Mary M. Sugrue

Validation of the IPSS-R in lenalidomide-treated, lower-risk myelodysplastic syndrome patients with del(5q).

Validation of the IPSS-R in lenalidomide-treated, lower-risk myelodysplastic syndrome patients with del(5q)

Current pathology practices in and barriers to MDS diagnosis.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell malignancies that represent a diagnostic challenge for pathologists. Accurate classification and prognostic scoring are essential to treating MDS. To understand factors that affect MDS management, a case-based survey was distributed to hematopathologists (n=53) and general pathologists (n=72) to identify perceived barriers, attitudes, and practices in MDS diagnosis. Results demonstrated confidence and practice gaps. Only 33% of general pathologists are confident in diagnosing MDS. Neither general pathologists nor hematopathologists are comfortable using the International Prognostic Scoring System to characterize risk. Thirty percent of general pathologists and 22% of hematopathologists would not include bone marrow aspirate and cytogenetics in initial testing of a neutropenic patient. Most practitioners tested appropriately for disease classification and prognosis; discrepancies were identified in testing to differentiate MDS from acute myeloid leukemia and testing in post treatment specimens. These results have implications in the management of MDS.

Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy

While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 patient cases of lower-risk MDS patients with 5q deletion and to analyze their outcome after failure of lenalidomide. The median survival following LEN failure was 23 months. We observed a negative impact on survival of advanced age, higher bone marrow blast count at LEN initiation, progression after LEN failure, and unfavorable cytogenetics. Among the treatment strategies, we observed a relatively prolonged survival of patients treated subsequently with hypomethylating agents and only a limited impact on survival of allogeneic transplantation. In conclusion, our work stresses the relatively short survival of this group of patient and defines the expected baseline for the needed future investigations in this group of patients.While lenalidomide (LEN) is the standard of care for the lower-risk myelodysplastic syndromes (MDS) patients with deletion 5q, 35% will not respond to or do not tolerate the drug. Moreover, most of the patients will lose their response after a few years. Defining the outcome of patients with LEN failure and determining the impact of subsequent therapies is therefore important to develop alternative strategies. Based on an international collaboration, we were able to compile a total of 392 patient cases of lower-risk MDS patients with 5q deletion and to analyze their outcome after failure of lenalidomide. The median survival following LEN failure was 23 months. We observed a negative impact on survival of advanced age, higher bone marrow blast count at LEN initiation, progression after LEN failure, and unfavorable cytogenetics. Among the treatment strategies, we observed a relatively prolonged survival of patients treated subsequently with hypomethylating agents and only a limited impact on survival of allogeneic transplantation. In conclusion, our work stresses the relatively short survival of this group of patient and defines the expected baseline for the needed future investigations in this group of patients.

Real-world analysis of the Celgene Global Drug Safety database: early discontinuation of lenalidomide in patients with myelodysplastic syndromes due to non-serious rash.

Background Lenalidomide is approved for treating transfusion-dependent anemia due to lower-risk del(5q) myelodysplastic syndromes (MDS). In clinical trials, rash was common, although severe rash was infrequent. To examine rash in patients with MDS treated with lenalidomide in the real world, the Celgene Global Drug Safety database was analyzed and compared with clinical trials. Materials and methods Adverse event reports in the post-marketing setting and in the MDS-003/004 clinical trials were analyzed by action taken with lenalidomide, seriousness/grade, time to onset, and treatment duration. Results Globally, 16,942 reports representing 36,793 adverse events from the post-marketing setting were submitted to the Global Drug Safety database between December 27, 2005 and June 13, 2013. Most rash adverse events were non-serious (Global Drug Safety database, 91%) or grade 1/2 (MDS-003/004 trials, 87%–93%). Unexpectedly, rash, occurring at a median of 9 days after treatment initiation, was the leading cause of permanent discontinuation of lenalidomide. Seventy-two percent of non-serious rash adverse events led to early permanent discontinuation within two cycles, while in the MDS-003/004 pivotal clinical trials, only 2%–3% of rash adverse events led to permanent discontinuation. Conclusion Non-serious rash was the most common reason for permanent discontinuation of lenalidomide in real-world settings. Managing lenalidomide-related rash using published recommendations might improve treatment duration and optimize patient outcomes.

