Citations

Abstract Abstract 2945 Background: We have previously reported on a Phase II trial using IL-1Ra and dexamethasone, in patients with SMM/IMM, showing that IL-1Ra targets the myeloma proliferative component which parallels a decrease in the C-reactive protein, a surrogate for IL-6 production. (Mayo Clinic Proceedings 84 :114 (Feb. 2009)). In early stage myeloma, IL-6 is a central myeloma growth factor and we have shown that abnormal production of IL-1 β in the myeloma microenvironment stimulates the generation of paracrine IL-6. These patients are the individuals most likely to benefit from anti-cytokine therapy in an attempt to delay/prevent the development of active myeloma. We now present updated results of this study including survival data. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. All patients received 100 mg of Anakinra (IL-1Ra) SQ qd for 6 months. Patients with evidence of reduction in M-protein levels continued receiving IL-1Ra alone. Patients with stable disease at 6 months or those with a rising M-protein before 6 months received low dose dexamethasone (20 mg qweek) in addition; the dose was adjusted based on response/toxicity. Results: Data were available on 47 patients based on intent to treat, and pts were classified as smoldering (72%) vs. indolent (28%). All SMM patients were in Group 1 or 2 and thirty-eight patients (81%) had greater than 20% bone marrow plasma cells. All 47 patients received IL-1Ra initially and 25/47 subsequently received IL-1Ra/Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI) on IL-1Ra alone which paralleled a decrease in the high sensitivity C-reactive protein (CRP) in all cases. Three patients achieved a minor response to IL-1Ra alone and 9 patients achieved a PR/MR after addition of dexamethasone. For the group of 47 patients, the median progression-free survival was 45 months and the median overall survival has not been reached. When patients were grouped into whether they exhibited a reduction in the C-reactive protein from baseline after 6 months of therapy, the median PFS for patients without (21 patients) or with (26 patients) a greater than one-third reduction in baseline CRP was 1 year vs more than 8 years (p<.01). Similarly, the median OS for patients without or with a reduction in baseline CRP was 7.9 years vs. median not reached (p=.02; see Figure). Toxicity included injection site reactions during the first month of therapy in 86% of patients. Grade 3–4 adverse events consisted mainly of asymptomatic neutropenia (17% of patients) and infection (18% of patients). Patients that progressed to active MM have been treated with standard therapies including lenalidomide, bortezomib, transplant, and novel therapies. In contrast, seven of the 26 patients with a CRP decrease continue with stable disease and minimal toxicity on IL-1Ra alone or in combination with standard agents. Conclusion: The above results suggest that agents such as IL-1Ra that specifically inhibit paracrine IL-6 production are effective at targeting the proliferative myeloma component and warrant further investigation in combination with standard myeloma therapies. Combination therapy that effectively targets both the proliferative and the IL-1 producing myeloma components may be useful in patients with active myeloma that have an elevated growth rate at diagnosis. Disclosures: Lust: Mayo Clinic: Patents & Royalties. Off Label Use: IL-1Ra use in smoldering myeloma. Donovan:Mayo Clinic: Patents & Royalties.

