ALBERT

Description: Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for MDS. Besides the innate heterogeneity of MDS, intensity of the conditioning regimen (myeloablative (MAC) versus reduced intensity/non-myeloablative (RIC)), specific agents used in conditioning, donor and source of stem cells and GVHD prevention regimens further influence outcomes. We sought to determine how conditioning regimens influenced MDS subgroup cohort outcomes. We retrospectively analyzed outcomes of 107 MDS patients (63 male and 44 females) with median age 61.8 (17-73 years) who underwent allogeneic SCT at our institution between 2008 and 2017. For the purposes of this report, patients were grouped according to WHO classification into non-RAEB (RCMD, RA, RARS RCUD or 5q deletion, n=49) and RAEB (RAEB1 and RAEB2, n=58) categories. Median time from MDS diagnosis to transplantation was 139 days (20-3175). No patients were in complete remission (CR) at time of SCT. Allogeneic donor types were matched related, matched unrelated, haplo-identical and cord blood in 30, 65, 10 and 2 patients, respectively. Stem cell source was peripheral blood (91 patients) and bone marrow in 14. Forty patients (median age 52.2 (17-61) years) underwent MAC and 67 (median age 63.7 (23-73) years) RIC. Twelve patients died within 100 days of transplantation, 3 due to disease progression, 5 to acute GVHD, and 4 to other transplant-related causes. Median overall survival (OS) for all 107 patients was 1.3 years with 54%, 47% and 40% alive at 1, 2 and at 5 years. OS was slightly higher in patients undergoing RIC with OS of 57%, 48% and 40% (median 1.532 years) versus 50%, 40% and 38% with MAC (median 0.92 years) at the same time points (p〉0.1). Median OS of the 49 patients with non-RAEB and 58 patients with RAEB MDS was 3.01 years versus 0.92 years (p〉0.1). GVHD was the most frequent cause of death (46%), followed by relapse/progression (28%), infection (14%) and other (12%). Of 29 patients undergoing RIC with non-RAEB MDS, median OS was 3.78 years while for 38 RAEB patients it was 1.17 years (p〉0.1). See table for OS according to conditioning regimen and WHO classification. For MAC, in 20 non-RAEB patients median OS was 2.2 years while the median OS was 0.69 years for 20 RAEB patients (p〉0.1). CR after SCT was achieved in 57 patients (53%), 33 receiving RIC (CR 49.2%) and 24 receiving MAC (CR 60%). Seven patients subsequently relapsed, 4 RIC and 3 MAC. Of the non-RAEB patients achieving CR, median OS in the 16 patients treated with 111 RIC was not reached and in 14 patients receiving MAC, median OS was 3.75 years (p〉0.1). For the 27 RAEB patients achieving CR, median OS was 4.4 years in 17 patients treated with RIC versus not reached in 10 patients treated with MAC. Overall, death in non-RAEB patients occurred in 26/49 (53%) compared to 38/58 (66%) RAEB patients and in 40/67 (59%) patients undergoing RIC versus 25/40 (63%) MAC patients (p〉0.5). The hematopoietic transplant comorbidity index did not predict OS outcomes in these MDS patients (p〉0.1) and the cytogenetic score according to the IPSS-R "very good -very poor" groups indicated no differences in OS in the non-RAEB patients but in RAEB patients significant differences according to the cytogenetic score was evident (P

Description: Abstract 1723 Background: Two multicenter studies (MDS-003/-004) found LEN leads to RBC transfusion independence (TI) in 〉 50% of pts with RBC transfusion dependent Low-/Int-1-risk MDS with del5q (List A et al. NEJM 2006;355: 1456–65; Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). RBC-TI ≥ 8 wks with LEN was associated with significantly reduced risk of AML progression and death (Fenaux P et al. Blood 2011;doi: 10.1182/blood-2011-01-330126). Alternative therapy is required for pts failing LEN therapy. Aims: To assess predictive factors of LEN response and long term outcomes (especially after primary or secondary LEN failure) of pts 〈 65 yrs included in MDS-003/-004; ie, those in whom intensive therapies including allogeneic stem cell transplantation (ASCT) may be considered. Methods: LEN was administered as follows (all 28-d cycles): 5 mg/d on d 1–28 and 10 mg/d on d 1–21 or 1–28. RBC-TI ≥ 26 wks and