Modified International Working Group Research Articles

Phase II Multicenter Study of Single-Agent Lenalidomide in Subjects with Mantle Cell Lymphoma Who Relapsed or Progressed After or Were Refractory to Bortezomib: The MCL-001 “EMERGE” Study

AbstractAbstract ▪905▪This icon denotes a clinically relevant abstract Introduction:Though dose-intensive strategies using chemoimmunotherapy have significantly improved mantle cell lymphoma (MCL) outcomes with prolonged progression-free survival (PFS), most patients still relapse over time. In the relapsed setting, MCL patients often develop chemoresistance and have a poor overall prognosis. The immunomodulatory agent lenalidomide has demonstrated tumoricidal and antiproliferative effects in MCL and clinical activity and safety in multiple phase II studies in aggressive non-Hodgkin’s lymphoma. The objective of the MCL-001 “EMERGE” study was to examine the safety and efficacy of single-agent lenalidomide in subjects with MCL who relapsed or were refractory to bortezomib. Methods:This phase II, multicenter, single-arm, open-label study examined single-agent lenalidomide administered at 25 mg/d PO on days 1–21 of a 28-day cycle until disease progression, unacceptable toxicity, or voluntary withdrawal. The subjects were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (<12 months) after or were refractory to bortezomib. The primary endpoints were overall response rate (ORR) and duration of response (DOR); secondary endpoints included complete response (CR), PFS, time to progression (TTP), overall survival (OS) and safety. Efficacy data were measured by investigators and an independent central review committee according to modified International Working Group criteria and analyzed by SAS. Results:134 subjects with relapsed or refractory MCL who were heavily pretreated (no limitation in number of prior therapies) were enrolled. The median age was 67 y (range, 43–83), two-thirds of them being 65 y or older and 93% with advanced stage disease (stage III-IV). The median number of prior therapies was 4 (range, 2– 10) with 78% of subjects having received ≥ 3 prior lines of treatment. The ORR to single-agent lenalidomide was 28% (CR/CRu 8%; Table 1) by independent central review, with a median DOR of 16.6 mo (95% CI, 7.7–26.7; Figure 1). The ORR was 32% (CR/CRu 16%) by investigator assessment, with a median DOR of 18.5 mo. Median time to response (central review) was 2.2 mo (3.7 mo to achieve CR). The median PFS was 4.0 mo (95% CI, 3.6–5.6); median OS was 19.0 mo (95% CI, 12.5–23.9). Subjects received an average dose of 20 mg/d of lenalidomide. Lenalidomide was dose reduced in 38% of subjects; treatment discontinuation due to an adverse event (AE; primarily myelosuppression) was reported in 19% of subjects. The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%) and fatigue (7%). Other AEs (any grade) included tumor flare reaction (13 subjects, 10%), deep vein thrombosis (5 subjects, 4%), pulmonary embolism (3 subjects, 2%) and invasive second primary malignancies (3 subjects, 2%). Conclusions:The EMERGE study demonstrated rapid and durable efficacy of lenalidomide in MCL subjects who relapsed or progressed after or were refractory to bortezomib. These results in heavily pretreated MCL subjects (median of 4 prior treatments), and with an expected toxicity profile support single-agent lenalidomide in subjects with relapsed or refractory MCL after bortezomib.Table 1Efficacy of single-agent lenalidomide in subjects with MCL relapsed or progressed after or refractory to bortezomibEfficacy Parameter (N=134)By Central Review (n=134)By Investigator Review (n=134)ORR, n (%)37 (28)43 (32)CR/CRu, n (%)10 (8)22 (16)PR, n (%)27 (20)21 (16)Median DOR, mo16.6 (95% CI, 7.7–26.7)18.5 (95% CI, 12.8–26.7)Median time to response, mo (range)2.2 (1.7–13.1)2.0 (1.7–15.9)Median TTP, mo5.4 (95% CI, 3.7–7.5)4.0 (95% CI, 3.6–7.5)Median PFS, mo4.0 (95% CI, 3.6–5.6)3.8 (95% CI, 3.5–6.8)CR(u) = complete response (unconfirmed); DOR = duration of response; ORR = overall response rate; PFS = progression-free survival; PR = partial response; TTP = time to progression. [Display omitted] Disclosures:Goy:Pfizer: Advisory board member, Advisory board member Other; Seattle Genetics: Advisory board member Other; J&J: Advisory board member, Advisory board member Other; Pharmacyclics: Advisory board member, Advisory board member Other; Millenium: Advisory board member, Advisory board member Other, Speakers Bureau; Celgene: Advisory board member Other. Off Label Use: This is a phase 2 clinical study of safety and efficacy for lenalidomide in patients with MCL. Sinha:Celgene: Research Funding. Williams:Celgene: Clincial Trial Research Support, Advisory Boards, Data Safety Committee Member, Consultant Other, Consultancy. Drach:Celgene: Speakers Bureau; Janssen: Speakers Bureau; Roche: Research Funding. Ramchandren:Seattle Genetics: Speakers Bureau. Herbrecht:Pfizer: Advisory board member Other. Zhang:Celgene: Employment. Cicero:Celgene: Employment. Fu:Celgene: Employment. Witzig:Celgene : Research Funding.

Phase 2 Study of Decitabine in Combination with Tretinoin in Myelodysplastic Syndromes and Acute Myelogenous Leukemia: Interim Results

AbstractAbstract 3815 Background:The activity of DNA methyltransferase inhibitor (DNMTI) monotherapy is suboptimal for most patients (pts) with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). DNMTI combinations studied to date have not convincingly produced higher response rates compared to DNMTI monotherapy, although time to response appears to be improved in some studies. We combined decitabine (DAC) with tretinoin (ATRA), an RAR ligand which can recruit histone acetyltransferases to gene regulatory regions, as a means to upregulate gene expression, and to induce apoptosis or differentiation, as is seen in in vitro studies of non-M3 AML. Our previous phase 1 study established 65 mg/m2/day of ATRA as the MTD (headache was DLT at 85 mg/m2/d) when given on days 10–19 following standard dose decitabine (20 mg/m2/d), given on days 1–5 of a 28-day cycle (Klimek VM, et al. Leuk Res, 2011;35:S70-S). Materials and Methods:MDS pts with any FAB or WHO subtype were enrolled if they had an IPSS score ≥ 0.5, were ineligible for allogeneic stem cell transplant (AlloSCT) at study entry, and had adequate hepatic and renal function. Prior DAC or 5-azacytidine (5-aza) responders who then progressed off treatment, and pts whose MDS progressed on 5-aza were eligible. Pts received up to 10 cycles of DAC (given on days 1–5) and tretinoin (65 mg/m2/d on days 10–19 of a 28-day cycle), allowing for delays due to infection or to allow count recovery as deemed necessary by the treating physician. Those with an ongoing response after 10 cycles continued DAC alone off-study. The primary endpoint is efficacy, assessed after even-numbered cycles using the 2006 Modified International Working Group MDS response criteria. Kaplan-Meier methodology was used to estimate duration of best response due to the censoring for patients undergoing AlloSCT. Results:36 eligible pts (27M, 9F; median age 66, range 45–84 yrs) were enrolled in the phase 2 cohort as of 6/2012. FAB/WHO subtypes included: RA/RCMD, n=3 (8%); RARS/RCMD-RARS, n=1 (3%); RAEB/RAEB-1 & 2, n= 24 (67%); RAEBt/AML, n= 6 (17%); CMML/CMML-1, n=2 (6%). IPSS risk categories included: Int-1, n=5 (14%); Int-2, n=16 (44%); High Risk, n=11 (31%), and pts with ≥ Int-1 (n=3) or ≥ Int-2 (n=1) risk disease who could not be definitively classified using the IPSS. Most pts (n=20) had IPSS poor risk cytogenetics (CG), 11 had IPSS good risk CG (all with normal karyotype), 3 had intermediate risk CG, and CG results were unknown in 2 pts. 15/36 (42%) had therapy-related disease (t-MDS/AML), all with IPSS poor risk CG and either IPSS Int-2 (n=9) or High Risk (n=6) disease. Marrow blasts were ≥ 5% in 26/36 pts: (5–10%, n=13; 11–20%, n=13; 21–30%, n=6). Prior MDS therapy included lenalidomide (n=2), thalidomide (n=1), 5-aza (n=3), DAC (n=1), and lintuzumab (n=1). Pts received a median of 4 cycles of therapy (range, 1–10), and started therapy 0.6–180 months (median, 1.42 months) from the time of diagnosis. Two pts were classified as treatment failures since they died during the first cycle of therapy. One pt with CMML-1 at baseline progressed to AML during the screening period, and was deemed ineligible. Two pts on study have not yet had a full response assessment. Best responses in the evaluable intent to treat cohort (n=33) include: CR, n=7 (21%); PR, n=1 (3%); mCR, n=3 (9%); mCR+HI, n=3 (9 %); HI alone, n=3 (9 %); Stable disease, n=10 (30%); Disease progression, n= 3 (9%). The composite CR rate (CR+mCR±HI) was 39% (13/33), and the overall response rate (CR+PR+mCR±HI+HI) is 51% (17/33). Median time from diagnosis to start of therapy for responders was 1.7 months (range, 0.8–180). The ORR for the 13 t-MDS/AML pts was 46% (6/13), including 5 pts with monosomy 17 and/or p53 loss by FISH. The median time to initial response and best response is 1.1 months and 2.3 months, respectively. The median response duration is 7.8 months, incorporating the 7 pts censored at the time they came off study to undergo AlloSCT. Conclusions:DAC/ATRA is active in IPSS Int-2 and High Risk MDS and in t-MDS/AML, which is characterized by poor risk cytogenetics and an increased frequency of p53 or chromosome 17p loss. Although our interim ORR appears similar to DAC and 5-aza monotherapy trials, our results were achieved in a higher risk cohort, and the CR rate is equal to or greater than some earlier monotherapy studies with a shorter median time to response. Ongoing and planned correlative studies may define pre-treatment biomarkers for response. Disclosures:Off Label Use: Tretinoin.