Abstract Abstract 2942 Background: Pomalidomide (pom) is a distinct immunomodulatory (IMid) drug with high response rates in relapsed MM, including patients previously treated with thalidomide, bortezomib and lenalidomide. However, its duration of response and long term outcome is unknown. We evaluated the long term outcomes of the first Mayo Clinic cohort of pts treated with Pom. Methods: Pts with relapsed/refractory myeloma with 1–3 prior therapies were enrolled. Pom 2 mg/d was given orally continuously on 28 day cycle with weekly dexamethasone 40 mg. All pts received DVT prophylaxis with aspirin, heparin or warfarin. Results: 60 pts with relapsed MM were enrolled from Nov 2007-Aug 2008. Median age was 65.5; 36 were male. Median time from diagnosis was 45.6 mo (9.–-192.5). Nineteen (32%) were high-risk according to mSMART (msmart.org), and 78% were ISS Stage 2/3. Prior therapies included transplant (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%) [previous IMiD 60%] and radiation (38%). Toxicities at least possibly attributed to Pom included G3/4 anemia (5/0%), leukopenia (17/3%) and thrombocytopenia (3/0%). G3/4/5 non-hematological toxicities occurred in 30 (50%) and included fatigue (18/0/0%), pneumonia (8/2/2%), hyperglycemia (5/0/0%) and constipation (5/0/0%). Only one pt had grade 3 neuropathy. Treatment adjustment for occurred in 30 pts (50%) for pom (mostly for neutropenia) and 35 pts (58%) for dex. A median of 11.5 cycles were administered. With median follow up of 30.1 months (mo), overall response was seen in 39 (65%) [4 sCR, 5 CR, 16 VGPR, 14 PR]. Median time to first reponse (≥PR) was 1.7 mo (0.8–14.8). Median duration of response (in responders of ≥PR) was 21.3 mo. Median PFS was 13 mo and the 2 year OS rate was 76%. Standard risk pts had median PFS of 18.4 mo and 2 year OS rate was 85%; high risk pts had median PFS of 9.2 mo and 2 year OS rate was 57%. (Figure 1) Conclusions: Pom/dex is highly effective and well tolerated in relapsed MM, with a response rate of 65% even in pts with multiple prior therapies, including other IMiDs, bortezomib and transplant. The response is also durable, with median duration in excess of 21 months. Pom/dex provides long term benefit with median PFS 13 months and 2 year OS rate of 76%. Disclosures: Kumar: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene Corporation: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Fonseca:Consulting :Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding. Lacy:Celgene: Research Funding.

Abstract Background: Radioimmunotherapy (RIT) is an emerging clinical treatment option for patients with non-Hodgkin’s lymphoma (NHL). Yttrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) RIT was approved by the FDA in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory follicular NHL. In 4 registrational trials of 90Y ibritumomab tiuxetan conducted between 1996 and 1999, 211 patients with B-cell NHL were treated. Of these 211 patients, 153 patients (73%) had follicular lymphoma (FL). With ongoing follow-up, long-term durable responses have been observed, but until now have not been more fully characterized. Methods: Responding patients with time to progression (TTP) of ≥12 months were identified and characterized as long-term responding (LTR) patients. Results: In the 4 registrational trials, 78 of the 211 patients (37%) were identified as LTR patients. Characteristics of these LTR patients were as follows: median age 58 years (range, 24 to 80), 44% >60 years old, 55% male, 76% with follicular lymphoma, and 41% with lymphomatous marrow involvement. LTR patients had a median of 2 prior regimens (range, 1–9): 59% had ≥2 prior therapies, 33% had ≥3 prior therapies, and 37% had no response to their last prior therapy. Thirty percent of LTR patients had bulky disease (tumor size >5 cm) and 83% had stage III/IV disease. At the time of this analysis, the median duration of response (DR) and TTP for LTR patients were 28 months (range 11–80) and 29 months (range 12–82), respectively, with a median follow-up of 50 months (range 13–82). The median DR to the last prior therapy for LTR patients was 12 months. The complete response rate (confirmed [CR] and unconfirmed [CRu]) among LTR patients was 65%, and the median DR and TTP were 29 and 31 months, respectively, for CR/CRu patients. In ongoing responders the median DR is 52 months (range 48–80). Among the 153 patients with FL, 59 (39%) were identified as LTR patients. Compared to the overall LTR patients, LTR patients with FL had similar disease characteristics, DR, TTP, and CR/CRu rates. Conclusions: Ongoing follow-up indicates that 90Y ibritumomab tiuxetan frequently produces durable long-term responses (TTP ≥12 months) in patients with relapsed or refractory B-cell NHL. Failure to respond to the therapy immediately prior to treatment with 90Y ibritumomab tiuxetan does not appear to affect the ability to achieve long-term responses with 90Y ibritumomab tiuxetan. Durable long-term responses were achieved in 37% of all patients and 39% of patients with FL treated in 4 registrational trials of 90Y ibritumomab tiuxetan at 30 centers in the US. Of these LTR patients, a high proportion were >60 years old and had received ≥3 prior therapies.

