A natural history of lower-risk myelodysplastic syndromes with ring sideroblasts: an analysis of the MDS-CAN registry.

Patients with lower-risk (LR) myelodysplastic syndromes (MDS) with ring sideroblasts (RS) have better prognosis than those without RS, but how they fare over time is not fully understood. This study's objective was to assess the natural history of LR MDS with RS ≥5% using MDS-CAN registry individual data. Kaplan-Meier estimates and generalized linear mixed models were used to describe time-to-event outcomes and continuous outcomes, respectively. One hundred and thirty-eight patients were enrolled; median times from diagnosis to enrollment and follow-up were 6.6 and 39.6 months, respectively. Within 5 years of enrollment, 65% of patients had ≥1 red blood cell transfusion dependence episode. Within 5 years of diagnosis, 59% developed iron overload, 38% received iron chelation therapy, 14% progressed to acute myeloid leukemia, and 42% died. Patients exhibited inferior health-related quality of life trends. These first real-world data in LR MDS-RS in Canada indicate a high level of morbidity and mortality over a 5-year period. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02537990.

Iron overload in myelodysplastic syndromes: Evidence based guidelines from the Canadian consortium on MDS.

In 2008 the first evidence-based Canadian consensus guideline addressing the diagnosis, monitoring and management of transfusional iron overload in patients with myelodysplastic syndromes (MDS) was published. The Canadian Consortium on MDS, comprised of hematologists from across Canada with a clinical and academic interest in MDS, reconvened to update these guidelines. A literature search was updated in 2017; topics reviewed include mechanisms of iron overload induced cellular damage, evidence for clinical endpoints impacted by iron overload including organ dysfunction, infections, marrow failure, overall survival, acute myeloid leukemia progression, and endpoints around hematopoietic stem-cell transplant. Evidence for an impact of iron reduction on the same endpoints is discussed, guidelines are updated, and areas identified where evidence is suboptimal. The guidelines address common questions around the diagnosis, workup and management of iron overload in clinical practice, and take the approach of who, when, why and how to treat iron overload in MDS. Practical recommendations for treatment and monitoring are made. Evidence levels and grading of recommendations are provided for all clinical endpoints examined.

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.

A phase II study of bortezomib and gemcitabine in relapsed mantle cell lymphoma from the National Cancer Institute of Canada Clinical Trials Group (IND 172).

Bortezomib and gemcitabine have each shown activity as single agents in mantle cell lymphoma (MCL), which is incurable. The purpose of this phase II study was to determine the efficacy and safety of the previously unstudied combination of bortezomib and gemcitabine in patients with relapsed or refractory MCL. Patients were eligible if they had relapsed MCL with 1-3 prior therapies. Patients were treated with gemcitabine 1000 mg/m(2) on days 1 and 8 and bortezomib 1.0 mg/m(2) IV on days 1, 4, 8, and 11, on a 21-day schedule. Twenty-six patients were evaluable for toxicity and 25 for response. The overall response rate was 60% and the median progression free survival was 11.4 months. The main adverse effects were hematological, with 40% and 48% of patients experiencing grade 3/4 thrombocytopenia and granulocytopenia, respectively. Bortezomib and gemcitabine is an active combination in relapsed and refractory MCL with clinically meaningful results. It offers a chemotherapy backbone to which other agents, less myelosuppressive, may be added.

A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study.

Sorafenib is a small molecule inhibitor of RAF kinase, VEGFR-2, c-KIT, and FLT3. In this randomized phase I study, eligible patients had relapsed/refractory acute myeloid leukemia (AML), and one prior induction regimen, or were age >65 with untreated myelodysplastic syndrome (MDS) or secondary AML. Sorafenib was given orally for 28 days (cont) or 14 days (int) every 4 weeks at three dose levels (100, 200, and 400 mg BID); 300 mg cont was also tested. Forty-two patients were enrolled (median age 71 [37-82]; prior chemotherapy: 22). Dose-limiting toxicity (DLT) was: 100 mg BID: 0/7 patients; 200 mg BID: 2/12 patients; 400 mg BID: 1/17 patients. Sorafenib 400 mg cont was not tolerated in this population: 6/8 received <14 days of treatment due to toxicity; no DLT was seen with 300 mg cont. One CR was seen in a patient with AML with FLT3-ITD. Flow cytometry studies suggest that sorafenib inhibits ERK phosphorylation via c-KIT. The recommended phase II dose in AML is 300 mg BID continuously, and testing in combination and in FLT3-ITD AML is warranted.