Red Blood Cell Transfusion Dependence Research Articles

Effect of Red Blood Cell Transfusion Dependence on the Natural History of Myeloproliferative Neoplasm-Associated Myelofibrosis.

There are 2 widely used criteria for red blood cell (RBC) transfusion dependence in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis: (1) the International Working Group-Myelofibrosis Research and Therapy (IWG-MRT) criteria (receipt of 2 U RBC in the preceding month); and (2) the Rand-Delphi definition (2 U RBC per month averaged over 3 months). We studied effect of these criteria on survival and risk of leukemic transformation in 259 subjects with MPN-associated myelofibrosis. On the basis of hemoglobin (Hb) and transfusion history, subjects were assigned to 1 of the 4 cohorts: (1) Hb≥ 100 g/L (n= 136; 52%) and no RBC transfusions in the preceding 4 months; (2) Hb< 100 g/L, and no RBC transfusions in the preceding 4 months (n= 56; 22%); (3) subjects who met IWG-MRT criteria, but not the Rand-Delphi criteria for RBC transfusion dependence (n= 34; 13%); and (4) subjects who met the Rand-Delphi criteria for RBC transfusion dependence (n=33; 13%). Three-year probability of survival among the 4 cohorts was 81% (95% confidence interval [CI], 71-87), 55% (95% CI, 36-71), 52% (95% CI, 31-69), and 47% (95% CI, 24-67), respectively (P= .0005). There was no significant difference in baseline characteristics or survival between cohorts 3 and 4 and they were combined for subsequent analyses. In multivariate analyses, subjects who met either definition of RBC transfusion dependence had significantly worse survival (hazard ratio, 2.61; 95% CI, 1.38-4.96; P= .01). RBC transfusion dependence is associated with worse survival irrespective of definition of transfusion dependence. No effect of anemia or RBC transfusion dependence on leukemic transformation was observed.

Polish experience of lenalidomide in the treatment of lower risk myelodysplastic syndrome with isolated del(5q).

BackgroundLenalidomide has been approved for the treatment of lower-risk myelodysplastic syndrome (MDS) with 5q deletion (del(5q)). We present for the first time a retrospective analysis of low-risk MDS with isolated del5q treated with lenalidomide, outside the clinical trials.Methods36 red blood cell (RBC) transfusion-dependent patients have been included in the study. Patients received lenalidomide 10 mg/day on days 1–21 of 28-day cycles.Results91.7 % of patients responded to lenalidomide treatment: 72.2 % achieved erythroid response, 19.4 % achieved minor erythroid response and 8.4 % of patients did not respond to treatment. Response depended on number of previous treatment lines (p = 0.0101), International Prognostic System Score (IPSS; p = 0.0067) and RBC transfusion frequency (p = 0.0139). Median duration of response was 16 months (range 6–60 months). Treatment was well tolerated. We observed hematological toxicity (grade 3 and 4): neutropenia in 16 (44.4 %) patients and thrombocytopenia in 9 (25 %) patients. Two patients (5.5 %) progressed to high-risk MDS and two subsequent progressed to acute myeloid leukemia. A Kaplan-Meier estimate for overall survival at 5 years in the study group was 79.0 ± 8.8 %.ConclusionsLenalidomide in this group of patients was beneficial for the treatment of RBC transfusion-dependency with well-known safety profile.

CC-486 in Patients with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML), or Chronic Myelomonocytic Leukemia (CMML): Safety, Tolerability, and Response

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 ( Disclosures Savona:Karyopharm: Consultancy, Equity Ownership; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy. Kolibaba:Celgene: Research Funding. Conkling:Celgene: Research Funding. Rifkin:Celgene: Scientific Advisory Board Other; Millennium/Takeda: Scientific Advisory Board, Scientific Advisory Board Other; Onyx/Amgen: Scientific Advisory Board, Scientific Advisory Board Other. Laille:Celgene: Employment, Equity Ownership. Kellerman:Celgene: Employment. Ukrainskyj:Celgene: Employment, Equity Ownership. Dong:Celgene: Employment. Skikne:Celgene: Employment, Equity Ownership.

A Randomized Phase II Study of Azacitidine Combined with Lenalidomide or with Vorinostat Vs. Azacitidine Monotherapy in Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML): North American Intergroup Study SWOG S1117

Background: Higher-risk MDS and CMML comprise a spectrum of disorders associated with cytopenias, high risk of transformation to acute myeloid leukemia (AML), and truncated survival. Initial treatment with a hypomethylating agent such as azacitidine (AZA) is considered standard of care. Whether addition of the histone deacetylase inhibitor vorinostat (VOR), which acts synergistically with AZA to reactivate epigenetically silenced genes, or addition of lenalidomide (LEN), which impacts the bone marrow microenvironment, improves response rates compared to AZA monotherapy is unknown.Methods: This Phase II study (ClinTrials.gov # NCT01522976) randomized higher-risk MDS (International Prognostic Scoring System (IPSS) Int-2 or High and/or bone marrow blasts >5%) and CMML patients (pts) with <20% blasts to receive AZA (75 mg/m2/d on d1-7 of a 28d cycle), AZA + LEN (10 mg/d on d1-21), or AZA + VOR (300 mg BID on d3-9). Eligibility criteria included: >18 years (yrs), no previous allogeneic transplant, no prior treatment with any of the study drugs, and adequate organ function; therapy-related (t)MDS was allowed. Pts continued treatment until disease progression, relapse, unacceptable toxicity, or lack of response. Dose reductions occurred for unresolved grade >3 adverse events (per NCI CTCAE) or delayed count recovery. The primary endpoint was improvement in overall response rate (ORR), by intention to treat and reviewed centrally, of one of the combination arms vs. AZA monotherapy per 2006 International Working Group MDS response criteria (complete response (CR) + partial response (PR) + hematologic improvement (HI)). Relapse-free survival (RFS) was from time of response. The study had 81% power to detect a 20% improvement in ORR from 35% to 55%.Results: Of 282 pts enrolled from 3/12–6/14, 276 are included in analyses (6 ineligible pts excluded): 92 on the AZA arm, 93 on AZA+LEN, and 91 on AZA+VOR. Baseline characteristics were well-balanced across arms (Table). Pts received a median of 23 weeks of therapy: 25 of AZA; 24 of AZA+LEN; and 20 of AZA+VOR and were followed for a median of 9 months (range: 0-26). Numbers of pts with notable adverse events >grade 3 for AZA:AZA+LEN:AZA+VOR included febrile neutropenia (10:13:13); gastrointestinal disorders (4:11:23); infections (2:3:3); and rash (2:12:1). Responses were assessable in 260 pts (94%). ORR for the entire cohort was 33%: 19% CR, 1% PR, and 13% HI, with a median RFS of 7 months. ORR was similar across study arms: 36% for AZA, 37% for AZA+LEN (p=1.0 vs. AZA), and 22% for AZA+VOR (p=.07 vs. AZA). CR/PR/HI rates across arms were also similar: 23%/0%/13% for AZA; 18%/1%/17% for AZA+LEN (CR p=.47 vs. AZA); and 14%/1%/7% for AZA+VOR (CR p=.18 vs. AZA); rates of bone marrow exams to assess response were 76%, 67%, and 73%, respectively. HI-P/HI-E/HI-N rates were 21%/15%/5% for AZA, 26%/14%/15% for AZA+LEN, and 12%/8%/4% for AZA+VOR. HI-N rates were higher in AZA+LEN vs. AZA (p=.05) but otherwise were similar across arms. Median time to best response across arms was 15 weeks in AZA, 16 weeks in AZA+LEN, and 16 weeks in AZA+VOR. ORR did not vary significantly across arms in subgroup analyses for tMDS, baseline red blood cell (RBC) transfusion dependence, and by IPSS risk group. ORR for CMML pts for AZA:AZA+LEN:AZA+VOR was 33%:53%(p=.15 vs. AZA):12%(p=.41 vs. AZA). Allogeneic transplantation rates were: 7 pts on AZA, 6 on AZA+LEN, and 9 on AZA+VOR. For AZA:AZA+LEN:AZA+VOR, median RFS was: 6:8:11 months (log-rank p=.3 for combination arms vs. AZA, Figure); and for pts on therapy >6 months, it was 7:7.5:13 months (log-rank p=.11 for AZA+VOR, .74 for AZA+LEN vs. AZA).Conclusions: In higher-risk MDS pts, ORR was similar for AZA monotherapy compared to AZA-containing combination arms, though some subgroups may have benefitted from combination therapy. Differences in types of response may have resulted from differential rates of follow-up bone marrow assessments. While a non-significant signal of a DFS advantage for combination therapy was observed, longer-term outcome data are being assessed. [Display omitted] [Display omitted] DisclosuresSekeres:Boehringer-Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: lenalidomide, vorinostat for higher-risk MDS. List:Celgene Corporation: Consultancy. Gore:Celgene: Consultancy, Research Funding. Attar:Celgene: Consultancy. Erba:Seattle Genetics: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau.

Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia

AbstractThe natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aim of this study was to develop a new CMML-specific prognostic scoring system (CPSS) in a large series of 558 patients with CMML (training cohort, Spanish Group of Myelodysplastic Syndromes) and to validate it in an independent series of 274 patients (validation cohort, Heinrich Heine University Hospital, Düsseldorf, Germany, and San Matteo Hospital, Pavia, Italy). The most relevant variables for overall survival (OS) and evolution to acute myeloblastic leukemia (AML) were FAB and WHO CMML subtypes, CMML-specific cytogenetic risk classification, and red blood cell (RBC) transfusion dependency. CPSS was able to segregate patients into 4 clearly different risk groups for OS (P < .001) and risk of AML evolution (P < .001) and its predictive capability was confirmed in the validation cohort. An alternative CPSS with hemoglobin instead of RBC transfusion dependency offered almost identical prognostic capability. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC transfusion dependency and cytogenetics, and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in patients with CMML.

Myelodysplastic syndrome incidence, transfusion dependence, health care use, and complications: an Australian population‐based study 1998 to 2008

We investigated the incidence of myelodysplasia (MDS), its transfusion requirements, and complications of red blood cell (RBC) transfusion dependence (TD) using a hospitalization data set from a population of 5.3 million. This study was a retrospective cohort analysis of a population data set that captures diagnostic and procedure data on all hospitalizations from more than 300 hospitals within the Australian state of Victoria from 1998 to 2008. There were 3149 incident cases of MDS. The age-standardized incidence rate was higher than reported from local cancer registries (for 2007 9.6 per 100,000 [95% confidence interval {CI}, 9.2-10.0] vs. 4.8). Median age was 79 years, 56.3% were males, and 34.6% were TD-MDS. Overall number of hospitalizations with transfusion increased over the study period, but not median transfusion episodes per patient. TD-MDS was associated with new diagnoses of congestive heart failure (CHF; incident rate ratio [IRR], 1.92; 95% CI, 1.41-2.60), but not diabetes (IRR, 1.29; 95% CI, 0.54-3.04) or liver disease (IRR, 1.91; 95% CI, 0.63-5.78). TD-MDS was associated with bacterial (IRR, 1.75; 95% CI, 1.37-2.24) and fungal infections (IRR, 3.13; 95% CI, 1.70-5.75) and leukemia (relative risk [RR], 1.42; 95% CI, 1.07-1.88) and sepsis as cause of death (RR, 1.23; 95% CI, 1.03-1.47) but not CHF (RR, 0.97; 95% CI, 0.71-1.32). There was a higher incidence of MDS compared with that reported by cancer registries. Overall hospitalizations increased over the study period with no change in transfusion episodes per patient. There were more incident cases of CHF and infections in TD-MDS; however, CHF was not a more frequent cause of death.

A Phase II Study of Low-Dose Pomalidomide (0.5mg/day) and Prednisone Combination Therapy in Patients with Myelofibrosis and Significant Anemia

AbstractAbstract 1728 Introduction:Pomalidomide (POM) is an investigational immunomodulatory drug (IMID) that has shown efficacy in preliminary studies, with or without prednisone, as therapy for myelofibrosis (MF) with anemia, by eliminating the need for red blood cell (RBC) transfusions. In our experience, however, single agent low dose POM (0.5 mg/d) has very modest efficacy in achieving RBC transfusion independence in MF patients (Shastri A et al Blood 2011; 118). To further understand and define its activity, we have undertaken a single center phase II open label study to assess the efficacy of low dose POM in combination with prednisone therapy. In a prior study this combination resulted in a 36% response rate according to International Working Group for Myelofibrosis Research and Therapy (IWG-MRT) response criteria (Tefferi A, et al. JCO 2009; 27:4563). In the current study, benefit was assessed by the RAND-Delphi consensus criteria, which has been suggested as a better tool to evaluate RBC transfusion dependence/independence in clinical trials (Gale RP et al. Leuk Res 2011; 35:8) than IWG-MRT criteria. Patients were also evaluated for an increase in hemoglobin of at least 2g/dL for duration of 8 weeks, without transfusion support.Table 1RAND-Delphi criteria for RBC transfusion dependence/independenceRBC-transfusionsSurveillance intervalRBC-transfusion-dependence≥2 U/month3 monthsRBC-transfusion-independenceNone3 monthsReduced RBC-transfusion-dependence50% decrease3 months Patients & Results:21 patients, 14 male and 7 female, were enrolled in the study: 2 (10%) had post essential thrombocythemia MF, and 19 (90%) had primary MF. Median age was 69 years (range 48–85) and 15 (71%) were previously treated; 5 had been treated with other IMIDs previously. Four (19%) had splenomegaly; 1 had prior splenectomy. Seven (33%) had abnormal cytogenetics and 10 (48%) had JAK2V617F mutation. All patients had hemoglobin <10g/dL at study entry; patients with higher hemoglobin that were transfusion dependent were allowed to enroll if it was a result of a blood transfusion given just prior to enrollment. Median hemoglobin was 8.5 g/dL (range 7.3–11.1), WBC 4.7×109/L (1–20.7), and platelets 155×109/L (35–1191). The use of anagrelide during the study was allowed to control high platelets, if indicated; other concomitant therapies, including growth factors, were not allowed. Patients were administered POM 0.5mg continuously daily in 28-day cycles and prednisone was administered as 30mg daily for the first month, 15mg daily for second month, 15mg every other day for third month and then stopped. Thirteen (62%) patients were transfusion dependent by the RAND-Delphi consensus criteria.After a median follow up of 7.8 months (3.3–11.9), 6 (28%) patients were still on the therapy. The median number of cycles administered to patients was 6 (2–12). Fourteen patients were taken off the study for lack of response (N=12) or for loss of a response (N=2). One patient was taken off due to the development of grade 3 pneumonitis. Three died from unrelated causes. Three patients were noted to have RBC transfusion response per RAND-Delphi criteria. One of the responders had JAK2V617F mutation. Median time to response was 52.7 days (48 – 55 days). No patient had an increase in hemoglobin of at least 2g/dL for at least 8 weeks. This is an ongoing trial and updated results along with complete toxicity profile will be presented at the meeting. Conclusion:POM administered in combination with prednisone to patients with MF and significant anemia has modest efficacy, comparable to single agent POM. A Phase III blinded, placebo-controlled study is underway globally for MF patients with significant anemia and RBC transfusion dependency. Disclosures:Verstovsek:Celgene: Research Funding.