Abstract Abstract 4048 Poster Board III-983 Introduction Iron deficiency is the most common nutritional disorder in the world with an estimated two billion affected persons. Although commonly considered environmental in origin, the existence of multiple genetic disorders of iron metabolism in man, rodents and other vertebrates suggest a genetic contribution to iron deficiency. Methods: The Hemochromatosis and Iron Overload Screening (HEIRS) Study is a multi-center, multi-ethnic study in which transferrin saturation (TS), serum ferritin (SF), and HFE mutations were determined in 101,168 adults. To identify genomic locations associated with iron deficiency, we performed a genome-wide association study (GWAS) using DNA collected from white HEIRS Study participants who had SF ≤ 12 μg/L (cases) and an equal number of white controls (SF > 100 μg/L in men, SF > 50 μg/L in women) frequency-matched to cases by sex and geographic location. Men aged ≥ 25 y and women ≥ 50 y were included in both groups. Tissue body iron, an index of iron deficiency, was estimated from serum transferrin receptor (sTfR) and SF. Genotyping was performed with the Illumina HumanCNV370K Beadchip platform. Quality control filters excluded single nucleotide polymorphisms (SNPs) or samples with > 5% missing genotypes, SNPs showing heterozygosity or Hardy-Weinberg deviations (P<10−7), and SNPs with minor allele frequency < 0.02. Population admixture/structure was assessed using principal component analysis. Regression analysis was used to examine the association between outcomes (case-control status, tissue body iron, serum ferritin, transferrin receptor, serum iron, total iron-binding capacity [TIBC], and unsaturated iron-binding capacity [UIBC]) and each SNP genotype variable; covariates included age, sex, and geographic location. Replication for 56 SNPs was conducted in a population attending primary care clinics at a Veterans Affairs (VA) medical center using the iPlex platform. Eligibility within the VA replication population was restricted to age and self-reported white ethnicity as for the HEIRS subset from a total of 2559 people (138 women). VA participants with SF ≤ 20 μg/L were classified as iron-deficient cases and frequency matched 1:2 with controls (men with SF > 100 μg/L and women with SF > 50 μg/L). Results The GWAS genomic control parameter was not significantly different from 1.0. There were 392 cases (96 men) and 390 controls (96 men) in the HEIRS subset GWAS with average age (SD) of 59 (10) y and 61 (11) y, respectively. Geometric mean SF (minimum, maximum), and mean (SD) for sTfR and tissue body iron in the HEIRS subset were 7.5 (1.2, 12) μg/L, 6.4 (3.77) mg/kg and -2.0 (2.50) for cases and 141 (51, 881) μg/L, 3.0 (0.98) mg/kg and 10.8 (2.5) for controls. After quality control tests, GWAS analysis included genotype data for 331,060 SNPs in 734 individuals (364 cases, 370 controls). For the VA replication population there were 67 male and 11 female cases, and 136 male and 27 female controls for whom DNA was successfully prepared; the average age (SD) was 68 (12) y for cases and 65 (11) y for controls. Regression analysis identified seven SNPs within four independent regions that replicated associations found in the GWAS (GWAS P<1×10-4 and VA P<0.05).The SNP rs6735681 on chromosome 2p24 was associated with serum iron (GWAS P<3.9×10-5, VA P=0.038). Three SNPs on chromosome 2p14 (rs6750096, rs2698541 and rs2698530) significantly influenced both TIBC and UIBC (GWAS P<2.9×10-5, VA P< 0.04 for all). Two SNPs in the TF gene region on chromosome 3q22 also showed significant effects on TIBC and UIBC (GWAS P<4.7×10-6, VA P<0.03 for all). The SNP rs10512064 on chromosome 9q21 was associated with serum ferritin concentration and tissue body iron (GWAS P<2.5×10-5, VA P<0.05 for both). Conclusion: From these GWAS and replication studies, we have identified three new genetic loci and one known iron gene, TF, associated with iron phenotype variability. These results point to specific loci as targets for gene identification and TF polymorphisms as determinants of iron metabolism, which in turn may play a role in regulation of body iron status. Disclosures: No relevant conflicts of interest to declare.

