Erythroid Stimulating Agents Research Articles

Hematological Response to Frontline Treatment in Lower Risk Myelodysplastic Syndromes (LRMDS) Is Associated with Better Overall Survival

Background The majority of LRMDS patients (pts) (70%) do not progress but unfortunately succumb to complications related to cytopenia, namely anemia and red blood cell transfusion dependency (RBC-TD) or their interplay with co-morbidities. RBC-TD is associated with worse outcome reflecting bone marrow failure and long-term sequela of RBC-TD. There is growing evidence that response to treatment and RBC transfusion independence (TI) are associated with favorable outcome. In lieu of 2 recent randomized clinical trials demonstrating efficacy of luspatercept & imetelstat in LRMDS, we assessed the impact of response to sequential lines of treatment in LR-MDS on overall survival (OS) to guide our treatment choices and to determine whether erythroid stimulating agents (ESA) should still be our 1 st line of therapy. Methods We included LRMDS pts (IPSS-R very low & low) from Moffitt Database who received ESA as frontline therapy (FL) and assessed subsequently outcomes with second line (SL) therapy (SOC or clinical trial). We excluded MDS/MPN and del5q pts. We also excluded all pts who eventually progressed to either higher risk MDS or AML to better reflect the majority LRMDS in that disease state. We assessed details of FL and SL. Pts who received FL & SL were then divided into 4 groups based on response to FL and SL therapy: group 1 (no/no), group 2 (no/yes) with response only to SL, group 3 (yes/no) response to FL only, and group 4 (yes/yes) with response to both lines of therapy. Response was defined as hematological improvement (HI) with ≥1.5 g/dl Hgb increase in non-TD pts and RBC-TI in TD pts at baseline for at least for 8 weeks. We compared median OS (mOS) among those groups. Results There were 603 LRMDS pts who met eligibility criteria and received ESA as FL (Table-1); 43% were RBC-TD, mean serum EPO was 132 (n=211 pts), 69% received epoetin, 17% darbepoetin and 14% with G-CSF. HI was observed in 42% of pts with no difference among ring sideroblasts (RS) +/- (46% vs 40%, p =.12). Response was higher among non-RBC-TD (52% vs 31%, p< .001). The median time to start ESA was 1.2 mo (0-249). The median time on ESA therapy was 11 mo (.4-213). 331 pts (55%) received SL which included HMA 43% (n= 142), lenalidomide 39% (n=130), luspatercept 7% (n=24), ATG 2% (n=8), investigational agent 4% (n=14), and other 4% (n=13) . The HI rate was 27% (91/331). No difference in HI based on RS nor RBC-TD was observed. The median duration on SL treatment was 6 mo (.1-93). 170 pts (28%) received 3 rd line of therapy with 7% HI, 88 pts (15%) received 4 th line of therapy with 3% HI and 39 pts (7%) had 5 th line of therapy with 2% HI. Among the 331 pts who received at least FL and SL, pts were divided into 4 groups based on response to (methods, table-2), the mOS was 114 mo among Yes/Yes response group, 103 mo among yes/no group, 97 mo no/yes and 64 mo among no/no ( P=.007; Figure-1). Response to FL was significantly associated with better OS after adjusting for RS (HR .74 ,95% CI .55-.99, p=.043). Conclusions Only half of patients who receive ESA as FL therapy for LRMDS received any subsequent therapies. Response rates were highest with ESA as FL than any SL therapy. HI with FL and/or SL is associated with improved OS. Lack of response to first line of therapy is associated with worse OS. Responses beyond SL were rarely observed. Identifying and moving agents with high HI rate as FL therapy and or selecting option based on predictors of best chance of response to a specific treatment as FL may lead to better overall survival.

Improved Overall Survival Among Luspatercept Responders and Predictors of Response

Introduction Luspatercept (luspa) is a first-in-class erythroid-maturation agent approved for red blood cells transfusion dependent (RBC-TD) lower risk myelodysplastic syndrome (LR-MDS) with ring sideroblast (RS) based on MEDALIST clinical trial. We aimed to explore impact of luspa on overall survival (OS) and predictors of response in a large cohort of pts treated with luspa, collected from Moffitt Cancer Center (MCC) and from Fondazione Italiana Sindromi Mielodisplastiche (FISiM). Methods We evaluated all pts with LR-MDS-RS treated with luspa from MCC cohort since FDA approval, and from a multicenter observational trial of FISiM for pts treated on a compassionate use program . Baseline RBC transfusion burden (TB) was defined as: non-transfusion dependent (NTD) (0 units in 8 weeks prior luspa), low TB (LTB) (1-5 units/8 weeks ) and high TB (HTB) (≥ 6 units/8 weeks). A hematological response (HI) was defined as an (i) objective Hgb increase of > 1.5 g/dl in NTD, and (ii) RBC-TI with Hgb increase of 1.5 g/dl, or RBC-TI without Hgb 1.5 g/dl increase, or >50% reduction in RBC TB among RBC-TD. Somatic mutation (MT) data were available for 137 pts. Results Between January 2020 and March 2023, 331 pts were treated with Luspa (Table-1). The median age was 69 years; 308 pts (93%) had MDS-RS, 86,1% were intermediate, low or very low risk MDS by R-IPSS and 82% (105/128) were moderate low (ML), low (L) or very low (VL) by IPPS-M. SF3B1 MT was detected in 86.3% (120/139) with a median VAF of 37.7. The mean Hgb level was 7.97 g/dl and 93.7% were RBC-TD. Majority had prior erythroid stimulating agents (ESA) (93.6%). In the MCC cohort 42.9% (52/121) had prior hypomethylating agents (HMA) therapy, and 31.4% (38/121) had prior lenalidomide (len). With a median follow up of 14.6 mos from starting luspa treatment, the median OS was not reached (NR) among responders to luspa compared to 24.5 mos for non-responders (p <.001) (Figure-1). The median OS benefit was more pronounced among pts with RBC-TI and Hgb> 1.5 g/dl increase compared to other categories of response. In the NTD group at baseline, the median OS among luspa responders was NR compared to 22.7 mos among non-responders (P< .001). In the LTB group at baseline median OS was NR as well among luspa responders compared to 29.9 mos in non-responders (p=.002) and finally among HTB group at baseline, the median OS among luspa responders was 35.4 mos compared to 21.2 mos in non-responders (p=.007). In multivariable analysis adjusting for IPSS-M and baseline RBC-TD, response to luspa was independently associated with improved OS, HR .39 (95% CI .18-.83), p= .015 The overall HI rate to luspa was 40.6% (134/330) (Table-1), 85% of pts needed dose escalation, HI correlated with baseline RBC-TB where 80% (16/20) NTD, 60.2% (65/108) LTB and 41.8% HTB (77/184) achieved HI respectively, p< .001. By IPSS-M, there was a trend for lower HI with higher risk disease (100% in VL, 60.3% in L, 36.7% in ML, 56.3% in MH, 16.7% in H risk pts, p=.051). There was a mild trend for higher response among SF3B1 MT pts compared to wild type, 54% (64/119) versus 42% (8/19), p=.34.The segregation of SF3B1 MT cases into three independent groups based on IPSS-M, showed that HI rate was better in SF3B1 β ( SF3B1 and any gene from BCOR, BCORL1, NRAS, RUNX1, SRSF2 or STAG2) and SF3B1 α (as any other mutant) than SF3B1 5q(concomitantpresence with isolated del5q): 50% (7/14), 58.8% (57/97), and 0% (0/5) respectively, p=.03. Among SF3B1 5qpts, 4 had been treated with len before luspa and only 1 had achieved an HI with prior len. Among pts with SF3B1 MT, we observed a trend for higher response in pts with the hotspot K700E, 62.7% (37/59) vs 47.4% (27/57) in non-K700E, p=.097. In pts with SF3B1 MT, divided by median VAF, we observed a trend for better HI with VAF was >38, 63.5% (33/52) vs 45.3% (24/53), p=.062. Among responders, the median duration of response was 14.1 mos. As of last follow up, 85% pts (191/224) discontinued treatment. Reason of discontinuation was lack of response in 126 pts, loss of response in 26 patients and adverse events in 6 pts. The most common reported adverse events were fatigue (n=10), GI symptoms (n=4), shortness of breath and arthralgia (1 each). Conclusions Our RWD in the largest luspa treated cohort demonstrates OS benefit to luspa response. Low baseline RBC-TB dependency, lower risk IPSS-M, SF3B1 MT, SF3B1-K700E mutation and SF3B1 α co-mutations correlated with higher response rates. Our data emphasizes the impact of RBC-TI in LR-MDS.

