Red Blood Cell Transfusion Independence Research Articles

RBC transfusion independence among lower risk MDS patients receiving hypomethylating agents: a population-level analysis

Most patients with lower risk myelodysplastic syndromes (LR-MDS) become red blood cell (RBC) transfusion dependent at some time during their disease course. Hypomethylating agents (HMAs) are frequently used in this setting; however, reported rates of in RBC transfusion independence (TI) achieved with HMA therapy vary significantly between studies. Here we study the real-life clinical effectiveness of HMA in inducing RBC TI in anemic LR-MDS patients using the Surveillance, Epidemiology and End Results (SEER)-Medicare database. We find that approximately 40% of LR-MDS patients who were receiving RBC transfusions and 33% who were dependent on RBC transfusions at HMA initiation ultimately achieved TI. The receipt of ≥3 transfusions in the 8-week period before HMA initiation was significantly associated with lower odds of achieving TI. Our study provides important population level estimates of clinical effectiveness of HMAs in LR-MDS.

S830 AVAPRITINIB, A POTENT AND SELECTIVE INHIBITOR OF KIT D816V, INDUCES COMPLETE AND DURABLE RESPONSES IN PATIENTS (PTS) WITH ADVANCED SYSTEMIC MASTOCYTOSIS (ADVSM)

Background: Anemia is common in myelofibrosis (MF) and current treatments are unsatisfactory. Anemia is not improved, and often initially worsened by ruxolitinib (rux), the only approved treatment for MF. Sotatercept is a first-in-class, activin receptor IIA (ActRIIA) “ligand trap” that sequesters ligands that bind to the ActRIIA, some of which inhibit terminal erythropoiesis. Aims: To evaluate the efficacy and safety of sotatercept in anemic subjects with MF, alone and with rux. Methods: This ongoing, single-institution, investigator-initiated, phase 2, open-label trial (ClinicalTrials.gov Identifier: NCT01712308) enrolls adults with primary MF or MF arising from polycythemia vera or essential thrombocythemia with anemia with or without RBC transfusion-dependence (per International Working Group for Myelofibrosis Research and Treatment criteria). Sotatercept is given subcutaneously every 3 weeks. Subjects on the sotatercept-only arm receive 0.75 or 1 mg/kg. Subjects on a stable dose (for ≥8 weeks) of rux receive 0.75 mg/kg of sotatercept and must have been on rux for ≥6 months. Responses include increases in hemoglobin (Hgb) of ≥1.5 g/dL (for ≥12 weeks) from baseline in anemia-only subjects (without transfusions) and RBC transfusion independence in RBC transfusion-dependent subjects. Subjects had to be on treatment for ≥84 days to be evaluable. Results: Of 48 subjects enrolled, 6 never began sotatercept and 1 received 0.3 mg/kg/dose; these subjects are not considered further. Of the remainder, 26 subjects received sotatercept only (12 received 0.75 mg/kg and 14, 1 mg/kg) and 15, sotatercept and rux. Baseline variables are displayed in the Table. Seven of 20 (35%) evaluable subjects in the sotatercept-only cohort responded; 4 of 10 anemia-only subjects and 3 of 10 RBC-transfusion-dependent subjects. Two other subjects who achieved ≥1.5 g/dL Hgb increases from baseline discontinued early for other reasons. Of 13 evaluable subjects receiving sotatercept and rux, 3 (23%) responded (all anemia-only subjects). An additional subject had a 1.5 g/dL Hgb increase from baseline that was not sustained for ≥84 days due to the need for a rux dose increase from 10 to 15 mg twice daily. The median numbers of cycles of sotatercept were 5 (range, 1–53) and 10 (range, 2–26), and median times on study were 4 (range, 1–39+) and 7 (range, 2–31+) months, respectively, in the sotatercept-only and sotatercept plus rux cohorts. Median time to response in the monotherapy cohort was 21 (range, 7–22) days and median duration of response was 12 (range, 4–39+) months. In the combination cohort, the 3 responses began at 7, 14 and 140 days, and are ongoing at 17+, 18+ and 30+ months. Several subjects in both cohorts required sotatercept to be held for Hgb ≥11.5 g/dL and resumed when Hgb <11 g/dL. Eight subjects remain on study, 4 in each cohort, including 2 responders in the sotatercept-only cohort and 3 in the combination cohort. Reasons for discontinuation (n = 33) include no or loss of benefit (11), censoring because of a transplant (6), MF progression (7), patient choice (3), inability to comply with study requirements (2), hypertension (1), leukemic transformation (1), loss of health insurance (1) and unrelated medical problems (1). Sotatercept was well tolerated. Most adverse events (AEs) were grades 1 or 2. Grade 3 myalgias/arthralgias occurred in 2 subjects (5%). Grade 3 hypertension occurred in 6 subjects (15%) and grade 2 in 2 (5%). These were not associated with high Hgb values. No grade 4 AEs occurred.Summary/Conclusion: Sotatercept improves anemia of MF, both when given alone and in subjects receiving rux.