Validation of the Lower Risk MD Anderson Prognostic Scoring System for Patients with Myelodysplastic Syndromes

AbstractAbstract ▪3826▪This icon denotes a clinically relevant abstract Background:The International Prognostic Scoring System (IPSS) is the most widely used clinical tool for risk stratification and tailoring treatment in myelodysplastic syndromes (MDS). Outcome of patients stratified as lower risk MDS by IPSS is variable, with a subset of patients experiencing inferior than expected outcomes. Identifying patients with higher risk disease behavior is indispensible for proper implantation of disease altering therapy. The Lower Risk MD Anderson Risk Model (LR-MDAS) is a recently proposed model provides prognostic refinement to identify such patients (Garcia-Manero et al, Leukemia 2008). To validate this model, we tested the new risk model in large external single institution cohort of patients. Methods:Data were collected retrospectively from the Moffitt Cancer Center (MCC) MDS database and chart review. The primary objective was to validate the new risk model when applied at time of initial presentation to MCC. The LR-MDAS was calculated as published using the sum of points generated from unfavorable (non-del(5q), non–diploid) cytogenetics, hemoglobin (hgb) <10g/dl, platelet count (plt) <50 k/uL or 50–200k/uL, bone marrow blast % >= 4, and age>= 60 years. Patients were divided into 3 prognostic categories. All analyses were conducted using SPSS version 15.0. (SPSS Inc, Chicago, IL). The Kaplan–Meier method was used to estimate median overall survival. Log rank test was used to compare Kaplan–Meier survival estimates between the groups. Cox regression was used for multivariable analysis. Results:Between January 2001 and December 2009, 479 patients with low or int-1 risk IPSS were captured by MCC MDS database. The median age was 69 years, MDS subtypes were coded as Refractory anemia (RA) 113 (24%), refractory anemia with ring sideroblasts (RARS) 73 (15%), MDS with del(5q) 19 (4%), refractory cytopenia with multi-lineage dysplasia (RCMD) 109 (23%), refractory anemia with excess blasts (RAEB) 147 (31%), and MDS-unclassified (U) 18 (4%). IPSS risk groups were low risk in 145 (30%), and intermediate-1 (int-1) 334 (70%). Only 31 patients (7%) had a poor risk karyotype by IPSS. Red blood cell transfusion dependence was documented in 42% (n=202), 22% had elevated serum ferritin ≥ 1000 ng/ml, and 45% (n=217) received azanucleoside treatment.Based on the LR-MDAS, 52 patients (11%) were category 1, 188 (39%) category 2, 232 (48%) category 3, and 7 (2%) were unknown. The median OS from time of referral to MCC for all patients was 32 months (95% CI 27–37 mo), Age, IPSS risk group, serum ferritin, and RBC transfusion dependence were all significant prognostic factors in univariate analysis. The median OS for the corresponding categories was, 1 - not reached (NR), 2– 50 mo (95%CI 33–68 mo), and 3 – 22 mo (95%CI 16–27 mo), from time of MCC referral, respectively. (Figure-1) (P < 0.005).Among 142 patients classified as low risk by IPSS, 25 patients (18%) were category 1 LR-MDAS, 81 (57%) category 2, and 36 (25%) category 3 with corresponding median OS of, NR, 62 month, and 35 month respectively (p=0.002). Among 330 patients risk stratified as int-1 IPSS group, 27 patients where category 1 LR-MDAS, 107 category 2, and 196 category 3 where median OS was NR, 28 months and 20 months, respectively. (p< 0.001) (Figure-2).When we applied IPSS risk stratification among each category of LR-MDAS to assess if IPSS can further refine prognosis within LR-MDAS categories, only in patients classified as Category 2 LR-MDAS the median OS was different among low and int-1 risk IPSS (62 month versus 28 month). (p <0.005).The rate of AML transformation according to LR-MDAS was 4%, 12%, and 20% for category 1,2, and 3, respectively. (p<0.02). In Cox regression analysis higher risk LR-MDAS predicted inferior OS (Hazard ratio (HR) 1.8 (95%CI 1.4–2.3) (p <0.005) independent of IPSS risk group (HR 2 95%CI 1.4–2.8) (p <0.005). Conclusion:Our data validates the prognostic value of the proposed LR-MDAS risk model, demonstrating predictive power for overall survival and AML transformation among low/int-1 risk IPSS. The LR-MDAS is complementary to the IPSS, offering further discrimination to identifying those patients with aggressive disease behavior that merit disease altering therapy. The utility of the model as treatment decision tool should be studied prospectively. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Multivariate Analysis of the Impact of Pre-Treatment Serum Ferritin Level On Response and Overall Survival in Patients with Myelodysplastic Syndromes Treated with Azacitidine

