Lenalidomide-Induced Cytopenias: Relationship to Hematologic Improvement in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 821-821 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Jaroslaw P. Maciejewski ◽  
Aristoteles Giagounidis ◽  
Kenton Wride ◽  
Robert D. Knight ◽  
...  
Keyword(s):  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Myelodysplastic Syndromes ◽  
Odds Ratio ◽  
Lower Risk ◽  
Multivariate Analyses ◽  
Mechanisms Of Action ◽  
Erythroid Response ◽  
Transfusion Independence ◽  
Rbc Transfusion

Abstract Background: Lenalidomide (LEN) is effective in MDS patients (pts) with or without deletion (del) 5q cytogenetic abnormalities. Common toxicities include neutropenia and thrombocytopenia. Both occurrence of cytopenias and response to LEN is more common in pts with the del 5q abnormality. This study analyzes whether development of treatment-related cytopenias is associated with response to LEN in lower-risk MDS pts. Methods: Transfusion-dependent, low/int-1-risk MDS pts were enrolled in the MDS-003 (del 5q pts) and MDS-002 (non-del 5q pts) studies. Pts were treated with 10 mg LEN (daily or 21/28 days). Baseline thrombocytopenia was defined as a platelet (plt) count <150,000/mm3; neutropenia as an absolute neutrophil count (ANC) <2000/mm3 (grade 1–4 using the CTC v2.0). Cytopenias were assessed within the first 8 weeks of LEN therapy, and given functional definitions based on frequency tables. Response was assessed using International Working Group criteria. Results: Of 147 evaluable pts in MDS-003, 59 (40%) had thrombocytopenia, 59 (40%) neutropenia, and 84 (57%) neutropenia and/or thrombocytopenia according to baseline labs. Of 210 evaluable pts in MDS-002, 69 (33%) had thrombocytopenia and 81 (39%) neutropenia at baseline. For both studies, median age was 71 and 72 years and MDS duration was 2.5 and 2.2 years, respectively. RBC transfusion independence (TI) was achieved by 99 pts (67%) in MDS-003 (List et al. NEJM 2006) and 56 pts (26%) in MDS-002. For pts with del 5q, development of thrombocytopenia correlated with TI, regardless of baseline plt count (p=0.005). Comparing pts who had a ≥50% drop vs those who did not, TI was achieved in 76% vs 47% of pts without baseline thrombocytopenia and in 67% vs 38% of pts with thrombocytopenia, respectively. Similar results held for pts without baseline neutropenia: 82% whose ANC fell ≥75% achieved TI, compared to 56% whose ANC fell <75% (p=0.018). In pts with baseline neutropenia, ANC drop did not correlate with TI (p=0.75). In pts with any baseline cytopenia, those whose ANCs fell by ≥75% and/or plt by ≥50% were more likely to achieve TI than those whose counts did not drop substantially, controlling for baseline cytopenias (71% vs. 60%, p=0.024). In multivariate analyses, both a treatment-related ANC drop ≥75% (odds ratio [OR]=2.68, p=0.04) and a plt drop ≥50% (OR=2.79, p=0.05) remained associated with TI in MDS-003. Neither was associated with duration of TI response, though there was a trend with drop in ANC (hazard ratio=2.04, p=0.06). In contrast, for pts without del 5q (MDS-002), no correlation exists between TI and drop in plt count (p=0.36 for patients without and p=0.16 for those with baseline thrombocytopenia), drop in ANC (p=0.43 for those without and p=0.44 for those with baseline neutropenia), or development of either cytopenia. No correlation with TI could be established in MDS-002 for drops of 25%, 50%, or 75% within 4, 8, or 16 weeks of therapy, in both univariate and multivariate analyses. Conclusions: In MDS pts with del 5q, treatment-related thrombocytopenia, and neutropenia in those with normal baseline ANCs, correlate with response to LEN, supporting the link between suppression of the del 5q clone and erythroid response. This correlation was not observed in non-del 5q MDS pts, indicating alternate mechanisms of action of LEN.

scholarly journals Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes

2021 ◽  
Vol 39 (13) ◽  
pp. 1426-1436
Author(s):  
Guillermo Garcia-Manero ◽  
Valeria Santini ◽  
Antonio Almeida ◽  
Uwe Platzbecker ◽  
Anna Jonasova ◽  
...  
Keyword(s):  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Controlled Trial ◽  
Phase Iii ◽  
International Prognostic Scoring System ◽  
Low Grade ◽  
Improvement Rate ◽  
Rbc Transfusion

PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion–dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed.

scholarly journals Relationship of Treatment-Related Cytopenias and Response to Lenalidomide in Patients With Lower-Risk Myelodysplastic Syndromes

2008 ◽  
Vol 26 (36) ◽  
pp. 5943-5949 ◽  
Author(s):  
Mikkael A. Sekeres ◽  
Jaroslaw P. Maciejewski ◽  
Aristotle A.N. Giagounidis ◽  
Kenton Wride ◽  
Robert Knight ◽  
...  
Keyword(s):  
Platelet Count ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Multivariate Analyses ◽  
Surrogate Marker ◽  
Two Phase ◽  
Transfusion Independence ◽  
Response Predictors ◽  
Phase Ii Studies ◽  
Risk Patients

PurposePatients with myelodysplastic syndromes (MDS) often require treatment with growth factors (GFs) or non-GF therapies. One non-GF drug, lenalidomide, is particularly effective at achieving transfusion independence (TI) in patients with lower-risk MDS with the del(5q) cytogenetic abnormality. However, approximately half of del(5q) patients and one quarter of non–del(5q) patients treated with lenalidomide experience significant cytopenias. Lenalidomide-induced cytopenias occurring early in treatment may serve as a surrogate marker of clonal suppression and, therefore, may be predictive of a TI response.Patients and MethodsWe analyzed 362 low-risk, transfusion-dependent patients with MDS, with or without the del(5q) abnormality, enrolled in two phase II studies (MDS-003 and MDS-002) to determine whether treatment-related cytopenias are correlated with lenalidomide response. Cytopenias were assessed during the first 8 weeks of therapy, and response was defined as TI; response predictors were explored in univariate and multivariate analyses.ResultsAmong patients with del(5q), 70% of those whose platelet count decreased by ≥ 50% achieved TI, as compared with 42% of those whose platelet count remained stable or declined by less than 50% (P = .01). Among patients without baseline neutropenia, 82% of those whose absolute neutrophil count (ANC) decreased by ≥ 75% achieved TI, as compared with 51% whose ANC remained stable or decreased by less than 75% (P = .02). These relationships were consistent in multivariate analyses. No relationship between the development of cytopenias and response could be established for lower-risk patients with MDS without del(5q).ConclusionThese findings support the hypothesis that a direct cytotoxic effect of lenalidomide specific to the del(5q) clone may be indicative of a TI response.

Hematologic Response to Three Alternative Dosing Schedules of Azacitidine in Patients With Myelodysplastic Syndromes

2009 ◽  
Vol 27 (11) ◽  
pp. 1850-1856 ◽  
Author(s):  
Roger M. Lyons ◽  
Thomas M. Cosgriff ◽  
Sanjiv S. Modi ◽  
Robert H. Gersh ◽  
John D. Hainsworth ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Refractory Anemia ◽  
Open Label ◽  
Open Label Study ◽  
Transfusion Independence ◽  
Dosing Regimens ◽  
Grade 3 ◽  
Myelomonocytic Leukemia ◽  
Rbc Transfusion