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

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

MDS-223: Response to Erythroid Stimulating Agents (ESA) and Flow Cytometric Characteristics of Bone Marrow Erythroid Precursors in IPSS-R Lower-Risk Myelodysplastic Syndrome Patients

Context: Standard treatment of anemia in lower-risk myelodysplastic syndromes (LR-MDS) is based on erythropoietic-stimulating agents (ESAs), but some patients are primary refractory (PR) or lose response (secondary refractory, SR). High serum erythropoietin (sEPO) is the main negative predictor, and treatment of ESA-resistant anemia is challenging, so more predictors are needed. EPO promotes differentiation of committed erythroid cells (COMe) into erythroid precursors (EP), constituted by early (EEP) and late (LEP) precursors. Flow cytometry (FC) can characterize COMe and EP. RED score is an FC parameter that assesses dyserythropoiesis. Objective: We aimed to correlate COMe, EP, and RED score with response to ESAs, WHO category, and sEPO in 44 anemic LR-MDS patients. Design: We evaluated 10 negative controls, 17 PR patients, 17 SR patients, and 10 long responders (LR, response duration >24 months). Fifty-nine percent had sEPO 500 mU/mL(H-EPO); 23% had single lineage dysplasia (MDS-SLD), 34% multilineage dysplasia (MDS-MLD), 23% ring sideroblasts (MDS-RS), and 20% deletion of 5q (MDS-5q-). FC analysis was performed on bone marrow aspirates for all subgroups at diagnosis and within SR subgroup at loss of response to ESA (SRII). We used anti-CD34, CD36, CD105, CD117, CD33, CD71, and CD45 antibodies to identify COMe, total erythroid cells (TOTe), and EP. Coefficients of variance of CD71 and CD36 were used to calculate RED score. Results: TOTe and COMe were increased in LR-MDS compared to controls (p=0.013 and p=0.04, respectively), with the exception of MDS-5q- cases. In the PR subgroup, LEP were increased and COMe were reduced compared to LR. In the SRII group, COMe were lower than at diagnosis (p=0.039). RED score was higher in PR compared to responders (p=0.011). MDS-5q- cases showed reduced TOTe (p=0.047), while MDS-RS cases had higher LEP and RED score (p=0.008 and p=0.012, respectively). Finally, LEP were increased in the H-EPO group compared to L-EPO (p=0.023). Conclusions: These data suggest that COMe seem to be positively associated with ESA response, whereas higher LEP and RED score are negatively associated and also correlate with MDS-RS and H-EPO. Finally, MDS-5q- cases displayed fewer TOTe and COMe, suggesting premature apoptosis of erythroid precursors.

Poster: MDS-223: Response to Erythroid Stimulating Agents (ESA) and Flow Cytometric Characteristics of Bone Marrow Erythroid Precursors in IPSS-R Lower-Risk Myelodysplastic Syndrome Patients

Poster: MDS-223: Response to Erythroid Stimulating Agents (ESA) and Flow Cytometric Characteristics of Bone Marrow Erythroid Precursors in IPSS-R Lower-Risk Myelodysplastic Syndrome Patients

U2AF1 and EZH2 Mutations Are Associated with Non-Immune Hemolytic Anemia in Myelodysplastic Syndromes

Introduction Hemolysis is a well-recognized clinical observation in a subset of myelodysplastic syndromes (MDS) patients (pts). However, the clinical consequence of hemolysis and the associated molecular phenotype in MDS is not well described in the literature. Nonimmune hemolysis in MDS is often attributed to ineffective intramedullary erythropoiesis or acquired hemoglobinopathies that have been described in rare cases of MDS. In this study, we report the prevalence of hemolysis among MDS pts, their clinical and genomic characteristics and its impact on outcomes. Methods We identified all pts in our institutional MDS database who had serum haptoglobin measured at time of diagnosis or referral. We considered serum haptoglobin &amp;lt; 10 mg/dl as a surrogate marker for intravascular hemolysis. We compared the baseline characteristics, response to treatment, and overall survival (OS) in those with hemolysis (haptoglobin &amp;lt; 10 mg/dl) to those in the non-hemolysis group. Further, we explored the mutational landscape among pts with hemolysis compared to the non-hemolysis group. Results Among 519 pts in our database with a known serum haptoglobin at first referral or diagnosis, 54 pts (10%) had serum haptoglobin &amp;lt; 10 mg/dl (the hemolysis group). The baseline characteristics were similar among the two groups except for a slightly younger age and lower platelets count in the hemolysis group. Other laboratory markers associated with hemolysis such as total bilirubin and LDH were significantly increased in the hemolysis groups. However, no difference was seen in coombs test results. Only 13% versus 9% were Coombs positive suggesting that hemolysis in MDS is typically not immune mediated (table 1). The median OS was 31 months versus 39 months among pts with hemolysis and no hemolysis respectively, (p=.98). There was a trend of inferior survival among pts with hemolysis in the low and intermediate risk revised IPSS (R-IPSS) risk groups. The median OS was 44 months with hemolysis compared to 89 months with no hemolysis in low risk R-IPSS (p=.2) and 19 months versus 34 months in intermediate risk group. (p=.7) The hematological improvement (HI) rate using erythroid stimulating agents (ESA) was 16% (3/19 pts) in the hemolysis group compared to 30% (39/130 pts) in the non-hemolysis group. (p=.2) The HI+ best response with hypomethylating agent (HMA) was 70% (22/31) compared to 45% (127/280) among hemolysis and non-hemolysis groups respectively, (p=.05). Table-2 summarizes the somatic mutations landscape between the hemolysis and non-hemolysis groups. U2AF1 and EZH2 hotspot mutations were statistically significantly more common among hemolysis group. Out of the 16 pts with U2AF1 mutations, 15 (94%) harbored a mutation at serine 34 (S34) in the hemolysis group while only 22 of 55 (40%) cases with U2AF1 mutation had an S34 hot spot mutation in the non-hemolysis group suggesting that the association between U2AF1 and hemolysis is allele specific. (p .0001) Conclusion Non immune hemolysis was observed in 10% of MDS patients. Inferior survival trends were observed among lower risk MDS patients with hemolysis. A decreased response rate to ESA and higher responses to HMA were also observed in the hemolysis group. U2AF1 mutation was observed in 30% of patients with hemolysis and occurred almost exclusively at the S34 hot spot. Our data suggest that nonimmune hemolysis is associated with allele specific somatic mutations and associated with key clinical outcomes. Future work will explore the contribution of altered splicing to these acquired hemoglobinopathies. Disclosures Komrokji: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; Geron: Honoraria. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding.