Maitake Mushroom Extract in Myelodysplastic Syndrome (MDS): A Phase II Study

Abstract 5043 Background:MDS is a heterogeneous group of hematologic diseases characterized by ineffective erythropoiesis and an increased risk of AML. MDS-related deaths are commonly due to infection resulting from impaired immunity, including quantitative and functional neutrophil defects. Maitake extract is from the fruit body of Grifola frondosa mushroom and is widely used in Asia as an adjunctive treatment for malignant diseases. This hot water extract is composed of a central beta 1,6-glucan core surrounded by beta 1,3-branches. Maitake extract enhances hematopoiesis by increasing G-CSF production with subsequent stem cell proliferation and differentiation of granulocyte-monocyte colony forming cells. Maitake also activates macrophages through Dectin-1 receptor binding, increases the weight and number of nucleated cells in the spleen and improves innate immune response in animal and human models. Activated macrophages may reduce iron stores. Compared to G-CSF, maitake may have fewer side-effects, is less costly, and may produce a comparable improvement in granulocyte function. Materials and Methods:MDS patients with IPSS Low and Int-1 risk disease and ANC>500, plts >20K were enrolled. Following double baseline measurements, patients received the maitake extract at 3mg/kg PO BID for 12 weeks. Primary endpoints include change in neutrophil counts and alterations in granulocyte function as measured by the respiratory burst test. The respiratory burst test is a highly sensitive and quantitative flow cytometric assay of granulocyte and monocyte function to assess the production of spontaneous reactive oxygen species (ROS) and stimulated response to 3 activators: opsonized E. coli, phorbol ester and the chemotactic peptide N-formylmethiolyl-leucyl-phenylalanine (fMLP). Results were compared to age-matched normal healthy volunteers. Responses were assessed using the modified International Working Group (IWG) MDS response criteria.Secondary endpoints include serial assessment of hemoglobin and platelet levels, reticulocyte count, monocyte function, and GM-CSF and G-CSF levels. Iron studies were assessed throughout treatment to determine whether the maitake indirectly alters iron stores potentially decreasing iron overload. Results:14 eligible patients (pts) (8M, 6F; median age 69, range 52–83 yrs) received the maitake extract. IPSS risk categories included: Low-risk, n=7; Int-1, n=7. WHO Stage: RA=2; RARS=1; RCMD=6; RCMD-RS=1; RCUD=1; MDS-U=1; CMML-1=2. Two pts received prior 5-azacytidine therapy.Mean fMLP-stimulated granulocyte function in pts at baseline was lower than control values. Monocyte baseline response to E. coli was significantly reduced (p<0.01); ROS production to phorbol ester was also lower than in controls.No patients met criteria for response using the modified IWG response criteria. Preliminary analyses showed that ROS responses to E. coli stimulation increased by weeks 7–9 in pts who were deficient at baseline. Monocyte ROS production increased in 2 pts by 2–6 fold at week 7. There was a 2–15 fold increase in the neutrophil response to fMLP by week 7 and a 2–35 fold increase in monocyte response to fMLP at week 9. Monocyte response to E. coli increased between 3–10 fold in 2 pts with peak values during weeks 7–9. The two pts with the most pronounced response by fMLP and ROS production also had eosinophilia, which resolved following study participation.The most common toxicities were diarrhea (grade 1) in 6 pts, eosinophilia (2–2.8 × normal) in 3 pts, increases in AST (grade 1) and ALT (grade 1) in 4 pts and nausea (grade 1) in 1 patient. Two pts were removed from the study, one for diarrhea possibly related to study medication and one for disease progression. Conclusion:Maitake mushroom extract is well tolerated without evidence of clinically significant adverse hepatic, renal or metabolic abnormalities. No clinical responses were seen. Based on our preliminary data, the maitake extract appears to enhance ROS in both unstimulated and stimulated cells, confirming preclinical data. The improvement in granulocyte and monocyte function in our in vitro studies suggests that maitake may enhance immune responses in MDS pts. Eosinophilia was noted but the significance remains uncertain at this time. The study is ongoing. Updated results will be presented. Disclosures:No relevant conflicts of interest to declare.