Abstract Previous work has suggested a relationship between disease activity and in vivo birth rates of chronic lynphocytic leukemia (CLL) cells, as measured by incorporation of deuterium into DNA during heavy water (2H2O) consumption. By extension, CLL-cell kinetics may be a useful prognostic marker in early stage disease, with an increased birth rate predicting shorter time to disease progression and poor prognosis. We are conducting a multi-center study to evaluate the relevance of proliferation rates to both known prognostic markers and to disease progression during 2.5 years of clinical follow up in previously untreated patients with early stage disease. Patients are given a daily dose of 2H2O for 6 weeks and CLL-cell birth rates are measured. We examined the leukemia cells of 36 patients for known prognostic markers (ZAP 70 expression, CD38 expression, IgVH mutation status) and CLL birth rates. Subjects were Rai Stage 0 (n=15), 1 (n=17), or 2 (n=4); mean age 57 +/− 9 (range 41–78); mean time from diagnosis to enrollment 2.1 +/− 2.2 y (range 0.1–10 y). ZAP-70 expression (20% cutoff) was positive in 44%, CD38 expression (30% cutoff) was positive in 35%, and use of unmutated IgVH genes was found in 45% of the subjects. CLL-cell birth rates ranged from 0.09 to 0.97% per day. Utilizing the previously published cut-off value of 0.35% newly divided cells per day, 33% of subjects had a high proliferation rate. Data on all biomarkers were available for 33 subjects. Nine subjects had 4/4 favorable prognostic indicators and 5 subjects had 4/4 unfavorable prognostic indicators. Agreement between prognostic markers, as assessed by kappa coefficient, was strongest for the ZAP-70 v. IgVH mutational status comparison. Comparisons were also significant for ZAP-70 v. CD38 and IgVH mutational status v. CD38. Birth rate was not significantly correlated with any of the other prognostic markers, suggesting it may be a useful independent predictor of disease progression. Isolation of CLL-cells from the bone marrow at the end of the 6 wk labeling period in 5 subjects revealed matching proliferation rates in the marrow and blood in 3 subjects. In 2 subjects, marrow enrichment was lower, suggesting a more slowly proliferating pool in the marrow, the pathophysiologic significance of which is unclear. In 5 subjects, kinetic analysis revealed a very delayed entry of newly divided cells into the blood compartment, presumably from tissue sites of proliferation. This parameter may reflect pool size of CLL-cells in tissues and correlation with lymph node burden is being evaluated. In summary, analysis of CLL-cell birth rates in vivo in these early stage patients provides unique information about the biology of CLL. Correlations with disease progression during the follow-up period will help determine the utility of this test as a prognostic biomarker.

Abstract Long noncoding RNAs (lncRNAs) are defined as RNA-like transcripts that are over 200 nucleotides and lack significant open reading frames. Some lncRNAs such as HOTAIR, MALAT1 and H19 have been found to be associated with clinical prognosis and are potential drivers of cancer progression in cancers of the breast, lung, and liver respectively. The role of lncRNAs in lymphoma is unknown. Dysregulation of eIF4E (a key component of the translation initiation complex eIF4F) influences global protein translation, especially the translation of “weak” mRNAs that can be malignancy-related. We and others have found that eIF4E is dysregulated in B-cell lymphoma. The aim of this study is to identify eIF4E-associated lncRNAs through next generation RNA-Sequencing (NGS RNA-Seq) and delineate their role in protein translation in lymphoma. RNA-immunoprecipitation (RNA-IP) was used to pull down eIF4E-bound lncRNA in lymphoma cells. eIF4E-bound lncRNAs were immunoprecipitated with eIF4E antibody or IgG control in Jeko, a mantle cell lymphoma (MCL) cell line and sent for microarray analysis and NGS-RNA-Seq for identification of lncRNAs. The microarray analysis showed that several lncRNAs were enriched with eIF4E antibody compared to IgG control. These included SNHG4 (13.6 fold), SNHG12 (4.8 fold), NCRNA00171 (4.8 