cytogenetic response (CyR; IWG 2000) are reported. Overall survival (OS) and AML progression were assessed using Kaplan-Meier method. Response rates and outcomes in pts 〈 65 yrs were retrospectively compared with pts ≥ 65 yrs. Primary failure was defined as lack of RBC-TI with LEN treatment and secondary failure as relapse after achievement of RBC-TI ≥ 26 wks. Cox proportional hazards models were used to evaluate the effect of potential risk factors (ie, age, sex, time since diagnosis, FAB classification, LEN dose, IPSS risk, WPSS risk, cytogenetics, bone marrow blast %, transfusion burden, no. of cytopenias, hemoglobin level, platelet and neutrophil counts, RBC-TI ≥ 26 wks [time-dependent variable] and CyR [categorical variable]) on OS and AML progression. Logistic model was used to evaluate the effect of potential risk factors on achievement of RBC-TI ≥ 26 wks. Results: The trials included 97 (33.9%) pts 〈 65 yrs. Of these, 73.2% were female; 20.6% were IPSS Low-, 52.6% Int-1-, and 4.1% Int-2-risk; 30.9% had del5q with ≥ 1 additional cytogenetic abnormality (8.2% had complex cytogenetics). At baseline (BL), median time since diagnosis was 2.4 yrs (range 0.2–20.7) and median RBC transfusion requirement was 6 units/8 wks (range 1–15). In pts ≥ 65 yrs (n = 189) most BL characteristics were similar except IPSS risk, which was lower (36.5% Low-, 37.0% Int-1-, 5.8% Int-2-risk; p =.012). RBC-TI ≥ 26 wks was achieved by 54 (55.7%) pts 〈 65 yrs (vs 49.7% pts ≥ 65 yrs; p =.563). The median duration of RBC-TI ≥ 26 wks in responders was not estimable in pts 〈 65 yrs or ≥ 65 yrs (log-rank p =.879). None of the potential risk factors assessed was a significant predictor of RBC-TI ≥ 26 wks in pts 〈 65 yrs, possibly due to small pt number. In pts 〈 65 yrs with available follow-up cytogenetics (n = 71), CyR was achieved by 32 (45.1%) pts (vs 64.5% pts ≥ 65 yrs; p =.014). At time of data cutoff, 51 (52.6%) pts 〈 65 yrs were alive (vs 36.0% pts ≥ 65 yrs; p =.008); 29 (29.9%) pts progressed to AML (vs 20.1% pts ≥ 65 yrs; p =.077). The 1-, 2-, and 3-yr AML-progression rates were 9.7%, 15.4%, and 24.0% in pts 〈 65 yrs; and 6.0%, 17.9%, and 22.3% in pts ≥ 65 yrs (log-rank p =.308). The 1-, 2-, and 3-yr OS rates were 91.7%, 78.1%, and 66.4% in pts 〈 65 yrs; and 83.1%, 65.2%, and 49.9% in pts ≥ 65 yrs (log-rank p

Description: Abstract 1337 Background: Oral azacitidine (CC-486) is bioavailable, biologically and clinically active, and well tolerated in patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (Garcia-Manero, J Clin Oncol, 2011). Because DNA methyltransferase (DNMT) inhibitors require active cell cycling to effect methylation reversal, prolonged administration of lower doses of azacitidine may provide more extensive reversal of DNA methylation compared with shorter administration. Purpose: We conducted analyses 1) to determine the pharmacokinetic (PK) and pharmacodynamic (PD; ie, DNA demethylating activity) profiles following subcutaneous (SC) AZA and various dosing schedules of oral azacitidine; 2) to assess the correlation between the PK and PD profiles of oral azacitidine administered in extended dosing schedules; and 3) to compare PD effects observed at different time points in the 28-day (d) treatment cycle with SC AZA or oral azacitidine administered for 7 days vs. the PD effects of 300mg QD oral azacitidine administered in extended dosing schedules in pts with MDS. Methods: This multicenter, phase 1 study had 2 parts. In Part 1, 41 pts with MDS, CMML, or AML received SC AZA (75mg/m2 QDx7d of a 28d cycle) for 1 cycle, then oral azacitidine doses ranging from 120 to 600mg (QDx7d of a 28d cycle) in subsequent cycles. In Part 2, 86 pts received oral azacitidine in 1 of 4 extended dosing schedules: 300mg QD or 200mg BID, each for 14d or 21d of repeated 28d cycles. PK parameters were derived from plasma concentrations. The correlation between PK and PD was determined using data from pts who had received oral azacitidine 200mg BID or 300mg QD for 14d or 21d for whom PD data were available at day 15 of the first 28d cycle (C1D15). The PD endpoint was reduction in percentage of highly methylated (≥70%) loci of DNA in whole blood, assessed using Illumina's Infinium