S829 SOTATERCEPT (ACE‐011) IN SUBJECTS WITH MPN‐ASSOCIATED MYELOFIBROSIS AND ANEMIA

Background:Anemia is common in myelofibrosis (MF) and current treatments are unsatisfactory. Anemia is not improved, and often initially worsened by ruxolitinib (rux), the only approved treatment for MF. Sotatercept is a first‐in‐class, activin receptor IIA (ActRIIA) “ligand trap” that sequesters ligands that bind to the ActRIIA, some of which inhibit terminal erythropoiesis.Aims:To evaluate the efficacy and safety of sotatercept in anemic subjects with MF, alone and with rux.Methods:This ongoing, single‐institution, investigator‐initiated, phase 2, open‐label trial (ClinicalTrials.gov Identifier: NCT01712308) enrolls adults with primary MF or MF arising from polycythemia vera or essential thrombocythemia with anemia with or without RBC transfusion‐dependence (per International Working Group for Myelofibrosis Research and Treatment criteria). Sotatercept is given subcutaneously every 3 weeks. Subjects on the sotatercept‐only arm receive 0.75 or 1 mg/kg. Subjects on a stable dose (for ≥8 weeks) of rux receive 0.75 mg/kg of sotatercept and must have been on rux for ≥6 months. Responses include increases in hemoglobin (Hgb) of ≥1.5 g/dL (for ≥12 weeks) from baseline in anemia‐only subjects (without transfusions) and RBC transfusion independence in RBC transfusion‐dependent subjects. Subjects had to be on treatment for ≥84 days to be evaluable.Results:Of 48 subjects enrolled, 6 never began sotatercept and 1 received 0.3 mg/kg/dose; these subjects are not considered further. Of the remainder, 26 subjects received sotatercept only (12 received 0.75 mg/kg and 14, 1 mg/kg) and 15, sotatercept and rux. Baseline variables are displayed in the Table.Seven of 20 (35%) evaluable subjects in the sotatercept‐only cohort responded; 4 of 10 anemia‐only subjects and 3 of 10 RBC‐transfusion‐dependent subjects. Two other subjects who achieved ≥1.5 g/dL Hgb increases from baseline discontinued early for other reasons. Of 13 evaluable subjects receiving sotatercept and rux, 3 (23%) responded (all anemia‐only subjects). An additional subject had a 1.5 g/dL Hgb increase from baseline that was not sustained for ≥84 days due to the need for a rux dose increase from 10 to 15 mg twice daily. The median numbers of cycles of sotatercept were 5 (range, 1–53) and 10 (range, 2–26), and median times on study were 4 (range, 1–39+) and 7 (range, 2–31+) months, respectively, in the sotatercept‐only and sotatercept plus rux cohorts. Median time to response in the monotherapy cohort was 21 (range, 7–22) days and median duration of response was 12 (range, 4–39+) months. In the combination cohort, the 3 responses began at 7, 14 and 140 days, and are ongoing at 17+, 18+ and 30+ months. Several subjects in both cohorts required sotatercept to be held for Hgb ≥11.5 g/dL and resumed when Hgb &lt;11 g/dL.Eight subjects remain on study, 4 in each cohort, including 2 responders in the sotatercept‐only cohort and 3 in the combination cohort. Reasons for discontinuation (n = 33) include no or loss of benefit (11), censoring because of a transplant (6), MF progression (7), patient choice (3), inability to comply with study requirements (2), hypertension (1), leukemic transformation (1), loss of health insurance (1) and unrelated medical problems (1).Sotatercept was well tolerated. Most adverse events (AEs) were grades 1 or 2. Grade 3 myalgias/arthralgias occurred in 2 subjects (5%). Grade 3 hypertension occurred in 6 subjects (15%) and grade 2 in 2 (5%). These were not associated with high Hgb values. No grade 4 AEs occurred.Summary/Conclusion:Sotatercept improves anemia of MF, both when given alone and in subjects receiving rux.image

Use of immunosuppressive therapy for management of myelodysplastic syndromes: a systematic review and meta-analysis