Final Results From the Phase 2 Continuation Study of the Lenalidomide and Azacitidine Combination in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Abstract 607 Background:Lenalidomide (LEN) and azacitidine (AZA) have activity in lower- and higher-risk MDS patients (pts), where both microenvironment and cell regulatory mechanisms play a role. The LEN/AZA combination was well-tolerated in the Phase 1 study (Sekeres JCO 2010) that established Phase 2 dosing, with an overall response rate (ORR) of 67%. Methods:The primary objectives for this multicenter, Phase 2 trial were to determine the efficacy and safety of combination therapy, with AZA 75mg/m2 daily × 5 days, and LEN 10mg daily × 21 days of a 28-day cycle (maximum of 7 cycles), in pts with higher-risk MDS (IPSS score ≥1.5, or World Health Organization (WHO) classification with ≥5% myeloblasts) not previously treated with AZA or LEN. Adverse Events (AEs) were assessed per NCI CTC v.3.0, with median decrease in absolute neutrophil count (ANC) or platelets (plt) calculated for the first 8 weeks of therapy. Subjects were enrolled to the Phase 1 study from 5/05 through 5/08, and to the Phase 2 continuation from 3/09 through 4/11, with results reported through 7/11. Bone marrow biopsies were performed after the 4th and 7th cycles, and pts could continue on AZA monotherapy off-study. Responses were assessed per modified International Working Group criteria as complete or partial response (CR, PR), or hematologic improvement (HI), and validated centrally. Time to progression was from date of CR, and overall survival (OS) from date of study enrollment. Results:A total of 36 pts were enrolled at 3 centers (18 Phase 1, 18 Phase 2); median age was 68 years (range 47–78), 13 pts (36%) were female, median interval from diagnosis was 8 weeks (range, 2–106), and median follow-up was 15 months (range 2–60). Prior MDS therapies included growth factors (19%), immunosuppressants (14%), and chemotherapy (17%). Median baseline hemoglobin was 9.7 g/dL, platelet count 65 k/uL, neutrophil count 840 k/uL, erythropoietin level 108 MIU/mL, and bone marrow blast percentage was 11%. IPSS categories were Int-1 (5 pts), Int-2 (20 pts), and High (11 pts); 8 pts had RAEB-1, 21 had RAEB-2, and 3 had CMML. Only 1 pt had a chromosome 5q deletion. Pts received a median of 5 cycles of therapy on-study. Grade 3/4 non-hematologic AEs (related or unrelated) included cardiac (11%), febrile neutropenia (31%), other infection (8%), pulmonary (11%), vascular access-related thrombosis (6%), CNS hemorrhage (6%), or other (11%). Three pts (8%) died while on-study. The most common grade ≤2, non-hematologic AEs related to treatment included constipation (47%), dermatologic (rash or injection site reaction) (44%), fatigue (39%), diarrhea (39%), nausea (19%), dizziness (19%), and dyspnea (19%). Median decrease from baseline in ANC was 35% and in plts was 18%. Of 35 patients evaluable, the ORR was 71%: 14 pts (40%) had a CR and 11 (31%) had HI, of whom 3 had bi- or tri-lineage HI. Median time to response was 3 months (range, 1–7). Three patients had progressive disease while on-study. Among pts achieving a CR, 7 (50%) continue to receive therapy; median age was 68 years (range, 50–76); IPSS was Int-1 (n=3), Int-2 (n=9), and High (n=2); WHO was RAEB-1 (n=5) and RAEB-2 (n=9); cytogenetic profiles were: 9 (64%) normal; 1 (7%) del (5q); 1 (7%) +8, 1 (7%) −7, 1 (7%) complex, and 1 (7%) unknown; median CR duration at last study assessment was 16 months (range, 3–36) and median OS at last assessment among CR pts was 27 months (range, 7–55). Seven CR pts (50%) evolved to AML a median of 20 months from achieving CR (range, 9–31); 10 (71%) remain alive at last study assessment. Conclusions:The LEN/AZA combination is well-tolerated and highly active in treating higher-risk MDS. The ORR seen in the Phase 1 study was supported by Phase 2 data, with good OS, even among progressing pts. Subsequent randomized studies will compare the LEN/AZA combination to AZA monotherapy and other AZA-based combinations. Disclosures:Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Use of lenalidomide, wapproved for lower-risk del(5q), will be discussed in higher-risk patients with MDS. Komrokji:Celgene: Honoraria, Research Funding, Speakers Bureau. Lancet:Celgene: Research Funding. List:Celgene: Consultancy. Maciejewski:Celgene: Membership on an entity's Board of Directors or advisory committees.

Identification of Patient Subgroups Demonstrating Longer Progression-Free Survival (PFS) Benefit with Bortezomib-Rituximab Versus Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma (FL): Biomarker Analyses of the Phase 3 LYM3001 Study

Abstract 265 Background: Treatment goals in patients with relapsed FL are to prolong PFS and improve overall survival (OS). To optimize treatment for individual patients, identification of subgroups most likely to benefit from a specific therapy is important. The international, randomized, phase 3 LYM3001 study in patients with relapsed or refractory FL demonstrated improved PFS with bortezomib-rituximab vs rituximab alone (median 12.8 vs 11.0 months, HR 0.822, p=0.039), plus increased overall response rate (ORR; 63% vs 49%, p=0.0004), complete response rate (CR/CRu; 25% vs 18%, p=0.035), and durable (≥6 months) response rate (50% vs 38%, p=0.002) in an unselected patient population. Here we present exploratory biomarker analyses aimed at identifying patient subgroups deriving a longer PFS benefit with bortezomib-rituximab and showing a trend for better OS. Methods: Patients received five 5-week cycles of bortezomib-rituximab (N=336) or rituximab (N=340). Response was assessed using modified International Working Group response criteria. Archived tumor tissue was collected at baseline from 502 (74%) patients; whole blood samples for germ-line DNA were collected on day 1 of cycle 1 from 619 (92%) patients. Protocol-specified candidate biomarkers were based on associations with bortezomib (NF-κB p65, PSMA5, p27, PSMB1/5/8/9) or rituximab (CD68, FCGR2A/3A) activity. Immunohistochemistry assays were used for protein analysis. Taqman SNP assays and PCR/LDR were used for genotyping. Statistical analyses included single-marker analyses, pair-wise combination analyses (n=1140 comparisons), and multiple comparison analyses of all evaluable patients in LYM3001. Clinical covariates included in the analysis were baseline FLIPI score, prior rituximab, time since last anti-lymphoma therapy, region, age, gender, race, Ann Arbor stage, high tumor burden, and number of prior lines of therapy. Results: Single markers and biomarker pairs (n=102) highlighted patient subsets that had significantly improved outcomes with bortezomib-rituximab vs rituximab. For 14 of the pairs, the PFS benefit was ≥6 months. Using false discovery rate (FDR) to control for multiple comparison corrections, one biomarker pair was significant. This pair (presence of the PSMB1 P11A C/G heterozygote, and low CD68 expression [0–50 CD68-positive macrophages in the follicular space]) was associated with significantly improved PFS in patients receiving bortezomib-rituximab vs rituximab (median 16.6 vs 9.1 months, HR 0.407, p 2 prior lines of therapy). There was also a trend towards an OS benefit (medians not reached, HR 0.426, p=0.0550), as well as a significantly higher ORR (73.7% vs 47.5%, p=0.0077), a higher CR rate (33.3% vs 23%, p=0.3044), and a significantly longer time to next therapy (median 33.1 vs 14.8 months, p=0.0013). In patients lacking this biomarker pair (N=238) no significant efficacy differences were seen. No other similar studies were available to confirm the reproducibility of these analyses. Therefore, we split the LYM3001 dataset into discovery and confirmation cohorts (7:3 ratio of biomarker-evaluable patients) to enable evaluation and confirmation in independent cohorts of patients The significant biomarker pair of PSMB1 P11A C/G heterozygote and low CD68 was identified in the discovery cohort (N=198) with a PFS advantage with bortezomib-rituximab vs rituximab of 5.7 months (median 14.2 vs 8.4 months, p=0.0003) and an indication of longer OS (HR 0.47, p=0.1291). This biomarker pair also showed a clear PFS advantage in the confirmation cohort (N=108, 8.7-month PFS benefit; median 18.2 vs 9.5 months, HR 0.44, p=0.0817). Other significant biomarker combinations, including combinations of molecular and clinical variables (e.g. high tumor burden) were identified and will be presented. Conclusions: Analyses of the phase 3 LYM3001 trial identified biomarker combinations present in a third of patients offering a significant PFS benefit with bortezomib-rituximab vs rituximab. Use of such biomarker assays in patients with relapsed or refractory FL may aid identification of subgroups deriving maximal benefit from the addition of bortezomib to rituximab therapy. Disclosures: Coiffier:Janssen-Cilag: Consultancy; Roche: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; MedImmune: Consultancy; CTI: Consultancy. Off Label Use: Bortezomib used in combination with rituximab in patients with relapsed/refractory follicular lymphoma. Li:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Henitz:Janssen Research & Development: Employment. Karkera:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Favis:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Gaffney:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Shapiro:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Theocharous:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Elsayed:Janssen Research & Development: Employment; Johson & Johnson: Equity Ownership. de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Rule:Johnson & Johnson: Advisory Board, Institutional grant, meeting attendance expenses, Honoraria. Walewski:Janssen-Cilag: Institutional/personal grants, advisory board; Hoffman La Roche: Honoraria, Institutional/personal grants, travel/accommodation expenses; Mundipharma: Honoraria; Celgene: Honoraria. de Vos:Millennium Pharmaceuticals, Inc: Consultancy. Crump:Janssen/Ortho-Biotech: Consultancy. Shpilberg:Janssen-Cilag: Consultancy, Honoraria. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Esseltine:Millennium Pharmaceuticals, Inc: Employment; Johnson & Johnson: Equity Ownership. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Ricci:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership.

