade 3/4 non-hematologic toxicity. Dose from Phase II will be based on MTD from phase I. Peripheral blood and bone marrow will be collected and analyzed for immune cellular microenvironment and effect of Len and AT-101 on molecular targets. Optional lymph node biopsy will be done at baseline and if tumor-flare reaction occurs. This study is expected to accrue a maximum of 26 pts in phase I and 34 pts in phase II, overall maximum sample size of 60 pts. Five pts in phase I have been accrued to date. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Relationship Between Lenalidomide Dose Modification and Duration Of Treatment In Newly Diagnosed Multiple Myeloma Patients

IntroductionA number of studies have shown clinical benefits for multiple myeloma (MM) patients who continue to stay on therapy with lenalidomide (LEN), including progression-free survival (PFS) and overall survival (OS) (Palumbo A, et al. NEJM. 2013, McCarthy P, et al. NEJM. 2013, Boccadoro. JCO. 2013). Dose modification is one factor used by physicians to achieve sustained duration of treatment (DOT), particularly to manage toxicities and/or pursue a continuous therapy regimen; in a clinical trial of LEN in newly diagnosed MM (NDMM) patients (pts) followed-up for a median of 30 mos, 42% of pts experienced a dose reduction (Palumbo A, et al. NEJM. 2012). This analysis evaluated whether there is supporting evidence, in a real-world setting, for physicians using LEN dose modification to achieve a longer time on therapy. ObjectiveMedical claims analysis was performed to evaluate the relationship between lenalidomide (LEN), dose modification and DOT among patients with NDMM. MethodsA retrospective cohort analysis was conducted using a claims database from a large US payer, covering approximately 14 million commercially insured and Medicare advantage members. Patients with at least two outpatient or one inpatient medical claims associated with a diagnosis of MM (ICD-9-CM code: 203.0x) between Jan 1, 2008 and Oct 31, 2012 were extracted from the database. Index date was defined as the date of the first diagnosis of MM. A minimum of 12 months pre-index and 6 months post-index enrollment with no MM treatment was required to define the NDMM patient population. To avoid DOT limitations imposed by fixed-length induction therapy, only pts without claims for stem cell transplant (SCT) were evaluated. DOT was compared among the group treated with LEN who had dose modification (increase or decrease in number of mg per day) relative to the group with no dose modification. ResultsAmong the 236 pts meeting the inclusion criteria, 69 (29%) pts had LEN dose reductions, 15 (6%) had dose increases, and 152 (64%) had no dose change. DOT in pts without a dose change was 7.33 months ± 7.62 (mean ± SD), while pts who had a dose reduction had significantly longer DOT of 14.63 months ± 10.47 (p<0.01). Of the 69 pts with dose reductions, DOT before dose reduction was 5.18 months ± 4.82 compared with 9.46 months ± 10.26 after dose reduction (p<0.01, paired). The subset of pts who were still on LEN therapy at the end of the data window (N=27) showed a similar association between dose reduction and DOT, with DOT of 20.29 months ± 11.62 and 11.99 months ± 9.29 in dose reduction and non-dose reduction subgroups (p<0.01), respectively. ConclusionNDMM pts who had dose reductions of LEN had twice the duration of therapy compared with pts without dose reductions. This analysis suggests that dose modification of MM treatment may be an effective tool to help pts achieve the benefits associated with longer time on therapy. Future clinical studies are needed to determine the best approaches to dose adjustment to improve disease control. Disclosures:Lang:Celgene: Research Funding. Off Label Use: Lenalidomide is a thalidomide analog indicated for the treatment of multiple myeloma, in combination with dexamethasone, in patients who have received at least one prior therapy. Binder:Celgene: Employment, Equity Ownership. Lin:Celgene: Research Funding. Milentijevic:Celgene: Consultancy. Huang:Celgene: Research Funding. Nagarwala:Celgene: Employment, Equity Ownership. Harwin:Celgene: Honoraria.

Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer

Lenalidomide, an immunomodulatory and anti-angiogenic drug, and temsirolimus, an mTOR inhibitor, have synergistic anti-cancer effects in preclinical models. We conducted a phase I study of the combination in patients with advanced cancers. A "3 + 3" study design was used. During the escalation phase, lenalidomide (orally, days 1-21) and temsirolimus (intravenously, once a week) were given at the following respective doses: level 1 (10 mg, 15 mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). The maximum tolerated dose, dose-limiting toxicity, and response were assessed. Forty-three patients were treated (median age: 58 years (range, 21-80); male/female: 26/17). The most common diagnoses were colorectal cancer (N = 5), sarcoma (N = 5), neuroendocrine carcinoma (N = 4) and adenoid cystic carcinoma (N = 4). Overall, 121 cycles (median: 2) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related hematologic toxicities (all reversible) were seen in 19 (72%) patients and included neutropenia (N = 12), thrombocytopenia (N = 6), and infection (N = 1). Grade 3 hyperglycemia and Grade 3 hypertriglyceridemia were noted in 21% and 20% of patients, respectively. Of 43 patients, 30 (70%) received prophylactic anticoagulation. There were no thrombotic events. Response was evaluable in 40 patients: one (2.5%) patient had a partial response and 19 (48%) had stable disease (SD), with SD ≥ 6 months in 6 (15%) patients. Tumor types with SD ≥ 6 months were soft tissue sarcoma (2/5; 40%), adenoid cystic carcinoma (1/4; 25%), parotid adenocarcinoma (1/2; 50%), adrenocortical carcinoma (1/3; 33%), and neuroendocrine carcinoma (1/4; 25%). The median progression-free survival duration was 2.2 months (95% CI, 1.5-2.9), and the median overall survival duration was 7.8 months (95% CI, 5.1-10.6). Lenalidomide and temsirolimus combination therapy was well tolerated and associated with clinical benefit in patients with soft tissue sarcoma, adenoid cystic carcinoma, neuroendocrine carcinoma, parotid carcinoma, and adrenocortical carcinoma.

Phase I clinical trial of lenalidomide in combination with sorafenib in patients with advanced cancer

Preclinical data have shown that lenalidomide and sorafenib target endothelial cells, inhibiting growth of ocular melanoma cells in a xenograft model. We conducted a Phase I study of lenalidomide and sorafenib in patients with advanced cancer. During the escalation phase, lenalidomide (days 1-21) and sorafenib (days 1-28) were given orally once daily at the following respective doses: level 1 (10 mg, 200 mg); level 2 (10 mg, 400 mg); level 3 (20 mg, 400 mg); and level 4 (25 mg, 400 mg) (1 cycle = 28 days). A "3 + 3" study design was used. Forty-one patients were treated (median age: 50 years). The most common diagnoses were adenoid cystic carcinoma (N = 9), ovarian adenocarcinoma (N = 7), and melanoma (N = 6); 142 cycles (median: 3) were administered. No dose-limiting toxicities were noted. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related toxicities were neutropenia, thrombocytopenia, skin rash, and thromboembolism. Of 38 patients who were evaluable for response, stable disease (SD) was noted in 53 % of patients (SD ≥6 months: 16 %). Tumor types with SD ≥ 6 months were as follows: ocular melanoma, 2/2 (100 %); other melanoma, 1/4 (25 %); adenoid cystic carcinoma, 2/9 (22 %); and ovarian cancer, 1/6 (17 %). The median progression-free survival duration was 3.5 months (95 % CI, 1.9-5.0), and the median overall survival duration was 12.3 months (95 % CI, 10.1-14.5). Lenalidomide and sorafenib was well tolerated and associated with disease stabilization for ≥6 months in patients with melanoma, adenoid cystic carcinoma, and ovarian adenocarcinoma.

Phase I clinical trial of lenalidomide with temsirolimus in patients with advanced cancer.

2604 Background: Lenalidomide (immunomodulatory and antiangiogenic drug) and temsirolimus (mTOR inhibitor) are potentially synergistic (Raje N, Blood 2004;104(13):4188). We conducted a phase I study of the combination in patients with advanced cancers. Methods: During the escalation phase, lenalidomide (PO days 1-21) and temsirolimus (IV, Q weekly) were given at the following respective doses: level 1 (10 mg, 15mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). A “3+3” study design was used. The maximum tolerated dose, dose-limiting toxicity, and response were assessed. Results: Forty- three patients were treated (median age: 58 (21-80) years; male/female: 26:17). The most common diagnoses were colorectal cancer (N=5), sarcoma (N=5) and adenoid cystic carcinoma (N=4). Overall, 121 cycles (median: 2) were administered. No dose limiting toxicities were observed. The maximum tested dose (level 4) was used for expansion. Grade 3-4 toxicity (all reversible) occurred in 19 (44%) patients: neutropenia (N=12), thrombocytopenia (N=6), and infection (N=1). Of 43 patients, 31 (72%) received anticoagulation prophylaxis. There were no thrombotic events. Of 36 patients who were evaluable for response, PR was noted in 1 (2.7%), and stable disease (SD) was noted in 17 (47%) patients (SD ≥6 months: 17%). Tumors with SD≥6 months were soft tissue sarcoma, 2/5 (40%), adenoid cystic carcinoma, 1/4 (25%), parotid ca, 1/2 (50%), adrenocortical ca 1/3 (33%), and neuroendocrine ca, 1/4 (25%) (Table). The median progression-free survival was 2.2 months (95% CI, 1.5-2.9) and overall survival was 7.8 months (95% CI, 5.1-10.6). Conclusions: Lenalidomide and temsirolimus combination was well tolerated and had antitumor activity in selected participants with advanced cancer. Clinical trial information: NCT01183663. [Table: see text]