Immunosuppressive therapy (IST) is one therapy option for treatment of patients with lower-risk myelodysplastic syndromes (MDS). However, the use of several different immunosuppressive regimens, the lack of high-quality studies, and the absence of validated predictive biomarkers pose important challenges. We conducted a systematic review and meta-analysis according to the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines and searched MEDLINE via PubMed, Ovid EMBASE, COCHRANE registry of clinical trials (CENTRAL), and the Web of Science without language restriction from inception through September 2018, as well as relevant conference proceedings and abstracts, for prospective cohort studies or clinical trials investigating IST in MDS. Fixed and Random-effects models were used to pool response rates. We identified nine prospective cohort studies and 13 clinical trials with a total of 570 patients. Overall response rate was 42.5% [95% confidence interval (CI): 36.1-49.2%] including a complete remission rate of 12.5% (95%CI: 9.3-16.6%) and red blood cell transfusion independence rate of 33.4% (95% CI: 25.1–42.9%). The most commonly used forms of IST were anti-thymocyte globulin alone or in combination with cyclosporin A with a trend towards higher response rates with combination therapy. Progression rate to acute myeloid leukemia was 8.6% per patient year (95%CI: 3.3-13.9%). Overall survival and adverse events were only inconsistently reported. We were unable to validate any biomarkers predictive of a therapeutic response to IST. IST for treatment of lower-risk MDS patients can be successful to alleviate transfusion burden and associated sequelae.

RBC and Platelet Transfusion Requirements in the First 30 Days after Allogeneic Hemopoietic Cell Transplantation and Transfusion Independence: A Single Center Retrospective Study of 1803 Recipients

Background Allogeneic hematopoietic cell transplant (allo-HCT) recipients often require substantial but variable transfusion support. Few studies have quantified their transfusion burden, or identified prognostic factors for increased transfusions to guide patient counseling or inventory management. Data on haploidentical HCT (Haplo-HCT) patients are especially scarce. Objectives To identify factors associated with increased RBC and platelet (PLT) transfusions, and provide for the first time data on a large cohort of Haplo-HCT patients. Methods We retrospectively evaluated 1803 consecutive first time adult allo-HCT patients transplanted at our center in 2011-17. Multivariate linear regression and Fine-Gray subdistribution hazards models were used to examine the associations between baseline characteristics (age, sex, disease stage, graft type, donor type, ABO compatibility and conditioning regimen) and log-transformed transfusion units in the first 30 days after HCT and time to reach transfusion independence respectively. Results The median age of the cohort was 53(18-78); 56.2% were male. Most common diagnoses were AML (38.8%), ALL (19.6%), and lymphoma (14.8%); 50.2% had advanced disease. Patients received nonmyeloablative/reduced intensity (58.9%) or myeloablative conditioning regimens (MAC, 41.1%), followed by peripheral blood stem cell (88.4%), bone marrow (6.9%) or umbilical (UC, 4.7%) HCT. Most grafts were from matched related (MRD, 38.7%) or unrelated (MUD, 49.1%) donors, and 7.6% were haploidentical. ABO incompatibility (Major 15.8%, minor 18.6%, bi-directional 8.5%) was present in 42.9% of the cases (Table 1). Most of the 1764 patients who survived 30+ days received RBC (88.2%) or PLT (97.2%) transfusions during the first 30 days, with a median of 3 (0-37) RBC and 5(0-144) apheresis PLT units. RBC and PLT transfusion independence was reached in 28 (95%CI: 26-31) and 12 (95%CI: 12-13) days respectively. Multivariate analyses showed that Haplo-HCT and UC graft were independently associated with more RBC and PLT transfusions, as were advanced disease, ABO incompatibility, older age, and MAC (P Conclusions We identified patient and transplant factors strongly associated with increased transfusions in the first 30 days after allo-HCT, and quantified the transfusion burden of Haplo-HCT relative to other types of HCT.

Clinical Benefit-Risk Profile of Lenalidomide in Patients With Lower-risk Myelodysplastic Syndromes Without del(5q): Results of a Phase III Trial

BackgroundIn the phase III MDS-005 study of patients with lower-risk, non-del(5q) myelodysplastic syndromes, lenalidomide was associated with a higher rate of ≥ 8 weeks red blood cell transfusion independence (RBC-TI) compared with placebo, but also with a higher risk of hematologic adverse events (AEs). Patients and MethodsThis analysis evaluated the ratio of clinical benefit-risk in patients treated with lenalidomide or placebo, and assessed the effect of lenalidomide dose reductions on response. Clinical benefit was a composite endpoint defined as RBC-TI, transfusion reduction ≥ 4 units packed red blood cells, hemoglobin increase ≥ 1.5 g/dL, or cytogenetic response. ResultsThe rate of clinical benefit was higher with lenalidomide than with placebo (31.9% vs. 3.8%). The ratio of response (RBC-TI and clinical benefit) to risk (hematologic AEs) favored lenalidomide over placebo. Patients who underwent ≥ 1 lenalidomide dose reduction had a longer duration of treatment, received a higher cumulative dose, and were more likely to experience clinical benefit versus patients without dose reductions. ConclusionDespite the occurrence of hematologic AEs, the overall benefit-risk profile supported lenalidomide treatment. Appropriate management of hematologic AEs by dose reductions may help patients with myelodysplastic syndromes to remain on treatment and achieve clinical benefit.

