Lenalidomide Failure Research Articles

Luspatercept for Treatment of Lower Risk Myelodysplastic Syndromes: Real World Data Replicates Medalist Study Results and Confirms Activity Among Hypomethylating Agents and Lenalidomide Treated Patients

Introduction: Luspatercept, TGF-B fusion trap protein, is a first in class erythroid maturating agent approved by FDA for treatment of red blood cell transfusion dependent (RBC-TD) lower risk myelodysplastic syndromes (LR-MDS) with ring sideroblasts (RS) based on the MEDALIST clinical trial. Red blood cell transfusion independence (RBC-TI) was observed in 38% of 153 patients (pts) treated with luspatercept compared to 13% of 76 pts in the placebo group. We present to our knowledge first real-world data (RWD) in a large cohort of pts treated at our center with luspatercept for LR-MDS. More importantly, we address impact of prior therapies on response namely hypomethylating agents (HMA) as the original clinical trials excluded HMA treated pts. Methods We identified all pts treated at Moffitt Cancer Center with luspatercept since the FDA approval. Baseline RBC transfusion burden (TB) was defined as: non- transfusion dependent (NTD) (0 units in 8 weeks prior luspatercept), low TB (LTB) (1-5 units /8weeks) and high TB (HTB) (≥ 6 units /8 weeks). A hematological response (HI) was defined as an (i) objective Hgb increase of > 1.5 g/dl in NTD, and (ii) RBC-TI with Hgb increase of 1.5 g/dl, or RBC-TI without Hgb 1.5 g/dl increase, or >50% reduction in RBC transfusion burden among RBC-TD. Results Between February 2020 and December 2021, 114 pts were treated with luspatercept. Table-1 summarizes baseline characteristics in comparison to Medalist trial, the median age was 70 years. Seventy-three pts (67%) had MDS-RS subtype, 91% were intermediate or lower risk MDS by R-IPSS. SF3B1 mutation (MT) was detected in 71% (80/112). The mean Hgb level was 7.90 g/dl and 47% were RBC HTB transfusion dependent. The median serum erythropoietin (epo) level at time of referral was 122 U/L (19% > 500 U/L) (n=77). Majority had prior erythroid stimulating agents (ESA) (89%) with 29% hematological response to prior ESA, 59 pts (53%) had prior HMA therapy, and 42 patients (47%) had prior lenalidomide (len). The overall HI rate to luspatercept was 39.5% (45/114). Table-2 summarizes detailed responses. HI correlated with baseline RBC-TB where 69% (9/13) NTD, 47% (21/47) LTB and 25% HTB (13/53) achieved HI respectively, p=.004. Almost 55% of pts needed dose escalation, 62 pts received 1.33 mg/kg and 63 pts received 1.75 mg among whom 40% (25 pts) demonstrated response to higher doses. Based on RBC-TB, 75% (6/8) NTD patients achieved HI with highest dose escalation, 40% (10/25) LTB pts achieved HI with dose escalation and 30% (9/30) HTB pts achieved response with dose escalation. Among responders, the median duration of response was 15.6 months (2.6-27.3). As off last follow up, 56 pts (49%) discontinued treatment. Reason of discontinuation was lack of response in 47 pts, loss of response in 4 patients and adverse events in 5 pts (58 pts are still on therapy). The most common captured adverse events were fatigue (n=8), GI (n=4), shortness of breath and arthralgia (1 each). The response rates were higher among SF3B1 MT pts compared to wild type, 48% (34/80) compared to 16% (5/32), p=.002. The response rate among pts with RS subtypes versus non-RS were 49% versus 28% respectively, p=.05. Among 14 pts with MDS/MPN-RS-T the HI rate was 79%. HI for pts with serum epo < 500 U/L, was 48% (30/62) compared to 13% 2/15) for those with serum epo > 500, p=.01. Majority of pts with high serum epo level were RBC HTB at baseline 67% (10/15). The HI rate was 30% (18/60) after HMA failure compared to 50% (27/54) in HMA naïve pts, (p=.03). More pts post HMA failure were RBC-HTB 62% compared to 30% in HMA naïve. The luspatercept HI among RBC-LTB HMA failure pts was 39% compared to 54% in HMA naïve LTB, however, it was 24% among HTB HMA failure compared to 25% among HMA naïve HTB. The HI rate was 33% (15/46) for len failure pts compared to 43% (29/67) naïve patients, (p=.3). In multivariable analysis both SF3B1 mutation status and baseline RBC TB independently correlated with luspatercept response but not HMA failure. Conclusions Our RWD confirms luspatercept clinical benefit and safety profile observed in the MEDALIST trial. Responses are dose dependent with 1/3 of patients who were dose escalated responding. Low baseline RBC-TB dependency and SF3B1 MT correlated with higher response rates. Luspatercept retained activity after HMA or lenalidomide failure however a trend of lower responses observed correlated with RBC-HTB among those patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Defining Unmet Need Following Lenalidomide Refractoriness: Real-World Evidence of Outcomes in Patients With Multiple Myeloma.