Retrospective Comparison of Azacitidine and Decitabine in the Treatment of Myleodysplastic Syndrome,

Abstract 3809 Introduction:Two DNA methyltransferase inhibitors, azacitidine and decitabine, are currently approved for the treatment of myleodysplastic syndrome (MDS) according to the results of several Phase II and III trials, which have demonstrated the efficacy of the agents. Despite widespread clinical use of DNA methyltransferase inhibitors, one of important practical issues is which drug should be chosen. In this retrospective study, we tried to compare azacitidine and decitabine for the treatment of MDS in regards to treatment response, toxicities, and survival. Methods: Between September 2006 and October 2010, a total of 149 patients were treated with either azacitidine (n=75) or decitabine (n=74) for MDS defined by the WHO classification and chronic myelomonocytic leukemia (CMML) in 3 Korean institutes; all are included in this analysis. Azacitidine 75 mg/m2/day was administered as a subcutaneous injection for 7 consecutive days and decitabine 20 mg/m2/day as a 1-hour intravenous infusion for 5 consecutive days. Both agents were repeated every 4 weeks. Treatment response was evaluated using modified International Working Group response criteria. Results: Median age of the patients, 100 males and 49 females, was 60 years (range, 23–83). WHO subtype at the time of decitabine treatment was RA in 18, RARS in 2, RCMD in 28, RCRS in 5, RAEB-1 in 46, RAEB-2 in 39, unclassified in 2, and CMML in 9. IPSS risk category was low/intermediate-1 in 72 and intermediate-2/high in 72. Median number of courses delivered to each patient was 5 (range, 1–31) for azacitidine and 4 (range, 1–24) for decitabine (P=0.033). Hematologic responses (CR/PR/mCR) were induced in 9 patients (12.0%) with azacitidine and in 22 (29.7%) with decitabine (P=0.008). The rates of overall response (CR/PR/mCR/HI) was not significantly different between azacitidine (52.0%) and decitabine (63.5%) (P=0.155). Median number of treatment courses to achieve any response was 2 (range, 1–6) for azacitidine and 1 (range, 1–5) for decitabine (P=0.269). Adverse events were evaluated for the first 6 courses for all patients, for a total of 584 courses. Major adverse events were cytopenia and cytopenia-related infection. Grade 3 or higher neutropenia was more frequent with decitabine (79.6%) than with azacitidine (72.2%) (P=0.040), but incidence of febrile episode requiring intravenous antibiotics was similar (12.4% with decitabine vs. 15.4% with azacitidine, P=0.298). Grade 3 or higher non-hematologic toxicities were infrequent and reversible with both agents. Median follow-up duration of surviving patients was 46.9 months (range, 11.8–55.5) for azacitidine and 22.7 months (range 3.3–33.3) for decitabine. Probabilities of overall survival (OS) at 2 years were 43.5% for azacitidine, and 55.5% for decitabine. The difference of OS in favor of decitabine over azacitidine was significant after adjustment for other variables (HR, 0.539; 95% CI, 0.325–0.895; P=0.017). Subgroup analysis showed that the survival superiority of decitabine over azacitidine was evident principally in patients with IPSS low/intermediate-1 (HR, 0.131; P=0.006), MDS duration of 1 year or less (HR, 0.534; P=0.022), or ECOG performance scale of 0–1 (HR, 0.589; P=0.060). In contrast, a tendency was noted for survival superiority of azacitidine over decitabine in patients with MDS duration over 1 year (HR, 2.107; P=0.235) or ECOG scale of 2–3 (HR, 2.492; P=0.074). Conclusions: Although both azacitidine and decitabine were effective in the treatment of patients with MDS, there were some differences between two agents in regards to response patterns, toxicities, and type of subgroups that showed more beneficial effects with the hypomethylating agent. Disclosures:No relevant conflicts of interest to declare.

Validation of New Prognostic Model Including Comorbidities in Patients with Myleodysplastic Syndrome Receiving Hypomethylating Therapy

Abstract 1708 Introduction:A new prognostic model including comorbidities, which are assessed using the Adult Comorbidity Evaluation-27 (ACE-27), was proposed for the patients with MDS by researchers from MD Anderson Cancer Center, Houston, TX (J Clin Oncol 2011;29: 2240). The model was developed after analysis of 600 patients who presented to the center. We aimed to validate the new prognostic model for the Korean patients with MDS who were treated with hypomethylating agents. Methods:Between September 2006 and October 2010, 149 patients were treated with either azacitidine or decitabine for MDS defined by the WHO classification and chronic myelomonocytic leukemia (CMML) in 3 Korean institutes. The new prognostic model included age (> 65 years, 2 score points), comorbidity assessed by ACE-27 (mild/moderate, 1 point; severe, 3 points), and IPSS (intermediate-2, 2 points; high, 3 points). Patients were divided into one of 3 risk groups: low (score 0–1), intermediate (scores 2–4), and high (scored 5–8). Risk group by the new prognostic model could not be assigned in 10 patients, thus a total of 139 patients were included in this analysis. Azacitidine 75 mg/m2/day was administered as a subcutaneous injection for 7 consecutive days (n=68) and decitabine 20 mg/m2/day as a 1-hour intravenous infusion for 5 consecutive days (n=71). Both agents were repeated every 4 weeks. Clinico-patholoical data including comorbidities were collected at time of hypomethylating therapy. Treatment response was evaluated using modified International Working Group response criteria. Results:Median age was 61 years (range, 23–83); 47 patients were over 65 years old. Overall comorbidity score assessed by ACE-27 was as follows: none (n=65), mild (n=53), moderate (n=15), and severe (n=6). IPSS risk category was low/intermediate-1 in 72, intermediate-2 in 55, and high in 12. Risk group measured by the prognostic model was low in 42 (30.2%), intermediate in 79 (56.8%), and high in 18 (12.9%). Hypomethylating therapy induced hematologic responses (CR/PR/mCR) in 28 patients (20.1%) and rate for overall responses (CR/CR/mCR/HI) was 57.6% (80/139). The treatment responses were not significantly different between 3 risk groups. At a median follow-up time of 27.0 months (range, 3.3–55.5) among surviving patients, 70 patients died and overall survival (OS) probability was 49.5% at 2 years; median OS was 24.1 months (95% CI, 11.7–36.5). OS was significantly different according to the presence of comorbidities (OS at 2 years, none vs. mild/moderate vs. severe, 63.4% vs. 37.5% vs. 33.3%, P=0.006) or risk groups by the prognostic model (OS at 2 years, low vs. intermediate vs. high, 71.1% vs. 46.1% vs. 18.5%, P<0.001). The survival differences by the prognostic model were maintained after adjustment for other variables (low vs. intermediate, HR, 2.810, 95% CI, 1.444–5.468, P=0.002; low vs. high, HR, 6.037, 95% CI, 2.708–13.459, P<0.001). Conclusions:The new prognostic model including comorbidities assessed by ACE-27 was useful to predict overall survival in patients with MDS receiving azacitidine or decitabine, although the model could not predict response to the hypomethylating agents. Disclosures:No relevant conflicts of interest to declare.

Activity of azacitidine in chronic myelomonocytic leukemia

Hypomethylating drugs are useful in the management of myelodysplastic syndrome (MDS). Two of these drugs, azacitidine and decitabine, have received FDA approval for the treatment of MDS and chronic myelomonocytic leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS included only a small number of patients with CMML. The objective of this study was to evaluate the efficacy and safety of azacitidine in the treatment of CMML. The records of thirty-eight patients diagnosed with CMML and treated with azacitidine at our institution were reviewed. Azacitidine was administered at 75 mg/m(2) /day for 7 days or 100 mg/m(2) /day for 5 days every 4 weeks. Patients who received at least 1 cycle of the drug were considered evaluable for response. Response was assessed by the modified International Working Group (IWG) criteria. The overall response rate was 39% (14 of 36); complete response (CR) rate was 11% (4 of 36); partial response (PR) rate was 3% (1 of 36); hematologic improvement (HI) was 25% (9 of 36). The median overall survival was 12 months. There was a statistically significant overall survival advantage in responders compared with nonresponders: 15.5 months versus 9 months, respectively (P = .04). Treatment was generally well tolerated. One of 2 patients had complete resolution of a skin rash that was due to monocytic infiltration. Azacitidine is active in the treatment of CMML. The therapy-associated toxicity is acceptable. Our results support further investigation of azacitidine in CMML, particularly in combination with other agents.