fold) and IPW (4.6 fold), GNASAS (3.5 fold), SNHG7 (3.3 fold), NCRNA00182 (2.7 fold), NCRNA00094 (2.6 fold), NCRNA00188 (2.4 fold) and NCRNA00201 (2.1 fold). The binding of these lncRNAs to eIF4E was further confirmed by RT-PCR in Jeko, Mino and Granta MCL cell lines. Next, we looked the expression of these lncRNAs by qRT- PCR in the MCL cell lines and normal controls. We found SNHG4 and IPW to be overexpressed in all the MCL cell lines, while SNHG12 and NCRNA00201 were overexpressed in the selected cell lines. No significant difference was found for the expression of NCRNA00171 and NCRNA00182 in any of the MCL cell lines compared to controls. Overall, these data suggest that several lncRNA have altered expression in malignant B-cells. Considering that the microarray assay only covered a limited number of lncRNAs, we further confirmed eIF4E bound lncRNA by NGS RNA-Seq in Jeko MCL and normal control. The binding of 10/13 lncRNA mentioned above with eIF4E were found upregulated by NGS-RNA-Seq. In addition several novel lncRNAs such as SNHG1 (161.6), AC091814.2 (98.8) and RP11-304L19.5 (64.2) showed up in NGS-RNA-Seq data. These data suggest that lncRNAs, such as SNHG12, SNHG4, and SNHG1 bind to eIF4E with high affinity in malignant B-cells and might play a role in protein translation. We knocked down the expression of SNHG4 through siRNA and demonstrated that cell proliferation and global protein translation was inhibited in lymphoma cells. To further confirm the role of SNHG4 in translation regulation, a plasmid, which contains a renilla luciferase driven by SV40 promoter, was co-transfected with SNHG4 siRNA into Mino cells. The luciferase signal, decreased compared with the cells transfected with nontargeting siRNA. These data suggest that SNHG4 is involved in the regulation of protein translation. In order to clarify the mechanism of lncRNAs bound to eIF4E we searched for RNA binding sites or motifs in eIF4E protein using the web-based tools, BindN and PPRInt. Interestingly two RNA binding motifs, KNKRGGRWLITLNKQQRRS and SHADTATKSGSTTKNR, were found in eIF4E based on the prediction. To examine whether lncRNAs bind with eIF4E through these RNA binding motifs, an eIF4E mutant plasmid with both RNA binding motifs deleted (eIF4EDel), was constructed and transfected transiently into HEK-293T cells along with eIF4EWT plasmid. RNA-IP data showed that the lncRNAs SNHG12, SNHG4 and SNHG1 were not able to bind with eIF4E in eIF4EDel-transfected cells compared with that of eIF4EWT, suggesting that these lncRNAs complex with eIF4E through RNA-binding motifs within the eIF4E. Overall, our results show that the lncRNAs, SNHG1 and SNHG4 are able to bind with eIF4E and regulate protein translation. Since lncRNAs had been found to play roles in the regulation of gene expression, including transcription, splicing and mRNA stability, our results may broaden the view of the functional role of lncRNAs in translation in lymphoma cells and in other cancers. Furthermore, our results also suggested that SNHG4 lncRNAs might be served as potential biomarkers for MCL and other B cell lymphomas for translation therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction Long-term survivors in multiple myeloma (MM), described as those surviving >10 years since their diagnosis, are uncommon. There is paucity of data describing this subgroup of patients and how they differ clinically from the rest. Methods Patients with MM diagnosed from 1998 to 2000 were identified in the National Cancer Data Base (NCDB). We obtained data associated with socio-demographics, type and location of care facility, as well as the use high dose chemotherapy/autologous stem cell transplant (ASCT) as initial treatment option. Four cohorts were created based on overall survival (OS): subgroup 1 (OS: < median); subgroup 2 (OS: median to 2X-median), subgroup 3 (OS: 2X-median to <10 years) and subgroup 4 (OS: >10 years). Results There were 27,987 MM patients. The median OS for the whole group was 26.7 months. Among them, 2,196 (7.9%) were long-term survivors. Subgroups 1, 2, and 3 comprised 54.8%, 19.0%, and 18.3% of the remaining patients, respectively. Majority were males (54.3%) with