Hepcidin Suppression By Momelotinib Is Associated with Increased Iron Availability and Erythropoiesis in Transfusion-Dependent Myelofibrosis Patients

Hepcidin Suppression By Momelotinib Is Associated with Increased Iron Availability and Erythropoiesis in Transfusion-Dependent Myelofibrosis Patients

Eltrombopag for Enhancement of Platelet Engraftment in Patients Undergoing Allogeneic Cord Blood Transplantation

BackgroundUmbilical cord blood (UCB) is an important alternative graft source for allogeneic hematopoietic cell transplantation (HCT) for patients without a HLA - matched donor. However, platelet recovery is significantly hampered following UCB transplantation, and patients remain platelet transfusion-dependent for prolonged periods of time. In the largest registry study to date, median time to platelet recovery over 20K/µL was over 70 days, and at 6 months only 50% of the patients had platelet engraftment. We hypothesized that eltrombopag (Revolade, GSK/Novartis), a thrombopoietin-receptor agonist, would enhance platelet engraftment after UCB transplantation.MethodsThis was a pilot multicenter open label single arm phase 2a study, in both adults and children (NCT01757145, NCT01940562). Oral eltrombopag was given from day +1 until platelet count exceeded 50K/µL for 14 consecutive days without platelet transfusion. Starting dose was 100 mg/d for adults and children weighing >40 kg and 50 mg/d for children weighing 20-40 kg. Based upon platelet response dosage was modified, with a maximal dose of 300mg/d for adults and 200mg/d for children. Study endpoints included safety, time to non-transfused platelet counts >20K/µL and >50K/µL, and platelet engraftment rate by day +50.ResultsBetween February 2013 and July 2016, 12 patients with hematological malignancies in complete remission were enrolled. The study cohort included 10 adults and 2 children, with a median age at transplantation of 50 (range 6-74) years (Table 1). Conditioning regimen was reduced-intensity in 7 patients and myeloablative in the remainder. Four patients received a single UCB unit, and 8 patients were given 2 units. The median total collected total nucleated cells (TNCs) *10^7/kg was 5.9 (range 2.7-8.6), and the median total collected CD34+ cells *10^5/kg was 3.1 (range 1.7-7.8).Patients received eltrombopag for a median of 76 days (range 15-175). Overall, eltrombopag was well tolerated even at maximal doses, and there was no need for dose reduction due to toxicity. No clinically significant side effects related to the study drug were reported. Of note, two patients developed mild, asymptomatic and transient indirect hyperbilirubinemia. No patient developed sinusoidal obstructive syndrome. No patient developed a thrombotic event while receiving eltrombopag. There was one case of lower extremity deep vein thrombosis, 6 months post-transplant (#03). No significant bone marrow fibrosis was documented even after prolonged eltrombopag administration.One patient (#07) died due to fungal respiratory infection on day +15 prior to engraftment. One patient (#01) had primary graft failure and autologous reconstitution, and is still alive in complete remission (CR) 5 years post-transplant. Among the 10 evaluable patients, median time to neutrophil engraftment was 23 (range 16-40) days. Median time to platelets>20K/µL and platelets>50K/µL was 55 (range 25-199) and 66 (range 31-230) days, respectively. Median time to RBC transfusion independence was 39 (range 13-157) days.Overall, 4 patients developed grade 2 (n=2) or grade 3 (n=2) acute graft versus host disease (GVHD), and 4 patients developed chronic GVHD (mild, n=3; moderate, n=1). There was no death attributable to GVHD.The median follow up time was 20 months (range 15 days - 61 months). At last follow up, 7 patients were alive, all still in CR at a median of 3.5 years post-transplant (range 1-5 years). Two patients died of relapse of their primary disease (#05, 7 months after transplant; #02, 29 months after transplant), for both these patients the UCB transplantation was the second transplant. Three patients died of infectious complications (#07, early death due to fungal respiratory infection on day +15; #08, pneumonia on day +157; #06 sepsis on day +153).ConclusionsIn the present study, eltrombopag was safe in the context of UCB transplantation. With the limitation of our small sample size, the use of eltrombopag was associated with enhanced platelet recovery time compared to published data. Further prospective studies are warranted to confirm these results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Spliceosome Mutations Are Common in MPN-Associated Myelofibrosis with RBC-Transfusion-Dependence and Correlate with Response to Pomalidomide

