scholarly journals Erratum: A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence

Leukemia ◽  
2017 ◽  
Vol 31 (5) ◽  
pp. 1252-1252 ◽  
Author(s):  
A Tefferi ◽  
◽  
H K Al-Ali ◽  
G Barosi ◽  
T Devos ◽  
...  
Keyword(s):  
Randomized Study ◽  
Myeloproliferative Neoplasm ◽  
Rbc Transfusion

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

Leukemia ◽  
2016 ◽  
Vol 31 (4) ◽  
pp. 896-902 ◽  
Author(s):  
A Tefferi ◽  
◽  
H K Al-Ali ◽  
G Barosi ◽  
T Devos ◽  
...  
Keyword(s):  
Odds Ratio ◽  
Randomized Study ◽  
Myeloproliferative Neoplasm ◽  
Placebo Response ◽  
Response Rates ◽  
Treatment Allocation ◽  
Transfusion Independence ◽  
Intent To Treat ◽  
Placebo Cohort ◽  
Rbc Transfusion

Abstract 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.

Use of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Instrument in Persons with MPN-Associated Myelofibrosis and Anemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4706-4706
Author(s):  
Stacie Hudgens ◽  
Tom Tencer ◽  
Robert Peter Peter Gale ◽  
Zeba M. Khan
Keyword(s):  
Cancer Therapy ◽  
Functional Assessment ◽  
Myeloproliferative Neoplasm ◽  
Well Being ◽  
Change Score ◽  
Patient Reported Outcome ◽  
Double Blind ◽  
Patient Reported ◽  
Outcome Index ◽  
Rbc Transfusion

Abstract Abstract 4706 Background. Myeloproliferative neoplasm (MPN)-associated myelofibrosis is characterized by anemia in almost all affected persons. The Functional Assessment of Cancer Therapy (FACT) measurement system is a patient-reported outcome (PRO) developed to document symptoms to diverse aspects of cancer treatment. One FACT version, FACT-An, specifically addresses symptoms of anemia related to cancer- therapy. FACT-An has been validated in diverse cancer populations but not in MPN-associated myelofibrosis. Methods. Data were from a phase-2 randomized double-blind Bayesian “pick-the-winner” trial of pomalidomide and prednisone in subjects with MPN-associated myelofibrosis and anemia (including RBC-transfusion-dependence). Details of the study, including definitions of anemia, response, RBC-transfusion-dependence and –independence were published previously. Change in quality of life (QOL) from randomization to the last cycle of therapy was evaluated by using the FACT-An physical well-being (PWB), functional well-being (FWB), trial outcome index (TOI) and anemia (An) domains. Minimally clinically important differences (MID) were used to determine the smallest difference in scores which subjects perceived as beneficial in the FACT-An domains of interest. Subjects were classified as meeting MID for responsiveness if their change score from baseline was greater than one standard error of measurement (SEM), indicating improvement. Results. 85 subjects were studied. All FACT-An domains showed strong reliability as measured by Cronbach's alpha. 31 were classified as anemia responders by clinical and laboratory criteria. Anemia responders showed greater improvement in PWB, FWB and TOI scores than non-responders (TOI presented below) across all FACT-An domains. Improvement began at the 2nd 28 d cycle of therapy and was sustained. Conclusion. We show anemia response defined by IWG-MRT criteria correlates with improved QOL measured by the FACT-An instrument in persons with MPN-associated myelofibrosis. Disclosures: Tencer: Celgene Corporation: Employment. Gale:Celgene Corporation: Employment. Khan:Celgene: Employment.

scholarly journals A Randomized Study to Determine the Optimal Dose of Darbepoetin Alfa in Patients with Low- or Intermediate-1 Risk Myelodysplastic Syndromes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4642-4642
Author(s):  
Hironori Harada ◽  
Hirohiko Shibayama ◽  
Jun Ho Jang ◽  
Ryutaro Shimazaki ◽  
Kinuko Mitani ◽  
...  
Keyword(s):  
Initial Dose ◽  
Research Funding ◽  
Controlled Trial ◽  
Randomized Study ◽  
Optimal Dose ◽  
Dose Evaluation ◽  
Erythroid Response ◽  
Evaluation Phase ◽  
The Mean ◽  
Rbc Transfusion

