Nancy Zhu

Levamisole tainted cocaine causing severe neutropenia in Alberta and British Columbia

BackgroundFive cases of severe neutropenia (neutrophil counts < 0.5 per 109 cells/L) associated with exposure to cocaine and levamisole, an antihelimithic agent no longer available in Canada, were identified in Alberta in 2008. Alberta and British Columbia (BC) public health officials issued an advisory and urged health care professionals to report cases to public health. This paper presents the findings of the public health investigations.MethodsCases were identified prospectively through reporting by clinicians and a retrospective review of laboratory and medical examiners data from January 1, 2006 to March 31, 2009. Cases were categorized as confirmed, probable or suspect. Only the confirmed and probable cases are included in this paper.ResultsWe compare cases of severe neutropenia associated with tainted cocaine (NATC) identified in Alberta and BC between January 1, 2008 to March 31, 2009. Of the 42 NATC cases: 23(55%) were from Alberta; 19(45%) were from British Columbia; 57% of these cases reported crack cocaine use (93% of those who identified type of cocaine used); 7% reported using cocaine powder; and the main route of cocaine administration was from smoking (72%). Fifty percent of the NATC cases had multiple episodes of neutropenia associated with cocaine use. Cases typically presented with bacterial/fungal infections and fever. One Alberta NATC case produced anti-neutrophil antibodies, and four were positive for anti-neutrophil cytoplasmic antibody (ANCA). Analysis of two crack pipes and one drug sample obtained from NATC cases confirmed the presence of both cocaine and levamisole. A further 18 cases were identified through the retrospective review of laboratory and medical examiner data in AlbertaInterpretationOur findings support a link between neutropenia and levamisole tainted cocaine; particularly from smoking the crack form of cocaine. Some patients may be genetically predisposed to develop levamisole-related neutropenia. Awareness of the differential diagnosis will assist clinicians with case timely detection and appropriate management.

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.

A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML, or AML with ⩽ 30% blasts.

Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

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.

Optimizing outcomes with azacitidine: recommendations from Canadian centres of excellence.

Myelodysplastic syndromes (mdss) constitute a heterogeneous group of malignant hematologic disorders characterized by marrow dysplasia, ineffective hematopoiesis, peripheral blood cytopenias, and pronounced risk of progression to acute myeloid leukemia. Azacitidine has emerged as an important treatment option and is recommended by the Canadian Consortium on Evidence-Based Care in mds as a first-line therapy for intermediate-2 and high-risk patients not eligible for allogeneic stem cell transplant; however, practical guidance on how to manage patients through treatment is limited. This best practice guideline provides recommendations by a panel of experts from Canadian centres of excellence on the selection and clinical management of mds patients with azacitidine. Familiarity with the referral process, treatment protocols, dose scheduling, treatment expectations, response monitoring, management of treatment breaks and adverse events, and multidisciplinary strategies for patient support will improve the opportunity for optimizing treatment outcomes with azacitidine.

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.

The fludarabine, cytarabine, and granulocyte colony-stimulating factor (FLAG) chemotherapy regimen is an alternative to anthracycline-based therapy for the treatment of acute myeloid leukemia for patients with pre-existing cardiac disease

We conducted a retrospective study assessing FLAG (fludarabine, cytarabine, and granulocyte colony‐stimulating factor) as first‐line treatment in 56 newly diagnosed acute myeloid leukemia patients considered ineligible for anthracycline‐based treatment due to advanced age, significant comorbidities, or pre‐existing cardiac disease. The median age was 69 (21–80); 46% received FLAG for pre‐existing cardiac disease and others due to age (32%), non‐cardiac comorbidities (20%), or previous anthracycline exposure (2%). The induction mortality was 16% and, among evaluable patients, 48% achieved a complete remission after the first induction course with an additional patient achieving a remission after a second course for a total complete remission rate of 50%. Four patients proceeded to an allogeneic stem cell transplant including two with pre‐existing cardiac disease. Among non‐transplanted patients, the relapse rate (RR) was 47%. When censored at time of stem cell transplant, the median relapse‐free survival was 14.7 months. The median overall survival was 9.3 months with 1‐ and 2‐yr survivals of 44% and 22%, respectively. There was no difference in clinical outcomes between patients treated with FLAG for cardiac reasons vs. other reasons. In conclusion, FLAG is a useful alternative to anthracycline‐based induction for Acute myeloid leukemia in those with significant comorbidities including pre‐existing cardiac disease.