Erythropoietin Treatment Is Associated with Decreased Blood Glucose Levels in Hematologic Patients

Background: Erythroid stimulating agents (ESAs) have pleiotropic effects, and in animal and human studies those exposed to high erythropoietin had lower blood glucose. Objective: To determine the association between ESA and glucose in anemia-treated patients with myelodysplastic syndromes (MDS) or multiple myeloma (MM). Patients and Methods: Patients’ glucose levels were compared while on to while off ESA, and all served as their own controls. To test the association between ESA and blood glucose, we employed a linear mixed model, accounting for variability in the number of measurements for each patient. Results: Charts of 20 patients were reviewed. Mean age was 77 ± 9.8 years (range 50–91). Thirteen patients had MDS, and 8 had MM (1 with both). Glucose (mean ± standard error of the mean) was 116.38 ± 5.21 mg/dL without ESA, as opposed to 105.64 ± 5.11 mg/dL with ESA (p < 0.0001). The 3 diabetic and 5 steroid-treated patients also demonstrated reduced glucose by approximately 19 mg/dL with ESA (p = 0.003 and p = 0.0001, respectively). There was no difference in collective hemoglobin levels between the 2 groups. Conclusion: ESA treatment for anemia is associated with lower blood glucose in hematologic patients. In those who also have diabetes mellitus, ESA might contribute to glucose control, and even to hypoglycemia. Glucose monitoring is thus advised. Further studies with both diabetic and nondiabetic patients are needed to clarify this association and underlying mechanisms.

Pro-inflammatory proteins S100A9 and tumor necrosis factor-α suppress erythropoietin elaboration in myelodysplastic syndromes

Accumulating evidence implicates innate immune activation in the pathobiology of myelodysplastic syndromes. A key myeloid-related inflammatory protein, S100A9, serves as a Toll-like receptor ligand regulating tumor necrosis factor-α and interleukin-1β production. The role of myelodysplastic syndrome-related inflammatory proteins in endogenous erythropoietin regulation and response to erythroid-stimulating agents or lenalidomide has not been investigated. The HepG2 hepatoma cell line was used to investigate in vitro erythropoietin elaboration. Serum samples collected from 311 patients with myelodysplastic syndrome were investigated (125 prior to treatment with erythroid-stimulating agents and 186 prior to lenalidomide therapy). Serum concentrations of S100A9, S100A8, tumor necrosis factor-α, interleukin-1β and erythropoietin were analyzed by enzyme-linked immunosorbent assay. Using erythropoietin-producing HepG2 cells, we show that S100A9, tumor necrosis factor-α and interleukin-1β suppress transcription and cellular elaboration of erythropoietin. Pre-incubation with lenalidomide significantly diminished suppression of erythropoietin production by S100A9 or tumor necrosis factor-α. Moreover, in peripheral blood mononuclear cells from patients with myelodysplastic syndromes, lenalidomide significantly reduced steady-state S100A9 generation (P=0.01) and lipopolysaccharide-induced tumor necrosis factor-α elaboration (P=0.002). Enzyme-linked immunosorbent assays of serum from 316 patients with non-del(5q) myelodysplastic syndromes demonstrated a significant inverse correlation between tumor necrosis factor-α and erythropoietin concentrations (P=0.006), and between S100A9 and erythropoietin (P=0.01). Moreover, baseline serum tumor necrosis factor-α concentration was significantly higher in responders to erythroid-stimulating agents (P=0.03), whereas lenalidomide responders had significantly lower tumor necrosis factor-α and higher S100A9 serum concentrations (P=0.03). These findings suggest that S100A9 and its nuclear factor-κB transcriptional target, tumor necrosis factor-α, directly suppress erythropoietin elaboration in myelodysplastic syndromes. These cytokines may serve as rational biomarkers of response to lenalidomide and erythroid-stimulating agent treatments. Therapeutic strategies that either neutralize or suppress S100A9 may improve erythropoiesis in patients with myelodysplastic syndromes.

Patient Blood Management.

Patient Blood Management is a book that considers a concept that transcends transfusion medicine. It is solely aimed at disease management rather than focusing on a single therapeutic modality, transfusion.The foreword by Denton A. Cooley sums up the essence of patient blood management (PBM) by stating that it is a “compelling concept to preempt anemia, correct bleeding disorders, and minimize blood loss.” He continues by stating that this is an evidence-based approach that has yielded the desired outcomes of improved patient’s health and reduced resource utilization. The preface, written by the three editors, expands on the concept and focuses on the intent of this PBM “book” by addressing the multiprofessional and multidisciplinary approach that spans a multitude of topics from preoperative anemia management to management of patients for whom blood is not an option. Although referred to as a book, this publication is more appropriately described as a “manual” on PBM. Recognizing the burgeoning data on patient outcome associated with a large number of possible interventions (beyond the current single approach—transfusion) applied together or as a single modality, this bundled care includes identification, diagnosis and treatment of anemia, blood conservation both surgical and phlebotomy, and “tolerating” anemia, while therapeutic modalities other than transfusions are implemented effectively. The manual’s content would encourage the reader to explore elsewhere for more detailed data and newer data that are constantly being added to the literature.The editors have gathered a long list of both new and senior contributors to PBM. Although these contributors have been asked to address specific topics, their knowledge of PBM extends far beyond the contributions seen in this manual.Knowing that this publication is an expansion of the original German version of this book, the extensive list of topics is impressive and covers most if not all related PBM topics and issues.To the casual reader, the history and development of PBM and additional material on the future of PBM in the new healthcare milieu would be of value. These items are not included in this book. While they are not necessarily needed in this manual, they would help explain the evolution of PBM and are addressed in other PBM textbooks. Offering the long view in medicine can usually explain the present and help form the future.Each of the chapters is well organized, and for the most part, presents the current thinking in PBM. Although weighted toward transfusion medicine, the editors’ reminder to focus on patients and improved outcome resonates throughout the manual.Despite overall enthusiasm expressed for PBM, some sections of the text offer recommendations that can be challenged since significant controversy exists on these topics. As an example, the sections on pharmacologic agents, parenteral iron, and erythroid-stimulating agents represent conclusions on the basis of old data that have been challenged and are in need of fresh interpretation. Other recommendations ignore the inconsistency of the data used to make a recommendation such as those present in section “transfusion guidelines.” In regard to transfusion indication, the threshold (“trigger”) in patients with coronary artery disease has not been established. Although addressed in the text, table 5.2 appears to present the information in what seems to be a more conclusive manner. Regardless, most of the recommendations are sound and useful.Although open to all disciplines of clinical medicine, the surgical approach to PBM dominates throughout the book. One can extrapolate to other patient populations since PBM is written as disease management of entities such as anemia, coagulation defects, and other hematologic conditions rather than concentrating solely on transfusion as a therapy.Caught between informative and instructive, the manual serves best as an initial overview of each of the topics. It does not lend itself as a guide to therapy nor does it fully expose all of the data and challenges of PBM in an in-depth fashion. The chapters address each topic in a thoughtful and balanced fashion without exposing areas on controversy in any details.There is no question in this reviewer’s mind that the primary audience is anesthesiologists and surgeons followed by internal medicine and others in related fields. Reading through the stimulating chapters and sections, one quickly finds oneself seeking to attain more information—which can be found, for example, in the section on PBM at www.blood.gov.au—to enhance their knowledge and repertoire on PBM. This manual is an essential step in increasing awareness on PBM and helps organize the topic, resulting in easy reading and, in turn, better patient care and outcome.