AbstractAbstract 1710 Introduction:Red blood cell (RBC) transfusion dependency independently predicted inferior overall survival (OS) (Itzykson R, et al. Blood. 2011;117:403-11). Transfusion dependency appears to have a major negative prognostic impact in patients with myelodysplastic syndromes (MDS) (Malcovati L, et al. J Clin Oncol. 2005;23:7594-603). The independent prognostic value of development of iron overload on OS and acute myeloid leukemia (AML) risk in MDS has been demonstrated (Sanz G, et al. Blood. 2008;112:abstract 640). Serum ferritin (SF) concentration predicts morbidity and mortality after hematopoietic cell transplantation (Sorror ML, et al. Blood. 2009;114:abstract 651). The prognostic impact of SF on overall response (OR) and OS in patients with MDS treated with azacitidine (AZA) remains unknown. Aim:To analyze the impact of pre-treatment SF levels on response and OS in patients with World Health Organization-defined MDS or AML with 20–30% bone marrow (BM) blasts who received AZA through a compassionate-use program in Spain. Methods:We report a retrospective multivariate analysis of the impact of SF level on OR and OS in patients treated with AZA. Hematologic response was assessed according to International Working Group 2003 (AML) and 2006 (MDS) criteria. SF levels were selected based on median SF value, dividing in two the first half for a better discrimination of the effect (< 500 ng/mL, 500–1000 ng/mL, and > 1000 ng/mL). Comparison of baseline characteristics between SF level groups was performed using Chi-Squared, Fisher’s exact, or Likelihood Ratio Chi-Square test for qualitative variables; and analysis of variance, Mann-Whitney and Wilcoxon, or Kruskal-Wallis test for quantitative variables. A logistic regression model was used to evaluate the effect of pre-treatment variables (ie, SF levels, sex, age, French-American-British classification, BM blast count, time since diagnosis, hemoglobin [Hb] level, International Prognostic Scoring System [IPSS] risk, and thrombocytopenia) on best OR (marrow complete response [mCR] + complete response [CR] + partial response [PR] + hematologic improvement [HI]). A Cox proportional hazards model was used to evaluate the effect of the mentioned variables on OS. All analyses were done using SAS System® version 9.2. Results:Of 240 patients enrolled, pre-AZA SF levels were available for 190 patients. The median pre-treatment SF level was 1001 ng/mL (range 21–5548). Baseline characteristics according to SF levels (< 500 ng/mL [n = 49], 500–1000 ng/mL [n = 46], and > 1000 ng/mL [n = 95]) are summarized in Table 1. OR rates were higher and OS was increased in patients with pre-AZA SF levels of ≤ 1000 ng/mL (Table 2 and Fig). In multivariate analysis, pre-treatment SF levels were predictive of best OR (P = 0.0001). Patients with SF levels > 1000 ng/mL had a reduced likelihood of OR (P < 0.0001 vs SF levels < 500 ng/mL). Baseline SF levels were also predictive of OS (P = 0.0002); patients with SF levels > 1000 ng/mL had the lowest likelihood of OS (P = 0.0012 vs SF < 500 ng/mL; and P = 0.0023 vs SF 500–1000 ng/mL). None of the other variables analyzed had a significant impact on OR or OS. Conclusion:Patients with pre-AZA SF levels > 1000 ng/mL had lower OR rates and inferior OS compared with patients with SF levels ≤ 1000 ng/mL. None of the other patient baseline characteristics analyzed had an impact on these outcomes. Our results suggest that higher OR rates and increased OS are obtained with AZA treatment in MDS patients with SF levels ≤ 1000 ng/mL, compared with patients with SF levels > 1000 ng/mL. This may advocate for early initiation of therapy before increasing SF level; however, prospective controlled clinical trials are needed to confirm this hypothesis. Acknowledgments:Regina Garcia Delgado, Dunia de Miguel, Alicia Bailen, José Ramón González, Joan Bargay, Jose F. Falantes, Rafael Andreu, Fernando Ramos, Mar Tormo, Rafael F. Duarte, Ma José Jiménez Lorenzo, Salut Brunet, Benet Nomdedeu, Antonio Figueredo, Javier Casaño, Llorenç Badiella, and Antonio Fernández Jurado submitted this abstract on behalf of the Asociación Andaluza de Hematología y Hemoterapia, Spain. [Display omitted] [Display omitted] [Display omitted] Disclosures:Garcia Delgado:Celgene Corporation: Research Funding. de Miguel:Celgene Corporation: Speakers Bureau. Bargay:Celgene Corporation: Research Funding. Ramos:Celgene Corporation: Speakers Bureau. Sanz:Celgene Corporation: Speakers Bureau.

Prognostic Impact of Posttransplantation Iron Overload after Allogeneic Stem Cell Transplantation

In patients referred for allogeneic hematopoietic stem cell transplantation (HSCT), iron overload is frequent and associated with increased morbidity and mortality. Both the evolution of iron overload after transplantation and its correlation with late posttransplantation events are unknown. We studied 290 patients undergoing myeloablative allogeneic HSCT between 2000 and 2009. Serum ferritin, transferrin saturation, transferrin, iron, and soluble transferrin receptor were determined regularly between 1 and 60 months after HSCT, and values were correlated with transplantation outcome. Ferritin levels peaked in the first 3 months posttransplantation and then decreased to normal values at 5 years. Transferrin saturation and iron behaved analogously, whereas transferrin and soluble transferrin receptor increased after an early nadir. Landmark survival analysis showed that hyperferritinemia had a detrimental effect on survival in all periods analyzed (0 to 6 months P < .001; 6 to 12 months P < .001; 1 to 2 years P = .02; 2 to 5 years P = .002). This effect was independent of red blood cell transfusion dependency and graft-versus-host disease. Similar trends were seen for other iron parameters. These data show the natural dynamics of iron parameters in the setting of allogeneic HSCT and provide evidence for a prognostic role of iron overload extending beyond the immediate posttransplantation period. Interventions to reduce excessive body iron might therefore be beneficial both before and after HSCT.

Pure red cell aplasia with follicular lymphoma showing regression and progression parallel to lymphoma

Malignant lymphomas occasionally accompany autoimmune diseases. Pure red cell aplasia (PRCA) is thought to arise via an autoimmune mechanism and rarely occurs in lymphoma. Here, we report a case of follicular lymphoma accompanying PRCA, in which lymphoma and PRCA showed parallel regression and progression in response to chemotherapy for lymphoma. An 83-year-old Japanese man presented with a chief complaint of dizziness. He was found to be anemic, and had a gastric ulcer and retroperitoneal mass. Biopsy of the gastric lesion suggested malignant lymphoma, and he was referred to our hospital. The initial laboratory results were as follows: hemoglobin, 73 g/L; mean corpuscular volume, 92.6 fL; and reticulocyte count, 2 9 10/L. Computed tomography (CT) imaging showed general lymphadenopathy, and excision biopsy of the axillary lymph node confirmed grade 1 follicular lymphoma. Fluorescence in situ hybridization (FISH) analysis of the lymph node was positive for fusion of the Bcl-2 and IgH genes. Bone marrow examination showed no lymphoma infiltration. He received six courses of R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone) chemotherapy and complete response was achieved. Even after completion of chemotherapy, his anemia persisted and he required regular transfusion of red blood cells. White blood cell and platelet counts were normal. Bone marrow examination showed remarkable erythroid hypoplasia without dysplasia, and lymphoma infiltration was not detected by FISH analysis. CT imaging indicated that thymoma was absent. Hemolytic anemia was unlikely, as lactic dehydrogenase, bilirubin, and haptoglobin were normal. The patient further did not show indications of thymoma or hemolytic anemia in his clinical course. Nine months after completion of chemotherapy, his anemia spontaneously resolved and he no longer required transfusions. Approximately 2 years after the initial therapy, CT imaging showed enlarged abdominal lymph nodes and the patient was diagnosed with recurrent lymphoma. He was observed without therapy, and 1 year after the recurrence, the disease gradually progressed accompanied by concomitant progression of anemia. At initiation of salvage therapy, hemoglobin was 82 g/L and reticulocyte count was 5 9 10/L. Bone marrow examination again showed erythroid hypoplasia without dysplasia or infiltration of lymphoma. Immunoglobulin M (IgM) antibody to parvovirus B19 was negative. With modified R-ESHAP chemotherapy (rituximab, etoposide, methylprednisolone, cytarabine, and carboplatin), his lymphoma achieved partial response. His anemia also improved; hemoglobin was 100 g/L and reticulocyte count was 85 9 10/L. However, as he suffered severe discitis, he could not continue chemotherapy. His lymphoma grew slowly, and his anemia progressed again. Bone marrow examination showed neither dysplasia nor infiltration of lymphoma. Rituximab mono-therapy was ineffective for lymphoma and anemia. Seven months after salvage chemotherapy, at the time of this report, the patient is alive with slowly progressive lymphoma and red blood cell transfusion dependence. His clinical course is shown in Fig. 1. PRCA has been reported to occur rarely in lymphoma [1–4]. In most reported cases, PRCA improved after the chemotherapy for lymphoma. However, steroids and other immunosuppressive agents, such as cyclophosphamide [5] and rituximab [6], used for lymphoma therapy are also G. Yamamoto H. Maki M. Ichikawa M. Kurokawa (&) Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan e-mail: kurokawa-tky@umin.ac.jp