Abstract [Background] Erythropoiesis stimulating agents (ESAs) are used as standard treatment for anemia in patients with myelodysplastic syndromes (MDS) of low- or intermediate-1 (Int-1) risk according to the International Prognostic Scoring System (IPSS). However, no randomized study has been conducted to determine the optimal dose of ESAs. We conducted a randomized controlled trial of darbepoetin alfa (DA), a long-acting ESA, to find the optimal dose and evaluate efficacy and safety. [Methods] This multicenter randomized controlled trial was conducted in 41 sites in Japan and South Korea. Main inclusion criteria were red blood cell (RBC) transfusion-dependent, IPSS low/Int-1-risk MDS patients with hemoglobin (Hb) ≤ 9.0 g/dL and serum erythropoietin (EPO) ≤ 500 mIU/mL. Eligible patients were randomized to receive weekly subcutaneous doses of DA at a fixed dose of 60, 120 or 240 μg for 16 weeks (initial dose evaluation phase). DA was administered for up to 48 weeks, with dose adjustment allowed from week 17 onward. Dosing frequency was allowed either once every week (QW) or once every 2 weeks (Q2W), with the maximum single dose of 240 µg (extended treatment evaluation phase). The primary endpoint was modified IWG 2000 erythroid response defined as the proportion of patients who achieved an erythroid response [major erythroid response (MaR; RBC transfusion-free with an increase in Hb ≥ 1.0 g/dL above baseline) or a minor erythroid response (MiR; a ≥ 50% reduction in RBC transfusion as compared to baseline)] in the initial dose evaluation phase. Mortality and progression to AML were evaluated for one year. Changes in serum drug concentration and pharmacokinetic parameters were also evaluated. [Results] A total of 52 subjects were randomized. The subjects’ baseline demographics (mean±SD) included Hb of 7.9±0.9 g/dL, serum EPO concentration of 221.1±134.2 mIU/mL, and total amount of RBC transfusion given within 56 days prior to the first DA treatment of 1459±707.2 mL. Among 50 subjects evaluable for efficacy, the proportion of those who achieved an erythroid response during the initial dose evaluation phase in the 60, 120 and 240 μg group was: 64.7% (11/17 subjects) including 17.6% with MaR; 44.4% (8/18 subjects) including 16.7% with MaR; and 66.7% (10/15 subjects) including 33.3% with MaR, respectively. The proportion of subjects achieving erythroid response was similar across the three groups, but the highest proportion of MaR was noted in the 240 μg group. The mean baseline Hb was similar among the groups (7.7, 8.0, 8.0 g/dL in the 60, 120, 240 μg group, respectively). During the initial dose evaluation phase, the mean Hb level continued to rise over the first 2 weeks of DA treatment and remained between 8.6-9.1 g/dL thereafter in the 240 μg group, whereas the mean Hb was slightly lower in the 60 μg group (7.6-8.1 g/dL) and 120 μg group (8.1-8.4 g/dL). During the extended treatment evaluation phase (week 17-48), an increase in DA dose resulted in an improved response from "no response" to MiR and eventually to MaR in 1 subject in the 60 μg group, and from MiR to MaR in 2 subjects each in the 60 and 120 μg groups. There was no major difference among the groups with respect to time to erythroid response. No clinically significant safety concerns were identified. After 1 year of starting the treatment with DA, the survival rate and the proportion of subjects free from AML estimated by Kaplan-Meier method were 84.5% and 96.0%, respectively. The low baseline serum EPO concentration and low RBC transfusion needs were identified as strong predictors of efficacy. [Conclusion] These results demonstrated that treatment with DA is effective and safe in reducing or eliminating transfusion requirements in transfusion-dependent, IPSS low/Int-1-risk MDS patients. Given the highest proportion of subjects achieving MaR in the 240 μg group and the absence of dose-dependent adverse events, the optimal dose was determined to be 240 μg QW. No adverse effects were observed in terms of mortality and proportion of progression to AML. Table. Erythroid Response during the Initial-Dose Evaluation Phase Overall 60 ug 120 ug 240 ug N 50 17 18 15 Major or Minor Response n(%) 29(58.0%) 11(64.7%) 8(44.4%) 10(66.7%) Major Response n(%) 11(22.0%) 3(17.6%) 3(16.7%) 5(33.3%) Disclosures Harada: Kyowa Hakko Kirin Co., Ltd.: Research Funding. Shibayama:Kyowa Hakko Kirin Co., Ltd.: Research Funding. Jang:Kyowa Hakko Kirin Co., Ltd.: Research Funding. Shimazaki:Kyowa Hakko Kirin Co., Ltd.: Employment, Equity Ownership. Mitani:Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding. Sawada:Kyowa Hakko Kirin Co., Ltd.: Consultancy. Kim:Kyowa Hakko Kirin Co., Ltd.: Consultancy.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3037-3037
Author(s):  
Onima Chowdhury ◽  
Jennifer O'Sullivan ◽  
Nikolas Barkas ◽  
Gemma Buck ◽  
Angela Hamblin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Myeloproliferative Neoplasm ◽  
Unmet Need ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Polycythaemia Vera ◽  
Advisory Committees ◽  
Epigenetic Regulators ◽  
Rbc Transfusion