a mean age at diagnosis of 67.2 years (range, 19-90). Compared to the other subgroups (1/2/3), the long-term survivor subgroup had a significantly higher proportion of patients with high educational level (37.8% vs 28.4%/31.6%/33.9%; P < 0.001), high annual household income (41.5% vs 31.0%/34.2%/36.4%; P < 0.001), residence in a metro area (79.2% vs. 77.8%/78.7%/78.3%).; P=0.003), initial treatment at an academic center (46.6% vs 28.1%/34.6%/39.0%; P < 0.001), and had ASCT as part of initial therapy (16.5% vs 2.5%/6.4%/10.9%; P < 0.001). Multivariable analyses showed that younger age, non-Black race, lower educational level, non-Medicare/Medicaid primary payor, treatment at academic centers, and receipt of ASCT as part of initial treatment were significant independent predictors of survival > 10 years. In contrast, sex, ethnicity, type or geographic location of residence, and median annual household income were not significant. Conclusions In the US, approximately 1 in 13 MM patients diagnosed in 1998-2000 are long-term survivors. There are disparities in long-term outcomes according to socio-demographic characteristics, type of treatment facility, and receipt of ASCT as part of initial therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 924 Background: Therapy-related myeloid neoplasia (t-MN), including myelodysplastic syndrome and acute myeloid leukemia, has been reported at a higher frequency with chlorambucil + fludarabine as compared to fludarabine alone, but has not been rigorously studied in the context of cyclophosphamide as an alkylator agent. The intergroup prospective randomized Phase 3 trial, E2997, compared FC with F alone as initial therapy for patients (pt) with chronic lymphocytic leukemia (CLL). FC therapy led to higher complete and overall response rates and longer progression-free survival at the initial analysis (Flinn et al JCO 2007). One rationale for combining F with C is that F can inhibit repair of DNA damage induced by C. FC did cause more myelosuppression that could lead to more long-term effects on myeloid hematopoietic function, including t-MN. Methods: E2997 enrolled 278 pts, 141 on FC and 137 on F. These cases were assessed for t-MN by required reporting of these events. Baseline genetic and molecular features of CLL were available through a companion lab correlative trial for 235 pts, 122 on FC and 113 on F. Results: With median follow-up of 6.4 yrs, there have been 13 (4.7%) reported cases of t-MN, 9 after FC and 4 after F. By cumulative incidence methodology, adjusting for the competing risk of death, the rates of t-MN at 7 yr are 8.2% after FC and 4.6% after F (p=0.18 by the Gray test). Median age at study entry of the t-MN pts was 60 (range 45–80) yrs vs 61 (range 33–86) yrs among those not reported to have t-MN. Median time from initial therapy to diagnosis of t-MN was 5 (range 0.7–8) yrs and did not differ between FC and F. Ten of 13 affected pts received 6 chemotherapy cycles. Additional therapy prior to occurrence of t-MN was given to only 2 of 9 FC pts, in contrast to 3 of 4 F pts. Thus, t-MN occurred in only 1 pt treated with F and no further therapy vs 7 who received FC and no further therapy. Ten of 12 pts with available cytogenetics at diagnosis of t-MN had an abnormality of chromosome 5 and/or 7, common to alkylating agent-induced t-MN, usually (n=8) with complex karyotype. Of the 9 pts with t-MN after FC, all 7 with available CLL data had lower risk IgVH mutated disease, in contrast to 1 of 4 with t-MN after F and 44% in the entire cohort. Conclusion: Our analysis suggests that a higher incidence of t-MN has occurred after FC than after F. t-MN after FC occurred most often without additional therapy and in IgVH mutated CLL which is associated with more favorable outcome. The increased incidence of t-MN after FC in this study, usually in the absence of additional treatment, suggests that FC is more leukemogenic than F. This finding emphasizes a need for longer follow-up of toxicity and survival before concluding that FC is preferable to F as the chemotherapy backbone for initial therapy of both low and high risk CLL. Disclosures: No relevant conflicts of interest to declare.