Methylation27 Bead Array. Results: SC AZA or oral azacitidine were rapidly absorbed and reached Tmax (median [min, max]) within 0.5 hr [0.2, 1.1] and 1.0 hr [0.3, 3.6] post-dose, respectively. Mean elimination half-life was 1.5 +/− 0.7 hr and 0.6 +/− 0.2 hr for SC and oral azacitidine, respectively. No drug accumulation was noted following multiple dose administration. Compared with SC AZA, 300mg oral azacitidine QDx14d and QDx21d provided mean cumulative exposures (AUC) per cycle of 38% and 56%, respectively. A PK/PD correlation (AUC C1D1 vs. change in methylation on C1D15 compared with baseline) was observed with oral azacitidine 300mg QD or 200mg BID administered for 14d or 21d (r2=0.659, p

Description: Abstract 3614 Background: Acute Myeloid Leukemia (AML) is a common form of leukemia in adults and often requires high resource use. About 84% of the total cost is attributed to hospital payments (Menzin 2002). The aggregate disease burden is difficult to estimate due to multiple complications and treatment courses. The standard treatment modality for AML is intensive chemotherapy with complete remission (CR) achieved in up to 60% of adults with de novo AML who are less than 70 years old (Tallman, 2005), while in the older adults CR rates occur in approximately 45% (Jabbour, 2006). For patients who relapse after CR there are a limited number of efficacious therapeutic options. These include best supportive care (BSC), additional cycles of chemotherapy and stem cell transplantation (SCT) in a minority of patients. Aim: To estimate the economic burden of the total treatment costs of AML in patients receiving therapy in the US and UK. Treatment costs are specifically assessed for induction therapy (IT), consolidation therapy (CT), for follow up during CR, and salvage therapy for relapsed or refractory disease. Methods: To identify the total costs of AML therapy, a systematic literature review was conducted of standard treatments employed during the past 5 years. Economic costs were estimated per course of treatment which included IT, CT, supportive treatment during CR, and salvage therapy including use of SCT. The total economic burden was calculated combining cost per patient with epidemiology data. Incidence rates for the US and UK and treatment outcome probabilities were calculated from the Surveillance Epidemiology and End Results (SEER), Eurostat and peer reviewed literature. Unit costs were identified using publicly available databases. Calculations were conducted for younger (65) patients given differences in incidence rates identified between these groups. Costs of treatment were calculated individually for each of the following treatment stages: 1) IT (standard dose chemotherapy (SDC) 1 cycle), 2) CT- 2 cycles of chemotherapy 3) follow up after CR (costs of BSC – 6 cycles), and 4) salvage therapy for relapse refractory disease. Results: The costs associated with hospitalization are the main component in all treatment stages (induction, consolidation, and relapse) ranging from 66% to 92% of the total costs. IT plus CT accounted for 19%-91% of the total cost per patient. When combining costs per patient with incidence data, it is estimated that the total economic burden of AML treatment ranges from £13 mln for population 〉65 and £38 mln for the

Description: Background: CC-486 is an oral formulation of the epigenetic modifier, azacitidine, in clinical development for treatment (Tx) of hematological cancers. Part 1 of this phase I, multicenter study showed no effect on pharmacokinetics (PK) of CC-486 when taken with food or with a proton-pump inhibitor (Laille, 2014). A prospective extension phase of this study is ongoing to assess the safety and efficacy of CC-486. Objectives: To assess safety, tolerability, and hematological response associated with an extended CC-486 dosing schedule in patients (pts) with MDS, AML, or CMML. Methods: Eligible pts were age ≥18 years, had confirmed WHO-defined MDS, CMML, or AML based on bone marrow (BM) aspirate and biopsy, and an ECOG performance status score 0-2. In the PK phase, pts received 2 to 3 single CC-486 doses and in the extension phase, pts received CC-486 300 mg QD for the first 21 days of repeated 