Phase II Multicenter Study of Arsenic Trioxide in Patients With Myelodysplastic Syndromes

2006 ◽  
Vol 24 (16) ◽  
pp. 2456-2464 ◽  
Author(s):  
Gary J. Schiller ◽  
James Slack ◽  
John D. Hainsworth ◽  
James Mason ◽  
Mansoor Saleh ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Primary Response ◽  
International Prognostic Scoring System ◽  
Risk Category ◽  
Moderate Activity ◽  
Expected Time ◽  
Transfusion Independence ◽  
Risk Patients

Purpose To evaluate the efficacy and safety of arsenic trioxide monotherapy in patients with myelodysplastic syndromes (MDS). Patients and Methods Patients received arsenic trioxide (0.25 mg/kg/d) on 5 consecutive days per week for 2 weeks, followed by 2 weeks’ rest (one cycle). Two patient cohorts were established according to International Prognostic Scoring System risk category: lower-risk (low or intermediate-1) or higher-risk MDS (intermediate-2 or high). For lower-risk MDS, hematologic improvement (HI) was the primary response end point. For higher-risk MDS, additional end points included complete or partial remission. Based on the expected time to response, patients receiving two or more cycles were prospectively evaluated. Results Hematologic adverse events included neutropenia, thrombocytopenia, and febrile neutropenia. Two patients died during the study due to treatment-related toxicities. Most common grade 3/4 nonhematologic events were pneumonia, fatigue, hemorrhage, pain, and dyspnea. Among patients who received one or more doses (n = 70) or completed two or more cycles (n = 51), the HI rates were 34% and 39% in lower-risk patients, and 6% and 9% in higher-risk patients, respectively; the overall major HI rates were 20% and 22%. One higher-risk patient achieved a complete remission (3%). Major HIs were observed in all hematologic lineages; erythroid responses were the most common. Transfusion independence or reduction by ≥ 50% occurred in 33% of patients dependent on RBC transfusions. The overall median duration of HI was 6.8 months (range, 2 to 40 months). Conclusion Arsenic trioxide monotherapy has moderate activity against MDS, with a manageable adverse effect profile. The further study of arsenic trioxide in MDS, particularly in combination with other agents, is warranted.

Arsenic Trioxide in Patients With Myelodysplastic Syndromes: A Phase II Multicenter Study

2006 ◽  
Vol 24 (16) ◽  
pp. 2465-2471 ◽  
Author(s):  
Norbert Vey ◽  
Andre Bosly ◽  
Agnes Guerci ◽  
Walter Feremans ◽  
Herve Dombret ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Lower Risk ◽  
International Prognostic Scoring System ◽  
Risk Category ◽  
Moderate Activity ◽  
Loading Dose ◽  
Median Response ◽  
System Risk

Purpose Evaluation of the safety and efficacy of arsenic trioxide in patients with myelodysplastic syndromes (MDS). Patients and Methods MDS patients diagnosed according to standard French-American-British criteria received a loading dose of 0.3 mg/kg per day of arsenic trioxide for 5 days followed by a maintenance dose of 0.25 mg/kg arsenic trioxide twice weekly for 15 weeks. Patients were divided into two cohorts: lower-risk MDS (International Prognostic Scoring System risk category low or intermediate 1) and higher-risk MDS (International Prognostic Scoring System risk category intermediate 2 or high). Modified International Working Group criteria were used for response evaluation. Results Of 115 patients enrolled and treated in the study, 67% of patients were transfusion dependent at baseline; median age was 68 years. Most treatment-related adverse events were mild to moderate. The overall rate of hematologic improvement (intent-to-treat) was 24 (19%) of 115, including one complete and one partial response in the higher-risk cohort. The hematologic response rates were 13 (26%) of 50 and 11 (17%) of 64 in patients with lower-risk and higher-risk MDS, respectively. Major responses were observed in all three hematologic lineages; 16% of RBC transfusion-dependent patients and 29% of platelet transfusion-dependent patients became transfusion independent. At data cut off, the median response duration was 3.4 months, with responses ongoing in nine patients. Conclusion Arsenic trioxide treatment consisting of an initial loading dose followed by maintenance therapy has moderate activity in MDS, inducing hematologic responses in both lower- and higher-risk patients. This activity combined with a manageable adverse effect profile warrants the additional study of arsenic trioxide, particularly in combination therapy, for the treatment of patients with MDS.