Obesity Is Poor Prognostic Factor in Lower Risk Myelodysplastic Syndrome

Abstract 5018 Background:Obesity was associated with a more than 2-fold greater risk of myelodysplastic syndrome (MDS) in a recent epidemiological study (Ma et al, Am J Epidemiol. 2009 June 15; 169(12): 1492–1499). The impact of obesity on outcome of disease in patients with an established diagnosis of MDS has not been studied. We examined the prognostic value of obesity in a large cohort of lower risk MDS patients treated at the Moffitt Cancer Center (MCC). Methods:Data were collected retrospectively from the Moffitt Cancer Center (MCC) MDS database and individual charts reviewed. The primary objective was to evaluate the impact of obesity on overall survival (OS) in lower risk patients with MDS. Patients with low or intermediate-1 (int-1) risk disease by International Prognostic Scoring System (IPSS) were included. Obesity was defined as a body mass index (BMI) ≥ 30 (Standard definition) measured at time of referral to MDS program at MCC. Patients were divided into two groups according to BMI ≥ 30 or BMI < 30. All analyses were conducted using SPSS version 19.0. Chi square and independent t-test were used to compare baseline characteristics between the 2 groups for categorical and continuous variables, respectively. The Kaplan–Meier method was used to estimate median overall survival. Log rank test was used to compare Kaplan–Meier survival estimates between two groups. Cox regression was used for multivariable analysis. Results:Between January 2001 and December 2009, 479 low/int-1 IPSS risk MDS patients were included. Among those, 132 (27.6%) had BMI ≥ 30 and 325 (67.8%) had BMI <30; BMI was missing in 22 patients (4.6%). The baseline characteristics between the two groups were comparable. No difference was noted in mean age, WHO subtype, karyotype, MD Anderson risk model group, red blood cell transfusion dependency (RBC-TD), or serum ferritin (Table-1).Table-1Baseline CharacteristicsBMI < 30 n= 325BMI ≥ 30 n=132p-valueAge ≥ 60232 (71%)91 (69%)0.65KaryotypeGood253 (77.8%)106 (80.3%)0.15Intermediate46 (14.2%)21 (15.9%)Poor24 (7.4%)3 (2.3%)Unknown2 (0.6%)2 (1.5%)MDASLow144 (44.3%)48 (36.4%)0.6Int-163 (19.4%)55 (41.7%)Int-215 (4.6%)24 (18.2%)High risk4 (1.2%)5 (3.8%)WHO typeRA73 (22.5%)33 (25%)0.7RARS51 (15.7%)20 (15.2%)RCMD71 (21.8%)34 (25.8%)Del 5q16 (4.9%)3 (2.3%)RAEB101 (31.1%)37 (28%)MDS-U13 (4%)5 (3.8%)RBC-TD143 (44.4%)48 (36.6%)0.3Ferritin>1000 (ng/ml)76 (32.5%)29 (30.5%)0.4HMA (yes)145 (44.6%)67 (50.8%)0.13MDAS MD Anderson Score risk group, int-1 intermediate-1, int-2:intermediate-2, RA: refractory anemia, RARS refractory anemia with ring sideroblasts, RCMD refractory cytopenia with multilineage dysplasia, RAEB refractory anemia with excess blasts, MDS-U MDS unclassified, RBC-TD red blood cell transfusion dependency, HMA hypomethylating agentThe median OS was 59 mo (95%CI 48–70) in patients with BMI <30 compared to 44 (95%CI 38–50) in patients with BMI ≥ 30. (p=0.03). There was no difference in rate of AML transformation according to BMI, 12.9% and 15.7% respectively for BMI ≥ 30 and BMI <30. (P=0.3). In Cox regression analysis obesity predicted inferior OS (Hazard ratio (HR) 1.7 (95%CI 1.15–2.4) (P=0.007) after adjustment for age, MD Anderson risk group, serum ferritin, RBC-TD, use of hypomethylating agents and tobacco use. Conclusion:Our data suggest that obesity is an independent adverse prognostic factor for OS in patients with lower risk MDS. Obesity may be associated with other comorbidities and metabolic dearrangements that contribute to the pathogenesis of the underlying disease. Disclosures:No relevant conflicts of interest to declare.

Telomere Elongation In Vivo and Clinical Response Upon Androgen Treatment in a Patient with Aplastic Anemia and a Heterozygous hTERT Gene Mutation,

Abstract 3427Telomere length both reflects and limits the replicative life-span of normal somatic cells and critically shortened telomeres are associated with a variety of disease states. In patients with aplastic anemia telomere lengths in granulocytes and lymphocytes can be found to be significantly shorter as compared to age-adjusted controls. Telomere shortening in peripheral blood cells therby mirrors telomere shortening in the underlying hematopoietic stem cell reserve, which can be severely diminished in acquired bone marrow failure syndromes. Genetic aberrations such as mutations in the gene for dyskerin or in subunits of the telomerase-complex such as the RNA subunit hTERC or mutations in the human telomerase gene (hTERT) have been described and linked to critically short telomeres found in blood cells.We report here on a 51 year old male patient with moderate aplastic anemia (AA) and a non-synonymous variation of codon 1062 of the hTERT gene (pAla1062Thr). Cells with deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-AP), i.e. cells with a PNH phenotype, were detected (1.2% of erythrocytes, 8% of reticulocytes and 15% of neutrophils). The patient was found to have dramatically shortened telomere length below 1% percentile of normal individuals both in lymphocytes (4.28 +/− 0.02 kbp) and granulocytes (4.14 +/−0.1 kbp). Based on the clinical presentation (i.e. predominance of red blood cell transfusion dependence and thrombocytopenia, but absence of immediate risk e.g. of infections or bleeding) we decided to initiate androgen treatment rather than to initiate standard immunosuppression.The initially red blood cell transfusion dependent and thrombocytopenic patient became completely red blood cell transfusion independent after twelve months of ongoing androgen treatment. A significant proportion of GPI-AP deficient red cells and reticulocytes could no longer be detected and only a very small proportion of GPI-AP deficient granulocytes (<1%) persisted.The clinical and hematological improvement during androgen therapy was mirrored by a continuous and persistent lengthening of telomere length in total peripheral blood mononuclear cells (MNCs) measured by qPCR as well as in both leukocyte subpopulations measured by Flow-FISH.To our knowledge, this represents the first case of sustained telomere elongation in hematopoietic stem cells induced by a pharmacological approach in vivo. Disclosures:No relevant conflicts of interest to declare.