BackgroundThe treatment paradigm for multiple myeloma (MM) continues to evolve with the development of novel therapies and the earlier adoption of continuous treatments into the treatment pathway. Lenalidomide-refractory patients now represent a challenge with inferior progression free survival (PFS) reported to subsequent treatments. We therefore sought to describe the natural history of MM patients following lenalidomide in the real world.MethodsThis was a retrospective cohort review of patients with relapsed MM who received lenalidomide-based treatments in the U.K. Data were collected for demographics, subsequent therapies, treatment responses, survival outcomes and clinical trial enrollment.Results198 patients received lenalidomide-based treatments at a median of 2 prior lines of therapy at a median of 41 months (range 0.5-210) from diagnosis. 114 patients (72% of 158 evaluable) became refractory to lenalidomide. The overall survival (OS) after lenalidomide failure was 14.7 months having received between 0-6 subsequent lines of therapy. Few deep responses were observed with subsequent treatments and the PFS to each further line was < 7 months. There was a steep reduction in numbers of patients able to receive further treatment, with an associated increase in number of deaths. The OS of patients progressing on lenalidomide who did not enter a clinical trial incorporating novel agents was very poor (8.8 months versus 30 months, p 0.0002), although the trials group were a biologically fitter group.ConclusionThese data demonstrate the poor outcomes of patients failing lenalidomide-based treatments in the real world, the highlight need for more effective treatments.

SF3B1 Mutations and Not TP53 Are Associated with Poor Outcomes in Patients with Del(5q) Myelodysplastic Syndromes (MDS)