28-day cycles. Tx-emergent adverse events (TEAEs) were coded by MedDRA v15.0 and graded using NCI-CTCAE v4.0. In addition to TEAEs for all pts, because PK-phase exposure was quite limited, TEAEs of interest are reported for the subset of pts who entered the extension phase (21-day dosing). Responses (complete or partial remission [CR, PR], CR with incomplete blood count recovery [CRi], marrow CR [mCR], hematologic improvement [HI], and transfusion independence [TI]) were defined by IWG 2006 (MDS) or IWG 2003 (AML) criteria. Baseline transfusion dependence (TD) was defined as ≥4 red blood cell (RBC) units or ≥2 platelet transfusions, in the 56 days before first dose. TI was defined as no transfusion for 56 consecutive days. The safety-evaluable cohort included all pts who received ≥1 CC-486 dose. Efficacy-evaluable pts had ≥1 post-baseline efficacy measurement during the extension phase as of data cut-off (June 6, 2014). Efficacy results are reported for the combined MDS and CMML pt population and separately for pts with AML. Results: A total of 32 pts (MDS n=19 [59%], CMML n=4 [13%], and AML n=9 [28%]) received ≥1 CC-486 dose and are evaluated for safety. Median (range) age of all pts was 72 (53-93) years, with 44% of pts age ≥75 years. Most pts were male (69%) and all were Caucasian. Median number of CC-486 Tx cycles for all pts was 4 (range 1-18), and within the MDS, CMML, and AML groups was 5 (1-18), 4 (2-17), and 1 (1-9), respectively. The mean ±SD Tx cycle length was 30 ±9.0 days overall (by group: 33 ±8.3 days in MDS, 25 ±5.4 in CMML, and 27 ±10.7 in AML pts). The most frequent types of TEAE were gastrointestinal (GI) and hematological (Table 1). CC-486 dose was adjusted due to GI TEAEs for 5 pts (16%), and due to hematological TEAEs for 8 pts (25%). Of all 32 pts, 30 pts (94%) entered the 21-day dosing extension phase. Of these pts, GI TEAEs (grade ≥2) were reported for 23 pts (77%). Of these, only 4 grade 3 (vomiting and diarrhea, 2 each) and no grade 4 TEAEs were observed. Hematological TEAEs (grade ≥3) were reported for 19 pts (63%). Neutropenic grade ≥2 TEAEs occurred in 12 (40%) of 30 pts, of which 29% were grade 2, 38% grade 3, and 32% grade 4. Febrile neutropenia occurred in 3 pts and grade 4 thrombocytopenia in 3. Most TEAEs occurred during the first 2 Tx cycles: GI, 73% and hematological, 55%. The efficacy-evaluable population at data cut-off included 27 pts (84%): 20 pts with MDS or CMML, and 7 pts with AML (Table 2). One pt with MDS achieved CR, 1 pt with AML achieved CRi, and 1 pt with AML achieved PR (pt was to proceed to transplant). Of HI-evaluable pts in the MDS+CMML and AML groups, respectively, 6/18 (33%) and 2/7 (29%) attained an HI response. Few pts were TD at baseline. Of pts who were RBC TD at baseline, 1/5 pts (20%) in the MDS+CMML group and 1/5 pts (20%) in the AML group attained RBC TI. Of 3 pts who were platelet TD at baseline, 1 pt with AML attained platelet TI. Conclusions: CC-486 can provide the flexibility to adjust dose or dosing regimen to improve tolerability or efficacy as needed. The safety and tolerability of CC-486 300 mg QD taken for the first 21 days of repeated 28-day cycles were consistent with the known safety profile of injectable azacitidine in these pts with MDS, CMML, and AML. Grade 3-4 gastrointestinal TEAEs were infrequent (

Description: Background: Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy with known immune dyregulation. In addition to their capacity to rapidly divide, AML cells directly inhibit the activation and proliferation of immune cells in culture. Immunosuppressive features observed in the bone marrow of AML patients include upregulation of Tregs and production of immunosuppressive cytokines (e.g., TGFβ). Irradiating AML cells diminishes their immunosuppressive capacity while maintaining antigen presentation, leading to increased activation of T cells in co-culture. We subsequently identified the immune checkpoint LAG3 as an important mediator of AML-induced immunosuppression and LAG3 modulation as potential treatment strategy. Methods: Normal PBMC were isolated from healthy donors. PBMC were co-cultured with non-irradiated and irradiated (40 Gy) human AML cell lines (Kasumi1 (K1), THP1) separately at a 1:2 ratio. On day 3 of co-culture, immunophenotypic characterization of T cells was performed on a flow cytometer using the following surface markers: CD3, CD4, CD8, CD25, CD137, CD154, PD-1, TIM3, TIGIT, and LAG3 and intracellular IFNg and FOXP3. Supernatant from co-culture media were analyzed for cytokine (IL-2, IL-6, IL-10 & TGFβ) secretion by ELISA. CFSE-labeled AML cells were incubated with healthy donor PBMCs in the presence or absence of LAG3, then viability was measured by 7-ADD on flow cytometry. PBMCs were also isolated from AML patients' peripheral blood and mononuclear cells were isolated from their respective bone marrow samples. Primary AML cultures were established in RPMI complete media with 20% FBS. CFSE-7-ADD killing assay was conducted after incubation of AML cells with autologous PBMCs. Results: Healthy donor PBMC co-cultured with irradiated K1 AML cells showed higher intracellular IFNg expression (11.8% ± 3.1 v. 7% ± 3.3; n=7, P=0.012) and higher CD137 expression (9.3% ± 1.21 v. 5.7% ± 3.4; n=7, P

Description: The discovery that acquired TTP results from autoantibodies to ADAMTS-13, a von Willebrand factor-cleavage protein (vWF-CP), provided rationale for rituximab immunosuppression as an adjunct treatment. We previously reported our experience with 5 refractory TTP patients treated with rituximab (Ann Hematology 2005, 84:232). Rituximab was administered at 375 mg/m2 IV weekly for 4 weeks. Therapeutic plasma exchanges (TPE) were held at least 24 hours post rituximab. All patients attained durable remissions with a median response of 15 months (range: 10–21). Literature review revealed 11 other studies reporting longest response duration of 23 months. Since our initial report, we treated 5 additional patients with TTP: 1 refractory and 4 newly diagnosed. Of the previously reported 5 patients with refractory TTP, 3 were female and 2 were male patients with a median age of 37 years (27–70). All patients achieved complete responses (CR). The median duration of response has increased to 32 months with a follow up period of 25 to 51 months. The longest response has been sustained 44 months after the first dose of rituximab. One patient developed clinical relapse after 26 disease-free months. She achieved CR2 after another 4 doses of rituximab with continued response 12 months after re-treatment. Time to response was shorter with re-treatment, 4 weeks vs. 5 weeks at initial therapy. Our first male patient with refractory TTP who was treated in 4/02 remained in remission for 25 months until his death from unrelated causes. One additional male patient with refractory TTP was treated preemptively due to recurrent loss of vWF-CP activity after achieving initial response with TPE and steroids. Treatment resulted in reappearance of vWF-CP activity, with continued response 30 months from first dose of rituximab. Four newly diagnosed female patients were treated: 3 had idiopathic TTP, and 1 had associated SLE. Median age was 20 years (range: 16–30). The cohort had a median platelet count of 28×109/L (range: 11–56), median hemoglobin of 10g/dL (range: 6–12) and a median lactate dehydrogenase of 868 IU/L (range: 618–1737). The median TPE’s received prior to rituximab therapy was 6 (range: 4–9) and after initiation of rituximab was 17 (range: 12–19). All patients achieved CR with median time to response of 4.5 weeks (range: 3–8). Responses are maintained 13 to 27 months after initial rituximab dose. The patient with SLE attained a complete clinical response but developed persistently low platelets unrelated to her TTP. Among the 10 patients treated, decreased or absent vWF-CP activity with presence of inhibitor were noted in 6 patients, 3 had normal levels and 1 was not tested. Our experience suggests that rituximab is safe and effective in TTP patients with refractory and newly diagnosed disease. Time to response was similar among refractory and newly diagnosed patients. To our knowledge, 44 months is the longest remission duration reported in the literature among refractory TTP patients treated with rituximab. Extended follow up is necessary to determine durable remissions among patients with newly diagnosed disease.