Abstract Background Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterised by the frequent presence of driver mutations in genes causing activation of JAK2 signalling pathways (JAK2, CALR and MPL). Additional mutations affecting epigenetic regulators and splicing machinery are common. Anaemia with RBC-transfusion-dependence is common in patients with advanced myelofibrosis and represents a major unmet need. The RESUME study assessed the rates of RBC-transfusion independence (TI) after therapy with Pomalidomide (POM) vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. 16% of patients in both the POM and placebo arms became TI. Aims The genetic landscape of strictly confirmed transfusion dependent MF is not fully characterised. Our aim was to analyse the genetics of transfusion-dependent myelofibrosis patients in the RESUME trial and correlate with clinical characteristics, outcome and therapy response. Methods DNA samples were available from 207 of 252 patients and analysed by targeted re-sequencing using a Fluidigm Access Array gene panel followed by next generation sequencing. The panel included JAK2, CALR, MPL, TET2, ASXL1, EZH2, DNMT3A, IDH1/2, CBL, IKZF1, U2AF1, CHEK2, TP53, SF3B1, SRSF2, SH2B3, BARD1, DAP3, HRAS, IRF4, KRAS, KIT, Mir662, NFE2, POLG, SCRIB, SETBP1, TCF12 and VPS45. Results 97% (95-99%) of subjects had a mutation in ≥1 targeted gene. 2 mutations were detected in 41% (34-48%) and ≥3 in 27% (21-33%). 7 had no detectable mutation. Mutations in JAK2V617F, CALR and MPL were identified in 66% (59-72%), 14% (8-19%) and 7% (4-11%) of subjects (Figure 1), with no driver mutation in 27 patients (13%; 9-18%) (triple-negative). 68% (61-74%) had additional non-driver mutations. 42% (35-48%) (N=86) had spliceosome mutations (U2AF1 [21%]; SF3B1 [11%]; SRSF2 [8%]; ZRSR2; [6%]). More spliceosome mutations were detected in men than women (47% [39-55%] vs 27% [15-40%]; p=0.009). Spliceosome mutations were mutually exclusive in 83 subjects and were less common in subjects with prior polycythaemia vera (17% [5-37%]) compared with prior essential thrombocythaemia (39% [22-58%]) and primary MF (46% [38-54%]; p=0.024). Mutations in epigenetic regulators (ASXL1, 28%; TET2, 8%; DNMT3A 5%; EZH2 4%) were detected at similar rates to those previously reported. High molecular risk (HMR) mutations (ASXL1, EZH2, IDH1/2, SRSF2) were detected in 36% [29-43%] of subjects. Only 10 of 105 subjects with an epigenetic regulator gene mutation had ≥1 related mutation. Subjects with JAK2V617F were significantly more likely than subjects with a CALR mutation to have: (1) ≥1 additional mutation (72% [64-79%] vs. 35% [18-54%], p=0.0001); (2) a spliceosome mutation (44% [36-53%] vs. 17% [6-36%], p=0.07), in particular a U2AF1 mutation (24% [17-32%] vs. 0%; p=0.004) and (3) a HMR mutation (38% [30-47%] vs. 21% [8-40%]; p=0.07). Survival at 1.5 years was 62% (55-67%) and was not significantly associated with the presence or number of mutations in this uniformly high-risk cohort. Survival in subjects without an SF3B1 mutation was better than those SF3B1-mutated (80% [56-91%]) vs. 59% [52-65%]; p=0.07). Driver mutation status did not influence the probability of achieving red blood cell (RBC) TI, regardless of therapy. Additional non-driver mutations were more often detected in those failing to achieve RBC-TI than those achieving RBC-TI (70% [63-77%] vs 56% [40-71%], p=0.07). Furthermore, those with additional non-driver mutations were less likely to achieve ≥50% reduction in RBC transfusions (24% [17-32%] vs. 39% [27-51%]; p=0.03). A significant correlation persisted in subjects receiving POM but not in those receiving placebo. There was also a significant correlation between U2AF1 mutations and RBC-TI in POM treated subjects compared with controls; U2AF1-mutated subjects were less likely to achieve RBC-TI (3% [1, 17%]) than U2AF1-unmutated subjects (25% [17, 34%], p=0.008). No other mutations were significantly correlated with response. Conclusion We found a high incidence of spliceosome mutations in persons with MPN-associated MF and RBC-transfusion-dependence. Mutation of U2AF1 correlated with response in subjects receiving POM but not in those receiving placebo. Incorporation of mutation profiling into clinical trial design may help to inform subgroups of patients that may benefit from the intervention. Disclosures Devos: Novartis: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Gisslinger:Shire: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria. Kiladjian:Celgene: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Celgene: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment; Pfizer: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy; Promedior: Research Funding; Genentech: Research Funding. Ribrag:argenX: Research Funding; BMS: Consultancy, Honoraria, Other: travel; NanoString Technologies: Consultancy, Honoraria; pharmamar: Other: travel; Infinity: Consultancy, Honoraria; MSD: Honoraria; Amgen: Research Funding; Gilead: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Honoraria, Other: travel; epizyme: Consultancy, Honoraria; Incyte Corporation: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Reiser:Celgene: Employment. Zhong:Celgene: Employment. Mead:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy; Cell Therapeutics: Consultancy; Celgene: Research Funding; Elstar: Research Funding; Evotek: Research Funding.