Spliceosome Mutations Are Common in MPN-Associated Myelofibrosis with RBC-Transfusion-Dependence and Correlate with Response to Pomalidomide

The use of immunosuppressive therapy in MDS: clinical outcomes and their predictors in a large international patient cohort

AbstractMost studies of immunosuppressive therapy (IST) in myelodysplastic syndromes (MDS) are limited by small numbers and their single-center nature, and report conflicting data regarding predictors for response to IST. We examined outcomes associated with IST and predictors of benefit in a large international cohort of patients with MDS. Data were collected from 15 centers in the United States and Europe. Responses, including red blood cell (RBC) transfusion independence (TI), were assessed based on the 2006 MDS International Working Group criteria, and overall survival (OS) was estimated by Kaplan-Meier methods. Logistic regression models estimated odds for response and TI, and Cox Proportional Hazard models estimated hazards ratios for OS. We identified 207 patients with MDS receiving IST, excluding steroid monotherapy. The most common IST regimen was anti-thymocyte globulin (ATG) plus prednisone (43%). Overall response rate (ORR) was 48.8%, including 11.2% (95% confidence interval [CI], 6.5%-18.4%) who achieved a complete remission and 30% (95% CI, 22.3%-39.5%) who achieved RBC TI. Median OS was 47.4 months (95% CI, 37-72.3 months) and was longer for patients who achieved a response or TI. Achievement of RBC TI was associated with a hypocellular bone marrow (cellularity < 20%); horse ATG plus cyclosporine was more effective than rabbit ATG or ATG without cyclosporine. Age, transfusion dependence, presence of paroxysmal nocturnal hemoglobinuria or large granular lymphocyte clones, and HLA DR15 positivity did not predict response to IST. IST leads to objective responses in nearly half the selected patients with the highest rate of RBC TI achieved in patients with hypocellular bone marrows.

Current treatment algorithm for the management of lower-risk MDS.

Lower risk myelodysplastic syndromes (MDS), defined as MDS with a Revised International Prognostic Scoring System score ≤3.5 points, will remain a challenging entity in 2018. Supportive care continues to be the linchpin of treatment, although the options to reduce transfusion needs are broadening. To achieve red blood cell transfusion independence in non-del(5q) patients, erythropoiesis-stimulating agents remain a mainstay of therapy as long as endogenous erythropoietin levels are <500 U/L (and preferably <200 U/L). Experimental strategies for patients ineligible for erythropoiesis-stimulating agents or relapsing after gaining transfusion independence include immunosuppressive agents, transforming growth factor β inhibitors, and lenalidomide. All these alternatives have shown reasonable response rates in selected patient populations with lower risk MDS. Patients with del(5q) disease can derive long-term benefit from lenalidomide, and some patients remain transfusion free for extended periods even after discontinuation of the drug. In rare cases in which thrombocytopenia is the main clinical problem leading to clinically significant bleeding events, thrombopoietin receptor analogues may alleviate bleeding, increase platelet counts, and rarely lead to trilineage responses. It seems prudent to use these drugs only in patients with confirmed bone marrow blast counts <5%. Allogeneic stem cell transplantation is reasonable for patients with high molecular risk of progression and those failing several lines of treatment with signs of progression toward higher-risk MDS.

Practical Strategies for Management of Lenalidomide-Associated Cytopenias in Myelodysplastic Syndromes With del(5q)