Clinical Activity of DNA Methyltransferase Inhibitors In Therapy-Related Myelodysplastic Syndromes: A Retrospective Study

AbstractAbstract 1891Therapy-related myelodysplastic syndrome (tMDS) is a poor-risk subtype of MDS with no standard treatment options, and yet patients (pts) with tMDS are often excluded from trials where they would have the opportunity to benefit from novel treatment approaches. DNA methyltransferase inhibitors are a treatment option for tMDS, and are being evaluated as a bridge to stem cell transplant in these often heavily pre-treated patients to avoid the organ toxicity of intensive chemotherapy. However, the response rate of tMDS to DNA methyltransferase inhibitor (DNMTI) therapy is unknown. In this retrospective study, adult patients tMDS were culled from a fully annotated, IRB-approved database of all MDS patients who received either decitabine (DAC) on both the 3-day and 5-day schedules or 5-azacytidine (5-aza) at our institution from 4/8/2002 to 6/18/2010. Patients who received interrupted therapy were only analyzed for response to their initial course of therapy. Patients who received sequential DNMTI therapy (i.e., DAC followed by 5-aza or 5-aza followed by DAC) were included, but response to only their initial therapy was assessed. Responses were determined using the modified International Working Group criteria (Cheson BD, et al, 2006). Of the 35 patients initially identified with tMDS who received DNMTI therapy, 4 were deemed inevaluable for response due to marrow involvement with the primary malignancy (n= 1), missing records (n=2), or delivery of < 1 full cycle of therapy (n=1). The 31 evaluable pts included 14 males and 17 females with a median age of 65 years (range 25–85). Therapy for the primary malignancy included chemotherapy alone (n=13), chemotherapy plus radiotherapy (n=14), radioactive iodine and radiotherapy (n=2), radioactive iodine and chemotherapy (n=2), and autologous stem cell transplant (n=3). Prior to DNMTI therapy, the MDS FAB subtypes were as follows: RA, n= 6; RARS, n= 3; RAEB, n= 19; RAEBt, n=2; CMMoL, n=1. Pre-DNMTI therapy included lenalidomide (n=4) and alloSCT (n=1). Of the 31 evaluable patients, 20 received DAC, including 7 pts who received tretinoin with DAC in a clinical trial, and 11 received 5-aza. DAC recipients received a median of 2 cycles of therapy (range, 1–12) and 5-aza recipients received a median of 5 cycles (range, 1–9). Best responses were as follows: CR, n=1; Marrow CR plus HI, n=6 (3 trilineage HI, 1 HI-P+ HI-N, 2 HI-P); Stable Disease, n=6; Progressive Disease, n=6; Failures (death during 1st cycle or before response evaluation), n=3. Rate of CR + mCR was 22% (n=7). Additional patients had inevaluable (aparticulate) marrows, or refused follow-up marrow studies, but showed signs of stable (n= 3), improved, (n=2; HI-P, HI-P+HI-N), or progressive cytopenias (n= 3). Median time to best response was 1.5 cycles (range 1–6). Fifty-eight percent (n=18) of 31 pts achieved stable disease or better responses (including 4 pts with stable cytopenias or HI with inevaluable marrow response). Four patients proceeded directly to transplant after DNMTI therapy. Two subsequently died from relapsed disease after transplant, while 1 pt is lost to follow-up and 1 pt is without evidence of MDS 2.5 years after transplant. Nine pts had persistence of their primary malignancy during DNMTI therapy, and 5/9 pts required interruption or cessation of their DNMTI therapy because of progressive primary malignancy. 24/31 pts died from complications of MDS (n=5) or subsequent AML (11), complications of MDS/AML with likely contribution from their primary malignancy (n=4), infection during DNMTI nadir (n=2), GVHD post AlloSCT (n=1), or unknown reasons (n=1). Living pts (n=7; median follow-up from start of DNMTI therapy = 12.5 months, range 4.1 – 35.1 months) include 5 who are not transplant candidates. In conclusion, DNMTI therapy produced modest clinical benefit in our tMDS cohort. In some patients, persistence of the primary malignancy interfered with our ability to deliver optimal DNMTI therapy and to assess response. Although DNMTIs represent a potential therapeutic option for tMDS, treatment of a larger cohort is required to clarify the response rate of these agents in tMDS. Disclosures:Klimek:Celgene: Consultancy.

Lenalidomide for the Treatment of Low- and Int-1-Risk MDS with Del(5q): Efficacy and Quality of Life Study.

Abstract 2763Poster Board II-739 Introduction:Chronic anemia of myelodysplastic syndromes (MDS) is associated with poor quality of life (QoL) and an inferior clinical course. Transfusion dependence in lower-risk patients is associated with reduced survival as a result of iron overload, heart failure, and progression to acute myeloid leukaemia. Lenalidomide is approved for the treatment of transfusion-dependent anemia in patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk MDS with deletion 5q [del(5q)]. Rapid and durable responses include transfusion independence with a rise in Hb, suppression of the del(5q) clone, and improvement in bone marrow morphological features. We present preliminary results of a prospective single-arm trial investigating the effect on QoL, efficacy, and safety of lenalidomide in the treatment of 49 adult patients with IPSS Low- and Int-1-risk MDS with del(5q) with/without additional cytogenetic abnormalities and Hb < 10 g/dL. Methods:Exclusion criteria include: ANC < 500/mm3; PLT count < 50,000/mm3; prior chemotherapy; and ongoing treatment with rHuEpo. Lenalidomide was administered orally at a starting dose of 10 mg/day. If necessary, dosing was reduced to 5 mg/day or 5 mg on alternate days. Treatment will be continued for a maximum of 12 months or until evidence of unacceptable non-hematological adverse events, lack of response, disease progression, or relapse following erythroid improvement. QoL was assessed at study entry and weeks 8, 12, and 24 using the QOL-E v.2 questionnaire. QoL scores are standardized in a 0–100 scale with lower scores representing a worse QoL. Response was evaluated according to the modified International Working Group (IWG) response criteria. Results:Twenty patients (5 M, 15 F, mean age 72 ± 10 years) are evaluable for erythroid responses and cytogenetic changes at 12 weeks and 13 patients have reached a 24-week follow-up. At baseline, mean disease duration was 3.4 ± 2.3 years. Seventeen patients were transfusion dependent (TD), 3 were transfusion free (TF). ECOG performance status was 0 in 14 patients and 1 in 6 patients. After 12 weeks from study entry, 17 (85%) patients obtained an erythroid response with a mean Hb level increase from baseline 8.6 ± 0.9 g/dL to 11.1 ± 2.4 (p=0.001). By 24 weeks, 11 of the 13 patients re-evaluated were erythroid responders obtaining transfusion independence and significant improvements in Hb (mean change from baseline 3.7 ± 2.7 g/dL, and increase to mean 11.1 ± 2.4 g/dL (p<0.001). Eight out of 20 cases (35%) reached normal Hb levels after 12 weeks and 8 out of 13 patients (62%) by 24 weeks. A cytogenetic response (at least 50% reduction in del[5q]) was observed in 5 responders out of 13 patients evaluated at 24 weeks. Additional cytogenetic abnormalities were observed in 4 responders. A progressive improvement in QoL was experienced in responders in the first 24 weeks of treatment. Physical QoL scores increased from 35 ± 9 at baseline to 69 ± 25 at week 24 (p = 0.086). Social-QoL scores significantly changed from 29 ± 20 at baseline to 83 ± 20 at week 12 (p = 0.021). Changes in physical QoL correlated with improvements in Hb (r = 0.768, p=0.001). Drug interruption followed by reduction to 5 mg/day was required in 16 patients within the first 8 weeks due to significant neutropenia, which was associated with thrombocytopenia in 3 patients and hospitalization because of infection in 2 patients. One patient withdrew from treatment because of progressive anemia. Conclusions:Preliminary results confirm that in Low- and Int-1-risk MDS patients with del(5q) lenalidomide induces clinically significant erythroid responses and transfusion independence. Most patients require a dose reduction mainly due to neutropenia. Responders experience improvements in physical and social QoL. Disclosures:Oliva:Celgene: Consultancy. Finelli:Celgene: Consultancy.