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

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

The impact of lenalidomide exposure on response and outcomes in patients with lower-risk myelodysplastic syndromes and del(5q)

Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies that primarily affect older adults, with consequent cytopenias, blood product transfusion needs, and truncated survival. Undertreatment of patients with International Prognostic Scoring System (IPSS) Lowor Intermediate (Int)-1-risk MDS and deletion 5q [del(5q)] may lead to insufficient correction of anemia, iron overload, compromised quality of life, and increased morbidity. It is recommended that patients with IPSS-defined lower-risk MDS and del(5q) initiate treatment with lenalidomide at 10 mg/day. Those who develop profound neutropenia or thrombocytopenia should undergo treatment interruption followed by dose reduction to manage adverse events while continuing treatment. It is not known whether initial lenalidomide dose (at 10 or 5 mg), subsequent dose reductions, or cumulative lenalidomide dose affect long-term outcomes in patients with del(5q) MDS. In this retrospective analysis, we combined data from IPSS-defined lower-risk del(5q) MDS patients treated with lenalidomide from study start in the phase 2 MDS-003 study and the phase 3 MDS-004 study to assess the impact of cumulative lenalidomide exposure on red blood cell transfusion independence (RBC-TI) ≥ 26 weeks, cytogenetic response, overall survival, and acute myeloid leukemia (AML)-free survival. In the phase 2, open-label MDS-003 study (NCT00065156), 148 patients received lenalidomide 10mg on days 1–21 (n= 46) or days 1–28 (n= 102) of 28-day cycles. In the phase 3, randomized, double-blind, placebo-controlled MDS-004 study (NCT00179621), 205 patients were centrally randomized using a validated interactive voice response system 1:1:1 to lenalidomide 10mg/day on days 1–21 of 28-day cycles (n= 69), or lenalidomide 5mg/day (n= 69) or placebo (n= 67) on days 1–28 of 28-day cycles. Key inclusion criteria for both studies included IPSS Lowor Int-1-risk del(5q) MDS with or without additional cytogenetic abnormalities, and RBC transfusion-dependent anemia. Outcomes (RBCTI ≥ 26 weeks, cytogenetic response, overall survival, and AML-free survival) were analyzed by initial lenalidomide dose group, total cumulative dose during cycles 1–3, and incidence of dose reductions. Further details on study design can be found in the Supplementary material; full methodology and key results for these studies have been reported previously. A total of 217 patients received an initial dose of lenalidomide 10mg (10 mg dose group) and 69 patients received an initial dose of lenalidomide 5mg (5 mg dose group) in the MDS-003 and MDS-004 studies. Patient baseline characteristics are shown in Supplementary Table 1; details of treatment received can be found in Supplementary Table 2. Overall, RBC-TI ≥ 26 weeks was achieved in 148 patients (51.7%) (Supplementary Table 3); rates of RBCTI ≥ 26 weeks were 57.1% for the 10mg dose group vs. 34.8% for the 5 mg dose group (p < 0.001). Of 181 evaluable patients, 103 (56.9%) achieved cytogenetic response (major or minor responses) (Supplementary Table 3): 65.2% of patients in the 10mg dose group vs. 30.2% in the

Selection of patients with myelodysplastic syndromes from a large electronic medical records database and a study of the use of disease-modifying therapy in the United States

Objectives Treatment patterns for patients with myelodysplastic syndromes (MDS) outside clinical trials are not well described. Our objective was to evaluate treatment patterns and patient characteristics that influence time to disease-modifying therapy in patients with MDS in the USA. Design, participants and outcome measures Patients with MDS treated with erythropoiesis-stimulating agents (ESAs), iron chelation therapy, lenalidomide (LEN) and the hypomethylating agents (HMAs) azacitidine and decitabine, were retrospectively identified in the GE Centricity Electronic Medical Record database between January 2006 and February 2014; LEN and HMAs were defined as ‘disease-modifying’ therapies. Multivariable Cox regression models were used to ascertain patient characteristics associated with time to disease-modifying therapy. Results Of the 5162 patients with MDS, 35.7%, 40.3% and 4.6% received 1, ≥1 and ≥2 therapies, respectively. ESAs were the first-line (72.5%) and only (64.0%) treatment in the majority of patients who received ≥1 therapy. ESA-only patients were older and had more comorbidities, including isolated anaemia. LEN and HMAs were first-line treatment in 12.4% of patients each; 32.7% received LEN or HMAs at any time. The majority of del(5q) patients (77.6%) received ≥1 therapy, most commonly LEN, compared with 40% of patients without del(5q). A shorter time to disease-modifying therapy was significantly associated with absence of comorbidities, diagnosis after February 2008, lower baseline haemoglobin level, age <80 years and male gender (p<0.002 for all). Conclusions A high proportion of patients diagnosed with MDS in the USA do not receive approved disease-modifying therapies. It is important to improve access to these therapies.