Abstract 1178: Phase I clinical trial of Lenalidomide in combination with Sorafenib in patients with advanced cancer.

Abstract Background: Preclinical data have shown that lenalidomide and sorafenib target endothelial cells, inhibiting growth of ocular melanoma cells and growth of tumors in a xenograft model (additive to synergistic activity)(Mangiameli et al, J Transl Med 2007;5:38). Patients and Methods: We conducted a phase 1 study in patients with advanced cancer. During the escalation phase (“3+3” design), lenalidomide (D1-21) and sorafenib (D1-28) were given orally at the following respective daily doses: Level 1 (10mg, 200mg); Level 2 (10mg, 400mg); Level 3 (20mg, 400mg); and Level 4 (25mg, 400mg) (1 cycle=28 days). Results: Forty-one patients were treated [median age: 50 yrs (16-72); men: 18 (44%); median no. of prior therapies: 3 (0-12); ≥2 metastatic sites: 80%]. The most common diagnoses were adenoid cystic carcinoma (N=9), ovarian adenocarcinoma (N=7) and melanoma (N=6). Overall, 140 cycles (median: 3; range, 1-17) were administered. No DLTs were noted during the escalation phase (N=19) and Level 4 (lenalidomide 25 mg/day D1-21 and sorafenib 400mg/day Day 1-28), the maximum tested dose was used in the expansion phase (N=22). Grade 3-4 treatment-related toxicities were as follows: neutropenia (N=7; 17%), thrombocytopenia (N=2; 5%), skin rash (N=2; 5%) and thromboembolism (N=2; 5%). Thirty-eight patients were evaluable for response. Stable disease (SD) was noted in 20 (53%) patients, including SD ≥6 months in 6 (16%). SD≥6 months by tumor type was as follows: ocular melanoma, 1/1 (100%); other melanoma, 2/5 (40%); adenoid cystic carcinoma, 2/9 (22%); and ovarian cancer, 1/5 (20%) (Table). The median progression-free survival (N=41) was 3.7 months (95% CI, 2.0-5.4) and median overall survival (N=41) was 12.3 months (95% CI, 10.1-14.5). Conclusions: Lenalidomide 25mg (D1-21) combined with sorafenib 400 mg (D1-28) was well tolerated and it was associated with disease stabilization for ≥6 months in selected patients with melanoma, adenoid cystic carcinoma and ovarian adenocarcinoma. Characteristics of patients with SD≥6 months Dose level Age/Sex/ECOG PS Diagnosis No. of metastatic sites/no.prior Rx Best RECIST Response,% No. of cycles Reason of treatment discontinuation Survival Status Progression-free survival, months Overall survival, months 3 74/M/2 Adenoid cystic carcinoma 2/1 −17 17 Travel issues Alive 19 19.5 4 55/F/2 Ovarian Cancer 2/10 −5 7 Progr.dis Alive 8 12.1 4 67/F/1 Ocular Melanoma 1/1 −6 7 Ipilimumab became available Alive 8 9.2 4 35/F/1 Melanoma 4/5 −4 14+ On study Alive 13+ 13 4 35/F/0 Adenoid cystic carcinoma 4/1 −1 6 Progr.dis Alive 8 10.5 4 65/M/1 Melanoma 2/1 −8 7 Progr.dis Alive 6 7.4 Citation Format: Prasanth Ganesan, Sarina Piha-Paul, Aung Naing, Gerald Falchook, Jennifer Wheler, Siqing Fu, David S. Hong, Razelle Kurzrock, Filip Janku, Shell Laday, Agop Y. Bedikian, Merrill Kies, Robert Wolff, Apostolia M. Tsimberidou. Phase I clinical trial of Lenalidomide in combination with Sorafenib in patients with advanced cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1178. doi:10.1158/1538-7445.AM2013-1178 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules

Multiple myeloma (MM)-induced osteoclast (OC) formation is mainly due to an imbalance of the receptor activator NF-κB ligand (RANKL)-osteoprotegerin (OPG) ratio in favor of RANKL in the bone microenvironment and to the CCL3 production by MM cells. The purpose of the study was to investigate the effect of the immunomodulatory drugs on RANKL/OPG ratio, the production of pro-osteoclastogenic cytokines, and MM-induced OC formation. We found that invivo concentrations of both lenalidomide (LEN) and pomalidomide (POM) significantly blunted RANKL upregulation normalizing the RANKL/OPG ratio in human osteoprogenitor cells (PreOBs) when co-cultured with MM cells and also inhibited CCL3 production by MM cells. A reduction in CD49d expression, a molecule critically involved in RANKL upregulation in the MM microenvironment, accompanied this effect. Consistently, the pro-osteoclastogenic property of MM cells co-cultured with PreOBs was reduced by both LEN and POM. We further investigated the effect of these drugs on the transcriptional profile of both MM cells and PreOBs by microarray analysis, which showed that adhesion molecules, such as ITGA8 and ICAM2, are significantly downregulated in MM cells. Our data suggest that LEN and POM inhibit MM-induced OC formation through normalization of the RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells.

A Phase 2 Multicenter Study of Continuous Dose Lenalidomide in Relapsed or Refractory Classical Hodgkin Lymphoma

Abstract 1623 Background:Relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) remains a clinical challenge with limited effective treatments after high dose therapy with autologous stem cell transplantation (ASCT). Lenalidomide (Revlimid®) is an approved anti-neoplastic therapy for multiple myeloma and myelodysplastic syndrome with del(5q). In ongoing investigations it has a manageable toxicity profile and promising clinical activity in a number of B cell malignancies. We previously reported a study of single agent lenalidomide administered at 25 mg on days 1–21 of a 28 day cycle (Fehniger et al., Blood 118:5119, 2011, n=38), that showed a 19% objective response rate and a 33% cytostatic response rate, with a subsets of patients (pts) obtaining prolonged benefit from lenalidomide therapy. We hypothesized that clinical efficacy may be improved by using a continuous dosing schedule. Methods:42 rel/ref cHL pts who previously underwent (or were not candidates for) ASCT were enrolled in a prospective, multi-center, phase 2 study of continuous dose, single agent lenalidomide. The treatment regimen for this cohort was 25 mg/day of lenalidomide on days 1–28 of a 28 day cycle. Treatment continued until progressive disease or an unacceptable adverse event at the lowest allowed dose (5 mg) of lenalidomide. The primary endpoint was overall response rate [complete remission (CR) + partial remission (PR)] as defined by the 2007 revised IWG criteria, and cytostatic response defined as CR + PR + stable disease (SD) > 6 months. Results:Median age at treatment was 38 (range 20–83) years. Median number of prior therapies was 3 (range 1–15). 31 pts (74%) had received a prior stem cell transplant (26 ASCT, 2 allogeneic, 3 both ASCT and allogeneic). 18 pts (43%) had not responded to their last prior therapy, and the median time from last prior therapy to enrollment on this study was 4 (range 1–126) months. Median time of follow-up from enrollment on this study was 15 (range 2–35) months. Of the 42 enrolled pts, 5 were removed from the study prior to receiving 2 cycles of lenalidomide due to cytopenias (n=2), venous thrombosis (n=1), increased ALT/AST (n=1), and withdrawal of consent (n=1) and were not evaluable for response. Median number of lenalidomide cycles administered per patient was 4 (range 2 to >24). For the 37 evaluable pts, we observed 3 CRs, 8 PRs, and 2 SD > 6 months for an overall response rate (CR + PR) of 30% (12/37) and an overall cytostatic response rate (CR + PR + SD > 6 months) of 35% (14/37). For patients that responded, the median time to treatment failure was 8.2 (range 4 to > 24) months. All 3 CRs were observed after 2 cycles, and PRs were observed after 2 (n=5), 4 (n=1), 7 (n=1), and 15 (n=1) cycles of lenalidomide. Currently, lenalidomide treatment continues in 2 patients with PR (at ≥21 and ’24 cycles). In general, the treatment was well tolerated, and the most common (> 10%) grade 3–4 adverse events were neutropenia (48%), leukopenia (29%), thrombocytopenia (26%), and anemia (12%). Using this continuous dosing regimen, the lenalidomide dose was reduced in 4 pts for cytopenias (n=3), skin ulceration (n=1), and discontinued in 8 pts for vertigo (n=1), myelodysplasia (n=1), pregnancy (n=1), rash (n=1), and cytopenias (n=4). For pts with dose reduction, the lenalidomide doses ranged from 20 mg to 5 mg. These results suggest a modest increase in the number of patients that required lenalidomide discontinuation due to toxicity (9.5% prior to cycle 2, 19% after cycle 2) with continuous dose lenalidomide initiated at 25 mg/day, compared with to the previous interrupted dose phase 2 study cohort with lenalidomide dosing on day 1–21 of a 28 day cycle (5.3% prior to cycle 2, 10.5% after cycle 2) patients. Conclusions:Compared with interrupted dose lenalidomide, continuous dose lenalidomide therapy has similar activity in pts with rel/ref cHL, with modest increases in therapy discontinuations and dose reductions. Exploration of lenalidomide combinations with other active agents in rel/ref cHL is warranted. Disclosures:Fehniger:Celgene: Research Funding. Off Label Use: This is a clinical trial of lenalidomide in relapsed/refractory classical Hodgkin lymphoma, which constitutes off-label drug use. Goy:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Carson:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Analysis of Second Primary Malignancies in Lenalidomide-Treated Patients with IPSS Low- or Int-1-Risk Myelodysplastic Syndromes