Immune Dysfunction in Patients with MDS Is Partially Corrected in EPO-Treated Patients: Differences According to WHO Classification

Background: The immune system has been shown to be involved in the pathogenesis of myelodysplastic syndromes (MDS), and is also affected by the disease. Recombinant erythropoietin (rHuEPO), or in general, erythroid stimulating agents (ESAs) have become a standard treatment for anemic patients with MDS. They were found to improve anemia, quality of life, and possibly survival. We have previously demonstrated that EPO has effects on cellular and humoral immunity and specifically, on immune function in patients with multiple myeloma (MM). Here we report our findings demonstrating the effect of ESAs on T cell (CD4+, CD8+ and CD4+CD25+) number and function in patients with MDS.Patients and Methods: We examined three groups: healthy subjects ('Control', 20 participants), MDS patients without ESA treatment ('MDS', 13), and MDS patients treated with an ESA ('MDS+EPO', 17). All diagnosed patients gave informed consent as approved by our IRB. Cell numbers were evaluated with flow cytometry. In a subset of patients, cell activation was assessed in response to phytohemagglutinin (PHA) by examining CD69 expression in both CD4+ and CD8+ cells. The co-stimulatory marker, CD28, and the inhibitory marker CTLA-4 (CD152) were evaluated as well. We also examined World Health Organization (WHO) subgroups, refractory anemia (RA) and RA with ringed sideroblasts (RARS) versus more advanced disease.Results: CD4+ and CD8+ T cell levels are reduced and increased respectively in MDS patients compared to control, and these changes are reversed in MDS+EPO (Table 1, CD4+, p<0.01; CD8+, p=0.05). The CD4+:CD8+ ratio (Table 1) is reduced and nearly equalized in MDS (1.16), but approaches that of the control (2.24) in MDS+EPO (1.94). CD4+CD25+ T cell numbers (including regulatory T cells), were lower in MDS patients and improve in the MDS+EPO group (Table 1). In vitro activation of T cells (CD4+CD69+ and CD8+CD69+) achieves an approximately 15-fold increase in healthy subjects. MDS patients without EPO sustained only a 7.17 fold increase in CD4+ activation versus 13.64 fold for the MDS+EPO group (p<0.01); for CD8+ T cells, 10.20 fold (MDS) versus 18.56 fold (MDS+EPO, p<0.01). The expression of the co-stimulatory marker CD28 was decreased in both CD4+ and CD8+ T cells in MDS, and approached normal in MDS+EPO in CD4+ T cells (Table 1). There was no significant change in inhibitory CTLA-4 (CD152) expression among the groups (not shown). Subgroup analysis demonstrated that ESA has a similar effect on CD4+ and CD8+ cells and their ratio in both RA/RARS and more advanced disease, similar to those of the whole cohort (Table 2, green). On the other hand, some parameters were affected by ESA only in one subgroup (Table 2, blue): The ESA effect on CD4+CD25+ cells was evident only in patients with advanced disease (Table 2, blue). ESA affected CD4+ and CD8+ cell stimulation (CD69) in RA/RARS, similar to that seen in the whole cohort (Table 2, blue). Of note, in more advanced disease, CD4+ and CD8+ cells achieved stimulation in the MDS group not treated with ESA, with no difference between MDS and MDS+EPO. This finding needs to be further addressed in larger cohorts and with additional markers of activation.Conclusions: MDS patients display T-cell abnormalities that are improved upon EPO treatment. MDS is a heterogeneous disease where the immune system both affects and is affected by the disease. As such, treatment with ESAs might ameliorate not only the anemia, but also the immune deficiencies and perhaps the disease itself. Future studies will clarify the immunomodulatory role of ESA in the various stages of MDS. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Optimal Treatment Order of Lenalidomide and Hypomethylating Agents for Lower-Risk Myelodysplastic Syndromes: A Report on Behalf of the MDS Clinical Research Consortium

▪IntroductionWhile lenalidomide (LEN) is the standard of care for treatment of red blood cell (RBC) transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS) with chromosome 5q deletion (del 5q), it is widely used off-label in the non-del5q setting. In the MDS-002 and MDS-005 studies, 26% of TD non-del5q LR-MDS patients became RBC transfusion independent after LEN treatment. National Comprehensive Cancer Network (NCCN) clinical guidelines list LEN as a second line treatment option for TD anemia in lower-risk non-del 5q MDS after hypomethylating agents (HMAs). Thatrecommendationhas led to wide use of HMAs as frontline therapy after erythroid stimulating agents (ESA) failure in LR-MDS. The response rate to LEN after HMA failure, however, is not known, as MDS-002 and MDS-005 excluded patients previously treated with HMAs. To assess the best order of LEN and HMA in optimizing response potential in lower-risk MDS, we examined response rates to each drug when treatment order (LEN followed by HMA or HMA followed by LEN) differed.MethodsWe identified patients with LR- MDS (International Prognostic Scoring System (IPSS) low or intermediate-1 (int-1) risk groups) within the MDS Clinical Research Consortium database who received both LEN and HMA as first or second line therapy after ESA failure or patients who had low chance of response to ESA. We excluded patients with isolated del5q or del q + one additional cytogenetic abnormality. The primary objective was to compare rates of erythroid hematological improvement (HI-E), defined using 2006 International Working Group criteria (IWG 2006), between patients who received LEN as first line therapy followed by HMA as second line (LEN 1st line group) versus those who received LEN as second line therapy after HMA (LEN 2nd line group).ResultsWe identified 144 patients who received both HMA and LEN as first and second line therapies: 80 patients were in group 1 (LEN 1st line) and 64 patients were in group 2 (LEN 2nd line). Baseline characteristics between the two groups are summarized in Table 1. There were no statistically significant differences between the 2 groups.The rate of HI-E was 20% (16/80) for the LEN 1st line group compared to 11% (7/64) in the LEN 2nd line group. (p=.046). There were no differences in response rates to HMA between the two groups: In the LEN 1st line group, response to 2nd line HMA was 30% (24/78) compared to 39% (25/64) for those who received HMA as first line (p=.2).There was no difference in overall survival (OS) between the two groups, The median OS was 79 months (mo) the LEN 1st line group compared to 61 mo in Len 2nd line group (p= .4). The rate of AML transformation was 9% in Len 1st line group compared to 22% in Len 2nd line group rate (p=.03). There was no difference in AML free survival (78mo versus 61mo respectively, p=0.4). In multivariable analyses adjusting for age, sex, and IPSS-R order of treatment still did not impact overall survival.ConclusionLEN yields a higher rate of HI-E in LR- MDS when used as first line therapy, but responses to HMAs were similar when used before or after LEN. The rate of AML transformation was lower when LEN was used as first line. The order of treatment does not impact overall survival. Lenalidomide should be used prior to HMA if it is to be considered for treatment of anemia in non-del5q LR-MDS. [Display omitted] DisclosuresKomrokji:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy; Boehringer-Ingelheim: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding.