Abstract Essential thrombocythemia (ET) is a myeloproliferative disorder (MPD) associated with thrombohemorrhagic complications. The disease uncommonly progresses to myelofibrosis or acute leukemia; the risk of transformation may be increased by cytoreductive treatments. Anagrelide (Xagrid®/Agrylin®) is a non-cytotoxic agent that selectively reduces platelet production. A retrospective analysis of an open-label, multi-center trial including MPD patients treated by long-term anagrelide was performed.1 The total safety population comprised 3660 MPD patients (2251 with ET) with a maximum follow-up of 11.4 years. Prior myelosuppressive therapy had been administered in 81% of patients; 33% of these patients were changed to anagrelide because of previous toxicity and 31% because of poor platelet control. Efficacy and safety data hereafter are described for the ET population. There were 934 ET efficacy evaluable patients: with a response seen in 78.7% of them (complete and partial response: 67.2% and 11.5%, respectively). This was similar to that of patients who failed previous therapy (78.8%) or were intolerant (75.6%). After the first year, platelet count decreases were well maintained. Results were similar for both sexes, different age groupings and ethnic origins. AEs occurred in 40.2% of the patients and were generally mild. Anagrelide was discontinued in 38.6% of patients (adverse events accounting for 29.2% of patients stopping treatment). At baseline, 163/934 (17.5%) patients reported ET-related symptoms including GI and other bleedings, arterial or venous thrombosis, angina, pulmonary embolism, transient ischemic attacks, peripheral ischemia and paresthesia. This had reduced to 7.9% (63/796, P<0.001) after 12 weeks and was maintained during follow up (4.3%: 15/470 at 1 year, 3.2%: 6/239 at 2 years, P<0.001.2 Transformation to AML/MDS occurred in 47/2251 (2.1%), but only in subjects who had previously been exposed to cytoreductive treatment. Mortality rate in the safety population was as to be expected in ET patients: 8.8%. Most common reason for death (> or =1%) were CML, reason unknown or unspecified and sepsis. Anagrelide (Xagrid®/Agrylin®) effectively reduces platelet counts and thrombohemorrhagic complications in patients with ET. This is independent of gender, age, ethnic origin and prior therapy. The drug demonstrates a recognized safety profile. Benefits are maintained during long-term follow-up without an increase in disease transformation.

Abstract Background In the primary analysis of the phase III COMFORT-I study, the JAK1/JAK2 inhibitor ruxolitinib (RUX) significantly improved splenomegaly, myelofibrosis (MF)-related symptoms, and quality of life (QoL) measures in patients (pts) with MF versus placebo (PBO). An additional analysis (median follow-up 51 weeks [wks)]) showed RUX was associated with a survival advantage versus PBO (Verstovsek et al. N Engl J Med2012). Longer term follow-up (median 102 wks) showed durable SV reductions and QoL improvements. At this time point, RUX continued to be associated with a survival advantage, despite all pts originally randomized to PBO having discontinued or crossed over to ruxolitinib shortly after the primary analysis (Verstovsek et al. ASH 2012. abstract 800). We report additional longer-term follow-up of pts from COMFORT-I. Methods In COMFORT-I, 309 pts were randomized (1:1) to RUX or PBO. RUX starting dose depended on baseline platelet count (100–200´109/L: 15 mg BID; >200´109/L: 20 mg BID). Doses could be titrated for lack of efficacy or excess toxicity as specified in the protocol. Pts receiving PBO could crossover to RUX after the primary analysis (ie, when all pts completed 24 wks and half the pts completed 36 wks of therapy) or at any time if they met protocol-specified criteria for worsening splenomegaly. The primary endpoint was the proportion of pts who achieved a ≥35% reduction in spleen volume (SV) at wk 24. Symptoms were assessed up to wk 24 using the modified MF Symptom Assessment Form v2.0. QoL continued to be evaluated beyond wk 24 using the EORTC QoL Questionnaire-Core 30 (QLQ-C30). Survival was estimated by Kaplan-Meier analysis according to original randomized treatment. To better understand the effect of crossover on the PBO arm, statistical modeling of survival was conducted using a