Impact of Red Blood Cell (RBC) Transfusion During Induction Chemotherapy in Newly Diagnosed Patients with Acute Myeloid Leukemia (AML),

Abstract 3600 Background:RBC transfusion dependency is a well known poor prognostic factor for patients with myelodysplastic syndromes, reflecting the underlying biology of disease and the impact of iron overload. To our knowledge, the impact of RBC transfusion (TX) on induction chemotherapy outcome in AML patients has not been investigated. Methods:Data were collected retrospectively in a cohort of newly diagnosed AML patients who received induction chemotherapy (3+ 7 regimen) at Moffitt Cancer Center. The primary objective of this study was to examine the relationship between number of RBC transfused units during first induction chemotherapy and outcome. Number of RBC units transfused only during the first cycle of induction were collected, and patients were divided into 2 groups, < 10 units RBC or ≥ 10 RBC units. All analyses were conducted using SPSS version 19.0. The Kaplan–Meier method was used to estimate median overall survival; chi-square test was used for comparison of categorical variables and t -test for continuous variables. Log rank test was used to compare Kaplan–Meier survival estimates between two groups and Cox regression for multivariable analysis. Results:135 AML patients who received 3+7 induction chemotherapy were included in this analysis. The median number of RBC units transfused during first induction chemotherapy was 10.0. Fifty nine patients received less than 10 units and 76 patients received 10 or more RBC units. Baseline characteristics were similar between patients with RBC units < 10 and those who received ≥ 10 units with respect to age, sex, history of antecedent MDS, karyotype, double induction requirement, and remission rates. (Table-1)Table 1:Baseline characteristicsVariable< 10 RBC units n=59≥ 10 RBC units n=76p-valueAge≥ 60 years28 (47.5%)42 (55.3%)0.4GenderMale33 (55.9%)54 (71.1%)0.07Prior MDSYes15 (25.4%)29 (38.2%)0.3KaryotypeGood3 (5.1%)4 (5.3%)0.36Intermediate38 (64.4%)46 (60.5%)Poor18 (30.5%)22 (28.9%)missing04 (5.3%)Double inductionYes31 (52.5%)29 (38.7%)0.12RemissionCR/CRi49 (83.1%)57 (76%)0.4MDS: myelodysplastic syndrome, CR: complete response, CRi complete response with incomplete count recoveryThe median OS for patients who received < 10 units was 538 days (95%CI 199.3–876.7) compared to 296 days (95%CI 234–358) for patients who received ≥ 10 RBC (P=0.001). (Figure 1) The impact of RBC TX was greater in younger patients (< 60 years), for whom median OS was 798 days compared to 275 days in patients who had < 10 and ≥ 10 RBC units respectively, (p=0.013). In patients ≥ 60 years, the median OS was 275 days compared to 240 days for patients who had < 10 and ≥ 10 RBC units respectively, (p=0.06). Relapse rate was 52.5% (n=31) for patients who received < 10 units compared to 39.5% (n=30) in those who received ≥ 10 RBC units (p=0.09). [Display omitted] In a multivariable Cox regression analysis including age ≥ 60 years, karyotype, achieving remission (CR/CRi), receiving double induction, and RBC transfusion ≥ 10 units; age≥ 60 years [HR 1.5 (95%CI 1.0–2.2), p=0.047], karyotype [HR 1.7 (95%CI 1.3–2.3), P<0.005], and CR/CRi [HR 3.7 (95%CI 2.3–6.0), p<0.005], RBC≥ 10 units [Hazard ratio 1.8 (95%CI 1.2–2.7,p=0.006) were independent prognostic variables for OS. Conclusion:To our knowledge, this is the first study to identify a relationship between induction outcome and number of RBC units transfused (≥ 10 units) in AML patients. We hypothesize that requirement for RBC transfusion may reflect underlying disease biology, relative resistance to intensive chemotherapy or may lead to iron overload. These findings warrant confirmation in a larger, prospective study. Disclosures:No relevant conflicts of interest to declare.

Impact of Iron Chelation Therapy on Overall Survival and AML Transformation in Lower Risk MDS Patients Treated At the Moffitt Cancer Center

Abstract 2776 Background:Elevated serum ferritin levels and red blood cell transfusion dependence are associated with poor outcome in patients with lower risk myelodysplastic syndromes (MDS). Few retrospective and observational studies suggest that iron chelation therapy (ICT) may favorably impact outcome in lower risk MDS. The vast majority of patients in those studies were treated with deferoxamine (Desferal). Two studies reported that oral deferasirox (Exjade) significantly decreases ferritin level over time in MDS. An ongoing randomized placebo-controlled trial (TELESTO) is designed to address the impact of deferasirox on overall survival (OS) in lower risk MDS. We examined the impact of ICT predominantly deferasirox in lower risk MDS patients treated at the Moffitt Cancer Center (MCC). Methods:Patients were retrospectively identified from the MCC database and individual patients’ records reviewed. Inclusion criteria included lower risk MDS patients defined as low or intermediate-1 (int-1) risk disease by the international prognostic scoring system (IPSS) and serum ferritin level ≥ 1000 ng/ml. Patients were divided into two comparator groups: ICT vs. no ICT. Baseline characteristics were compared between the two groups; chi square test was used for categorical variables and t-test for continuous variables. The primary endpoint was overall survival compared between the two groups using Kaplan-Meier estimates. Cox regression was used for multivariate analysis. All analyses were conducted using SPSS version 19.0 statistical software. Results:Between July 2001 and July 2009, 97 patients with lower risk MDS and serum ferritin ≥ 1000 ng/ml were identified. Forty five (46.4%) received ICT and 52 did not. The ICT included deferasirox in 35 patients and deferoxamine in 10 patients. The baseline characteristics between the two groups (ICT and no ICT) are summarized in (table-1). No statistically significant difference in baseline characteristics was observed except more patients in the ICT group were transfusion dependent. The median duration of follow up was 85.7 month from time of diagnosis.Table 1:Baseline characteristicsICTNo ICTP-valueAge (mean, years)6765.50.54Serum Ferritin (mean, ng/ml)268030380.77Caucasian Race (%)97.8%92.3%0.43Male gender (%)73.3%63.5%0.3WHO subtypeRA8 (17.8%)14 (26.9%)0.6RARS11 (24.4%)10 (19.2%)RCMD17 (37.8%)14 (26.9%)Del 5q2 (4.4%)1 (1.9%)RAEB-16 (13.3%)9 (17.3%)RAEB-II1 (2.2%)2 (3.8%)CMML01 (1.9%)MDS,nos01 (1.9%)IPSSLow15 (33.3%)9 (17.3%)0.07Int-130 (66.7%)43 (82.7%)MDASLow7 (15.6%)10 (19.2%)0.48Int-125 (55.6%)21 (40.4%)Int-29 (20%) 416 (30.8%)High(8.9%)5 (9.6%)KaryotypeGood38 (84.4%)44 (86.3%)0.3Intermediate5 (11.1%)7 (13.7%)poor2 (4.4%)0ECOG PS012 (26.7%)7 (13.5%)0.06131 (68.9%)34 (65.4%)22 (4.4%)10 (19.2%)310 (19.2%)1 (1.9%)RBC Transfusion45 (100%)43 (82.7%)0.003The median OS was 59 months (95%CI 22–48) for patients who received ICT compared to 33.7 months (95%CI 38–80) for patients who did not receive ICT (P= 0.013). After adjustment for age and cytogenetics in Cox multivariable analysis, ICT was associated with better OS (HR 0.52, 95%CI 0.31–0.87, P= 0.013). The rate of AML transformation was 21.2% in patients who did not receive ICT compared to 15.6% in those who had ICT. (p=0.33). Conclusion:ICT in lower risk MDS patients with elevated serum ferritin ≥ 1000 ng/ml was associated with improved overall survival and a trend to lower AML transformation. Results of ongoing randomized clinical study with deferasirox are needed to confirm the retrospective data. Disclosures:Komrokji:Novartis: Honoraria, Research Funding.