Results of a randomized study of the JAK inhibitor ruxolitinib (INC424) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF).

2011 ◽  
Vol 29 (18_suppl) ◽  
pp. LBA6501-LBA6501 ◽  
Author(s):  
C. N. Harrison ◽  
J. Kiladjian ◽  
H. K. Al-Ali ◽  
H. Gisslinger ◽  
R. J. Waltzman ◽  
...  
Keyword(s):  
Response Rate ◽  
Randomized Study ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Phase Iii ◽  
Baseline Risk ◽  
Risk Category ◽  
Spleen Volume ◽  
Number Of Patients ◽  
Grade 3

LBA6501 Background: MF, a myeloproliferative neoplasm characterized by dysregulation of the JAK pathway, is associated with splenomegaly, constitutional symptoms and reduced lifespan. Ruxolitinib is a potent and selective JAK1 and JAK2 inhibitor. Methods: COMFORT-II, a randomized (2:1) phase III study, compared the efficacy and safety of ruxolitinib PO BID with BAT (other agents or no therapy) in adults with intermediate-2 or high-risk (Cervantes et al, Blood 2009) PMF, PPV-MF or PET-MF and palpable splenomegaly. The primary endpoint was the proportion of patients (pts), stratified by baseline risk category, achieving ≥ 35% reduction in spleen volume at week (wk) 48 determined by MRI or CT. The key secondary endpoint was the proportion achieving ≥ 35% reduction in spleen volume at wk 24. Results: 219 pts were randomized: 146 to ruxolitinib and 73 to BAT. Both arms included 49% high- and 51% intermediate-2 risk pts. The wk 48 response rate was 28.5% vs 0% (ruxolitinib vs BAT, P < .0001). The wk 24 response rate was 31.9% vs 0% (ruxolitinib vs BAT, P < .0001). Median duration of response to ruxolitinib was 48 wks. The most common (> 20%) adverse events (AEs) of any grade were (ruxolitinib vs BAT) thrombocytopenia (44.5% vs 9.6%), anemia (40.4% vs 12.3%), diarrhea (24.0% vs 11.0%), and peripheral edema (21.9% vs 26.0%). Grade 3-4 AEs occurring in ≥ 5% of pts in the ruxolitinib arm were: anemia (11%) and thrombocytopenia (7.5%). The most frequent grade 3-4 AEs in the BAT arm were anemia, thrombocytopenia, pneumonia and dyspnea (each 4.1%). Seven deaths occurred on treatment or within 28 days after end of treatment: 4 (2.7%) ruxolitinib and 3 (4.1%) BAT. Disposition of discontinuations were (ruxolitinib vs BAT) 8.2% vs 5.5% due to AEs and 1.4% vs 12.3% due to withdrawn consent. Conclusions: The COMFORT-II study demonstrates that ruxolitinib provides marked and sustained clinical benefit in spleen size and an acceptable safety profile relative to BAT, extends the positive results of COMFORT-I which compared ruxolitinib with placebo, and may result in a new standard of care for a large number of patients with MF.

Darbepoietin in Autologous Peripheral Blood Stem Cell Transplantation (ASCT): A Pilot Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5101-5101