Background: Genetic alterations are increasingly being recognized to play an important role in both diagnosis and prognosis of MDS. In general, SF3B1 mutated MDS is known to have favorable outcomes whereas those with mutated TP53 have dismal survivals. However, it is unclear if the impact of these mutations applies to all subtypes of MDS including del(5q), a unique entity that is known for its sensitivity to lenalidomide and better prognosis. A prior study suggests TP53 mutations are associated with worse outcomes in del(5q) MDS (Jadersten et al. 2011), but a more recent study did not find this association and instead they showed SF3B1 mutants (MT) conferred shorter survival compared to wild-type (WT) (Meggendorfer et al. 2017). Herein, we describe our experience of del(5q) MDS patients and assess the prognostic impact of somatic mutations in this population. Methods: We retrospectively reviewed our database of 132 patients with del(5q) MDS who were treated at the Moffitt Cancer Center from 2001 to 2019. Sixty-three patients had molecular data available for analysis. Fisher's exact test of independence was used to determine significance for categorical variables. Univariate and multivariate analyses were conducted using log-rank and Cox regression, respectively. Kaplan-Meier analysis with log-rank test was used to estimate survival outcomes. Results: A total of 132 patients (47M/85F) with a median age of 70 at diagnosis were included in this analysis (Table 1). The majority had isolated del(5q) (86.3%) and the remaining with del(5q) plus other aberration(s) but not meeting criteria as complex cytogenetics. Among patients who received lenalidomide (n=98), 50%, 42.9%, and 7.1% achieved hematologic improvement (HI) or better, no response (NR), and disease progression (DP)/death with a median overall survival (OS) of 93.2, 72.4, and 25.6 months from the time of diagnosis, respectively (p&amp;lt;0.0001) (Figure 1). The median OS of the entire cohort was 73.3 months (median follow-up of 131.3 months), and OS from the time patients stopped lenalidomide was only 26 months. Of the 63 patients with molecular data available, 23.8% were found to have TP53 mutations with a median variant allele frequency (VAF) of 20.4% and 10% SF3B1 MT (median VAF 38.9%). Other common mutations include TET2 (19%) and DNMT3A (17%) as shown in Figure 2. Interestingly, TP53 status did not impact OS (MT 86.4 vs. WT 73.3 months; p=0.72), but those with SF3B1 mutations had a significantly shorter median OS compared to WT (23.9 vs. 83.5 months; p=0.001) (Figure 3). When test for effects of multiple genes had on survival, no combinations were found to be predictive. Univariate analysis showed lenalidomide response significantly impacted OS (HI compared to NR: HR 0.19, 95% CI: 0.05-0.68, p=0.005). Multivariate regression confirmed lenalidomide response and SF3B1 status are independently associated with outcomes. Conclusions: SF3B1 mutations, typically correlate with favorable risk in MDS, are associated with significantly worse prognosis compared to WT in patients with del(5q) MDS. On the contrary, there was no significant difference in OS in patients with TP53 MT vs. TP53 WT. A substantial portion of patients benefited from lenalidomide; however, after lenalidomide failure survivals were limited. Despite the known overall associations between MDS and mutations such as SF3B1 and TP53, our data suggests the del(5q) subset behaves differently which adds to the heterogeneity of the disease. Further studies are needed to clarify the impact of treatments and somatic mutations on outcomes. Disclosures Sallman: Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Komrokji:BMS: Honoraria, Speakers Bureau; Agios: Speakers Bureau; Abbvie: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria.

Pomalidomide, dexamethasone, and daratumumab in relapsed refractory multiple myeloma after lenalidomide treatment

Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1–21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.

Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial

Myelodysplastic syndromes are characterised by ineffective erythropoiesis leading to anaemia. Sotatercept (ACE-011) is a novel activin receptor type IIA fusion protein that acts as a ligand trap to neutralise negative regulators of late-stage erythropoiesis. The aim of the study was to establish a safe and effective dose of sotatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes. This open-label, multicentre, dose-ranging, phase 2 trial took place at 11 treatment centres in the USA and France. Eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low-risk or intermediate-1-risk myelodysplastic syndromes, had anaemia requiring red blood cell (RBC) transfusions, and were ineligible for, or refractory to, erythropoiesis-stimulating agents (ESAs). Patients were not eligible if they had chromosome 5q deletion myelodysplastic syndromes without documented failure of lenalidomide. Patients were randomly assigned to receive either 0·1 or 0·3 mg/kg sotatercept subcutaneously, using a permuted-block method with stratification for serum erythropoietin concentration and transfusion burden. Patients were assigned to 0·5, 1·0, and 2·0 mg/kg groups in a non-randomised fashion. The primary efficacy endpoint was the proportion of patients who achieved haematological improvement-erythroid (HI-E), according to International Working Group 2006 criteria. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT01736683 and at EU Clinical Trials Register, number 2012-002601-22, and is ongoing. Between Dec 5, 2012, and July 22, 2015, 74 patients were enrolled into the study (seven to receive 0·1 mg/kg sotatercept, six to 0·3 mg/kg, 21 to 0·5 mg/kg, 35 to 1·0 mg/kg, and five to 2·0 mg/kg). 36 (49%; 95% CI 38-60) of 74 patients achieved HI-E; 29 (47%; 95% CI 35-59) of 62 patients with a high transfusion burden achieved HI-E (RBC-transfusion reduction from baseline of 4 or more units for at least 56 days), and seven (58%; 95% CI 32-81) of 12 patients with a low transfusion burden achieved HI-E (haemoglobin increase of 1·5 g/dL or more sustained for at least 56 days in the absence of transfusions). The most commonly reported adverse events were fatigue in 19 (26%) of 74 patients and peripheral oedema in 18 (24%) of 74 patients. Grade 3-4 treatment-emergent adverse events (TEAEs) were reported in 25 (34%) of 74 patients; four (5%) patients had grade 3-4 TEAEs that were considered to be treatment related. The most common grade 3-4 TEAEs were lipase increase and anaemia, which each occurred in three (4%) of 74 patients. 17 (23%) of 74 patients had at least one serious TEAE, and one patient died from a treatment-emergent subdural haematoma due to a fall. Sotatercept, a novel activin-receptor fusion protein, was well tolerated and effective for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes in whom previous ESA treatment had failed. Treatment with sotatercept could be beneficial for these patients who have few available treatment options. Celgene Corporation.

Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy.

While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 patient cases of lower-risk MDS patients with 5q deletion and to analyze their outcome after failure of lenalidomide. The median survival following LEN failure was 23 months. We observed a negative impact on survival of advanced age, higher bone marrow blast count at LEN initiation, progression after LEN failure, and unfavorable cytogenetics. Among the treatment strategies, we observed a relatively prolonged survival of patients treated subsequently with hypomethylating agents and only a limited impact on survival of allogeneic transplantation. In conclusion, our work stresses the relatively short survival of this group of patient and defines the expected baseline for the needed future investigations in this group of patients.

Outcome of Patients Treated for Myelodysplastic Syndromes after Failure of Lenalidomide Therapy

▪RationalThe immunomodulatory drug, Lenalidomide (LEN) has proven to be impressively effective for patients (pts) with myelodysplastic syndromes (MDS) harboring deletion 5q and is currently evaluated for registration for pts without del5q. However, we know from prior studies that response rate is limited to 60% of del5q and 25% of non-del5q pts. Moreover, response duration is limited to 24 to 36 months (m) in del5q and 12 to 18m in non-del5q pts. There is no standard option after failure of LEN and so defining the outcome is important in order to define the impact and efficacy of current and future strategies.MethodsThis is an international retrospective study from US, French, German and Italian academic centers. Adult pts were included if they were diagnosed with MDS and received at least one cycle of LEN. Patients were excluded from this analysis if LEN was combined with chemotherapy, hypomethylating agents (HMA), or given preemptively after allotransplant. Median overall survival after LEN failure was the primary endpoint.Results425 pts were included and analyzed separately between del5q and non-del 5q patients.In the del5q cohort (n= 203), median age was 70 years with a female predominance (n=133). 86 pts has del5q syndrome, 43 RARS/RCMD, and 74 pts RAEB-1/2. 34% of pts were previously treated with ESA and 79% were RBC transfusion dependent (TD) at the onset of LEN. Median duration of LEN treatment was 8 months and 115 pts (57%) were responders. Reasons for stopping LEN were loss of HI 55%, no response and SD 27%, no response and PD 11%, intolerance 7%. Median overall survival after LEN failure was 31 months. In pts with lower risk IPSS, ESA resistance, and RBC-TD (n=43), median OS was 43 months. After failure, 64 pts were treated with best supportive care (BSC), 26 were allotransplanted, 69 received HMA, 18 received growth factors, 13 received conventional chemotherapy for progression, and 9 pts received other treatments. There was a significant survival benefit for treated pts vs BSC (39 vs 14m, p=0.01) and for pts treated with HMA post LEN as compared to BSC (31 vs 14m, p=0.003). Advanced age, complex cytogenetics, exposure to HMA prior to LEN, and RAEB negatively impacted outcome in multivariate analysis. Primary vs secondary failure did not influenced outcome but patients with PD without prior HI (11%) had a shorter survival.In the non-del5q lower risk MDS cohort (n= 222), median age was 70 years with a male predominance (n=153). 62 pts had RARS, 104 RCMD, 28 RA/MDS-U, and 28 pts RAEB-1. 62% of pts had received ESA, 30% had received HMA, and 95 % of the pts were RBC-TD at the onset of LEN. Median duration of LEN treatment was 4 months and 55 pts (24%) were responders. Reasons for stopping LEN were loss of HI 24%, no response and SD 65%, no response and PD 10%, intolerance 1%. Median OS after LEN failure was 40m. In pts with lower risk IPSS, ESA resistance, and RBC-TD (n=68), median OS was 37 m. After LEN failure, 43 pts were treated with BSC, 21 pts were allotransplanted, 85 pts received HMA, 15 pts received growth factors, 15 pts received conventional chemotherapy for progression, 40 pts received other treatments. There was a survival benefit for treated pts vs BSC (42 vs 29m) but this was not statistically significant (p=0.26). None of the therapeutic options including transplantation were able to demonstrate a significant survival benefit as compared to BSC. Based on multivariate model, RAEB and prior HMA exposure negatively impacted outcome after LEN failure. Response to LEN did not favorably influence OS (31m for responders vs 43m in non responders, p=0.12, and 48m vs 47m respectively, p=NS, when survival is calculated from LEN onset), suggesting the absence of disease modifying effect in non del5q MDSConclusionsThis is the first large study analyzing the outcome of MDS pts after lenalidomide failure Survival without treatment remains relatively poor in both groups and there is only a limited impact of conventional approaches. HMA may represent an interesting option for del5q pts. This study stresses the unmet need for new strategies and gives the basis for the design of future clinical trials. [Display omitted] [Display omitted] DisclosuresPrebet:CELGENE: Research Funding. Off Label Use: lenalidomide. Park:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hospira: Research Funding; Celgene: Research Funding. Platzbecker:Amgen, Inc.: Honoraria; Celgene: Honoraria; Novartis: Honoraria; GlaxoSmithKline: Honoraria, Research Funding. Vey:Celgene: Honoraria; Janssen: Honoraria; Roche: Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Gore:Celgene: Consultancy, Honoraria, Research Funding. Komrokji:Pharmacylics: Speakers Bureau; Celgene: Consultancy, Research Funding; Novartis: Research Funding, Speakers Bureau; Incyte: Consultancy.

Pooled analysis of the reports of pomalidomide after failure of lenalidomide and (or) bortezomib for multiple myeloma.

The use of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma is not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the effectiveness of pomalidomide after failure of lenalidomide and (or) bortezomib. We searched published reports including pomalidomide, lenalidomide and (or) bortezomib. Seven reports were identified. Pomalidomide-based regimen was pomalidomide plus low-dose dexamethasone (POM + LoDEX). Six randomized controlled trials enrolling a total of 641 patients that evaluated the treatment effects of pomalidomide after lenalidomide and (or) bortezomib failure in patients with multiple myeloma were included. Pooled results showed that the overall response rate (ORR) was 31% in the POM + LoDEX group. Analysis of heterogeneity showed very little (p = 0.997, I(2) = 0%), suggesting that response rates of POM + LoDEX therapy were consistent across those included trials. Stable disease was achieved in 40% of 603 patients (heterogeneity: p = 0.980, I(2) = 0%). In those >65 years, overall response was achieved in 32% of 71 patients (heterogeneity: p = 0.77, I(2) = 0%). POM + LoDEX showed promising activity in the 95 patients with high-risk cytogenetic abnormalities: ORR was 27% (heterogeneity: p = 0.97, I(2) = 0%). In the pooled analysis, toxicity consisted primarily of myelosuppression: Grade 3 or 4 neutropenia was seen in 53% (heterogeneity: p = 0.857, I(2) = 0%). Pomalidomide may produce clinical benefits in patients who had shown refractory on prior lenalidomide and (or) bortezomib therapy. Moreover, elder patients and high-risk cytogenetic abnormalities were not negative predictors for pomalidomide response after lenalidomide and (or) bortezomib failure. Copyright © 2015 John Wiley & Sons, Ltd.