CASE STUDY A male patient aged 67 years with a 2-year history of refractory anemia and myelodysplastic syndromes (MDS) with del(5q) started lenalidomide (Revlimid) treatment as a participant in the MDS-001 trial (List et al., 2005). At the time of the study, this patient had been transfusion-dependent since 2001, and at study entry he had received a total of 12 units of red blood cells (RBCs). The patient started lenalidomide at 25 mg daily for 21 days of each 28-day cycle on April 2, 2002. (Please note that as a result of subsequent trials, the approved starting dose for lenalidomide in patients with del[5q] MDS is 10 mg.) The patient developed treatment-related pancytopenia in the first 3 weeks of treatment (see Figure on next page). On day 24, lenalidomide was withheld. Platelet and white blood cell (WBC) counts were recovered during a 21-day period, and treatment was resumed with lenalidomide at 10 mg daily. During this initial dose interruption, the patient's hemoglobin level improved. He achieved RBC-transfusion independence (TI) during week 5 of treatment-his last RBC transfusion was on April 22, 2002. Bone marrow (BM) analysis, including fluorescence in situ hybridization, after 3 months of therapy, did not show the del(5q) abnormality. A repeat BM analysis after 57 months of treatment revealed minimal residual dyspoiesis, normal metaphase cytogenetics, and normal cell morphology. Subsequent BM biopsies showed transient trisomy 8 abnormalities but no del(5q) abnormality. The patient required one additional dose reduction during the first year of treatment. The patient did not require hospitalization during lenalidomide treatment but did have a history of seasonal allergies and a propensity for acute sinusitis. He received a single dose of pegfilgrastim (Neulasta) and a short course of antibiotics for active infections, generally one course of antibiotics per year. This patient continued on lenalidomide at 5 mg daily for 21 days of every 28-day cycle without further dose reduction. The patient achieved durable RBC-TI and continued to receive treatment for more than 11 years. The levels of hemoglobin, platelets, and WBCs for an 11-year period in this patient are shown in the Figure. This patient had one normal platelet count in 11 years of lenalidomide treatment but no bleeding episodes. The average platelet count in the 11-year period was 67 × 1,000/∝L (normal range, 150-425 × 1,000/∝L). Similarly, the WBC count remained below normal, with an average of 3.1 × 1,000/∝L (normal range, 3.4-10.4 × 1,000/∝L). He remained active and continued working as an aerospace engineer until age 75. This case demonstrates how effective management of cytopenias, through dose interruptions and modifications in the early weeks of treatment, helps to enable long-term lenalidomide treatment and a high quality of life. Despite the persistence of moderate, asymptomatic cytopenias, the patient was able to remain on lenalidomide therapy and maintained RBC-TI for more than 11 years. The patient died on October 4, 2014, at age 79.5, due to coronary artery disease and heart failure.

Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia.

Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012–2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8–50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4–4.5) and 42×109/L (interquartile range, 11–100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.

Azacitidine in Lower-Risk Myelodysplastic Syndromes: A Meta-Analysis of Data from Prospective Studies.

After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients with lower-risk myelodysplastic syndromes (LR-MDS). Optimal choice of these agents as front-line therapy in non-del(5q) LR-MDS is unclear. Because azacitidine clinical data mainly describe experience in higher-risk MDS, we performed a meta-analysis of patient-level data to evaluate azacitidine in patients with red blood cell (RBC) transfusion-dependent LR-MDS. We searched English-language articles for prospective phase II and III azacitidine clinical trials and patient registries published between 2000 and 2015, and Embase abstracts from 2015 conferences. Patient-level data from identified relevant studies were provided by investigators. Meta-analyses followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Efficacy endpoints were RBC transfusion independence (TI) and Clinical Benefit (RBC-TI, erythroid response, and complete or partial remission, per International Working Group 2006 criteria for MDS). Data for 233 patients from 6 clinical studies and 1 registry study met criteria for inclusion in analyses. Overall, 90.3% of patients had non-del(5q) LR-MDS. Pooled estimates from random-effects models of RBC-TI and Clinical Benefit were 38.9% and 81.1%, respectively; for the ESA-refractory subgroup, they were 40.5% and 77.3%; and for patients with isolated anemia, they were 41.9% and 82.5%. In multivariate analyses, planned use of ≥6 azacitidine treatment cycles was significantly predictive of response. Azacitidine effects in these patients, most with non-del(5q) LR-MDS, were promising and generally similar to those reported for lenalidomide in similar patients. The choice of initial therapy is important because most patients eventually stop responding to front-line therapy and alternatives are limited. Lower-risk myelodysplastic syndromes (LR-MDS) are primarily characterized by anemia. After erythropoiesis-stimulating agent (ESA) failure, lenalidomide and hypomethylating agents are the only remaining treatment options for most patients. This meta-analysis of 233 azacitidine-treated red blood cell (RBC) transfusion-dependent patients with LR-MDS (92.3% non-del[5q]) from 7 studies showed 38.9% became RBC transfusion-independent. There is no clear guidance regarding the optimal choice of lenalidomide or hypomethylating agents for patients with non-del(5q) LR-MDS following ESA failure. Clinical presentation (e.g., number of cytopenias) and potential outcomes after hypomethylating agent failure are factors to consider when making initial treatment decisions for LR-MDS patients.

Clinical characteristics and outcomes according to age in lenalidomide-treated patients with RBC transfusion-dependent lower-risk MDS and del(5q)

BackgroundParticularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed.MethodsWe assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials.ResultsA total of 33.9, 34.3, and 31.8% patients were aged <65 years, ≥65 to <75 years, and ≥75 years, respectively. Age <65 years was associated with less favorable International Prognostic Scoring System (IPSS) risk and additional cytopenias at baseline versus older age groups, significantly lower cytogenetic response rates (p = 0.022 vs. ≥65 to <75 years; p = 0.047 vs. ≥75 years), and higher rates of acute myeloid leukemia (AML) progression (Gray’s test, p = 0.013). Lenalidomide was equally well tolerated across age groups, producing consistently high rates of red blood cell transfusion independence ≥26 weeks.ConclusionsBaseline disease characteristics and AML progression appear to be more severe in younger lower-risk MDS patients with del(5q), whereas older age does not seem to compromise the response to lenalidomide.Trial registrationClinicalTrials.gov NCT00065156 and NCT00179621

Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX).