Abstract 1704 Background:Lenalidomide (LEN) is approved in the US for the treatment of RBC transfusion-dependent patients with IPSS Low- or Int-1-risk myelodysplastic syndromes (MDS) with del(5q), with or without other cytogenetic abnormalities. In a phase 3 trial, treatment with LEN 5 mg and 10 mg resulted in RBC transfusion independence (TI) for ≥ 26 weeks in 43% and 56% of such patients, cytogenetic response in 25% and 50%, and a significant improvement of health-related quality of life (p <.05 for both 5 mg and 10 mg). Achievement of RBC-TI ≥ 8 weeks was associated with a significantly reduced risk of AML progression and death (p <.05 for both) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). In newly diagnosed multiple myeloma patients, results of phase 3 trials showed a numerical imbalance in the occurrence of second primary malignancies (SPMs) between patients treated with LEN (in combination with melphalan or immediately after high-dose melphalan therapy and stem cell transplantation) and control cohorts. SPMs were analyzed in clinical trials of LEN across indications, including MDS. Methods: This was a single arm analysis of SPM data retrieved from RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS with or without del(5q) who received LEN as monotherapy in 5 studies (MDS-001, -002, -003, -004, and -007). The cutoff date was February 28, 2011. SPMs were defined using MedDRA (Medical Dictionary for Regulatory Activities) categories of invasive SPMs (hematologic malignancies and solid tumors) and non-melanoma skin cancers (NMSC). Acute myeloid leukemia (AML) is considered part of the natural history of disease progression in MDS. Although further follow-up is needed, results of a phase 3 study showed no obvious evidence for an increased risk of AML progression in LEN-treated RBC transfusion-dependent patients with IPSS Low- or Int-1-risk MDS and del(5q) (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). AML was not included in the present analysis. The overall number of SPMs (invasive malignancies and NMSC), and the number and incidence rate (IR) of all invasive SPMs were evaluated, with IR defined as the number of new events per 100 person-years (pys). The IR of invasive SPMs was compared with the IR of new events of invasive cancer as reported from the SEER (Surveillance, Epidemiology, and End Results) cancer registry (2.1/100 pys for persons aged ≥ 65 years) (Howalder N et al. National Cancer Institute, 2011). Results: The combined population of all 5 studies comprised 557 LEN-treated patients. The median age was 71 years (range 27–95 years) and 72% of patients were aged ≥ 65 years. 88 patients (15.8%) had a prior history of cancer including malignant melanoma, meningioma, breast cancer, lung cancer, squamous cell carcinoma, and basal cell carcinoma. A total of 28 patients (5.0%) developed ≥ 1 SPM, including 17 (3.1%) with an invasive SPM and 12 (2.2%) with NMSC; 1 patient had both an invasive malignancy and a NMSC. Two of the 17 patients with invasive SPMs had a B-cell malignancy and 15 had solid tumors of heterogeneous type. Of the 28 patients with SPMs in total, 5 patients had a prior history of cancer. The IR of invasive SPMs was 2.60/100 pys (95% confidence interval 1.56–4.07), which is consistent with the IR reported in the SEER database among patients in this age group (2.1/100 pys for persons aged ≥ 65 years). The median time to onset of SPMs was 13.5 months (range 0.3–48.6 months). Conclusion: There was no clear evidence to associate LEN treatment with an increased risk of developing SPMs in patients with Low- or Int-1-risk MDS with or without del(5q). The IR of invasive SPMs among these LEN-treated patients is what would be expected from population-based estimates of invasive cancer incidence among persons in this age group. The collection of data on SPMs in LEN-treated patients including post-marketing information is ongoing. Disclosures:Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene Corporation: Consultancy, Honoraria, Research Funding. Fenaux:Merck: Honoraria; Johnson & Johnson: Honoraria; Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Cephalon: Honoraria; Novartis: Honoraria. Benettaib:Celgene Corporation: Employment, Equity Ownership. Brown:Celgene Corporation: Employment, Equity Ownership. Zhong:Celgene Corporation: Employment, Equity Ownership. Brandenburg:Celgene Corporation: Employment, Equity Ownership. Mufti:Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Treatment with lenalidomide modulates T‐cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia

Lenalidomide, an immunomodulatory agent, has activity in lymphoproliferative disorders. The authors, therefore, evaluated its effects on T-cell immunophenotype and cytokine production in patients with chronic lymphocytic leukemia (CLL). To study the immunomodulatory effects of lenalidomide in CLL, the authors recruited 24 patients with untreated CLL enrolled in a phase 2 clinical trial of lenalidomide and obtained peripheral blood specimens for immunologic studies consisting of enumeration of T cells and assessing their ability to synthesize cytokines after activation through T-cell receptor (TCR). After 3 cycles of therapy, patients had a significant reduction in percentage (%) and absolute lymphocyte count (ALC) and an increase in percentage of T cells, percentage of activated CD8(+) T cells producing IFN-γ, and percentage of regulatory T (T(R) ) cells when compared with their respective levels before treatment. After 15 cycles of treatment, responder patients had significant reduction in percentage of lymphocytes and ALC, percentage of activated CD4(+) T cells producing IL-2, IFN-γ, or TNF-α, and percentage of T(R) cells when compared with their perspective levels after 3 cycles of treatment. Furthermore, the numbers of activated CD4(+) T cells producing IL-2, IFN-γ, or TNF-α, activated CD8(+) T cells producing IFN-γ, and T(R) cells normalized to the range of healthy subjects. Treatment with lenalidomide resulted in the normalization of functional T-cell subsets in responders, suggesting that lenalidomide may modulate cell-mediated immunity in patients with CLL.

The immunostimulatory effect of lenalidomide on NK-cell function is profoundly inhibited by concurrent dexamethasone therapy

AbstractLenalidomide combined with dexamethasone is an effective treatment for refractory/relapsed multiple myeloma (MM). Lenalidomide stimulates natural killer (NK) cells and enhances antitumor responses. We assessed NK cell number and function in 25 patients with MM participating in a clinical trial of lenalidomide and dexamethasone. NK cell numbers increased from a mean of 2.20 ± 0.05 × 105/mL (baseline) to a mean of 3.90 ± 0.03 × 105/mL (cycle 6; P = .05); however, in vitro NK-cell–mediated cytotoxicity decreased from 48.9% ± 6.8% to 27.6% ± 5.1% (P = .0028) and could not be rescued by lenalidomide retreatment. Lenalidomide increased normal donor NK-cell cytotoxicity in vitro from 38.5% to 53.3%, but this was completely abrogated by dexamethasone. Dexamethasone suppression of NK cell–mediated cytotoxicity was partially reversed by a 3-day washout, but these cells remained refractory to lenalidomide-induced enhanced function. Lymphocyte subset depletion experiments revealed that lenalidomide's enhancement of NK cell–mediated cytotoxicity was mediated by CD4+ T-cell production of interleukin 2 and that dexamethasone acted by suppressing interleukin-2 production. Similarly, the reduced ability of NK cells from patients with MM to respond to lenalidomide was also due to impaired CD4 T-cell function. Our findings indicate that lenalidomide immunostimulatory effects on patient NK cells are severely blunted by concurrent dexamethasone administration.