Azacitidine (AZA) After Failure of Lenalidomide (LEN) in Low/Int-1 Risk MDS with Del 5q

Abstract 2786 Background:LEN is currently the reference treatment of low/int 1 (lower) risk MDS with del 5q, yielding RBC transfusion independence (TI) in two thirds of the cases, with a median RBC-TI duration of 2.2 years. (MDS 003 trial, List, NEJM, 2006). In case of primary or secondary failure of LEN, however combined analysis of MDS 003 and MDS 004 trial showed prognosis to be unfavorable and treatment approaches uncertain. We report results of treatment with AZA in 13 lower risk MDS with del 5q with primary or secondary failure of LEN. Methods:The 13 cases were treated between November 2005 and June 2011 in 10 centers of the Groupe Francophone des Myelodysplasies (GFM). At onset of LEN, median age was 71 years, M/F 0.43, 7 patients (pts) had RAEB 1 and 6 RA, 11 had isolated del 5q and 2 had 1 additional chromosomal abnormality. IPSS was low in 6 and int 1 in 7 patients. The LEN dose was 5mg/d, 10mg/d 3 weeks/4weeks, 10mg/d in 8, 3 and 2 patients, respectively. 11 (85%) patients had achieved RBC-TI, for a median duration of 26.3m (range 5.8–57.3)(secondary failures), while 2 patients had not achieved RBC-TI (primary failures). At onset of AZA, 11 patients had progressed with a change in WHO category (RA to RAEB1, or RAEB 1 to RAEB2) in 8 patients, and/or acquisition of additional chromosomal abnormalities in 9 patients, 5 eventually having complex karyotype, of whom 2 had chromosome 17 abnormality leading to TP53 gene deletion (TP53 mutation analysis is in progress); IPSS was low (n=0), int 1 (n= 3), int 2 (n=2), high (n=8). Prior to onset of AZA, attempts had been made to increase the LEN dose from 5 to 10 mg/d in 2 patients, without success. Results:AZA was administered at the FDA/EMEA approved schedule (75mg/m2/dx7) in 12 pts, and reduced (5 day schedule) in 1 pt. The median number of cycles administered was 6 (range 1–23). Five patients (46%) achieved a response according to IWG 2006 criteria, including CR, PR, HI in 1, 0 and 4 pts respectively. All 5 responders achieved RBC –TI. 4 patients received less than 4 cycles of AZA: 2 stopped AZA after 1 cycle for hematological toxicity, 1 stopped after 3 cycles for progression, 1 pt died from septic shock after 3 cycles. Response duration was 2.9+, 4.4+, 6.2+, 13.8, and 24.6 months, respectively. No responder was allografted, but the age of responders was 68, 70, 78, 78 and 86 years, respectively. Median survival from onset of AZA was 8.8 m (range 0.8–24.9). The 5 responders were still alive 3+, 4.4+, 6.2+, 13.9+ and 24.8+ m after onset of AZA, while median survival in non-responders was 8.7 months. Among the 5 patients who responded to AZA, 4 had at onset of AZA a high IPSS, 3 had complex karyotype and 2 one additional chromosomal abn, while 4/5 had previously achieved RBC-TI with LEN (with a median duration of 26.1 months). Neither of the 2 patients with TP53 deletion responded to AZA. Finally, among the 2 primary failures to Lenalidomide, one achieved HI with AZA (of 4.4+ months duration) and the other died within 2 months. Conclusion:In this relatively small series almost 40% of the patients with lower risk MDS and del 5q who progressed under LEN could be salvaged by AZA, and might expect survival prolongation. The appearance of novel chromosomal abnormalities or complex karyotype at progression did not predict poor response to AZA, while we are currently analyzing the prognostic value of TP 53 mutations, which occur frequently at th at disease stage (Jadersten, JCO 2011), on response to AZA. Disclosures:Fenaux:Celgene: Honoraria, Research Funding.