Purpose Azacitidine (AZA) is effective treatment for myelodysplastic syndromes (MDS) at a dosing schedule of 75 mg/m2/d subcutaneously for 7 days every 4 weeks. The initial phase of this ongoing multicenter, community-based, open-label study evaluated three alternative AZA dosing schedules without weekend dosing. Patients and Methods MDS patients were randomly assigned to one of three regimens every 4 weeks for six cycles: AZA 5-2-2 (75 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 75 mg/m2/d for 2 days); AZA 5-2-5 (50 mg/m2/d subcutaneously for 5 days, followed by 2 days no treatment, then 50 mg/m2/d for 5 days); or AZA 5 (75 mg/m2/d subcutaneously for 5 days). Results Of patients randomly assigned to AZA 5-2-2 (n = 50), AZA 5-2-5 (n = 51), or AZA 5 (n = 50), most were French-American-British (FAB) lower risk (refractory anemia [RA]/RA with ringed sideroblasts/chronic myelomonocytic leukemia with < 5% bone marrow blasts, 63%) or RA with excess blasts (30%), and 79 (52%) completed ≥ six treatment cycles. Hematologic improvement (HI) was achieved by 44% (22 of 50), 45% (23 of 51), and 56% (28 of 50) of AZA 5-2-2, AZA 5-2-5, and AZA 5 arms, respectively. Proportions of RBC transfusion–dependent patients who achieved transfusion independence were 50% (12 of 24), 55% (12 of 22), and 64% (16 of 25), and of FAB lower-risk transfusion-dependent patients were 53% (nine of 17), 50% (six of 12), and 61% (11 of 18), respectively. In the AZA 5-2-2, AZA 5-2-5, and AZA 5 groups, 84%, 77%, and 58%, respectively, experienced ≥ 1 grade 3 to 4 adverse events. Conclusion All three alternative dosing regimens produced HI, RBC transfusion independence, and safety responses consistent with the currently approved AZA regimen. These results support AZA benefits in transfusion-dependent lower-risk MDS patients.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3168-3168 ◽  
Author(s):  
Uwe Platzbecker ◽  
Ulrich Germing ◽  
Katharina Götze ◽  
Philipp Kiewe ◽  
Thomas Wolff ◽  
...  
Keyword(s):  
Lower Risk ◽  
Extension Study ◽  
Intermediate Risk ◽  
Phase 2 ◽  
Employment Equity ◽  
Erythroid Response ◽  
Transfusion Independence ◽  
Equity Ownership ◽  
Rbc Transfusion

Abstract 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). Disclosures Platzbecker: 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.

Lenalidomide (LEN) In Lower-Risk Myelodysplastic Syndromes (MDS) with Karyotypes Other Than Deletion 5q and Refractory to Erythropoiesis-Stimulating Agents (ESAs)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4002-4002
Author(s):  
David Sibon ◽  
Giovanna Cannas ◽  
Fiorenza Barraco ◽  
Thomas Prebet ◽  
Norbert Vey ◽  
...  
Keyword(s):  
Median Duration ◽  
Lower Risk ◽  
Conflicts Of Interest ◽  
Response Duration ◽  
Median Response ◽  
Erythroid Response ◽  
Vein Thrombosis ◽  
Transfusion Independence ◽  
Wbc Count ◽  
Rbc Transfusion

Abstract Abstract 4002 Background. In lower-risk MDS, anemia is the main therapeutic challenge. ESAs can frequently correct anemia, but not all pts respond and median response duration to ESAs is only about 2 years. LEN yields RBC transfusion-independence (TI) in 65% of lower risk MDS with del(5q)] and about 25% of lower risk MDS without del 5q (Raza A, et al, Blood, 2008, 111, 1). However, in the last study, pretreatment with ESAs was not always documented, and the efficacy of LEN on anemia of non-del(5q) MDS refractory to ESAs remains unknown. Patients and Methods: 31 consecutive lower-risk non-del(5q) MDS with anemia refractory to ESAs were treated with LEN through a compassionate program. Pts wn@ere from 7 centers of the Groupe Francophone des Myélodysplasies. They had previously received an ESA during at least 12 weeks, including epoetin alfa (80,000 U qw, n= 17), epoetin beta (60,000 qw, n=3), darbepoetin (500 μg q2 w, n=11), and GCSF was added in 20 patients. Results: At inclusion in the program, median age was 69 (range 41–87), including RA (n=3), RAEB-1 (n=2), RARS (n=11), RCMD (n=12), and RCMD-RS (n=3). Karyotype was fav (n=27), int (n=2), and unfav (n=2). IPSS was low (n=15), int-1 (n=16). Median ESAs treatment duration was 3 months (3-36+). According to IWG 2006 criteria, 18 pts were primary resistant to ESAs while 13 relapsed after a 12 months median duration of erythroid response (range 3–36). At onset of LEN, median Hb level was 8.9 g/dl (range 6.3–9.9), median endogenous EPO level 172 UI/l (48-1092 UI/l). The starting doses of LEN were 5 (n=10) or 10 mg (n=21), daily (n=26) or daily × 3 wks q28d cycle (n=5). 20 pts also received ESAs including EPO alone (n=6) and EPO+GCSF (n=14). Deep vein thrombosis (DVT) prophylaxis was made in 22 pts (71%) with aspirin (n=20), heparin (n=1) or warfarin (n=1). With a median follow-up of 16 months (range 3–27), 13 (42%) pts obtained an erythroid response (IWG 2006 criteria). All responses occurred within the first 3 months of treatment. 4 of the responders (31%) relapsed at 4, 9, 15, and 16 months whereas 9 (69%) were still responding after 3+ to 24+ months. Median response duration was 12 months. Of the 24 RBC-TD patients, 10 (42 %) achieved RBC-TI of 12 months median duration (range 3+-22+). The most common drug-related grade 3/4 adverse events were neutropenia (n=6, 19%) and thrombocytopenia (n=6, 19%). No pt developed DVT. One pt with RCMD and complex karyotype developed AML and died at 3.1 months from treatment onset, 2 additional pts who resisted to LEN died 5 and 6 months after LEN interruption. According to IWG 2006 criteria, the proportion of erythroid responses was significantly lower in the 8 patients who had developed neutropenia or thrombocytopenia: 1/8 vs 12/23, p = 0.038. Among the 24 RBC-TD patients, the proportion of RBC-TI was significantly lower in the 8 patients who had developed neutropenia or thrombocytopenia: 1/8 vs 9/16, p = 0.05. Median RBC-TI duration was significantly lower in the 8 patients who had developed neutropenia or thrombocytopenia: 0 vs 9 months, p=0.05. Other factors such as age, sex, WHO classification, time between diagnosis and treatment, response to ESAs, interval between ESAs and REV, WBC count, hemoglobin level, platelet count, LEN dose, combination to ESAs, did not significantly influence response to LEN, and RBC-TI duration. Conclusion: In this cohort of lower-risk non-del(5q) MDS refractory to ESAs LEN yielded RBC transfusion independence in more than 40% of the pts and was well-tolerated. Treatment-induced cytopenia was associated with fewer erythroid responses and shorter response duration. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion–Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study