7001 Background: MMB, an oral JAK inhibitor, has been shown in early trials to reduce spleen volume, improve disease associated symptoms (Sx) and improve RBC transfusion requirements in patients (pts) with MF. This study of previously RUX treated pts with MF tested the superiority of MMB vs BAT in splenic volume reduction, Sx amelioration, and transfusion requirement at 24 weeks. Methods: Eligibility included primary or post-ET/PV MF; DIPSS high risk, Int-2, or symptomatic Int-1; prior RUX ≥4 weeks who either required transfusions or dose reduction to &lt;20 mg BID with at least one of Gr ≥3 thrombocytopenia, anemia, or bleed; palpable spleen ≥5cm; and no Gr ≥2 peripheral neuropathy. Stratification was by transfusion dependency and baseline TSS (modified MPN-SAF Total Sx Score) &lt;18 or ≥18. Pts were randomized 2:1 to 24 weeks of open-label MMB 200 mg QD or BAT. Assessments included spleen volume by MRI, and patient-reported Sx using a daily eDiary for TSS. 1° endpoint was splenic response rate (SRR; ≥35% reduction in volume from baseline). 2°endpoints, evaluated sequentially, were rates of TSS response (TSS RR; ≥50% reduction from baseline), RBC transfusion, RBC transfusion independence (TI) and RBC transfusion dependence (TD). Results: 73 of 104 (70%) and 40 of 52 (77%) pts receiving MMB or BAT, respectively, completed the 24 week randomized treatment phase. BAT for 88% of pts included RUX, and 27% of pts were on RUX in combination with other drugs. Efficacy results are in Table. The most common Gr ≥3 adverse events in MMB pts were anemia (13%) and thrombocytopenia (7%), and in BAT pts, anemia (13%), thrombocytopenia (6%) and abdominal pain (6%); treatment emergent peripheral neuropathy occurred in 11 (11%) of MMB (1 Gr3) and in no BAT pts. Conclusions: In previously RUX-treated patients with MF, 24 weeks of MMB was not superior to BAT for SRR, but significantly better in improving disease related symptoms and transfusion independence. Clinical trial information: NCT02101268. [Table: see text]

A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence.

RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26%; P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 109/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence.

Efficacy, safety, and pharmacokinetics of subcutaneous azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes.

Clinical and pharmacokinetic effects of azacitidine in higher-risk myelodysplastic syndromes were established in mainly Caucasian populations. Because of inter-ethnic genotype variability of drug-metabolizing enzymes, it is important to evaluate azacitidine in populations expected to use the drug. In this single-arm study, Taiwanese patients with higher-risk myelodysplastic syndromes received azacitidine 75 mg/m2 /day for 7 days/28-day cycle for up to six cycles. Response-evaluable patients had baseline and cycle 6 marrow assessments. Clinical outcomes are compared descriptively with those from a phase 3 study comprising mainly Caucasian patients (N = 179). Pharmacokinetics in a subgroup of Taiwanese patients are descriptively compared with a historical control of North American patients (N = 45). Median age of Taiwanese patients (N = 44) was 64 years (range 36-90), and 46% had poor cytogenetics. Median number of azacitidine cycles was six (1-6). No response-evaluable patient (n = 33) achieved complete or partial remission; however, 22 patients (50%) achieved hematologic improvement, 12 of 32 patients attained RBC transfusion independence and 7 of 18 attained platelet transfusion independence. Most common grade 3-4 treatment-emergent adverse events were neutropenia (52%) and leukopenia (39%). Pharmacokinetic profiles were similar for Taiwanese (N = 12) and North American (N = 45) patients. Maximum plasma concentration was higher in Taiwanese patients; however, mean azacitidine exposure was within the range for North American patients. These data confirm the safety and efficacy of azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes. Clinical outcomes were generally comparable with those for Caucasian patients. No meaningful differences in azacitidine pharmacokinetics were observed for Taiwanese patients, and no initial dose adjustment is necessary.

Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS): Long-Term Results from Phase 2 PACE-MDS Study

▪Background: Management of anemia is a common therapeutic challenge in patients with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014).Aims: This is an ongoing, phase 2, multicenter, open-label, long-term extension study to evaluate the effects of luspatercept in patients (pts) with low-intermediate risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, and pt-reported QoL.Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), ESA refractory or EPO > 500 U/L, no prior HMA, and no current lenalidomide or ESA. Luspatercept was administered SC every 3 wks for up to 5 doses in the base study (NCT01749514), including 7 dose escalation cohorts (n=27 total, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, starting dose 1.0 mg/kg, max 1.75 mg/kg). A 2-year extension study (n=32) is ongoing (NCT02268383).Results: Data (as of 4 Mar 2016) were available for the 32 extension study pts. Of these, 13 pts received < 4U RBC/8 weeks pretreatment (low transfusion burden, LTB) and 19 pts received ≥ 4U RBC/8 weeks (high transfusion burden, HTB). Median age was 72 yr (range 29-90 yr), 59% had prior ESA. Median Hgb for LTB pts was 8.5 g/dL (range 6.4-10.1 g/dL) and median RBC transfusion burden for HTB pts was 6 U/8 weeks (range 4-14 units). 91% pts were RS+ (≥ 15% RS in bone marrow).IWG HI-E was achieved in 11/13 (85%) LTB pts and 15/19 (79%) HTB pts. 11/22 (50%) pts with at least 2 units transfused in 8 weeks prior to dosing with luspatercept achieved RBC transfusion independence for at least 8 weeks. The range of transfusion independence was 9 to 80+ weeks, with most responders still receiving treatment. IWG HI-E response rates were 83% for RS+ pts, 90% for EPO < 200 U/L, 86% for EPO 200-500 U/L, and 50% for EPO > 500 U/L; 85% for ESA-naïve and 79% for those who had prior ESA treatment. RBC transfusion independence was achieved in 58% for EPO < 200 U/L, 50% for EPO 200-500 U/L, and 33% for EPO > 500 U/L.Luspatercept was well tolerated, with 3 related grade 3 adverse events of myalgia, worsening of general condition, and blast cell count increase. The most common related AEs (≥ 2 pts in both base and extension studies) were fatigue, bone pain, diarrhea, myalgia, headache, hypertension, and injection site erythema.Conclusions: Long-term treatment with luspatercept was well tolerated and led to erythroid response in 81% of low-intermediate risk MDS pts who enrolled into the extension study. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). DisclosuresPlatzbecker:Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Donovan:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.

Luspatercept Response in ESA-NaïVe/RS+ Patients and RS- Patients with Low-Intermediate Risk Myelodysplastic Syndromes (MDS)

Background: Management of anemia is a common therapeutic challenge in patients with myelodysplastic syndromes (MDS). Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014 and Attie K, Am J Hematol, 2014).Aims: This is an ongoing, phase 2, multicenter, open-label study to evaluate the effects of luspatercept in patient (pts) with low-intermediate risk MDS. Endpoints included erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥ 8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, safety, and pt-reported QoL.Methods: Inclusion criteria included age ≥ 18 yr, Hgb < 10 g/dL (if < 4U RBC/8 weeks), no prior HMA, and no current lenalidomide or erythropoiesis-stimulating agent (ESA). An expansion cohort of up to 56 patients was added to this phase 2 study to evaluate response to luspatercept in pts who do not qualify for the phase 3 MEDALIST trial (for RS+ positive patients with baseline EPO ≥ 200 U/L and ≥ 2U RBC/8 weeks). These include pts with low transfusion burden (< 4U RBC/8 weeks) who are either 1) ring sideroblast (RS)+ (≥ 15% RS in bone marrow) with baseline EPO ≤ 200 U/L and no prior ESA use, or 2) RS- with any baseline EPO level and any prior ESA use. Patients are treated with 1.0 mg/kg of luspatercept every 3 weeks for up to 5 doses, with titration up to 1.75 mg/kg. Patients may rollover to an open-label extension study for up to an additional 2 years of treatment.Results: Results for the initial patient cohorts have demonstrated a high proportion of HI-E and RBC-TI responses in RS+ patients. Data for the additional ESA-naïve RS+ patients with low EPO levels and RS- patients with 3 months of treatment will be presented at the meeting.Conclusions: Erythroid response to luspatercept has been demonstrated in RS+ patients with lower-risk MDS and is being explored in ESA-naïve RS+ patients with low EPO levels and RS- patients. A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; NCT02631070). DisclosuresDonovan:Acceleron Pharma: Employment. Wilson:Acceleron Pharma: Employment, Equity Ownership. Zhang:Acceleron Pharma: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership, Patents & Royalties. Attie:Acceleron Pharma: Employment, Equity Ownership. Giagounidis:Celgene Corporation: Consultancy.