Racial Disparities in Patients with Myelodysplastic Syndrome (MDS): Clinical and Molecular Depiction

▪BackgroundLittle is known about racial disparities amongst patients with MDS. The incidence of MDS is higher in Caucasians, who represent the majority of patients included on clinical trials. We explored the differences in disease features and outcomes between Caucasians, African Americans (AA), and Hispanics.MethodsUsing our MDS database, patients with a diagnosis of MDS were identified and categorized into the aforementioned racial groups. We compared baseline characteristics, risk stratification, treatment, and overall survival (OS). Data on recurrent somatic mutations (SM) by next generation sequencing was available for 349 patients and compared between the groups.ResultsAmong 2538 MDS patients, 63 (2%) patients were AA and 107 (4%) were Hispanic. Table-1 summarizes baseline characteristics. In Hispanic patients, 42% were <60 years, 30% had t-MDS, and the mean platelet (plt) count was lower. In AA patients, the mean hemoglobin (hgb) was lower and the serum EPO was higher. More Hispanic and AA females were diagnosed with MDS compared to Caucasians.A higher percentage of Hispanic patients underwent allogenic stem cell transplant (33% versus 13% in Caucasian and 10% in AA) (p= <.005). There was no difference in treatment with hypomethylating agents or lenalidomide. Only 1 AA and 7 Hispanic patients were enrolled on clinical trials, compared to 113 Caucasians. Among patients evaluable for response, none of the 7 AA patients treated with erythroid stimulating agents (ESA) had a hematologic improvement, compared to 10% among Hispanics and 39% in Caucasians.The median OS was 37, 30, and 47 months (mo) among Caucasian, AA, Hispanic (p=0.022). Among patients with low/int-1 risk IPSS, the median OS was 55, 45, and 81 mo respectively (p=0.1), and among int-2/high risk IPSS, the median OS was 17, 17, 26 mo respectively (p=0.1). There was no difference in the rate of AML transformation.Data on 349 patients who had recurrent somatic mutation (326 Caucasian, 8 AA, and 15 Hispanic) were reviewed. The most common somatic mutations in Caucasian patients were TET-2 30%, ASXL-1 18%, SF3B1 14%, DNMT3A 14%, SRSF2 11% and p53 11%. In AA, the most common SM were IDH1 25%, EZH2 25%, DNMT3A, ASXL-1, TP53, ETV6, NRAS, in13% each. The most common SM in Hispanic patients were SRSF2 20%, RUNX-1 20%, TET-2, IDH-2, UA2F1, ASXL-1 and p53 in 13% for each. No splicing mutation or TET-2 was observed among AA patients. There was a higher trend for IDH-1 mutation among AA (25%) vs 6% in Caucasian and none in Hispanic (p=.07).ConclusionWe observed differences in several baseline characteristics between races. Hispanic patients were younger, had more therapy related MDS and thrombocytopenia. AA patients had higher serum EPO levels and decreased response to ESAs. Hispanic patients had better overall survival, especially in lower risk disease. Preliminary data suggests potential racial differences in recurrent somatic mutations observed in MDS. [Display omitted] [Display omitted] DisclosuresSweet:Novartis: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Incyte Corporation: Research Funding; Karyopharm: Honoraria, Research Funding. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Recombinant Erythropoietin and Darbepoetin Alpha Exert a Similar Dose-Dependent Osteopenic Effect Which May Advocate for "Start Low, Go Slow" Dosing Strategy in Clinical Practice

Background and rationale: Identifying risk factors for bone loss is of utmost importance in the prevention of osteoporotic bone fractures. We and others have recently described the dramatic erythropoietin (EPO)-induced bone loss. Recombinant EPO and its long-acting derivative, darbepoetin alpha (DA), are frequently and interchangeably used in clinical practice for similar indications including diseases (e.g. multiple myeloma) in which bone mass may be compromised already, as a part of the disease process. Here, we examined in a murine model, the dose response to the erythroid stimulating agents (ESA) EPO and DA, in the erythroid and bone compartments.Methods:C57B6/JRcchsd 9-week old female mice were treated for two weeks with either EPO or DA using two dose intensities. EPO and DA were administered subcutaneously thrice or once weekly, respectively, for a total weekly dose of 27IU/mouse or 540IU/mouse, hereafter defined correspondingly as intermediate (ID) and high dose (HD) subgroups. Bone morphometry of the distal femoral metaphysis was assessed using microCT. Flow cytometry was used for immunophenotyping of bone marrow (BM) cells. One-way ANOVA was used to compare variables among the treatment groups.Results: First, we found that ID-DA induced bone loss to a similar extent as ID-EPO as reflected by a significant (p<0.05) reduction in the trabecular bone fraction (BV/TV, -31%), bone mineral density (BMD, -53%) and trabecular number (Tb.N, -17%). HD-EPO and HD-DA resulted in even higher degrees of bone mass reduction: -48% in BV/TV and -57% in Tb.N (p<0.01 for both). Noteworthy, despite modestly superior gain (~10%) in hemoglobin level (21 and 22.5 mg/dl p< 0.01 in HD-EPO and ID-EPO, respectively; mean hemoglobin levels in diluent-treated mice was 16.4), administration of HD-EPO resulted in substantially higher bone loss compared to ID-EPO. This was manifested in ~80% further reduction in BV/TV as well as 2.5-fold further drop in Tb.N as demonstrated by ΔBV/TV and ΔTb.N (i.e. reduction relative to the control) of 48% versus 27% and 57% versus 23%, respectively (p<0.02 for both parameters). By flow cytometry EPO, but not DA, induced a 35% reduction in alkaline phosphatase positive CD11b negative (ALPL+/CD11b-) preosteoblast population in the bone marrow (p<0.01). The percentage of CD115+ BM cells, containing osteoclast precursors, was increased by 26-30% following both EPO and DA treatments (p<0.05 for EPO/DA versus control and non-significant p>0.05 for EPO versus DA groups). In view of the established role of B cells in bone metabolism, we determined the effects of EPO and DA on BM B cell compartment. HD-EPO but not ID-EPO induced a "maturation arrest"-like state in the bone marrow B cell population, increasing the proportion of B220+/CD19-/CD43high/IgM- pre-pro-B two-fold and B220+/CD19+/CD43high/IgM- pro-B cells 2.8-fold (p<0.05) while reducing the proportion of B220+/CD19+/CD43low/IgM+immature B cells by 2.3-fold (p<0.01). Intriguingly, these alterations were not noted following DA treatment.Conclusion:Applying clinically comparable dosing regimen, both recombinant EPO and DA exert a similar, dose-dependent bone loss, not directly proportional to the erythroid response. However, DA, in contrast to EPO, spares the preosteoblast and bone marrow B cell populations. These finding suggest a different mechanism of action of these closely related ESA preparations on the skeletal and immune systems thus warranting further exploration. Finally, our findings advocate for initiating and maintaining patients with the lowest possible doses of EPO/DA to minimize untoward skeletal and other extra-erythropoietic effects, while achieving the desired correction of anemia.This study was supported by a grant from the Israel Cancer Association to DN, YG and MM. DisclosuresNo relevant conflicts of interest to declare.