Azacitidine Treatment of Lenalidomide-Resistant Myelodysplastic Syndrome with Deletion 5q

Abstract 2774 Background:Lenalidomide is a highly effective treatment for lower risk transfusion dependent myelodysplastic syndrome (MDS) patients with deletion 5q [del(5q)]. Approximately two thirds of patients become transfusion independent for a median duration of 2 years or longer (List et al, NEJM). Effective treatment alternatives after lenalidomide treatment failure are limited. We examined the response to treatment with azacitidine in del(5q) MDS patients after lenalidomide treatment failure. Methods:MDS patients with del(5q) who were treated with azacitidine after lenalidomide failure were identified through the Moffitt Cancer Center (MCC) MDS database and individual charts reviewed. Data collected included demographics, disease baseline characteristics, duration of response to lenalidomide, responses to azacitidine by international working group (IWG) 2006 criteria, transformation to acute myeloid leukemia (AML), and overall survival (OS). Descriptive statistics were used for analysis and Kaplan Meier estimates were used for OS and AML transformation. All analysis was conducted using SPSS version 19.0 statistical software. Results:Between July 2005 and June 2011, 18 del(5q) MDS patients treated with azacitidine were identified. The median age was 66 years (50–83), all patients were Caucasian, and male predominance (67%; 12 patients). ECOG performance status was 0–1 in 94% of the patients. The median duration of follow up from date of azacitidine initiation was 645 days. According to the WHO classification, 7 patients (38.9%) had MDS with isolated del(5q), 7 patients (38.9%) refractory cytopenia with multilineage dysplasia (RCMD), 2 patients (11.1%) refractory anemia with excess blasts 1 (RAEB-1), and 2 patients (11.1%) refractory anemia (RA).The international prognostic scoring system (IPSS) risk category was low in 2 (11.2%), intermediate 1 (int-1) in 14 (77.8%), and int-2 in 2 (11.2%) patients. Based on karyotype, 7 patients (38.9%) had isolated del(5 q), 9 (50%) del 5q +1 abnormality, and 2 (11.2%) with del 5q +2 or more cytogenetic abnormality. All patients were transfusion dependent.The median number of lenalidomide cycles prior to azacitidine was 12 (1–38), with median duration of response 319 days (17–1169). The median number of azacitidine cycles administered was 6 (2–23). The median duration of treatment was 183 days (43–592). The best response to azacitidine by IWG 2006 criteria was one (7.1%) complete response (CR), 2 (5.6%) marrow CR (mCR), 7 (38.9%) hematological improvement (HI), 4 (22.2%) had stable disease, and 4 (22.2%) had progressive disease (PD). The overall response rate was 56%.The HI cell lineage responses were 9 out of 18 (50%) erythroid, 3 out of 13 (23%) HI-P (Platelets), and 2 out 9 (22.2%) HI-N (neutrophils). The median OS was 749 days (95%CI 435–1063) from the time of starting azacitidine. The rate of AML transformation was 27.8% (n=5); median time to AML transformation from azacitidine start was 864 days (95%CI 360–1368). Conclusion:To our knowledge this is the first report demonstrating the activity of azacitidine in patients with del(5q) MDS after lenalidomide treatment failure. Response rates are similar to those reported in non-del(5q) patients providing azacitidine as an effective option for salvage treatment. Larger cohort of patients is needed to confirm these findings. Disclosures:Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy.

Functional T Cell Array Reveals Pre-Treatment Expanded Terminal Effector Memory Response Is Associated with Lenalidomide Failure in Non-Del(5q) Myelodysplastic Syndrome.