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.

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.

Clinical relevance of mutations in patients with myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with normal karyotype.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7053-7053 ◽  
Author(s):  
Guillermo Montalban-Bravo ◽  
Ana Alfonso Pierola ◽  
Koichi Takahashi ◽  
Marina Konopleva ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Myeloproliferative Neoplasms ◽  
Univariate Analysis ◽  
Normal Karyotype ◽  
Median Number ◽  
Gene Panel ◽  
Prognostic Impact ◽  
Risk Patients

7053 Background: Clinical outcomes of patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are heterogeneous. Specific mutations and mutation patterns are known to define prognostic groups in normal karyotype acute myeloid leukemia. Whether this is the case in MDS and MDS/MPN remains unknown. Methods: We evaluated 325 previously untreated patients with MDS or MDS/MPN with normal karyotype evaluated from 2012 to 2016. Next generation sequencing (NGS) on whole bone marrow DNA analyzing a panel of 28 or 53 genes was performed at the time of diagnosis. Results: A total of 225 (69%) patients had MDS and 100 (31%) had MDS/MPN including 77 (24%) patients with chronic myelomonocytic leukemia (CMML). Median age was 69 years (31-92). Among patients with MDS, 189 (84%) had lower-risk and 36 (16%) had higher-risk based on IPSS. NGS data was obtained by 53-gene panel in 93 (29%) patients and by 28-gene panel in 232 (71%). A total of 202 (62%) patients had detectable mutations. Median number of mutations was 1 (range 0-6). Detected mutations are detailed in Table 1. A total of 111 (34%) patients, 70 with MDS and 41 with MDS/MPN, received therapy with hypomethylating agents. Median follow up was 12 months (0-167). By univariate analysis, NRAS (HR 3.28, CI 1.25-8.62, p=0.016) and TP53 (HR 4.9, CI 1.44-16.67, p=0.011) predicted for shorter overall survival (OS) among MDS patients. After multivariate analysis including IPSS-R, only TP53retained its impact in OS (HR 5.25, CI 1.44-19.13, p=0.012). Among MDS/MPN patients, no mutation was found to significantly impact OS. Conclusions: With the exception of TP53mutations, no other identified mutation seemed to independently define prognosis of patients with MDS or MDS/MPN with normal karyotype. In view of the high proportion of lower-risk patients, longer follow up is required to better define prognostic impact of mutations in this population. [Table: see text]

scholarly journals Relation between chelation and clinical outcomes in lower-risk patients with myelodysplastic syndromes: Registry analysis at 5 years

2017 ◽  
Vol 56 ◽  
pp. 88-95 ◽  
Author(s):  
Roger M. Lyons ◽  
Billie J. Marek ◽  
Carole Paley ◽  
Jason Esposito ◽  
Katie McNamara ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Risk Patients ◽  
Registry Analysis

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 Lower risk but high risk

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 428-434
Author(s):  
Amy E. DeZern
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Genetic Information ◽  
Lower Risk ◽  
Molecular Genetic ◽  
Scoring Systems ◽  
International Prognostic Scoring System ◽  
Disease Characteristics ◽  
Prognostic Scoring Systems

Abstract Risk stratification is crucial to the appropriate management of most cancers, but in patients with myelodysplastic syndromes (MDS), for whom expected survival can vary from a few months to more than a decade, accurate disease prognostication is especially important. Currently, patients with MDS are often grouped into higher-risk (HR) vs lower-risk (LR) disease using clinical prognostic scoring systems, but these systems have limitations. Factors such as molecular genetic information or disease characteristics not captured in the International Prognostic Scoring System–Revised (IPSS-R) can alter risk stratification and identify a subset of patients with LR-MDS who actually behave more like those with HR-MDS. This review describes the current identification and management of patients with LR-MDS whose condition is likely to behave in a less favorable manner than predicted by the IPSS-R.

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.

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