Dexamethasone and lenalidomide have distinct functional effects on erythropoiesis

AbstractCorticosteroids and lenalidomide decrease red blood cell transfusion dependence in patients with Diamond-Blackfan anemia (DBA) and myelodysplastic syndrome (MDS), respectively. We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34+ cells and from CD34+ cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number of burst-forming units-erythroid (BFU-E), whereas lenalidomide specifically increased colony-forming unit-erythroid (CFU-E). Use of the drugs in combination demonstrated that their effects are not redundant. In addition, dexamethasone and lenalidomide induced distinct gene-expression profiles. In coculture experiments, we examined the role of the microenvironment in response to both drugs and found that the presence of macrophages, the central cells in erythroblastic islands, accentuated the effects of both agents. Our findings indicate that dexamethasone and lenalidomide promote different stages of erythropoiesis and support the potential clinical utility of combination therapy for patients with bone marrow failure.

Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine

AbstractPrognostic factors for response and survival in higher-risk myelodysplastic syndrome patients treated with azacitidine (AZA) remain largely unknown. Two hundred eighty-two consecutive high or intermediate-2 risk myelodysplastic syndrome patients received AZA in a compassionate, patient-named program. Diagnosis was RA/RARS/RCMD in 4%, RAEB-1 in 20%, RAEB-2 in 54%, and RAEB-t (AML with 21%-30% marrow blasts) in 22%. Cytogenetic risk was good in 31%, intermediate in 17%, and poor in 47%. Patients received AZA for a median of 6 cycles (1-52). Previous low-dose cytosine arabinoside treatment (P = .009), bone marrow blasts > 15% (P = .004), and abnormal karyotype (P = .03) independently predicted lower response rates. Complex karyotype predicted shorter responses (P = .0003). Performance status ≥ 2, intermediate- and poor-risk cytogenetics, presence of circulating blasts, and red blood cell transfusion dependency ≥ 4 units/8 weeks (all P < 10−4) independently predicted poorer overall survival (OS). A prognostic score based on those factors discriminated 3 risk groups with median OS not reached, 15.0 and 6.1 months, respectively (P < 10−4). This prognostic score was validated in an independent set of patients receiving AZA in the AZA-001 trial (P = .003). Achievement of hematological improvement in patients who did not obtain complete or partial remission was associated with improved OS (P < 10−4). In conclusion, routine tests can identify subgroups of patients with distinct prognosis with AZA treatment.

Hypoalbuminemia Is An Independent Prognostic Factor In Myelodysplastic Syndromes

AbstractAbstract 4001 Background:Low serum albumin level is known to be an adverse prognostic factor in patients with malignancies such as multiple myeloma. We previously reported that severe hypoalbuminemia (<3.0 g/dl) at day +90 post allogeneic hematopoietic stem cell transplant (AHCT) was an independent predictor of non-relapse and overall mortality in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) (Kharfan-Dabaja et al Biol Blood Marrow Transplant. 2010 Jul). In this study we examined prognostic value of serum albumin level in patients with MDS. Methods:Data were analyzed from the Moffitt Cancer Center (MCC) MDS database with chart review verification. The primary objective was to examine the role of serum albumin at time of presentation to MCC as a prognostic marker for overall survival (OS). Patients were divided into 3 groups of serum albumin levels (≤ 3.5, 3.6–4.0 and > 4.0 g/dl). The Kaplan–Meier method was used to estimate median OS. The log rank test was used to compare Kaplan–Meier survival estimates between two groups. Cox proportional hazards regression was used for multivariable analysis. Results:Between January 2001 and December 2009, 844 patients were captured by the MCC MDS database. The median age was 69 years. MDS subtypes were coded as refractory anemia (RA) (n=98;12%), refractory anemia with ring sideroblasts (RARS) (n=76;9%), del(5q) (n=20;2.4%), refractory cytopenia with multi-lineage dysplasia (RCMD) (n=96;11%), refractory anemia with excess blasts (RAEB) (n=255;30%), therapy related MDS (n=22;2.6%), and MDS-NOS (n=275; 33%). The distribution of IPSS risk groups was: 18.7% Low risk, 42.9% Intermediate-1 (Int-1), 19.9% Int-2, 5.3% High risk, and 13.2% unknown. Baseline characteristics for the three patient groups defined by serum albumin level are summarized in (Table-1). There was no difference in red blood cell transfusion dependency (RBC-TD) rate between the 3 groups (p=0.21). The median OS for all patients was 36 months (95% confidence interval (CI) 31.5–40.5 mo). Age, IPSS risk group, RBC-TD, Serum ferritin were statistically significant prognostic factors in univariable analysis.The median OS was 19 mo (95%CI= 14.9–23.1 mo), 35 mo (95%CI= 28.7–41.3 mo), and 53 mo (95%CI= 44.7–61.3 mo) for patients with serum albumin levels ≤ 3.5 g/dl, 3.6–4.0 g/dl, > 4.0 g/dl, respectively. (Figure-1) (p= <0.005). After adjustment for age, RBC-TD, OS was statistically significantly inferior among MDS patients with lower serum albumin (Hazard Ratio (HR) = 0.79.; 95%CI= 0.69–0.90; p= 0.001), and higher-risk IPSS group (HR=1.67; 95%CI=1.48-1.87; p= <0.005).The overall rate of AML transformation was 29.2%. Rate of AML transformation was higher in patients with lower serum albumin, 38% in patients with serum albumin ≤ 3.5 g/dl, 30% for patients 3.6–4.0 g/dl, and 23% in patients with serum albumin > 4.0 g/dl (p-value 0.005).Among patients in the Low/Int-1 IPSS risk group, the median OS was 28 mo (95%CI=15.7-40.3 mo), 48 mo (95%CI=38.8-58.0 mo), and 60 mo (95%CI=47.6-72.4 mo) for patients with serum albumin levels ≤ 3.5 g/dl, 3.6–4.0 g/dl and > 4.0 g/dl, respectively (p=0.003). Among patients in the Int-2/High IPSS risk group, the median OS was 16 mo (95%CI 13.3–15.7 mo), 22 mo (95%CI 18.0–26.0 mo), and 21 mo (95%CI 8.8–33.2 mo) respectively for patients with serum albumin levels ≤ 3.5 g/dl, 3.6–4.0 g/dl and > 4.0 g/dl, respectively p=0.03). Conclusion:In this retrospective analysis of a large single institution MDS database, serum albumin is found to be an independent prognostic factor for OS and AML transformation in MDS patients. The prognostic power of low serum albumin was greatest among patients with Low/Int-1 IPSS risk group, but remained an independent variable across all risk groups. Serum albumin may also be a surrogate marker of general health, co- morbidities, and performance status.Table-1Baseline CharacteristicsSerum albumin ≤ 3.5 g/dlSerum albumin 3.6–4.0 g/dlSerum albumin > 4.0 g/dlAGE (mean)686865IPSS risk Group16 (11%)74 (23.5%)67 (25.6%)Low73 (50.3%)152 (48.3%)132 (49.4%)Int-139 (26.9%)72 (22.9%)57 (21.3%)Int-216 (11.7%)17 (5.4%)11 (4.1%)HighSerum Ferritin (mean)21741067805RBC Transfusion Dependency82 (49.7%)166 (47.6%)377 (47%) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Achievement of Red Blood Cell (RBC) Transfusion Independence with Azacitidine (AZA) Leads to Improved Survival In Patients with Higher-Risk Myelodysplasias Regardless of Baseline Transfusion Needs

