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.

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.

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.

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.

Clinical Management of Myelodysplastic Syndromes With Interstitial Deletion of Chromosome 5q

2006 ◽  
Vol 24 (16) ◽  
pp. 2576-2582 ◽  
Author(s):  
Stephen D. Nimer
Keyword(s):  
Myelodysplastic Syndromes ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Normal Karyotype ◽  
Transfusion Independence ◽  
Chromosome 5Q ◽  
Transfusion Requirements ◽  
Definition Of ◽  
Classification And Treatment ◽  
Rbc Transfusion

Deletions of the long (q) arm of chromosome 5 [del(5q)]occur in patients with myelodysplastic syndromes (MDS) including, but not limited to, those who meet the WHO definition of the 5q− syndrome. Del(5q) MDS patients frequently have symptomatic anemia, and its treatment has traditionally consisted of RBC transfusions and, for some, iron chelation therapy. Erythropoietin, darbepoetin, hypomethylating agents, and lenalidomide can enhance erythropoiesis in MDS patients with anemia, increasing hemoglobin levels and abrogating RBC transfusion requirements. Lenalidomide is particularly active in treating the anemia of del(5q) MDS, which is especially relevant given the low response rate to erythropoietin in this group of patients. In a recent study of 43 MDS patients, 10 of 12 patients (83%) with del(5q) MDS achieved sustained RBC transfusion independence (or a > 2 g/dL increase in hemoglobin), compared with 57% of those with a normal karyotype and 12% of those with other karyotypic abnormalities. Complete cytogenetic remissions were achieved in 75% (nine of 12) of the del(5q) MDS patients, suggesting that lenalidomide targets a fundamental pathogenetic feature of MDS that is more pronounced in the presence of chromosomal 5q deletions. This review highlights some issues about the classification and treatment of del(5q) MDS.

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

2018 ◽  
Vol 2 (14) ◽  
pp. 1765-1772 ◽  
Author(s):  
Maximilian Stahl ◽  
Michelle DeVeaux ◽  
Theo de Witte ◽  
Judith Neukirchen ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Immunosuppressive Therapy ◽  
Clinical Outcomes ◽  
Lower Risk ◽  
Patient Cohort ◽  
Transfusion Independence ◽  
Key Points ◽  
Rbc Transfusion

Key Points IST leads to a response in nearly half, and to RBC transfusion independence in about a third, of selected lower-risk MDS patients. Hypocellularity of bone marrow and the use of horse ATG plus cyclosporine are associated with increased rates of transfusion independence.

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

2019 ◽  
Vol 60 (13) ◽  
pp. 3181-3187 ◽  
Author(s):  
Amer M. Zeidan ◽  
Weiwei Zhu ◽  
Maximilian Stahl ◽  
Rong Wang ◽  
Scott F. Huntington ◽  
...  
Keyword(s):  
Lower Risk ◽  
Population Level ◽  
Hypomethylating Agents ◽  
Transfusion Independence ◽  
Level Analysis ◽  
Rbc Transfusion

A Randomized Phase IIa Study of Vorinostat in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes: Preliminary Results

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5084-5084 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Lewis B. Silverman ◽  
Ivana Gojo ◽  
Laura Michaelis ◽  
Simrit Parmar ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Treatment Options ◽  
Low Risk ◽  
Red Blood Cell Transfusion ◽  
Study Medication ◽  
Cutaneous Manifestations ◽  
Preliminary Results ◽  
Transformed Cell Lines

Abstract Effective treatment options for patients with lower-risk myelodysplastic syndromes (MDS) are limited. However, around one-third of patients experience transformation to acute myeloid leukemia, and absent transformation, complications of chronic cytopenias (including infection), and iron-overload syndromes can be fatal. Although 5-azacitidine, decitabine, and lenalidomide have improved treatment options for patients with MDS, these are not routinely used in patients with lower-risk disease. Histone deacetylase (HDAC) enzymes are overexpressed in several tumor types including MDS, and regulate transcriptional and post-transcriptional processes. Vorinostat (Zolinza®) has been shown to inhibit class I and II HDAC enzymes, and has been approved by the FDA for the treatment of cutaneous manifestations of T-cell lymphoma in patients with persistent or recurrent disease, on or following 2 prior systemic therapies. Vorinostat induces cell-cycle arrest, apoptosis, or differentiation in a variety of cultured transformed cell lines, and has demonstrated activity against leukemias in in vivo non-clinical models and in phase I and II clinical trials. Efficacy data in these early phase trials prompted an investigation of vorinostat monotherapy in lower-risk MDS. The potency and tolerability of vorinostat suggest it may be effective in the treatment of MDS. Here, we report preliminary results of a randomized phase II study evaluating once-daily and three-times-daily (tid) intermittent dosing schedules of vorinostat in patients with low and intermediate-1 risk MDS. Primary objectives included assessment of the efficacy, safety, and tolerability of vorinostat. Eligible patients were aged ≥18 years, had either previously untreated disease, or were ≥4 weeks from any prior treatment regimen (including growth factors). Patients’ performance status was ≤2 on the ECOG performance scale, they had adequate organ function, and were either red blood cell transfusion dependent or had a hemoglobin level of ≤11g/dL at the time of screening, or had platelets ≤100 × 109/L at the time of screening. Eligible patients were assigned to 1 of 2 oral dosing regimens: vorinostat 400 mg daily or vorinostat 200 mg tid. Treatment was administered over a 21-day cycle (14 days’ therapy and 7 days’ rest), with patients receiving up to 8 cycles, or until the patient experienced unacceptable toxicity, disease progression, or withdrew consent. In total, 18 patients (12 male, 6 female; mean age 67.4 years) have been randomized, including 5 with low-risk MDS and 13 with intermediate-1 risk MDS, as defined by the International Prognostic Scoring System. Of the patients enrolled, 12 (3 low-risk and 9 intermediate-1 risk MDS) were evaluable for response and have received between 2 and 6 cycles of treatment. Stable disease has been reported in all 12 patients, with a reported duration of between 22–146 days (low-risk MDS) and 1–136 days (intermediate-1 risk MDS). A total of 11/18 (61%) patients have discontinued, 2 due to adverse events (1 event of grade 4 neutropenia [unrelated to study medication] and 1 event of grade 3 neuropathy [drug related]), 1 due to deviation from protocol, 4 due to lack of efficacy, 3 due to physician decision, 1 due to progressive disease, and 1 because of withdrawal of consent. Most adverse events were gastrointestinal disorders: diarrhea in 10 patients (7 grade 1, 3 grade 2), nausea in 9 patients (6 grade 1, 3 grade 2), and vomiting in 6 patients (5 grade 1, 1 grade 2). Grade 4 neutropenia, anemia, and thrombocytopenia were observed in 2, 1, and 1 patients, respectively; however these were unrelated to study medication. Data from this study indicate that vorinostat administered in a 21-day cycle has acceptable safety and tolerability.

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