Activity of Azacitidine (AZA) in Chronic Myelomonocytic Leukemeia (CMML)

Background: CMML is a distinct clinicopathologic entity recognized by the World Health Organization (WHO). Treatment of CMML by AZA was approved by the US Food and Drug Administration on the basis of a phase III randomized trial conducted by the Cancer and Leukemia Group B, for the treatment of myelodysplastic syndromes (MDS). Only 14 patients with CMML were included in the pivotal trial.Methods: We retrospectively reviewed our institutional experience of CMML treatment with AZA. 39 patients were treated between May 1996 and January 2006. AZA was given at 75 mg/m2 subcutaneously daily for seven days every 4 weeks or 100 mg/m2 daily for 5 days every 4 weeks. Patients who received at least 2 cycles of therapy were considered evaluable for response (N=34). All patients were evaluated for toxicity. The modified International Working Group standardized response criteria for MDS were used for evaluation. The response to AZA, duration of response, tolerability and survival are presented.Results: Patients had a median age of 68.5 years (range: 46–83); male: female ratio was 4.5:1. 28 patients (72%) had a WBC >12,000/μl (myeloproliferative form of CMML). 6 patients had 20–30% blasts in their bone marrow. The International Prognostic Scores were as follows: Low (N=3), Intermediate-1 (N=13), Internediate-2 (N=14), High (N=7), unknown in 2 patients (due to lack of aspirate particles in one and cytogenetics in the other). CMML was secondary to chemotherapy/radiotherapy in 5 patients. Overall response was seen in 14 patients (41%): 5 patients (15%) had a complete response (CR), 9 patients (26%) had hematologic improvement. Mean duration of response was 16.2 months (range: 3–50+); 2 patients are still alive and being treated with CR for >50 months. Average number of cycles to respond was 2.4 cycles (range: 1–6). Splenomegaly was present in 8 patients (20%). Treatment resulted in normalization of spleen size in 1 patient, decrease in 3 patients and no effect in 4 patients. Mean overall survival was 13.2 months (range 1–72). Average survival in responders was 23.5 months (5–72) while average survival in non-responders was 7.48 months (<1–23). Treatment was well tolerated. The most common non-hematological toxicities were nausea and fever.Conclusions: AZA appears to be effective and well tolerated in CMML.

Final Results from a Phase I Combination Study of Lenalidomide and Azacitidine in Patients with Higher-Risk Myelodysplastic Syndromes (MDS)

Background: Lenalidomide (LEN) and azacitidine (AZA) have demonstrated single agent activity in lower- and higher-risk MDS patients (pts). Response rates may be improved by combining LEN's immunomodulatory, anti-angiogenic, and cytotoxic properties with AZA's cytotoxic effects and hypomethylating activity.Methods: The primary objective of this multicenter, Phase I trial of the Rare Diseases Clinical Research Network Bone Marrow Failure Consortium was to determine the safety of combination therapy, the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs, defined as Grade 3/4 non-hematologic toxicity per NCI CTC 3.0, or >50% prolonged decrease in absolute neutrophil count (ANC) or platelets (plt) without recovery by Day 56). Responsewas a secondary objective, using modified International Working Group response criteria. Pts with higher-risk MDS (IPSS score □1.5, or FAB or WHO classification with □5% myeloblasts) and untreated with AZA or REV were enrolled using a “3+3” dose escalation design (see Table) from 6/06 through 5/08, with results reported through 7/08. Cycles lasted 28 days, to a maximum of 7 cycles.Results: In all, 19 pts were enrolled; 1 was excluded for a diagnosis of AML. Median age was 68 years (range 52–78), 7 pts (37%) were female, median interval from diagnosis was a median of 5 weeks (range, 2–106), and median follow-up was 5 months (range 1–13). Median baseline hemoglobin was 9.9 g/dl, platelet count 69 k/ul, neutrophil count .84 k/uL, erythropoietin level 99 MIU/ml, ferritin level 893 ng/ml, and bone marrow blast percentage was 11%. Four pts had RAEB-1, 10 had RAEB-2, and 1 had CMML; IPSS categories were Int-1 (3 pts), Int-2 (9 pts), and High (6 pts). Only 1 pt in cohort 4 had a chromosome 5q deletion. No DLTs occurred in any dosing cohort, and the MTD was not reached. Grade 3/4 non-hematologic toxicities included atrial fibrillation (1), monocular blindness (1), basal cell skin carcinoma (1), CNS hemorrhage (1), febrile neutropenia (2), shortness of breath (1), and perforated appendix (1). Median decrease in ANC was 21% and in plts was 1% (mean was 20%). Although cycle 2 was delayed for 2 patients due to neutropenia, there were no dose-reductions for toxicities. Of the 17 pts evaluable for response, the overall response rate was 71%: 7 (41%) had a complete response (CR), 1 (6%) a partial response (PR), 3 (18%) had hematologic improvement (HI), and 1 (3%) a marrow CR.Conclusions: The combination of LEN and AZA is well-tolerated, and early results suggest efficacy superior to single agent activity in higher-risk MDS. Incorporating safety and efficacy data, the optimal dose of the combination regimen appears to be AZA 75 mg/m2 SC days 1–5 and REV 10 mg PO days 1–21. An investigation of sequential dosing of AZA followed by REV is planned.Dosing CohortAZA DoseRev DoseIPSS CategoriesGrade 3/4 non-heme toxicitiesMaximum Response175 mg/m2 SC days 1-55 mg PO days 1-141 Int-1 2 Int-212 CR 1 progression275 mg/m2 SC days 1-55 mg PO days 1-212 Int-2 1 High21 CR, 1 PR, 1 HI375 mg/m2 SC days 1-510 mg PO days 1-211 Int-2 2 High02 CR, 1 stable disease450 mg/m2 SC days 1-5, 8-125 mg PO days 1-141 Int-1 2 Int-222 CR, 1 stable disease550 mg/m2 SC days 1-5, 8-125 mg PO days 1-212 Int-2 1 High21 HI 1 stable disease 1 progression650 mg/m2 SC days 1-5, 8-1210 mg PO days 1-211 Int-1 1 Int-2 1 High21 HI 1 BM CR 1 not yet evaluable

Outcome of Patients (pts) with Myelodysplastic Syndrome (MDS) and Chronic Myelomonocytic Leukemia (CMML) Post Decitabine Failure.