Description: After failure of DNA methyltransferase inhibition (DNMTi) there is no standard of care therapy for high-risk myelodysplastic syndromes (MDS), and median survival for higher risk disease is less than 6 months (Prebet et al, JCO 2011; Jabbour et al, Cancer 2015). Pevonedistat, a first in human small molecule inhibitor of the NEDD8 activating enzyme (NAE), downregulates Cullin ring ligases (CRL) which interferes with the shuttling and degradation of proteins in the proteasome and leads to accumulation of CRL substrates. Combining pevonedistat (Pev) with azacitidine (AZA) resulted in synergistic cell killing in in vitro and xenograft models of acute myeloid leukemia (AML) (Smith et al, Blood 2011), elicited favorable response rates in treatment naïve elderly or unfit AML patients (Swords et al Blood 2018), and is currently under study in treatment-naïve MDS. The study presented herein (NCT03238248) investigates the utility of adding pevonedistat to azacitidine (PevAz) after DNMTi failure in MDS and MDS/MPN overlap syndromes. Methods: In this on-going single-arm phase II study, MDS and MDS/MPN patients were eligible if they were refractory to DNMTi treatment, progressing after at least 2 cycles of therapy; had failed to achieve a complete remission (CR) after at least 4 cycles of DNMTi therapy; or had relapsed after an initial response to DNMTi therapy. Enrolled subjects received AZA 75mg/m2 sc/iv daily on days 1-5 and Pev 20mg/m2 iv on days 1, 3 and 5 of each 28-day cycle. Survival is the primary endpoint and is assessed at regularly scheduled study visits and every 3 months after ending protocol-directed therapy. Hematologic and bone marrow response rates are secondary endpoints. Responses to treatment are determined by the MDS International Working Group (IWG) response criteria (Cheson et al, Blood 2006) or for MDS/MPN, by the modified MDS/MPN IWG response criteria (Savona et al, Blood 2015). Results: As of the data cutoff on 15 MAR 2019, 23 subjects (21 with MDS, 2 with MDS/MPN) had enrolled and initiated treatment. Subjects had previously been treated with AZA (n=11/23), decitabine (n=11/23), and ASTX727 (n=4/23); some subjects had been treated with more than one DNMTi prior to enrollment. Median number of cycles of any prior DNMTi therapy was 7 (range 2-35). 65% of subjects were female. Median age at enrollment was 67 years (range 51 - 85). 65% had Intermediate-2 or High risk disease by IPSS at time of enrollment. Median number of PevAz cycles completed prior to the data cutoff was 4 (range 1-19). One subject had not reached the first response assessment at the time of the data cutoff and data was unavailable for one subject. The overall response rate including complete and partial remission, hematologic improvement and clinical benefit (CB) was 42.9% (9/21), and CR rate (including 1 CR + 4 marrow CR) was 23.8% (5/21) with a median duration of response (DOR) of 8.7m (range 2.8m-15.7m). An additional 38.1% (8/21) had stable disease as best response (Table 1). The most common Grade 〉2 adverse events (any attribution) include thrombocytopenia (39%), anemia (35%), leukopenia (26%), neutropenia (22%), infections (17%), and febrile neutropenia (13%). Six subjects experienced Grade ≤ 2 elevations in AST/ALT and 4 had Grade ≤ 2 elevation in bilirubin, whereas only one subject experienced Grade 〉 2 LFT abnormality (increase in ALT). There was one death on study due to intracerebral hemorrhage related to a previously undiagnosed metastatic carcinoma. PevAz treatment was discontinued in other subjects due to disease progression (n=7), adverse event (n=1), lack of response (n=1), or to pursue allogeneic stem cell transplant after achieving a satisfactory response to PevAz (n=3). Ten subjects were continuing PevAz therapy on study as of the data cutoff. Summary: PevAz was well-tolerated in MDS and MDS/MPN patients who had previously failed DNMTi, with the most common adverse events of cytopenias, which are a common feature of these diseases. 5/21 subjects achieved CR/mCR with meaningful DOR, and the ORR of 42.9% exceeded expectations for MDS patients with previous failure of DNMTi therapy; both MDS/MPN patients responded with CR and CB. For these patients whose treatment options are limited and prognosis very poor, these preliminary data are especially encouraging and warrant further investigation. This therapy combination is being tested in a phase 3 study in treatment naïve high risk MDS, CMML and low-blast AML. Disclosures Watts: Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Byrne:Karyopharm: Research Funding. Bradley:AbbVie: Other: Advisory Board. Savona:Sunesis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties.