The Proinflammatory Protein S100A9 Suppresses Erythropoietin Elaboration in Patients with Myelodysplastic Syndromes

Introduction: Accumulating evidence implicates innate immune activation in the pathobiology of myelodysplastic syndromes (MDS) and its inflammatory bone marrow microenvironment. Excess elaboration of S100A9 accompanied by secondary induction of TNFα and IL-1β, characterize the inflammatory milieu found in lower risk MDS. Erythroid stimulating agents (ESA) and lenalidomide (LEN) are erythropoietic promoters with known anti-inflammatory properties. To date, the role of such inflammation parameters in endogenous erythropoietin (Epo) regulation and response to such treatments has not been investigated. Herein, we investigated the role of these inflammatory cytokines on Epo elaboration and response to ESA and LEN in MDS.Materials and Methods: The HepG2 hepatoma cell line was used to investigate Epo elaboration in vitro. Serum collected from 311 MDS patients from 3 centers (AOU Careggi, University of Firenze; Saint Louis hospital in Paris; H. Lee Moffitt Cancer Center in Tampa) were investigated. 125 were obtained prior to ESA treatment and 186 prior to LEN or LEN+EPO treatment. ELISAs for S100A9, S100A8, TNFα, IL1β and EPO were performed. Clinical data were analyzed from all patients. Spearman's correlation, Mann-Withney and Jonckheere-Terpstra tests were used for analysis of continuous variables. Chi-square test was used for analysis of non-continuous variables.Results: Median age of the patients was 76 years [41-94]. IPSS was low, intermediate-1, intermediate-2 and high risk in 47%, 49%, 3% and 1% of patients, respectively; whereas 28%, 42%, 22%, 7% and 1% of patients were very low, low, intermediate, high and very high risk according to IPSS-R. Serum S100A9 concentration was significantly higher in patients with lower risk versus higher risk MDS (17,798 pg/ml vs 15,291 pg/ml, p=0.01). No significant difference was observed for TNFα and IL1 β according to IPSS or IPSS-R. ELISA quantitation following 24h in vitro stimulation of HepG2 cells with S100A9 (10 to 20 µg/ml), TNFα (10 to 100 ng/ml) or IL1β (10 to 100ng/ml) showed that each cytokine significantly suppressed Epo elaboration in a concentration-dependent manner. To validate these findings, we assessed the relationship between serum concentration of these inflammatory cytokines and Epo level in MDS patients. We observed a significant negative correlation between TNFα and Epo concentration (r=-0.158, p=0.01), and a corresponding significant negative correlation between S100A9 and Epo (r=-0.143, p=0.01). We also found a significant positive correlation between S100A9 and S100A8 (r=0.757, p<0.001), S100A9 and TNFα (r=0.222, p<0001), S100A9 and IL1β (r=175, p=0.004), and IL1β with TNFα concentration (r=257, p<0.001). Moreover, we found that ESA responders had a significant higher serum TNFα concentration prior to treatment than non-responders (12 pg/ml vs 6 pg/ml, p=0.02) with a corresponding significantly lower Epo concentration in ESA responders. There was no significant correlation between S100A9 serum concentration and EPO response. Finally, in patients treated with LEN + ESA, we observed a significant positive correlation between S100A9 and duration of LEN or LEN + ESA response (r=-0.418, p=0.03). In vitro, 1µM LEN significantly reduced suppression of Epo elaboration by S100A9 or TNFα in HepG2 cells. Magnitude of LEN's improvement in EPO elaboration was greater for S100A9 vs TNF (43% vs 17%, p=0.08).Moreover, in peripheral blood mononuclear cells (PBMC) from MDS patients, 1µM LEN significantly decreased steady state S100A9 generation, and LPS-induced TNFα elaboration.Conclusion: These findings demonstrate that S100A9 and its NFκ-B transcriptional target, TNFα, directly suppress Epo elaboration and endocrine response to anemia in MDS. These inflammatory proteins may serve as rational biomarkers for response to lenalidomide and/or ESA treatment and merit prospective validation. Therapeutic strategies that either neutralize S100A9 or suppress elaboration of this alarmin may improve erythropoiesis in MDS by restoring Epo response and suppressing innate immune effectors. DisclosuresFenaux:Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. List:Celgene Corporation: Honoraria, Research Funding.

Lenalidomide and Risk of Acute Myeloid Leukemia (AML) Transformation Among Myelodysplastic Syndrome (MDS) Patients

Introduction: Lenalidomide is currently approved by the FDA for treatment of transfusion-dependent, lower risk, deletion 5q (del(5q)) MDS patients. In practice, lenalidomide is often used for treatment of non-del(5q) anemic, lower risk MDS patients as endorsed by national guidelines. The risk of AML transformation among non-del(5q) MDS patients treated with lenalidomide has not been well studied, nor among del(5q) MDS patients outside the context of original clinical trials. We conducted a retrospective cohort study of 1,248 MDS patients treated with or without lenalidomide at the Moffitt Cancer Center (MCC) to investigate the association between lenalidomide and AML transformation.Methods: Patients treated for MDS at MCC in 2004-2012 were identified through MCC’s data warehouse, including data from the Cancer Registry, electronic medical records and disease-specific databases. A total of 1,248 MDS patients, ages 18+ years, were identified, corresponding to International Classification of Diseases for Oncology Third Edition (ICD-O-3) codes 99801, 99803, 99833, 99843, 99853, 99863, 99873, 99891 and 99893. A total of 150 cases of AML transformation were verified by two hematologists confirming the MDS diagnosis and AML transformation. Incidence rates and 95% confidence intervals (CI) for AML transformation were estimated based on the Poisson distribution. Cox proportional hazards ratios (HR) and 95% CIs were calculated to estimate age-adjusted associations between lenalidomide treatment and AML transformation in the overall cohort, and stratified by lower (low and intermediate-1) risk versus higher (intermediate-2 and high) risk IPSS. To obtain additional details on lenalidomide treatment and potential confounders, medical chart abstraction was conducted for all AML cases and a sample of MDS patients from the baseline cohort who had not developed AML; these controls were matched to cases 1:1 on age at MDS diagnosis (<60 versus 60+ years), gender, follow-up time (+/- 6 months), date of diagnosis, (+/- 1 year), lower versus higher risk IPSS, and presence or absence of del (5q). Based on the abstracted data for the nested case-control sample, associations between lenalidomide and AML transformation were adjusted for cytogenetic risk, use of erythroid-stimulating agents (ESA), percent bone marrow myeloblasts, and MDS histology.Results: Overall, 1,248 MDS patients were followed for an average of 30 months, including patients treated with (n=210) or without (n=1,038) lenalidomide. AML transformation was observed among 16 patients treated with lenalidomide (2.4 per 100 person-years) and 134 patients treated without lenalidomide (5.5 per 100 person-years), corresponding to an age-adjusted HR of 0.44 (95% CI=0.26-0.74). Only two of the 150 MDS patients who transformed to AML had MDS del(5q). When stratified by IPSS, there was no increased risk of AML transformation associated with lenalidomide among patients with lower risk IPSS (HR=0.27, 95% CI=0.12-0.64) or patients with higher risk IPSS (HR=0.99, 95% CI=0.51-1.93). Based on the nested case-control analysis, 16.0% and 20.7% of MDS-AML cases and matched MDS controls who did not develop AML were treated with lenalidomide, respectively, corresponding to an adjusted odds ratio (OR) of 1.16 (95% CI=0.52-2.56). Although a significant interaction was noted between lenalidomide and IPSS in relation to AML in the cohort analysis (Figure 1), lenalidomide was not associated with AML transformation among lower risk (OR=0.44, 95% CI=0.10-1.94) or higher risk (OR=2.06, 95% CI=0.69-6.18) MDS patients after adjustment for prognostic factors in the case-control analysis.Conclusion: To our knowledge, this study represents the largest cohort investigated outside the context of clinical trials for the rate of AML transformation among MDS patients treated with lenalidomide and the first to specifically examine non-del(5q) patients. Lenalidomide treatment was not associated with an increased risk of AML transformation among this large cohort of MDS patients. [Display omitted] DisclosuresRollison:Celgene, Inc.: Research Funding. Off Label Use: Lenalidomide given as treatment for non-del(5q) MDS and/or multiple myeloma . Shain:L&M Healthcare/Onyx/Amgen: Research Funding, Speakers Bureau; Envision/Celgene: Research Funding, Speakers Bureau. Lee:Celgene, Inc.: Research Funding. Hampras:Celgene, Inc: Research Funding. Fulp:Celgene, Inc.: Research Funding. Fisher:Celgene, Inc: Research Funding. Al Ali:Celgene, Inc: Research Funding. Padron:Icyte: Speakers Bureau; Novartis: Speakers Bureau. Lancet:Celgene, Inc: Consultancy, Research Funding. Xu:Celgene, Inc.: Employment, stock options Other. Knight:Celgene, Inc: Employment, stock options Other. List:Celgene, Inc.: Consultancy. Dalton:Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene, Inc.: Research Funding. Komrokji:Celgene: Consultancy, Research Funding.