Lenalidomide in the treatment of chronic lymphocytic leukemia

Introduction: Insights into the role of the tumor microenvironment and of immune dysfunction in chronic lymphocytic leukemia (CLL) have opened the way for further augmenting the therapeutic armamentarium for CLL patients. In this respect, lenalidomide represents an exciting drug since it is able to eliminate CLL cells without immunosuppression.Areas covered: Mechanism of action and clinical trials of lenalidomide in CLL, and suggestions for its future utilization are reviewed. The most relevant papers and the meeting abstracts published up to July 2010 were used as sources for this review. This review will help readers understand the mechanism of action of lenalidomide and will provide a comprehensive summary regarding efficacy and safety of this drug in CLL patients.Expert opinion: Lenalidomide shows good activity against CLL. However, the toxicity profile is significant and can result in serious and potentially life-threatening side effects. Definitive data from ongoing trials will aid better definition of its status in CLL therapy. Moreover, clarification of the exact mechanism(s) of action in CLL will allow more precise use of lenalidomide and design of more efficacious combination therapies.

Hypercalcemia Following Treatment with Lenalidomide in Chronic Lymphocytic Leukemia (CLL).

Abstract 4413 BACKGROUNDIn concert with emerging effectiveness data, we are learning that the side effect profile of lenalidomide (L) in CLL may be different from that observed with other malignancies, such as multiple myeloma (MM) or myelodysplastic syndrome (MDS). In particular, at lower doses than typically used for MM or MDS, a unique tumor flare response (TFR) has been observed for which the mechanism is still unclear, but may be related to a “cytokine release” phenomenon. CASE REPORTHere we would like to describe 3 cases of hypercalcemia that occurred in 3 of 17 patients with fludarabine refractory CLL treated at the Moffitt Cancer Center: 2 patients who were on a clinical trial of lenalidomide plus rituximab (LR), and 1 patient who was treated with L outside of a clinical trial setting. Case 1Pt #1 was initiated on (LR) on 12/2007 for CLL with bulky LAN, elevated wbc (110K), and 90% bone marrow (BM) involvement. By day 6, his calcium peaked at 11.78 and was accompanied by a drop in wbc to 15K. He had no other evidence of TFR, and was specifically without complaints of back pain or tender/progressive LAN. He was treated with IV fluids and steroids which promptly corrected his calcium, after which L was resumed. His course has been complicated by neutropenia requiring G-CSF. Although LAN remains stable, he has had an excellent BM response, with only 40% CLL seen on reevaluation in 06/2009. Case 2Pt #2 was initiated on LR on 8/2008 for CLL with bulky LAN, mildly elevated wbc (20.5K) and 60% BM involvement. By day 4 his calcium peaked at 16.94, at which time he presented to our urgent care center with weakness, sweats, back pain, nausea and vomiting. No tender or progressive LAN was appreciated. He was treated with IV fluids, pamidronate, calcitonin and steroids which normalized his calcium. An attempt was made to restart L, which again produced hypercalcemia after 4 days. No further attempts were made to resume this medication. A workup performed during the first episode of hypercalcemia was notable for a slight elevation in the PTHrp (8.5). Case 3Pt #3 was initiated on L alone on 6/2008 for CLL with bulky LAN, elevated wbc (283.6K), and 95% BM involvement. By day 4, his calcium peaked to 14.64, and was associated with a TFR, including a rise in wbc (306K), LDH (1285), and enlarging/painful LAN. The hypercalcemia was treated with IV fluids, zoledronate, and steroids. Bendamustine was immediately initiated for the treatment of CLL with dramatic improvement on lymph nodes and WBC counts. Following 1 cycle of bendamustine, L was resumed, with stabilization of his disease.Workup in these patients was unremarkable, with normal VitD/PTH levels, and only a mild elevation of PTHrp in Pt#2 (see table), in whom hypercalcemia had reoccurred upon rechallenge with L. Pt#1 and #3 were successfully retreated without recurrent hypercalcemia, though, Pt#3 received prior cytoreductive therapy with bendamustine. CONCLUSIONHypercalcemia is a rare complication of advanced B-cell malignancies seen with lymphokine/cytokine mediated bone disruption. Increased production of l,25-(OH) 2D by lymphocytes may also lead to hypercalcemia, and in CLL it is mainly associated with Ritcher's transformation or presence of osteolytic lesions. Here we report on 3 cases of hypercalcemia, which were identified during L treatment in CLL, and which had not been observed in other studies of L. We hypothesize that the hypercalcemia could be a direct reflection of increased cytokine levels, including IL-6, TNFα, and, MIP-1α, which are known to influence osteoclastogenesis. Interestingly, IL-6 is known to act synergistically with PTHrp in experimental models to drive hypercalcemia, which may be relevant for the patient who developed recurrent hypercalcemia on rechallenge with L. Levels of cytokines at different time points are now under investigation and are anticipated for presentation at the meeting. These events indicate that serum chemistries of patients initiating treatment with lenalidomide should be closely monitored during the first weeks of treatment.Table 1:Pt_DoseCalcium level before treatmentMaximum CalciumPhosPTH/PTH-rpVit DFISHWBC ChangeLDH Change12.5mg9.411.7857 / 018del 11q□ 94.83□ 12122.5mg9.916.9446 / 8.551del 13q□ 7.39□ 17310mg9.314.644.66 / --del 11q; del 13q14□ 23.14□ 753 Disclosures:Off Label Use: Lenalidomide is an immune modulator drug currently being studied for efficacy in conjunction with Rituxan in chronic lymphocytic leukemia. This abstract summarizes a unique side effect, hypercalcemia, seen among a small cohort of patients on this study.. Lancet:Celgene: Research Funding. Pinilla:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; exelixis: Research Funding.