Description: The mechanisms of HSCM are not completely understood and involve the action of multiple cytokines and adhesion molecules. Historically, HSCM for AHSCT has been done using high dose chemotherapy, usually C, with growth factor (G-CSF or GM-CSF). However, the need for the chemotherapy in this instance has not been defined. We, retrospectively compared three HSCM approaches; C and GSCF, G-CSF and GM-CSF, and G-CSF alone in our institution from 2005–2007. Results: C (2.5gm/m2) with G-CSF (10mcg/kg) was used in 25 patients (pts) (n=18 multiple myeloma [MM], n=5 non-Hodgkin’s lymphoma [NHL], n=1 Hodgkin’s disease [HD] and n=1 systemic sclerosis). G-CSF 5mcg/kg with GM-CSF 5mcg/kg was used for HSCM in 10 pts (n=8 NHL and n=2 MM). G-CSF alone (10mcg/kg for at least 4 days) was used in 49 pts (n=28 MM, n=13 NHL, n=2 HD and n=6 other diagnosis). The age range was 35–72 in the C and G-CSF group, 30–69 in the G-CSF and GM-CSF, and 25–72 in the GCSF alone group. The median CD34+cells/kg collected was 6.4×106 (range 0.97–131), 12×106 (range 0.23–6.7), and 4.59×106 (range 0.66–7.38) in the C and GCSF, G-CSF and GM-CSF, and the G-CSF groups respectively. The collection sessions ranged from a median of 2.0 days (1 day in 44% pts, 2 days in 28%, 3 days in 16% and 4 days in 12% of pts) in the C and G-CSF group; to 2.5 days (1 day in 20% of pts, 2 days in 30%, 3 days in 30% and 4 days in 20% of pts) in the G-CSF and GM-CSF group; and 2 days (1 day in 22% of pts, 2 days in 37%, 3 days in 30% and 4 days in 10% of pts) in the G-CSF alone group. 3 pts (12%) failed HSCM with C plus GCSF, 1 subsequently collected with G-CSF alone. 5 pts (50%) failed HSCM with G-CSF +GMCSF, 2 of these had previously failed G-CSF alone, and 2 were re-mobilized with AMD 3100 protocol and 1 with C and GCSF. 6 pts (12%) failed HSCM with G-CSF alone, 3 subsequently underwent HSCM with higher dose of G-CSF and 2 were enrolled on AMD-3100 study. 2 pts (8%) with C and G-CSF HSCM developed neutropenic fever and needed hospitalization. All pts who had adequate HSCM (at least 2×10e6/kg) and subsequently underwent AHPCT had white blood and platelet engraftment. There was no difference in the day to engraftment based on the HSCM strategy. These data show that HSCM with G-CSF alone results in similar stem cell yield and stem cell collection sessions to C and G-CSF. Although the latter strategy achieved a higher median number of HSC (4.9 vs. 6.4 xe6/kg), this was not statistically significant (p= 0.08) in this group of pts. A higher percentage of pts achieved target stem cell collection in one day with C plus G-CSF (44%), than G-CSF alone (22%). On the other hand, the combination of C plus G-CSF carries risks related to high dose chemotherapy and necessitates hospitalization for its administration and management of neutropenic fever. The G-CSF+GM-CSF combination was the least effective in adequate HSCM. Analysis of DFS in the three mobilization strategies is pending.