Background and aims: Prognosis in pts with MDS post decitabine failure is reported to be poor, but there are no published data pertaining to survival, particularly in relation to pts who might benefit from specific strategies such as allogeneic stem cell transplantation (SCT) or investigational agents. In this regard, we report the results from our institution.Materials and Methods: A total of 87 pts with MDS (n=67) and CMML (n=20) after failure of decitabine regimens from 2003 until June 2007 were analyzed. Responses to decitabine and subsequent therapies were coded according to the modified International Working Group criteria (IWG). Acute myeloid leukemia (AML) was defined by 30% or more of bone marrow blasts. Ps were classified according to the IPSS score and the MD Anderson score (MDAS) at the time of start of decitabine therapy and at the time of failure.Results: Twenty-five (29%) pts had secondary MDS. Among 49 evaluable pts for IPSS risk category at the start of decitabine, 13 (26%) were int-1, 23 (48%) int-2, and 13 (26%) high-risk disease. According to the MDAS, 32 (37%) were high-risk, 31 (36%) int-2, 17 (19%) int-1, and 7 (8%) low-risk disease. Cytogenetics were diploid in 35 (40%) pts; 39 (45%) pts had ≥ 10% bone marrow blasts; 35 (40%) pts had primary resistance to decitabine and 52 (60%) had disease recurrence. Best response to decitabine was complete response (CR) in 21 (24%) pts, partial response (PR) in 2 (2%) pts, a bone marrow CR in 14 (16%) pts, and hematologic improvement (HI) in 14 (16%) pts. The median number of cycles of decitabine administered was 7 (range, 1–20). After a median of 21 months (range, 6 to 39) from decitabine failure, 13 (15%) pts remained alive. The median survival post decitabine failure was 4.3 months; the estimated 12-month survival was 28%. Upon failure, 22 (25%) pts transformed into AML, of whom only 3 were alive. At failure 15 (42%) were high-risk, 15 (42%) were int-2, and 6 (8%) were int-1 among 36 patients assessed for the IPSS score. Among 58 pts assessed by the MDAS, 32 (55%) were high-risk, 17 (29%) int-2, 7 (12%) int-1, and 2 (4%) were low-risk disease. The estimated 12-month survival rates were 27%, 33%, and 33% for respectively, patients with high-risk, int-2, and int-1 risk disease (p=0.99). The 12-month survival rates were 100%, 54%, 41%, and 18% for respectively, pts with low, int-1, int-2, and high-risk disease according to the MDAS (p=0.01). Post decitabine failure, 20 pts received idarubicin and cytarabine (IA); the objective response rate (ORR) was 20%; 39 pts received investigational agents with an ORR of 26%; 5 pts received an allogeneic SCT: 3 achieved and remained in CR. At the last follow-up, 13 pts were alive, 5 in CR post allogeneic SCT in 2, post clofarabine in 1, and post IA in 1, and 1 in marrow CR post IA.Conclusion: Outcome of pts post decitabine failure is poor with a median survival of 4.3 months. The MDAS can predict survival at the start of decitabine therapy and upon decitabine failure, with patients with low-risk disease having favorable outcome.

CNTO 328, a Monoclonal Antibody to Interleukin-6, Is Active as a Single Agent in Castleman's Disease: Preliminary Results of a Phase I Study.

Castleman's disease is a rare lymphoproliferative disorder in which overproduction of interleukin (IL)-6 causes a polyclonal B cell proliferation resulting in lymph node enlargement and debilitating symptoms, including autoimmune phenomena, systemic inflammatory manifestations (e.g., fever, fatigue, and weight loss) and markedly abnormal laboratory findings (e.g., anemia, hyper-γ-globulinemia, hypoalbuminemia, thrombocytosis and increases in acute-phase proteins like CRP, ESR and fibrinogen). There is no satisfactory systemic treatment for Castleman's disease. CNTO 328 is a chimeric monoclonal antibody that binds with both high specificity and high affinity while neutralizing the biological activity of human IL-6. In an ongoing phase 1 study of CNTO 328, 22 patients with Castleman's disease (9 newly diagnosed) were treated according to the following schedule: 3 mg/kg q 2 weeks (n= 1), 6 mg/kg q 2 weeks (n=2), 12 mg/kg q 2 weeks (n=3), 9 mg/kg q 3 weeks (n=5), 12 mg/kg q 3 weeks (n=8), or 6 mg/kg weekly (n=3). Disease types included hyaline vascular (9), plasmacytic (11), mixed (1) and undetermined (1). No patients are known to be either HIV+ or HHV−8+. The average number of infusions received was 23 with median drug exposure of 295 days (up to 1015 days). CNTO 328 was well tolerated with 10 patients (45%) having no drug-related toxicity greater than grade 1 and three patients (14%) with drug-related toxicity of grade 3 or higher (anemia, vomiting, herpes zoster). The most common drug related side effects, seen in more than 10% of patients were elevated ALT, hypertriglyceridemia, hypercholesterolemia and upper respiratory tract infection. There were no deaths attributed to CNTO 328. Most patients (18/22 or 82%) experienced clinical benefit response, defined as improvement in at least one of the 6 measures (hemoglobin, fatigue, anorexia, fever/night sweats, weight, or size of largest lymph node) with all other measures stable or better on at least one assessment. Additional evidence of clinical benefit included increased hemoglobin [median maximum increase of 2.15 g/dL (range: 0.3–7.2 g/dL)]. A high frequency of tumor response (both complete response [CR] and partial response [PR]) as per modified International Working Group criteria was confirmed by independent radiological review. Seven of 11 evaluable patients [64%, 95% CI (31%, 89%)] treated with 12mg/kg on either the q 2 week or q 3 week schedule responded (1 CR, 5 PR, 1 unconfirmed PR), with time to initial response ranging from 9 to 36 weeks. No radiologic response was seen at doses lower than 12mg/kg. All 6 patients who required steroids at study entry were able to discontinue steroid use. Complete suppression of CRP (a surrogate for IL-6 activity) on at least one follow up assessment was observed in 83% of patients with post-baseline CRP values (median baseline level of 13.6 mg/L (range 1-260 mg/L). These interim results appear to demonstrate substantial benefit of CNTO 328 in Castleman's disease, which merits further investigation.

A limited number of 5-azacitidine cycles can be effective treatment in MDS

Hypomethylating agents, such as 5-azacitidine (5-AZA) and 5-aza-2'-deoxycytidine (decitabine), have recently been approved for the treatment of myelodysplastic syndromes (MDS). Several randomized trials have shown favorable results concerning response rate, survival, transformation to acute leukemia, and quality of life. In these trials, treatment was administered continuously until progression. In the retrospective study presented here, we evaluated the outcome of patients with higher risk MDS or secondary acute myeloid leukemia (sAML) treated with a limited number of 5-AZA cycles. A total of 32 patients received 5-AZA alone (n=30) or in combination with valproic acid and all-trans retinoic acid (n=2). 5-AZA was administered subcutaneously at a fixed dose of 75 mg/m(2) daily for 7 days and repeated every 28 days. 5-AZA was given for a median of four courses. Treatment was continued for two more cycles as consolidation in patients who had achieved complete remission (CR), marrow CR, or stable disease with hematologic improvement. The overall response rate was 50% according to the modified International Working Group criteria. Complete remissions were achieved in 15.6% and stable disease in 34.4% of patients. Peripheral blood counts normalized in 6.3% of patients while hematologic improvement was achieved in 25%. The median time to AML in responding patients was 45 weeks, while AML occurred after a median of 14 weeks in non-responding patients (P= .038). The median survival of all patients was 60 weeks; the median survival of responders was 74 weeks compared with 26 weeks in non-responders (P= .047). In this retrospective analysis, 5-AZA was associated with a survival advantage in responding patients with higher risk MDS or sAML. These favorable results suggest that patients may benefit even from a limited number of courses of 5-AZA. A randomized controlled clinical trial is required to prospectively validate these findings.

A Phase II Trial of Combination Therapy with Thalidomide, Arsenic Trioxide, Dexamethasone, and Ascorbic Acid (TADA) in Patients with Overlap Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) or Chronic Idiopathic Myelofibrosis (CIMF).