IMiDs: A Novel Class of Immunomodulators

IMiDs are structural and functional analogues of thalidomide that represent a promising new class of immunomodulators for treatment of a variety of inflammatory, autoimmune, and neoplastic diseases. The discovery of the antiangiogenic and T-cell co-stimulatory functions of IMiD compounds has led to the investigation of these agents for treatment of hematologic neoplasms such as multiple myeloma and myelodysplastic syndromes, as well as certain solid tumors. The second-generation IMiDs, such as lenalidomide and CC-4047, exhibited a greatly enhanced potency for immunomodulation and antiangiogenesis in nonclinical studies when compared with the parent compound, thalidomide. In clinical studies, the IMiDs appear to have reduced sedative and neurotoxicity effects, which are often associated with long-term thalidomide dosing. The precise mechanism of action of IMiDs in the treatment of specific diseases is not entirely clear and may differ for various diseases depending on their underlying pathobiologies. Although IMiDs have similar effects on inflammatory cytokine secretion, T-cell modulation, angiogenesis, and expression of adhesion molecules, each IMiD has a unique potency profile for these activities, which may ultimately indicate selective applicability of specific IMiDs for distinct diseases and conditions. Clinical trials of lenalidomide, the primary second-generation IMiD, have shown clinical benefits in both myelodysplastic syndrome and multiple myeloma and a better safety profile than that of thalidomide, with no evidence of teratogenicity. It is anticipated that lenalidomide and other IMiD compounds will become important alternatives to thalidomide because of their more potent anti-inflammatory and anticancer properties, as well as their improved side-effect profiles.

Emerging Data on IMiDs in the Treatment of Myelodysplastic Syndromes (MDS)

Myelodysplastic syndromes (MDS) encompass a spectrum of clinically diverse hematopoietic stem cell malignancies for which there are few treatment options. These disorders display remarkable heterogeneity in their hematologic and pathologic features, with a wide-ranging natural history. Complex interactions between the affected clone and the bone marrow microenvironment drive the pathogenesis and progression of MDS, resulting in ineffective hematopoiesis, blast accumulation, and a variable predisposition for progression to acute leukemia. For early stage, lower-risk patients with MDS, the mainstay of therapy is supportive care, especially red blood cell transfusions, to alleviate the symptoms of anemia. However, these interventions do not target the underlying pathobiology of disease and have questionable impact on the natural disease course. Dysregulated inflammatory, apoptotic, and angiogenic cytokines play major roles in the pathobiology of MDS and represent attractive therapeutic targets. Lenalidomide is an orally bioavailable analogue of thalidomide with more potent immunomodulatory, antiangiogenic, and antitumor activities than the parent compound and with a better safety profile. In nonclinical studies, the effects of lenalidomide include potentiation of clonogenic response to erythropoietin, activation of integrin-mediated adhesion, cell cycle arrest, sensitization to apoptotic signals, and abrogation of cellular response to receptor-initiated trophic signals. These effects have the potential to impact survival and apoptosis of erythropoietic progenitor cells and their progeny. Data from clinical trials of lenalidomide in MDS have shown erythropoietic- and cytogenetic-remitting activities that frequently result in transfusion independence, particularly in patients with 5q- deletion and lower-risk MDS. Decreases in microvessel density in bone marrow specimens from responding patients provide supportive evidence of an antiangiogenic effect in MDS. Adverse effects, most commonly myelosuppression, are generally manageable with dose reduction and growth factor support. Multicenter phase II and III studies are under way to further assess the erythroid and cytogenetic response rates in distinct subtypes of MDS, including 5q- deletion, and to optimize its clinical application.