Subsequent Primary Malignancies Among Myelodysplastic Syndrome Patients Treated with or without Lenalidomide

Introduction: Lenalidomide is approved by the FDA for treatment of transfusion-dependent, lower risk, deletion 5q (del(5q)) MDS patients and used widely in practice for non-del(5q) MDS patients with anemia. Recently, subsequent primary malignancies (SPM) have been reported to be associated with lenalidomide treatment of multiple myeloma, and it is unclear if this observation is disease-specific or more broadly related to a particular therapy. The SPM risk in lenalidomide-treated MDS patients has not been evaluated previously. To investigate whether lenalidomide is associated with an increased risk of SPM in MDS patients, we conducted a large, retrospective cohort study of 1,248 MDS patients treated with or without lenalidomide at the Moffitt Cancer Center (MCC).Methods: Patients treated for MDS at MCC in 2004-2012 were identified through MCC’s enterprise wide data warehouse which combined clinical information from a variety of sources, including the Cancer Registry, electronic medical records and disease-specific databases. A total of 1,248 MDS patients, ages 18+ years, were identified, corresponding to International Classification of Diseases for Oncology Third Edition (ICD-O-3) codes 99801, 99803, 99833, 99843, 99853, 99863, 99873, 99891 and 99893. A total of 41 cases of SPM were verified by two hematologists for confirmation of both the baseline MDS diagnosis and the SPM diagnosis. SPM incidence rates were estimated based on the Poisson distribution. Cox proportional hazards ratios (HR) and 95% confidence intervals (CI) were calculated to estimate the age-adjusted association between lenalidomide treatment and SPM in the overall cohort, and stratified by lower versus higher risk IPSS. To obtain additional details on lenalidomide treatment and potential confounders, medical chart abstraction was conducted for all SPM cases in addition to a sample of MDS patients from the baseline cohort who had not developed SPM; these controls were matched to cases 1:1 on age at MDS diagnosis (<60 versus 60+ years), gender, follow-up time (+/- 6 months), date of diagnosis, (+/- 1 year), lower versus higher risk IPSS, and presence or absence of del (5q). Based on the medical record data abstracted for the nested case-control sample, associations between lenalidomide and SPM were estimated using odds ratios (OR) and 95% CI’s calculated through conditional logistic regression, with adjustment for age at diagnosis, use of erythroid-stimulating agents (ESA), use of azacitidine and MDS histology.Results: Overall, 1,248 MDS patients were followed for an average of 30 months, including patients treated with (n=210) or without (n=1,038) lenalidomide. Incident SPM’s were observed for 5 patients treated with lenalidomide (0.7 per 100 person-years) and 36 patients treated without lenalidomide (1.4 per 100 person-years), corresponding to an age-adjusted HR of 0.53 (95% CI=0.21-1.36) (Figure 1). Of the 41 SPM’s observed, 33 were solid tumors comprised of 15 types, and 8 were hematological malignancies other than AML; no differences in SPM risk were observed by type of SPM. When stratified by IPSS, there was no increased risk of SPM observed for patients with low risk or intermediate-1 MDS (HR=0.36, 95% CI=0.11-1.20) nor for patients with intermediate-2 and high risk MDS (HR=2.30, 95% CI=0.45-11.65). Of the 41 SPM cases and 41 matched controls included in the nested case-control analysis, 12.2% (n=5) and 29.3% (n=12) were treated with lenalidomide, respectively, corresponding to an adjusted OR of 0.03 (95% CI=0.01-0.63). Similar associations were observed for lenalidomide whether given as part of first line treatment or subsequent therapy, and for lenalidomide given alone or in combination with other drugs.Conclusion: To our knowledge this is the first report to address rate of SPM among MDS patients treated with lenalidomide. SPM was not associated with lenalidomide treatment among a large cohort of patients with a broad spectrum of MDS diagnoses. [Display omitted] DisclosuresRollison:Celgene, Inc.: Research Funding. Off Label Use: Lenalidomide for the treatment of non-del(5q) MDS and/or multiple myeloma. Shain:Envision/Celgene: Research Funding, Speakers Bureau; L&M Healthcare/Onyx/Amgen: Research Funding, Speakers Bureau. Lee:Celgene, Inc.: Research Funding. Hampras:Celgene, Inc: Research Funding. Fisher:Celgene, Inc: Research Funding. Al Ali:Celgene, Inc: Research Funding. Padron:Icyte: Speakers Bureau; Novartis: Speakers Bureau. Lancet:Celgene: Consultancy, Research Funding. Olesnyckyj:Celgene: Employment, stock options Other. Kenvin:Celgene: Employment, stock options Other. Knight:Celgene, Inc: Employment, stock options Other. Dalton:Genentech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene, Inc.: Research Funding. List:Celgene, Inc.: Consultancy. Komrokji:Celgene: Consultancy, Research Funding.

Biosimilar epoetin in elderly patients with low-risk myelodysplastic syndromes improves anemia, quality of life, and brain function

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and a risk of progression to acute myeloid leukemia (AML). Anemia affects the course of disease, quality of life (QOL), and cognitive function of MDS patients. Erythroid-stimulating agents (ESAs) are effective; however, not all patients respond to ESAs. To evaluate the effectiveness of a biosimilar epoetin α (Binocrit) for the treatment of anemia in low-/intermediate-1 risk MDS patients and to evaluate the impact of ESAs on QOL and on cognitive function, 24 consecutive patients aged over 65years were treated with Binocrit at 40,000IU once a week for 12weeks and were followed for at least 3months. Responsive patients continued with 40,000IU once a week for a further 12weeks. Changes in QOL were assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An), while cognitive assessment was carried out by mini-mental state examination (MMSE). All patients completed 12weeks of therapy. Sixteen patients (66.67%) achieved an erythroid response (ER), 15 patients (62.5%) became transfusion independent and remained free from transfusion requirement for at least 3months, while two patients had reduction in transfusion requirement of at least four RBC transfusions/8weeks compared with the pretreatment transfusion requirement. Seven patients were nonresponders (29.1%), of whom four patients were low risk and three intermediate-I risk. Seven transfusion-independent patients were low risk, and eight were intermediate-1 risk. Median hemoglobin (Hb) values were significantly higher after treatment in responders (p < 0.001). ER was maintained after 24weeks. Statistically significant positive correlations between improvement in Hb and variations in patients' mini-mental (Spearman's Rho = 0.54, p < 0.01) and FACT-An scores (Spearman's Rho = 0.59, p < 0.003) were demonstrated. This preliminary study shows that Binocrit is promising for the treatment of anemia of MDS patients. ER positively correlates with improvements in patients' cognitive status and positive changes in QOL.