AbstractAbstract 1856 Background:Sixty to 80% of patients (pts) with higher-risk myelodysplastic syndromes (MDS) require RBC transfusions to manage symptoms of anemia. Transfusion-associated complications include iron overload, transmitted infections, alloimmunization, and decreased overall survival (OS) (Cancer 2006;106:2087; JCO 2005;23:7594). The phase 3 AZA-001 study compared azacitidine (AZA) with conventional care regimens (CCR) in pts with higher-risk MDS (Lancet Oncol 2009;10:223). For all pts randomized to AZA, the reported median number of RBC transfusion events in the 56-day pre-randomization baseline (BL) period was relatively low (1.0, range 0 – 10), since 68/179 (38%) AZA-treated pts required no RBC transfusions (Haematologica 2009:Abstract 0813). However, pretreatment transfusion burden in the 111 RBC transfusion-dependent (TD) pts treated with AZA was substantial in many cases. It is unknown to what extent pts with higher RBC transfusion requirements at BL achieve transfusion independence (TI) and derive an OS benefit from AZA treatment. Aim:To assess OS in pts with higher-risk MDS treated with AZA in the AZA-001 study who were RBC TD at BL, based on pretreatment transfusion needs and posttreatment transfusion status. Methods:In AZA-001, 179 pts with higher-risk MDS (FAB-defined RAEB, RAEB-t, or CMML with >10% blasts, and IPSS risk Int-2 or High) were randomized to AZA (75 mg/m2/d SC × 7d q 28d). Of these pts, 111 (62%) were RBC TD at BL and 50 pts (45%) achieved TI during AZA treatment (Lancet Oncol, 2009;10:223). (Because so few pts who received CCR became TI on treatment [13/114, 11%], this analysis included only AZA-treated pts.) Erythropoietic stimulating agents were not permitted on study. BL RBC TD was defined as receiving ≥1 transfusion during the 56-day pre-randomization BL period, and per IWG 2000 criteria, TI on treatment required an RBC transfusion-free period ≥56 consecutive days. BL characteristics of pts who remained TD and of pts who achieved TI were evaluated and compared descriptively. Median OS was estimated using Kaplan-Meier (KM) methods for pts with pretreatment RBC transfusion burden of ≥1 (ie, all pts in the analysis), 1, or ≥2 transfusions (similar to IWG 2006 criteria for TD). The KM OS distributions for the on-treatment TI and TD groups were compared within in each cohort defined by pre-treatment RBC transfusion burden using the log-rank test. Results:Among the 111 AZA-treated pts who were RBC TD at BL, median age was 70 yrs (range 42 – 83), 77% were male, and 91% had ECOG performance scores of 0–1. Most pts (84/111, 76%) required ≥2 RBC transfusions in the 56-day pre-randomization BL period (Table). Median number of RBC transfusions at BL was 2 (range 1 – 10) in pts who achieved TI, and 3 (range 1 – 9) in pts who remained TD. Of pts who required ≥2 RBC transfusions at BL, 35 (42%) achieved TI. One-third (7/21) of pts with the highest RBC transfusion requirements at BL (≥5 transfusions) achieved TI during AZA treatment. Median OS was improved 3-fold for all cohorts of pts who achieved RBC TI with AZA, regardless of RBC transfusion burden at BL, compared with median OS in pts who remained TD (log-rank p<0.0001, all comparisons). Similarly, OS at 2 years in pts who achieved RBC TI during AZA treatment was 60–75% greater than OS at 2 years in pts who remained TD (Table). Of pts with the highest RBC transfusion needs at BL, 73% who achieved TI were alive at 2 years compared with only 12% of pts who remained TD. Generally, pts who remained TD on AZA were more likely to have WHO AML (20-30% blasts), higher LDH, and require platelet transfusions at BL than pts who achieved TI. However, pts who achieved TI on AZA more often had IPSS poor cytogenetics and 3 cytopenias at BL than pts who remained TD. Conclusion:A substantial proportion of pts with higher-risk MDS who required ≥2 RBC transfusions pretreatment achieved TI with AZA. TI in this analysis was associated with a marked improvement in OS. [Display omitted] Disclosures:Seymour:Celgene: Honoraria, Speakers Bureau. Santini:Celgene: Honoraria. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Merck: Honoraria; Cephalon: Honoraria; Novartis: Honoraria; J&J: Honoraria. Giagounidis:Celgene: Consultancy, Honoraria. Sanz:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Finelli:Celgene: Consultancy. Lucy:Celgene: Employment, Equity Ownership. Backstrom:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership.

Myelodysplatic Syndrom

AbstractAbstract 4980 Background::Myelodysplastic syndrome of 5q- type is generally considered to have a favorable course. But, even in the Lenalidomide era, it has been evidenced that it may be prone to transformation into more advanced disease, especially in patients who fail to reach transfusion independence or complete cytogenetic response or both. In this setting, it has been demonstrated that gain of chromosome 8 and loss of chromosome 7 are among the genetic cooperating events leading to clonal evolution. Treatment choices in such patients are not well codified and outcome is not predictable. Purpose:We combined 5′-Azacytidine to Lenalidomide as induction therapy to obtain the best response possible before reduced-intensity conditioning regimen (RIC) allogeneic hematopoietic stem cell transplantation for advanced disease developed from 5q- myelodysplastic syndrome. Methods:A female patient born in 1949 was diagnosed with myelodysplastic syndrome of the 5q- type in 1997. The disease remained stable and the patient free of transfusion requirement until 2004. From 2004 to 2007, due to symptomatic anemia, many treatment lines, based on erythropoiesis-stimulating agents, have been attempted, but without success. Transfusion in red blood cells became necessary once every four weeks in 2006. In 2007, she has been started on Lenalidomide 10 mg daily. A prompt hematologic improvement was observed at two months of treatment, inducing the disappearance of the macrocytic feature and freedom of transfusion requirement. However, cytogenetic control at twelve months on Lenalidomide showed the persistence of the 5q loss. In 2010, at 24 months on Lenalidomide, a recurrence of macrocytic and symptomatic anemia, with red blood cell transfusion dependence, along with neutropenia and thrombocytopenia, was observed. Cytological evaluation of the bone marrow was consistent with transformation into RAEB-1 whereas cytogenetic control showed the occurrence of two 5q- subclones: one expressing trisomy 8, another one displaying monosomy 7. Lenalidomide has been continued on a daily basis, in combination with 5′-Azacytidine which was administered at 75 mg/m2/day as 7-day cycles every 28 days. Results:Platelet transfusions were necessary during the first two cycles and red blood cell transfusions until the fourth cycle. Neutropenia persisted throughout the treatment duration, with temporary recovery obtained under periodic courses of G-CSF. No infectious complication has been observed. At day 1 of the sixth cycle, bone marrow has been reevaluated. On cytological evaluation, the blast excess has disappeared, dropping from 8% to 1%, nuclei hypolobulation was still present in less than 10% of the megakaryocytic lineage and some dysplastic features were still evident in less than 10% of the erythroblastic and granulopoietic lineages. Conventional cytogenetic evaluation and FISH showed the complete disappearance of the 5q- clone and subclones. Conclusion:We found that combining Lenalidomide with 5′-Azacytidine may be an effective therapeutic choice in myelodysplastic syndrome of 5q- type previously treated with Lenalidomide alone and transformed into advanced disease. It may allow for inducing cytological and cytogenetic complete response prior to RIC allogeneic hematopoietic stem cell transplantation in eligible patients. Disclosures:No relevant conflicts of interest to declare.