Martha Lenis

Patient-related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS-CAN prospective study.

Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi‐centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS‐related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System (IPSS‐R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age‐adjusted IPSS‐R, frailty (Hazard ratio 2·7 (95% confidence interval [CI] 1·7–4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1–2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS‐R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients.

Lenalidomide and metronomic melphalan for CMML and higher risk MDS: A phase 2 clinical study with biomarkers of angiogenesis

Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.

Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient‐related factors and measuring from time of first red blood cell transfusion dependence: an MDS‐CAN analysis

Analyses suggest iron overload in red blood cell (RBC) transfusion‐dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient‐related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient‐related factors. TD International Prognostic Scoring System (IPSS) low and intermediate‐1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease‐modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non‐ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P < 0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P = 0·03). In matched pair analysis, OS remained superior for ICT patients (P = 0·02). In this prospective, non‐randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease‐modifying agents. This provides additional evidence that ICT may confer clinical benefit.

43 A PREDICTIVE MODEL OF RESPONSE TO ERYTHROPOIETIC STIMULATING AGENTS IN PATIENTS WITH MYELODYSPLASTIC SYNDROME

Downregulation of cereblon (CRBN) gene expression is associated with resistance to the immunomodulatory drug (IMiD) lenalidomide and poor survival outcomes in multiple myeloma patients. However, the importance of CRBN gene expression in patients with myelodysplastic syndrome (MDS) and its impact on lenalidomide therapy are not clear. In this study we are following up our earlier investigation (results were published in EJH). We are presenting data from larger sample of patients and in addition bringing the results from lower risk MDS patients without del(5q), marked as non-5q-, treated with lenalidomide. We evaluate cereblon expression in mononuclear cells isolated from peripheral blood (PB) [43 lower risk MDS with isolated 5q deletion (5q-), 53 non-5qand 32 healthy controls] and from bone marrow (BM) [27 lower risk MDS with 5q-, 38 non-5qlower risk MDS and 25 healthy controls] to gain insight into, firstly, the role of cereblon in lower risk MDS patients with or without 5q deletion, and secondly, into the mechanism of lenalidomide action. Patients with 5qlower risk MDS have the highest levels of CRBN mRNA in comparison with both lower risk MDS patients without del(5q) and healthy controls. Five non-5qanemic patients who were treated with lenalidomide showed all lower levels of CRBN mRNA. All these patients did not respond to the treatment. CRBN gene expression level was analyzed by using the reverse transcriptase quantitative “best coverage” TaqMan PCR assay with primers in exon 9 and 10 and probe on exon 9. This assay allowed the detection of the full-length CRBN transcript but not alternative splicing forms without exon 10 (binding site of IMiDs on CRBN). We found that a high level of full-length CRBN mRNA in both bone marrow and peripheral blood mononuclear cells of lower risk MDS with isolated 5q deletion corresponds to the efficacy of lenalidomide in these patients. Moreover, we found that patients who stopped responding to lenalidomide and whose disease progressed showed a sudden decrease of CRBN gene expression. Supported by the research grant NT/13836 from the IGA, Ministry of Health, Czech Republic.

Income and outcome in myelodysplastic syndrome: The prognostic impact of SES in a single-payer system

We examined the prognostic impact of SES, estimated by census median household income, in 312 adult MDS patients. Age, progression to AML, use of recombinant erythropoietin, WHO diagnosis and IPSS risk category were independent predictors of survival but there was no association between SES and survival. Unexpectedly, progression to AML was more prevalent in the highest income quartile (HR 3.96 for highest vs. lowest; p=0.0032). The previously demonstrated association of low SES with poor outcome MDS in the United States may have been driven primarily by reduced access to care rather than other SES-linked factors such as co-morbidity.