Distribution of serum erythropoietin levels in lower risk myelodysplastic syndrome cases with anemia

International guidelines for myelodysplastic syndrome (MDS) state that the standard therapy for lower risk MDS patients with symptomatic anemia of serum erythropoietin (EPO) <500 IU/L is erythroid-stimulating agents (ESAs). The objective of this study is to examine the distribution of EPO levels in lower risk MDS patients, and to inquire into the relationship of EPO distribution to hemoglobin levels and transfusions. Twenty cases of lower risk MDS (low or intermediate-1 by the International Prognostic Scoring System) with hemoglobin level <90 g/L at our institution were enrolled. Eight received more than two units of transfusions per month. Median hemoglobin level was 78 g/L. EPO levels ranged between 26.4 and 11300 IU/L (median 645 IU/L), including 10 cases (50 %) with >500 IU/L. EPO levels were inversely correlated to hemoglobin levels, especially in the cases without transfusion support (p < 0.001, R = 0.92). The rate of the cases with EPO <500 IU/L was significantly higher in the group without transfusion than the others (p = 0.020). Considering that, in Japan, the indication for transfusion is around 70 g/L of hemoglobin for chronic diseases, it may be possible to improve anemia in a subset of lower risk MDS cases by administration of ESAs before transfusions are required.

Prognostic Factors Of Response and Survival To Azacitidine (AZA) +/- EPO In RBC Transfusion Dependent (TD) IPSS Low and Int-1 (LR) MDS Resistant To EPO, With Particular Emphasis Of Genetic Lesions: A Study By The GFM

BackgroundAlthough anemia of LR MDS initially responds to erythroid stimulating agents (ESA) in 40-50% of patients, response is generally transient. AZA may lead to RBC transfusion independence (RBC-TI) in 30-40% of LR-MDS patients but it has not been studied prospectively in those resistant to ESA. While prognostic factors of response and survival to AZA have been largely analysed in high risk MDS, including by our group (Itzykson, Blood, 2011), they remain uncertain in LR-MDS, especially regarding new genetic factors. We previously reported (J Clin Oncol 30, 2012 # 6523) in a randomized phase II trial comparing AZA and AZA+EPO in 93 LR-MDS that were RBC-TD and resistant to ESA, a similar erythroid response rate in the 2 treatment arms (NCT01015352). Here, we report prognostic factors of response and overall survival in this trial, including genetic markers (SNP array-based karyotype and somatic mutations). MethodsPatients included in the trial received AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) or with added EPO 60000U/week (AZA+EPO arm). Erythroid response was evaluated after 4 and 6 cycles of AZA, according to the IWG 2000 criteria. Responders were then eligible for 12 AZA+/-EPO maintenance cycles. Affymetrix SNP array 6.0 (SNPa) analysis was performed at baseline on marrow mononuclear cells, and mutations of SF3B1, TET2, DNMT3A, ASXL1, JAK2 and 19 other genes were screened by next generation sequencing and validated by Sanger sequencing. The following factors were analysed for their prognostic value on erythroid response (IWG 2000) and survival: age, gender, IPSS, IPSS cytogenetics, WHO diagnosis, time since MDS diagnosis, SNPa karyotype, SF3B1, TET2, DNMT3A, ASXL1 and JAK2 mutations. ResultsIn the 93 patients, M/F was 65/28; median age 72 y (IQR: 65-78); WHO diagnosis: RA 5.3%, RARS 40.9%, RCMD 15.1%, RCMD-RS 17.2%, RAEB-1 12.9%, CMML 7.5%, MDS-U 1%. Median MDS duration prior to inclusion was 37.2 months. IPSS was low in 35 and int-1 in 57 patients (NA in 1). IPSS cytogenetics was fav in 65, int in 9, defav in 2 patients, and failed or not done at study entry in 17 (but cytogenetics at MDS diagnosis was available in 16 of them). An abnormal SNPa karyotype was present in 33/79 patients analysed, including 9 with normal conventional cytogenetics. SF3B1, TET2, DNMT3A, ASXL1 and JAK2 mutations were detected in 59/86, 29/87, 12/87, 5/89 and 3/87 patients. Of the 19 other genes analysed, 12 showed no mutation and 7 (UA2F1, CBL, EZH2, RUNX1, ETV6, KIT, IDH2) were mutated in ≤3 patients and were not further considered in this analysis. In ITT analysis (N=93), erythroid response was 34% after 4 courses (37.5 % vs. 31% in the AZA and AZA+EPO arms, respectively, p=0.82) and 30% after 6 courses (35% vs. 24%, p=1.00). In univariate analysis, none of the factors listed above, including genetic markers, significantly predicted treatment response after 4 or 6 courses, while a trend was observed for a higher response rate after 6 cycles for SF3B1 mutated versus wt. patients (35.6 vs. 14.8 % respectively, P=0.07). Median follow-up of the 93 patients was 30 months (IQR: 23-34). Five patients developed AML (1 in AZA arm and 4 in AZA+EPO arm, P=0.19), all 5 in non-responders after 6 cycles. Median OS was 42.2 months and 2.5 years-OS 79.2% (95%CI: 71.2-88.1), with no difference between randomization arms (P=0.69). In univariate analysis, a shorter time since MDS diagnosis (HR=0.97, 95%CI: 0.95-0.99,P=0.011), IPSS int-1 (HR=2.83, 95%CI: 1.05-7.63, P=0.04), an abnormal SNPa karyotype (HR=3.01, 95%CI: 1.26-7.22, P=0.013) and presence of ASXL1 mutation (HR=5.08, 95%CI: 1.48-17.48, P=0.010) were associated with worse survival. In multivariate analysis, however, only time since MDS diagnosis (HR=0.97, 95%CI: 0.95-0.99) and abnormal SNPa karyotype (HR=2.92, 95%CI: 1.07-8.01) remained of prognostic value. ConclusionsIn this prospective AZA trial in LR-MDS resistant to ESA, no significant prognostic factor for response to AZA+/- EPO was identified, but a trend for better response (p=0.07) was seen in SF3B1 mutated patients, i.e 2/3 of patients. Among mutations analysed, only ASXL1 mutation predicted survival in univariate analysis, while abnormal SNPa karyotype predicted survival both in univariate and multivariate analysis (together with MDS duration). Thus, SNP array-based karyotyping and ASXL1 gene mutation analysis may become important tools to predict the long-term outcome of ESA resistant LR-MDS treated by AZA Disclosures:Guerci-Bresler:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Fenaux:Celgene, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gardin:Celgene, inc: Research Funding.

Safety and efficacy of intravenous iron therapy in reducing requirement for allogeneic blood transfusion: systematic review and meta-analysis of randomised clinical trials

Objectives To evaluate the efficacy and safety of intravenous iron, focusing primarily on its effects on haemoglobin, requirement for transfusion, and risk of infection. Design Systematic review and meta-analysis of...