Abstract 1759Poster Board I-785Lenalidomide (LEN) is a thalidomide derivative with proven efficacy for the treatment of patients with myelodysplastic syndrome (MDS). High rates of erythroid and cytogenetic response in patients with chromosome 5q deletion [del(5q)] produced the first FDA-approved karyotype-specific treatment for this disease. Transfusion-independence rates of approximately 25% have been reported previously for patients with non-[del(5q)] and efficacy in this population has been linked to the promotion of erythroid differentiation. Because impaired erythroid differentiation in lower-risk MDS may occur through several pathophysiological mechanisms, the identification of additional factors with predictive value for both response and failure to LEN are needed to optimize success of treatment. In addition to affecting erythroid differentiation, LEN has well-known potential for immune modulation and generates highly potent effector T cell responses in vitro and in vivo by potentiating T cell receptor signaling. Immune deregulation mediated by autoreactive effector T cells has been linked to impaired erythropoiesis and granulopoiesis in a distinct subset of MDS patients raising the question of whether LEN impacts the disease process in this subset of patients. To understand the relationship between T cell deregulation and LEN response, we conducted a pilot study of 13 low/INT-1-risk non-del (5q) MDS patients (7 responders and 6 non-responders) treated with LEN and determined 23 covariates related to functional T cell response measured prior to treatment and then correlated to treatment outcome. Of these 23 covariates, multiple T cell immune parameters were analyzed but were not associated with response including interferon-g (IFNg) production by CD4+ T cells (p=0.9) and CD8+ T cells (p=0.27), Tumor Necrosis Factor (TNF)-a production by CD4+ T cells (p=1.0) and CD8+ T cells (p=0.8), TCR-associated proliferation within the CD4+ (p=1.0) and CD8+ (p=0.4) compartment, CD4/CD8 ratio (p=0.3), percentage of CD4+ (p=0.5) and CD8+ (p=0.5) T lymphocytes, and the percentage of naïve and three different types of memory CD4+ T cells. Analysis was performed using two-group comparison statistical tests (two-sample t-test and Wilcoxon rank sum test) to compare responders (R) vs non-responders (NR). Only one factor was independently linked to LEN response. Results showed that a higher percentage of CD8 T cells (mean 56% in NR vs 32% in R) with a Terminal Effector Memory [TEM]) phenotype (CD45RA+/CD62L-) was associated with LEN failure (p=0.02). This population of T cells occurs at a low frequency in healthy individuals but can be induced to differentiate in vitro under constant exposure to long-term antigen and cytokine stimulation. We have shown previously that CD8+ TEM T cells are expanded in patients with impaired myelopoiesis due to immune dysregulation in Large Granular Lymphocyte (LGL) leukemia. In conclusion, these results suggest that CD8+ terminal effector memory expansion may be linked to immune deregulation in MDS and represents an important biomarker with negative predictive importance for LEN response in non-del(5q) low-risk MDS. DisclosuresNo relevant conflicts of interest to declare.

CC-10004 but not thalidomide or lenalidomide inhibits lamina propria mononuclear cell TNF-α and MMP-3 production in patients with inflammatory bowel disease

Background Thalidomide, one of whose activities is to inhibit Tumour Necrosis Factor (TNF)-α production, has been reported to be an effective treatment for refractory inflammatory bowel disease (IBD). TNF-α driven production of matrix metalloproteinase (MMP)-3 by gut lamina propria mononuclear cells (LPMCs) is a major pathway of tissue injury in IBD; however the effect of thalidomide and newer more potent immunomodulatory derivatives on this pathway has not been studied. Aim To investigate the effect of thalidomide, CC-4047 (pomalidomide), CC-5013 (lenalidomide), and CC-10004 (apremilast) on gut LPMC TNFα and MMP-3 production in patients with IBD. Methods Gut LPMCs and myofibroblasts were isolated from patients with IBD, and cultured with thalidomide, CC-4047, CC-5013, and CC-10004. MMP-3 and TIMP-1 levels were determined by western blotting and real-time PCR, and TNF-α levels by ELISA. Results CC-10004 significantly reduced both TNF-α production and MMP-3 production by cultured LPMCs. Thalidomide and CC-4047 and CC-5013 had no significant effect on the production of TNF-α or MMP-3 by LPMCs. Conclusion These results provides a mechanistic rationale for both the failure of lenalidomide (CC-5013) in a recent randomised controlled trial in Crohn's disease, and for the evaluation of CC-10004 as a novel oral therapy in the treatment of CD and UC.