Background: Both CIMF and MDS/MPD are clonal hematopoietic disorders characterized by cytogenetic abnormalities and myelofibrosis with resultant organomegally. Arsenic Trioxide (ATO) has demonstrated efficacy in MDS in two multicenter trials, including patients with MDS/MPD. Ascorbic acid (AA) enhances the activity of ATO by depleting intracellular glutathione. Thalidomide (Thal), in combination with ATO or steroids, is efficacious in patients with MDS and in patients with CIMF.Methods: We conducted a multicenter trial of Thal (50mg/d PO x 2 weeks, then 100mg/d), ATO (0.25mg/kg IV d1-5 of week 1, then twice weekly weeks 2–12), Dexamethasone (4mg/d PO x 5d every 4 weeks), and AA (1000mg PO 1–2 hours prior to each ATO infusion) over a 12-week cycle in patients with CIMF or MDS/MPD, from 1/05 to 7/07. Patients continued on Thal for an additional 3 months. Bone marrow was assessed at baseline and after week 12, as was spleen size. The primary endpoint was response as defined by the Modified International Working Group (IWG) treatment response criteria for MDS, and the IWG criteria for myelofibrosis with myeloid metaplasia (MMM).Results: Twenty-eight patients have been enrolled; 27 were evaluable for response. The median age was 66.5 years; 23 patients (82%) had MDS/MPD: 8 with CMML and 15 with MDS/MPD-u, with cytogenetics of: normal (13), +22p (1), +8 (2), −Y (1), +9 (1), −12p (1), complex (2), unknown (2). Five patients (18%) had CIMF with cytogenetics of: normal (3), dup Chr6 (1), unknown (1); Of 14 patients tested, 5 had the JAK2V617F mutation: 1 with CIMF and 4 with MDS/MPD. No patient had the MPL515 mutation. Thirteen patients had splenomegally, and 15 received prior therapies, including erythropoietin agents (9), 5-azacytidine (2), hydroxyurea (1), anagrelide (2), investigational agents (1), and prednisone (2). Median baseline lactate dehydrogenase (LDH), leukocyte count, and platelet count were: 300U/L, 12.1k/L, and 126.5k/L, respectively. Reasons for starting therapy included anemia (8 (29%)), thrombocytopenia (9 (32%)), or disease-related symptoms (11 (39%)). Seven patients (25%) did not complete the entire 12 week course of therapy: 3 withdrew consent, 1 had a low platelet count, 2 due to an adverse event, and 1 due to no response. Responses occurred in 7 patients (26% of total, 35% of those completing 1 cycle of therapy): 6 (21%) by the IWG MMM criteria, 4 (14%) by the IWG MDS criteria, and 3 (11%) by both. Using the IWG MMM criteria, 1 patient with MDS/MPD had a partial remission and 5 had clinical improvement: 2 with MDS/MPD and 1 with CIMF had hemoglobin responses, and 2 had a spleen response. Using the modified IWG MDS criteria, 1 patient with CIMF and 2 with MDS/MPD had erythroid responses; 1 with MDS/MPD had a platelet response. No patient with a JAK2V617F mutation responded. Grade3/4 non-hematologic toxicities included edema (4), fatigue (4), pleural effusion (2), dyspnea (3), motor and sensory neuropathy (1), pericardial effusion (1), zoster (1), and hematoma (1). There were no thrombotic episodes.Conclusion: The TADA regimen is well-tolerated and yields clinical responses in patients with MDS/MPD or CIMF, even in the absence of the JAK2V617F mutation.

Therapy of Early Stage Myelodysplastic Syndrome (MDS) with Anti-Thymocyte Globulin (ATG) and Etanercept.

Immunosuppressive therapies have proven valuable in treating ineffective hematopoiesis in patients with Myelodysplastic Syndrome (MDS). Following an encouraging pilot trial, we evaluated the combination of equine anti-thymocyte globulin (ATGAM) and the soluble TNF receptor etanercept in a phase 2 trial. So far 23 patients with MDS (6-RA, 4-RARS, 12-RCMD, 1-RAEB-1) in IPSS risk groups low (n=8) or intermediate-1 (n=15) have been enrolled. All patients were platelet or red blood cell transfusion dependent. Nineteen patients completed therapy with I.V. ATGAM at 40mg/kg/day for four consecutive days, followed by etanercept, 25mg s.c. twice a week for 2 weeks every month for 4 months. The regimen was well tolerated and the majority of adverse events were anticipated infusional reactions related to ATGAM administration. Responses were assessed by modified International Working Group criteria. Twelve patients had hematological improvement (HI)-erythroid, 2 HI-neutrophil, and 3 HI-platelet. Five patients achieved red blood cell and one patient platelet transfusion independence. There was one complete remission in a patient with a co-existing diagnosis of multiple sclerosis. Thus, the overall response rate by intent to treat analysis among the 23 patients was 61%. Four patients did not complete their first course of therapy due to anaphylactic reaction, thrombosis of a pre-existing femoral graft, myocardial infarction, and patient preference. Among patients who completed treatment 74% had a hematological response, with duration of at least 5 months. Combination therapy with ATG and etanercept was active and safe in unselected patients with low and intermediate-1 risk MDS.

Bendamustine Is Safe and Effective in Patients with Rituximab-Refractory, Indolent B-Cell Non-Hodgkin Lymphoma.

Background: Bendamustine (Treanda®) is a purine analog/alkylator hybrid with single-agent activity in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), multiple myeloma, and breast cancer. The objective of this phase 3 multicenter study was to evaluate the efficacy and safety of single-agent bendamustine HCl in patients with relapsed, rituximab-refractory NHL.Methods: Eligible patients had previously treated, rituximab-refractory, indolent-histology NHL. Rituximab-refractory was defined as no response or progression within 6 months of1.first dose of rituximab induction,2.completion of rituximab maintenance therapy or progression before the next scheduled rituximab dose, or3.completion of a combination of rituximab and chemotherapy.Patients received bendamustine 120 mg/m2 intravenously over 60 minutes on days 1 and 2 every 21 days for 6 cycles (2 additional cycles at investigator discretion; max 8). Tumor response was determined by modified International Working Group Response Criteria for NHL. The primary endpoint was overall response rate (ORR) with secondary endpoints of response duration (RD) and progression-free survival (PFS).Results: Results for the first 38 of 100 enrolled patients are presented. The median age was 60 years, 63% were male, and 63% had stage III/IV disease. Histologies included follicular (53%), CLL/small lymphocytic lymphoma (26%), and marginal zone (21%) lymphoma. Patients had received a median of 3 prior courses of treatment (range 1–10) and 2 prior rituximab-containing courses (range 1–6). Prior alkylator or purine analog-based treatment was administered to 79% and 37% of patients, respectively. Eighteen (47%) patients were considered to be chemoresistant. Four (11%) patients received prior radioimmunotherapy. The ORR in the primary analysis population was 84%, including 29% complete responses (CR), 3% CR unconfirmed, and 53% partial responses. The median RD was 9.3 months and the median PFS was 9.7 months. The primary hematologic toxicity was reversible myelosuppression; grade 3/4 hematologic side effects included leukopenia (60%), neutropenia (60%), thrombocytopenia (24%), lymphocytopenia (95%), and anemia (5%). Febrile neutropenia was not observed. Common nonhematologic adverse events (grades 1/2, 3, 4) were nausea (68%, 5%, 0%), vomiting (42%, 0%, 0%), and fatigue (42%, 13%, 3%).Conclusions: In this multicenter study, single-agent bendamustine was well tolerated and produced a high rate (84%) of durable responses. It is the first chemotherapeutic agent to demonstrate significant clinical activity in rituximab-refractory indolent lymphoma. These results compare favorably with prior reports of radioimmunotherapy in this patient population. An updated analysis of all 100 patients will be available for the annual meeting.

A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome

AbstractThis multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.

Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia

Hypomethylating agents have activity in myelodysplastic syndrome (MDS) and have received approval for the treatment of both MDS and chronic myelomonocytic leukemia (CMML). The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of decitabine in CMML. Nineteen adults with a diagnosis of CMML treated on decitabine studies were analyzed. Decitabine was given at 100 mg/m(2) per course every 4 weeks. The median number of courses given was 9 (range, 1-18). Overall, 11 patients (58%) achieved complete response (CR) and 2 (11%) had hematologic improvement (HI), for an overall response rate of 69% according to the modified International Working Group (IWG) criteria. Median survival was 19 months. Severe (grade 3-4) extramedullary side effects were rare. Decitabine is active in CMML. Studies of combinations of decitabine with topoisomerase I inhibitors or other active anti-CMML agents are indicated.