2021 ◽  
Vol 39 (1) ◽  
pp. 48-56
Author(s):  
David P. Steensma ◽  
Pierre Fenaux ◽  
Koen Van Eygen ◽  
Azra Raza ◽  
Valeria Santini ◽  
...  
Keyword(s):  
Phase Ii ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Treatment Options ◽  
Competitive Inhibitor ◽  
Telomerase Activity ◽  
Transfusion Independence ◽  
Human Telomerase ◽  
Transcription Expression ◽  
Rbc Transfusion

PURPOSE Patients with lower-risk (LR) myelodysplastic syndromes (MDS) who are RBC transfusion dependent and have experienced relapse after or are refractory to erythropoiesis-stimulating agent (ESA) have limited treatment options. High telomerase activity and human telomerase reverse-transcription expression in clonal hematopoietic cells have been reported in patients with MDS. Imetelstat, a first-in-class competitive inhibitor of telomerase enzymatic activity, targets cells with active telomerase. We report efficacy, safety, and biomarker data for patients with LR MDS who are RBC transfusion dependent and who were relapsed/refractory to ESAs. PATIENTS AND METHODS In this two-part phase II/III study (MDS3001), the primary end point was 8-week RBC transfusion independence (TI) rate, with key secondary end points of 24-week RBC TI rate, TI duration, and hematologic improvement-erythroid. RESULTS Data from the phase II part of the study are reported. Of 57 patients enrolled and treated (overall population), 38 were non-del(5q) and hypomethylating agent and lenalidomide naïve (subset population). The 8- and 24-week RBC TI rates in the overall population were 37% and 23%, respectively, with a median TI duration of 65 weeks. In the subset population, 8- and 24-week RBC TI rates were 42% and 29%, respectively, with a median TI duration of 86 weeks. Eight-week TI rate was observed across all subgroups evaluated. Cytogenetic and mutational data revealed a reduction of the malignant clones, suggesting disease modification activity. The most common adverse events were cytopenias, typically reversible within 4 weeks. CONCLUSION Imetelstat treatment results in a meaningful, durable TI rate across a broad range of heavily transfused patients with LR MDS who are ineligible for or relapsed/refractory to ESAs. Biomarker analyses indicated effects on the mutant malignant clone.