Author(s):  
Anna Chierichini ◽  
Barbara Anaclerico ◽  
Paola Anticoli Borza ◽  
Susanna Fenu ◽  
Carolina Nobile ◽  
...  
Keyword(s):  
Pilot Study ◽  
Side Effects ◽  
Median Time ◽  
Randomized Study ◽  
Supportive Therapy ◽  
Number Of Patients ◽  
Cost Efficacy ◽  
Long Acting ◽  
The Impact ◽  
Rbc Transfusion

Abstract In patients undergoing ASCT, RBC transfusions are depending on donor availability and correlated with early and late side effects such as immune reactions and infections. Three weeks long acting Darbepoietin is currently available, but its role in ASCT in terms of efficacy, safety and cost has not yet been established. Aim: This pilot study was activated in ASCT patients to test the impact of Darbepoietin on the haemoglobin level; RBC transfusion requirement; the total cost of Darbepoietin therapy during the first 30 days after ASCT. Material and methods. From September 2006 to June 2007, 10 patients - 5 males, median age 57 years (range 20–71) - with Multiple Myeloma (MM n=7) in 1st response, Non-Hodgkin (NHL n=2) and Hodgkin (HL n=1) Lymphoma in 2nd complete remission entered the study. As conditioning regimens, the patients received Mel 200 (n=8) or BEAM (n=2). Baseline Hb and Epo median values were: 12,1g/L (range 10.3 – 16.2 g/L), and 28.7mU/mL (range, 4.1–220 mU/L), respectively. The median value of CD34+ cells infused was 4.99 x109/L (range 3.04 – 5.07) and the median time to engraftment was 10 days (range 8–11). To prevent anaemia, patients were given i.c. single dose 500 U Darbepoietin on day +1, associated with iron therapy and B12 vitamin /weekly, plus folinic acid and B6 vitamin/daily. RBC transfusion was mandatory for Hb level ≤ 8g/L. Results: At day +30, in 9/10 patients (7 MM, 1 NHL and 1HL) the median Hb value was 13.2 g/L (range 10.2 – 15.1g/L), and none of them were transfused. Only 1 NHL received 1 RBC unit on day +7 because of Hb was 8g/L; in this case, the baseline dosage of Epo was high (220 mU/L). On the follow-up (median time 4 months, range 1–11), no thromboembolic events or other side effects occurred. Finally, in our Country the price of 1 vial Darbepoietin and 1 RBC transfusion (packed, filtered and irradiated) is 744.60 and 340 euro, respectively. Therefore,, the cost of the entire supportive therapy in our 10 patients has been 7.786 euro. Comments Despite the small number of patients, from this pilot study we can drawn the conclusion that Darbepoietin seems an effective and safe therapy and could represent an appropriate support in ASCT patients with baseline low/normal Epo level. Only a prospective, randomized study on a large number of patients will be able to answer the question on the Darbepoietin cost-efficacy in ASCT.

Phase-2 Study of Sotatercept (ACE-011) in Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 478-478 ◽  
Author(s):  
Prithviraj Bose ◽  
Naval Daver ◽  
Elias J. Jabbour ◽  
Allison Pike ◽  
Kate J Newberry ◽  
...  
Keyword(s):  
Research Funding ◽  
Transforming Growth Factor ◽  
Injection Site Reaction ◽  
Myeloproliferative Neoplasm ◽  
International Prognostic Scoring System ◽  
Cell Transplant ◽  
Phase 2 ◽  
Medical Problems ◽  
Phase 2 Study ◽  
Rbc Transfusion

Abstract Introduction: Anemia is common in MPN-associated myelofibrosis (MF), and current therapies (e.g., erythropoiesis stimulating agents, androgens, danazol, immune modulatory drugs and corticosteroids) are unsatisfactory. Furthermore, anemia is not improved and initially worsened by ruxolitinib, an important MF therapy. New drugs with novel mechanisms of action are needed. Sotatercept is a first-in-class activin receptor type IIA (ActRIIA) ligand trap consisting of the extracellular domain of ActIIRA linked to the human IgG1 Fc domain. Sotatercept binds to and sequesters ligands of the transforming growth factor beta (TGF-ß) superfamily, thus relieving their blockade of terminal erythroid differentiation. Pre-clinically, sotatercept corrects ineffective erythropoiesis in ß-thalassemia (Dussiot, M. et al. Nat Med 2014) and its murine ortholog RAP-011 improves erythropoiesis in Diamond Blackfan anemia (Ear, J. et al. Blood 2015). Clinical trials in persons with lower risk myelodysplastic syndromes (Komrokji, R. et al. ASH 2014) and chemotherapy-induced anemia (Raftopoulos, H. et al. Support Care Cancer 2016) have shown promising results. Methods: This is an ongoing phase-2 study of sotatercept, 0.75 or 1 mg/kg subcutaneously every 3 weeks (1 cycle), in subjects with MF, whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). Subjects must be RBC-transfusion-dependent (Gale, R.P. et al. Leuk Res 2011), have hemoglobin <10 g/dL on every determination during the 84 days preceding study entry without RBC transfusions, or have hemoglobin <10 g/dL despite intermittent RBC transfusions without fulfilling the criteria for transfusion dependence. Primary endpoints include anemia response and safety. Secondary endpoints include time to and duration of anemia response. Anemia response is a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions). Subjects must have received ≥5 cycles of sotatercept to be evaluable for response. Results: 18 subjects are enrolled to date. 1 subject received 6 cycles at a sub-therapeutic dose of 0.3 mg/kg and was not considered for efficacy evaluation, but was evaluable for safety. Of the remaining 17 subjects, 11 received 0.75 mg/kg and 6, 1 mg/kg. Median age was 67 years (range, 47-84 years); 10 were male and 7 female. 14 had PMF and 3, post-ET MF. 12 subjects had JAK2 V617F, 1 had MPLW515L and 2 had CALR exon 9 mutations. 1 subject was triple negative and 1 subject had no JAK2 or MPL mutation but was not tested for CALR mutations. All 17 subjects had intermediate-2 or high risk disease by the Dynamic International Prognostic Scoring System. Table 1 summarizes baseline variables for these 17 subjects. Median number of cycles of sotatercept received is 5 (range, 1-13). 14 of the 17 subjects received ≥5 cycles and were evaluable for response. The 3 other subjects received 1, 2 and 2 cycles and discontinued due to unrelated medical problems, hypertension and stem cell transplant (SCT), respectively. 5 of 14 (36%) evaluable subjects have responded; 4 of whom continue on study in ongoing response. All responders are female and all female subjects evaluable for response responded. Responses occurred across phenotypic driver mutation categories and in both transfusion-dependent (n=3) and -independent (n=2) subjects. 40% and 25% of evaluable patients responded in the 0.75 mg/kg and 1 mg/kg dose cohorts, respectively. Most adverse events (AEs) were grades 1 or 2. The only AEs possibly attributable to sotatercept include grade 3 hypertension leading to discontinuation, and grade 1 myalgia, bone pain, pain in extremity and injection site reaction. 5 subjects remain on study. 12 have discontinued because of no response (5), SCT (2), unrelated medical problems (1), hypertension (1), disease progression (1), transformation to AML (1) and withdrawal of consent (1). Conclusion: Sotatercept improves anemia and RBC-transfusion-dependence in persons with MF and is well-tolerated. Enrollment to the trial is ongoing; updated results will be presented. A separate cohort of subjects receiving ruxolitinib has been added and will also be discussed. Based on the preponderance of responses at the 0.75 mg/kg dose, this dose has been selected for the combination cohort. Disclosures Daver: Incyte: Consultancy, Other: Advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

A randomized study of lenalidomide (LEN) with or without EPO in RBC transfusion dependent (TD) IPSS low and int-1 (lower risk) myelodysplastic syndromes (MDS) without del 5q resistant to EPO.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7002-7002 ◽  
Author(s):  
Andrea Toma ◽  
Sylvie Chevret ◽  
Olivier Kosmider ◽  
Jacques Delaunay ◽  
Aspasia Stamatoullas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lower Risk ◽  
Randomized Study ◽  
Gene Expression Signature ◽  
Open Label ◽  
Entire Cohort ◽  
Expression Signature ◽  
Erythroid Response ◽  
Transfusion Independence ◽  
Rbc Transfusion

7002 Background: ESAs, the first line treatments of anemia in non del 5q lower risk MDS, yield only 40-50% responses. LEN gives RBC transfusion independence (TI) in about 25% of ESA resistant (or relapsing) TD lower risk MDS without del 5q (Raza, Blood, 2008), and a gene expression signature can predict response (Ebert, Plos Med 2008). We randomized in this patient population LEN alone and LEN+EPO. Methods: In this prospective multicenter open-label phase II study (NCT01718379), lower risk MDS patients without del 5q, with TD (≥4 RBC units during the previous 8 weeks (w)) with ESA resistance or relapse after a response were randomized between LEN alone, 10mg/d x 21 d/4 w (L arm) or LEN (same schedule) + EPO beta, 60 000 U/w (LE arm). The primary endpoint was erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles. Secondary objectives included identification of biomarkers of response. Results: Between July 2010 and June 2012, 132 patients (pts, 66 / arm), median age 73 (range 46-88), M/F: 88/44 were enrolled. Median TD was 6 RBC units/8w (range 2-18). IPSS was Low in 45% and Int-1 in 55% pts. Pretreatment characteristics did not differ between the 2 groups. All but 3 pts, who withdrew consent (2L+1LE), were evaluable for response. In this ITT population, HI-E was obtained in 15 pts (23.4%) in L arm and 26 (40.0%) in LE arm (RR= 1.7, p= 0.043, chi2 test), and TI in 9 (14.1%) versus 16 (24.6%) pts (RR=1.7, p= 0.13). In the 99 pts who completed 4 treatment cycles, 41 achieved HI-E, including 15/49 (30.6%) in L arm versus 26/50 (52.0%) in LE arm (p= 0.03), and TI in 9 (18.4%) versus 16 (32.0%) pts (RR= 1.7, p=0.12). Side effects (cytopenias and 1 DVT/arm) were similar in the 2 arms. A 29-gene expression profile signature predicting HI-E to L or LE, different from that previously published, was identified and a polymorphism in the CRBN gene (Kosmider, submitted) was significantly associated with HI-E in the entire cohort (p=0.034). Conclusions: LEN + EPO yielded a significantly better erythroid response than LEN alone in lower risk MDS patients with anemia resistant to ESA alone. A gene expression signature and a CRBN gene polymorphism correlated with the erythroid response. Clinical trial information: NCT01718379.

Sign in / Sign up

Export Citation Format

Share Document