Description: Introduction: Anemia represents the main therapeutic challenge in pts with lower-risk MDS (Fenaux P, Adès L. Blood. 2013;121:4280-6). Prospective studies evaluating LEN for the treatment of red blood cell transfusion-dependent pts showed significant clinical activity in both non-del(5q) and del(5q) International Prognostic Scoring System-defined lower-risk MDS (Raza A, et al. Blood. 2008;111:86-93; Santini V, et al. Blood. 2014;124:abstract 409; List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). Hematologic adverse events (AEs) are common, but manageable, with LEN treatment (Giagounidis A, et al. Ann Hematol. 2008;87:345-52). However, there has been no direct comparison of safety profiles in non-del(5q) and del(5q) pts. This pooled analysis compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). Methods: This retrospective analysis of pooled data from 7 prospective clinical trials compared the incidence of AEs in LEN-treated lower-risk MDS pts with or without del(5q). The non-del(5q) group included 416 pts from 4 studies: MDS-005 (n = 160), MDS-002 (n = 215), MDS-001 (n = 24), and PK-002 (n = 17). The del(5q) group included 243 pts from 5 studies: MDS-003 (n = 148), MDS-004 (n = 69), MDS-007 (n = 11), MDS-001 (n = 8), and PK-002 (n = 7). A TEAE was defined as an AE that began or worsened in severity on or after the first dose of LEN through to 28 days after the last dose of LEN. Pts received the recommended starting dose of 10 mg LEN for ≥ 1 cycle; in study MDS-005, pts with impaired creatinine clearance (CrCl; ≥ 40 to 〈 60 mL/min) had a LEN 5 mg starting dose in order to achieve a similar area under the curve as pts with normal CrCl who were receiving LEN 10 mg. Results: Among the LEN-treated lower-risk MDS pts with or without del(5q) in this pooled analysis, the most commonly reported TEAEs (any grade) occurring in ≥ 5% of pts were hematologic: neutropenia [49.3% vs 73.7% for non-del(5q) vs del(5q), respectively], thrombocytopenia (37.3% vs 64.2%), and anemia (16.8% vs 20.2%). Overall, 84.6% of non-del(5q) pts and 96.3% of del(5q) pts experienced grade 3-4 hematologic TEAEs, including neutropenia [45.2% vs 72.0% for non-del(5q) and del(5q), respectively], thrombocytopenia (31.3% vs 52.7%), and anemia (11.8% vs 12.8%) (Table). Non-hematologic TEAEs were similar for both non-del(5q) and del(5q) pts, except deep-vein thrombosis (1.2% vs 4.9%, respectively) and hypertension (0.2% vs 3.7%). Acute myeloid leukemia was reported as a TEAE in 3 non-del(5q) and 9 del(5q) pts. Bleeding events (any grade) occurring concurrently with grade 3-4 thrombocytopenia were observed in 20.7% of non-del(5q) and 24.4% of del(5q) pts. Infection (any grade) occurring concurrently with grade 3-4 neutropenia was observed in 33.6% of non-del(5q) and 54.0% of del(5q) pts. Analysis of grade 3-4 hematologic TEAEs for pts receiving long-term (〉 12 months) LEN treatment by time of onset (0 to 6, 〉 6 to 12, and 〉 12 to 18 months) showed that onset rates of grade 3-4 neutropenia during the first 6 months were higher versus rates at 〉 6 to 12 months for non-del(5q) (42.9% vs 19.5%, respectively) and del(5q) pts (65.4% vs 21.3%). Rates decreased similarly for thrombocytopenia in non-del(5q) (13.0% vs 5.2%) and del(5q) pts (40.4% vs 6.6%). At 〉 12 to 18 months, onset rates of neutropenia and thrombocytopenia for non-del(5q) pts were 15.6% and 9.1%, respectively; rates for del(5q) pts during this period were 23.5% and 4.4%. Grade 3-4 TEAEs resulted in discontinuation of LEN in 27.4% of non-del(5q) and 20.6% of del(5q) pts (Table); however, the criteria for discontinuation differed between studies. Conclusions: In this analysis of pooled data from 7 studies, the safety profiles of LEN-treated lower-risk MDS pts were similar between non-del(5q) and del(5q) pts. Neutropenia and thrombocytopenia were the most common TEAEs in both groups; however, the frequency of these TEAEs was lower in non-del(5q) pts. Among non-del(5q) and del(5q) pts receiving long-term treatment with LEN, onset rates of thrombocytopenia and neutropenia were lower at 〉 6 to 12 months versus the first 6 months of treatment. In summary, TEAEs in lower-risk MDS pts with or without del(5q) treated with LEN 10 mg for ≥ 1 cycle are predictable, well characterized, and clinically manageable. Disclosures Almeida: Shire: Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy. Off Label Use: Lenalidomide used to treat MDS patients without del(5q). Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Vey:Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Skikne:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene International: Employment, Equity Ownership. Séguy:Celgene International: Employment. Zhong:Celgene Corporation: Employment, Equity Ownership. Fenaux:CELGENE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; JANSSEN: Honoraria, Research Funding.