Randomized Phase III Study of Lenalidomide Versus Placebo in RBC Transfusion-Dependent Patients With Lower-Risk Non-del(5q) Myelodysplastic Syndromes and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents

2016 ◽  
Vol 34 (25) ◽  
pp. 2988-2996 ◽  
Author(s):  
Valeria Santini ◽  
Antonio Almeida ◽  
Aristoteles Giagounidis ◽  
Stefanie Gröpper ◽  
Anna Jonasova ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Phase Iii ◽  
International Prognostic Scoring System ◽  
Double Blind Study ◽  
Double Blind ◽  
Erythropoiesis Stimulating Agents ◽  
Endogenous Erythropoietin ◽  
Erythroid Response ◽  
Rbc Transfusion

Purpose This international phase III, randomized, placebo-controlled, double-blind study assessed the efficacy and safety of lenalidomide in RBC transfusion–dependent patients with International Prognostic Scoring System lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. Patients and Methods In total, 239 patients were randomly assigned (2:1) to treatment with lenalidomide (n = 160) or placebo (n = 79) once per day (on 28-day cycles). The primary end point was the rate of RBC transfusion independence (TI) ≥ 8 weeks. Secondary end points were RBC-TI ≥ 24 weeks, duration of RBC-TI, erythroid response, health-related quality of life (HRQoL), and safety. Results RBC-TI ≥ 8 weeks was achieved in 26.9% and 2.5% of patients in the lenalidomide and placebo groups, respectively (P < .001). Ninety percent of patients achieving RBC-TI responded within 16 weeks of treatment. Median duration of RBC-TI with lenalidomide was 30.9 weeks (95% CI, 20.7 to 59.1). Transfusion reduction of ≥ 4 units packed RBCs, on the basis of a 112-day assessment, was 21.8% in the lenalidomide group and 0% in the placebo group. Higher response rates were observed in patients with lower baseline endogenous erythropoietin ≤ 500 mU/mL (34.0% v 15.5% for > 500 mU/mL). At week 12, mean changes in HRQoL scores from baseline did not differ significantly between treatment groups, which suggests that lenalidomide did not adversely affect HRQoL. Achievement of RBC-TI ≥ 8 weeks was associated with significant improvements in HRQoL (P < .01). The most common treatment-emergent adverse events were neutropenia and thrombocytopenia. Conclusion Lenalidomide yields sustained RBC-TI in 26.9% of RBC transfusion–dependent patients with lower-risk non-del(5q) myelodysplastic syndromes ineligible for or refractory to erythropoiesis-stimulating agents. Response to lenalidomide was associated with improved HRQoL. Treatment-emergent adverse event data were consistent with the known safety profile of lenalidomide.

scholarly journals Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis

Blood ◽  
2019 ◽  
Vol 133 (8) ◽  
pp. 790-794 ◽  
Author(s):  
Pierre Fenaux ◽  
Jean Jacques Kiladjian ◽  
Uwe Platzbecker
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Transforming Growth Factor ◽  
Primary Myelofibrosis ◽  
Transforming Growth Factor Β ◽  
Poor Quality ◽  
Transfusion Independence ◽  
Differentiation Factors ◽  
Rbc Transfusion

AbstractAnemia of lower-risk myelodysplastic syndromes (MDSs) and primary myelofibrosis (PMF) generally becomes resistant to available treatments, leading to red blood cell (RBC) transfusions, iron overload, shortened survival, and poor quality of life. The transforming growth factor-β superfamily, including activins and growth differentiation factors (GDFs), is aberrantly expressed in lower-risk MDSs and PMF. Luspatercept (and sotatercept), ligand traps that particularly inhibit GDF11, lead to RBC transfusion independence in 10% to 50% of lower-risk MDSs resistant to available treatments, and have started to be used in PMF.

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.

scholarly journals Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1020-1030 ◽  
Author(s):  
U. Platzbecker ◽  
P. Fenaux ◽  
L. Adès ◽  
A. Giagounidis ◽  
V. Santini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Working Group ◽  
Lower Risk ◽  
Response Assessment ◽  
Response To Treatment ◽  
Response Criteria ◽  
Patient Response ◽  
Erythroid Response ◽  
Clinical Responses

Abstract The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for “hematological improvement” criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between “procedures” and “criteria” for hematologic improvement–erythroid assessment and a new categorization of transfusion-burden subgroups.

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