generalized Gamma distribution. Results Median follow-up was 149 wks at the time of this updated analysis. Of 155 pts originally randomized to RUX, 77 remain on therapy. Of 154 pts originally randomized to PBO, 111 crossed over to RUX; the median time to crossover was 41.1 wks (range, 5.1–65.4). At wk 24, pts originally randomized to RUX had a mean SV reduction of −31.6%; this was durable for pts who continued on RUX, where the mean SV reduction at wk 144 was −34.1%. Fifty-nine percent (91/155) of pts originally randomized to RUX achieved a ≥35% SV reduction at any time during study; for these pts, the probability of maintaining this response for >132 weeks from the time of their initial response was 0.53. Pts originally randomized to RUX who continued on therapy experienced durable improvements in the Global Health Status/QoL and functional domains of the EORTC QLQ-C30. Overall survival favored RUX (HR=0.69; 95% CI: 0.46, 1.03; P= 0.067; Fig 1), with 42 and 54 deaths among pts originally randomized to RUX and PBO, respectively. Modeling of the hazard function of death over time to explore the effect of crossover to RUX in pts originally randomized to PBO showed a decrease in hazard for these pts, which corresponded to an increased proportion of pts crossing over to RUX. In pts originally randomized to RUX who continued on therapy, there was no substantial change in the rate, distribution, or severity of nonhematologic adverse events (AEs) with longer-term therapy; most nonhematologic AEs were grade 1 or 2. Mean and median hemoglobin and platelet count remained stable with longer-term therapy. Consistent with this, the incidence of new onset grade 3 or 4 anemia and thrombocytopenia observed after the first 6 months of RUX therapy decreased relative to that seen in the first 6 months of therapy (Fig 2). With approximately 1 year of additional follow up, 4 new cases of acute myeloid leukemia were reported: 2 pts originally randomized to PBO (376 and 666 days after crossover to RUX) and 2 pts originally randomized to RUX (848 and 1143 days after starting RUX). Conclusions After a median follow-up of 149 wks, the hazard ratio for overall survival favored pts originally randomized to RUX over those originally randomized to PBO, the majority of whom crossed over to RUX. The hazard of death for pts originally randomized to PBO decreased as pts crossed over to RUX. SV reductions and QoL improvements were sustained with longer-term therapy. The incidence of new onset grade 3 or 4 anemia and thrombocytopenia decreased with longer-term therapy. Collectively, these data reinforce the durable efficacy and longer-term safety of RUX in pts with MF. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Mesa:Genentech: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Lilly: Research Funding. Gotlib:Incyte Corporation: Travel support, Travel support Other; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees; Incyte Corporation: Research Funding. Levy:Incyte Corporation: Equity Ownership; Incyte Corporation: Employment. Gupta:Incyte Corporation: Consultancy; Novartis: Consultancy; Inctye Corporation: Research Funding; Novartis: Research Funding; Novartis: Speakers Bureau. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Miller:Novartis: Consultancy; Incyte Corporation: Consultancy; Novartis: Research Funding; Incyte Corporation: Research Funding; Novartis: Honoraria; Incyte Corporation: Honoraria. Talpaz:Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Winton:Incyte Corporation: Research Funding; Incyte Corporation: Membership on an entity’s Board of Directors or advisory committees. Arcasoy:Incyte Corporation: Research Funding. Lyons:Lilly: Research Funding; Amgen: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding; Gilead: Consultancy; Seattle Genetics: Research Funding; Gilead: Research Funding; Ariad: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Paquette:Incyte Corporation: Consultancy. Raza:Novartis: Speakers Bureau; Onconova Inc: Research Funding. Vaddi:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sun:Incyte: Employment; Incyte: Equity Ownership. Peng:Incyte Corporation: Employment; Incyte Corporation: Equity Ownership. Sandor:Incyte: Employment; Incyte: Equity Ownership. Kantarjian:Ariad: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding.