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Many patients with lower-risk myelodysplastic syndromes (LR MDS) require long-term red blood cell (RBC) transfusions to manage anemia. The consequences of RBC transfusions in LR MDS with ring sideroblasts (LR MDS-RS) are not well known. We estimated the association between cumulative RBC dose density and clinical and patient-reported outcomes using data from the MDS-CAN registry for patients enrolled between January 2008 and December 2018. Outcomes included overall survival, hospitalization, and health-related quality of life (HRQoL). A total of 145 enrolled patients with LR MDS and RS ≥5% had a median follow-up time of 27.1 months; 45 had no transfusions during follow-up, 51 had1 transfusion per month, and 49 had ≥1 transfusion per month. The cumulative density of RBC transfusions was associated with significantly greater mortality, hospitalization, and inferior HRQoL, suggesting that exposure to RBC transfusion may constitute a significant treatment burden in patients with LR MDS-RS.

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.

Objectives: Reactive oxygen species (ROS) are under scrutiny as a participant in the pathophysiology of myelodysplastic syndrome (MDS) and the progression of MDS to acute myeloid leukemia (AML). Me...

Salvage options for patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) include inotuzumab ozogamicin (InO), a recombinant, humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. However, the benefit of InO in patients with dim CD22 expression remains unclear. We present a case of a patient with B-ALL who responded to InO despite only dim surface expression of CD22 by flow cytometry, achieving a survival benefit concordant with that reported in the literature and maintaining a good quality of life as a transfusion-independent outpatient. Our observation has broad relevance to clinicians who manage patients with B-ALL who are candidates for InO.

Background: The incorporation of patient-reported outcomes with traditional disease risk classification, was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). A recently reported model, FA-IPSS(h), found that patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), among higher-risk IPSS population, further stratifies them into distinct sub-groups with different survival outcomes (Efficace et al, 2018). Compared to the IPSS, the revised IPSS (IPSS-R) is more refined in prognostic assessment and an IPSS-R score of > 3.5 may identify higher risk disease (Pfeilstocker et al, 2016). The Edmonton Symptom Self Assessment Scale (ESAS) Global Fatigue Scale (GFS), is a single-item fatigue rating scale (0-10, with 10 being the highest degree), which has been previously recommended by the National Comprehensive Cancer Network to screen for fatigue in all cancer populations. Aims: (1) to validate the FA-IPSS(h), among the Canadian MDS registry (2) investigate whether a modified index, integrating higher risk by IPSS-R with patient reported fatigue according to the GFS, is able to identify individual subgroups with divergent overall survival (OS). Methods: All adult patients diagnosed with MDS with an IPSS-R score >3.5 within 6 months before the date of registration were eligible for this analysis. Fatigue was assessed both by the QLQ-C30 questionnaire and the GFS. Frailty was assessed by the Canadian Study of Health and Aging (CSHA) 9 point Rockwood clinical frailty scale. Survival was calculated using standard Kaplan-Meier analysis. Results: This analysis included 331 patients. Median age was 73 years (range, 30-98 years), 65.7% were male, median blast % was 6% (range, 0-30), median IPSS-R score was 5.2 (range, 3.5-10) and 55% had high and intermediate-2 (Int-2) IPSS risk, 68% had high and very high IPSS-R risk disease, 66% were exposed to a hypomethylating agent. Median fatigue scores increased with Rockwood frailty scores. The median QLQ-C30 fatigue score was 33 (interquartile range (IQR), 22-55.6) and 4 (IQR, 2-6) by the GFS with 59% recording high fatigue (>4). At a median follow-up of 17 months (IQR, 9-30 months), 233 deaths were observed. The actuarial median OS was 19.3 months (95% CI, 16.5-21.7). We applied the FA-IPSS(h) using QLQ-C30 fatigue cutoffs of 45 (figure 1a) and found a significant difference in OS (p3.5 + Low Fatigue (3.5 + High Fatigue (≥45) (n=96). We found a significant difference in OS between these 2 groups, median OS 19.5 months (95% CI, 17.2-24.3) in group A versus 15.2 months (95% CI, 11.9-22.0) in group B (p=0.02) (figure 1b). We found similar results with these refinements, using the QLQ-C30 cutoff of 33 (the median in our patient population) (p4), was able to distinguish OS using the IPSS (p3.5 (p=0.005) (figure 1d). Conclusions: We were able to externally validate the FA-IPSS (h) using a threshold QLQ-C30 fatigue score of 45, as originally described and 33 (Canadian median), using both the IPSS and IPSS-R (score >3.5) classifications to define higher risk MDS. The easier to deploy ESAS GFS score of >4 further discriminates survival using the IPSS and IPSS-R. This emphasizes the power of self-reported fatigue at refining OS predictions in higher risk MDS and further bolsters the importance of considering patient related outcomes in global assessments. Disclosures Geddes: Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees. Leber:Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leitch:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau. Shamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Delage:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Elemary:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chodirker:Hoffman Laroche: Honoraria. Buckstein:Novartis: Honoraria; Celgene: Research Funding; Takeda: Research Funding; Celgene: Honoraria; Astex: Honoraria.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by cytopenias and progression to acute myeloid leukemia (AML). Although several treatments for MDS are available, the mainstay of therapy for most patients remains supportive care. This includes red blood cell (RBC) transfusion to correct anemia, which leads to iron overload. RBC transfusion dependence and iron overload portend inferior overall survival. Some studies indicate that iron chelation therapy (ICT) may have beneficial effects on clinical endpoints in MDS; however, these data are from non-randomized trials and the validity of the results is vigorously debated. A consistent observation in clinical studies of ICT in MDS has been hematologic improvement (HI) in some patients, including a reduction in RBC transfusion requirements and even transfusion independence. Here, we review data on HI with ICT in lower risk MDS, preclinical data examining mechanisms by which HI may occur, and identify areas for future investigation.

The incorporation of patient-reported outcomes with traditional disease risk classification was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). In the present Canadian MDS registry analysis, we validate a recently reported prognostic model, the Fatigue-International Prognostic Scoring System among higher-risk patients [FA-IPSS(h)], which incorporates patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), with a threshold of ≥45 points, in higher IPSS score, stratifying them into distinct subgroups with different survival outcomes. We further validated this concept, using the Revised IPSS >3·5 as cut-off for the definition of higher-risk MDS, and patients' reported fatigue according to Edmonton Symptom Self-Assessment Scale (ESAS) Global Fatigue Scale (GFS), a single-item fatigue rating scale, which is easier to deploy. This emphasises the power of self-reported fatigue at refining overall survival predictions in higher-risk MDS and further bolsters the importance of considering patient-related outcomes in global assessments.

ObjectiveTo determine the prevalence of physician burnout during the pandemic and differences by gender, ethnicity or sexual orientation.Design, setting and participantsWe conducted a cross-sectional survey (August–October in 2020) of internal medicine physicians at two academic hospitals in Vancouver, Canada.Primary and secondary outcomesPhysician burnout and its components, emotional exhaustion, depersonalisation and personal accomplishment were measured using the Maslach Burnout Inventory.ResultsThe response rate was 38% (n=302/803 respondents, 49% women,). The prevalence of burnout was 68% (emotional exhaustion 63%, depersonalisation 39%) and feeling low personal accomplishment 22%. In addition, 21% reported that they were considering quitting the profession or had quit a position. Women were more likely to report emotional exhaustion (OR 2.00, 95% CI: 1.07 to 3.73, p=0.03) and feeling low personal accomplishment (OR 2.26, 95% CI: 1.09 to 4.70, p=0.03) than men. Visible ethnic minority physicians were more likely to report feeling lower personal accomplishment than white physicians (OR 1.81, 95% CI: 1.28 to 2.55, p=0.001). There was no difference in emotional exhaustion or depersonalisation by ethnicity or sexual orientation. Physicians who reported that COVID-19 affected their burnout were more likely to report any burnout (OR: 3.74, 95% CI: 1.99 to 7.01, pConclusionBurnout affects 2 out of 3 internal medicine physicians during the pandemic. Women, ethnic minority physicians and those who feel that COVID-19 affects burnout were more likely to report components of burnout. Further understanding of factors driving feelings of low personal accomplishment in women and ethnic minority physicians is needed.

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular (HyperV) more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18/79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype. This article is protected by copyright. All rights reserved.

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.

Treatment of Burkitt lymphoma (BL) with intensive, multi-agent chemotherapy with aggressive central nervous system (CNS) prophylaxis results in high cure rates, although no regimen is standard of care. We examined population-based survival outcomes of adults with BL treated with a modified combination of cyclophosphamide, vincristine, doxorubicin, prednisone and systemic high-dose methotrexate (MTX) (CODOX-M) with IVAC (ifosfamide, mesna, etoposide, cytarabine and intrathecal MTX) (CODOX-M/IVAC) ± rituximab over a 15-year period in British Columbia. For the 81 patients identified (including 8 with CNS involvement and 18 with human immunodeficiency virus-associated BL), 5-year progression-free survival (PFS) and overall survival (OS) were 75% [95% confidence interval (CI): 63-83%] and 77% (95% CI: 66-85%), respectively, with no treatment-related deaths. Those who completed the regimen per protocol (n = 38) had significantly improved 5-year PFS 86% (P = 0·04) and OS 92% (P = 0·008), as did those under 60 years with 5-year PFS 82% (P = 0·005) and OS 86% (P = 0·002), which remained significant in multivariate analysis [PFS: hazard ratio (HR) 3·36, P = 0·018; OS HR 4·03, P = 0·012]. Incorporation of high-dose systemic methotrexate also significantly affected multivariate survival outcomes (OS HR 0·28, P = 0·025). Stem cell transplant in first remission had no effect on OS or PFS. This large, real-world analysis of BL patients treated with CODOX-M/IVAC ± rituximab demonstrates excellent survival outcomes comparable to clinical trials. These results help to serve as a benchmark when comparing curative therapies for BL patients as novel regimens are incorporated into clinical practice.

Background Analyses suggest MDS patients with higher serum ferritin levels (SF) have inferior overall survival (OS), in one study across MDS subtypes. Multiple analyses suggest those with high SF receiving iron chelation therapy (ICT) have superior OS, but which MDS subtypes benefit from ICT remains undefined. Methods We performed survival analyses of MDS subtypes by receipt of ICT. Results 182 MDS were lower IPSS risk and received red blood cell (RBC) transfusions; 63 received ICT. For the entire cohort, receiving ICT independently predicted superior OS in a multivariate analysis (hazard ratio for death 0.3, p = 0.01). Features differing for ICT and non-ICT patients, respectively, were: age; IPSS risk group; number of RBC units transfused; and SF, p ≤ 0.03 for all. At a median follow up of 76.5 and 28.4 months, 65.1% and 63.0% were alive. Median OS (months) for ICT and non-ICT patients was: RA, 140.9 and 36.3, p = 0.0008; RARS/RARS-t, 133.4 and 73.3, p = 0.02. For RCMD/RCMD-RS, p = NS, however, 3 (20%) had significant erythroid improvement with ICT; other subtypes had small numbers. Discussion In this retrospective analysis, RA and RARS/RARS-t patients receiving ICT had superior OS to non-ICT patients. These findings should be verified and other MDS subtypes examined in larger prospective analyses.

Background Myelodysplastic syndromes (MDS) are characterized by frequent mutations in RNA splicing factor genes. Protein arginine methyltransferase 5 (PRMT5) regulates the activity of the splicing machinery through methylation of key spliceosome proteins. PRMT5 inhibitors have demonstrated preferential killing of acute myeloid leukemia cells with splicing factor mutations. JNJ-64619178 is a potent, selective, oral PRMT5 inhibitor that causes accumulation of splicing abnormalities in preclinical models. It is hypothesized that inhibition of PRMT5 by JNJ-64619178 may target splicing factor gene mutant MDS clones, leading to recovery of normal hematopoiesis. Here we present Part 2 of a phase 1 study of JNJ-64619178 evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of JNJ-64619178 in adult patients (pts) with lower risk MDS (International Prognostic Scoring System [IPSS] score Low or Intermediate-1) who are red blood cell (RBC) transfusion-dependent and relapsed or refractory to erythropoiesis-stimulating agent (ESA) treatment. Methods Dosing was initiated at 2 mg, 14 days on/7 days off (intermittent) on a 21-day cycle, a tolerable dose from the ongoing dose escalation in solid tumors and lymphomas in Part 1. Confirmation of tolerability followed a modified 3+3 design with de-escalation allowed based on the totality of the data. Enrollment was expanded at the selected, tolerable dose level to further evaluate safety, PK, PD, and preliminary clinical activity. Results As of 29 May 2021, 21 pts were enrolled. Median age was 71 (range 52-85). Revised IPSS score was Very Low (10%), Low (71%) or Intermediate (19%). Pts had a median of 1 prior line of therapy post-ESA (range 0-4), including lenalidomide (33%), hypomethylating agents (29%), and luspatercept (19%). SF3B1 mutations were identified in 71% of pts. Median treatment duration was 3.1 months (range 0.03-6.37). No dose-limiting toxicities were observed. While the 2 mg intermittent starting dose was tolerable, lower dose schedules of 1 mg intermittent and 0.5 mg continuous (once daily [QD]) dosing were evaluated to reduce myelosuppression, and enrollment was expanded at 0.5 mg QD (n=13 pts). Fifteen pts (71%) experienced ≥1 treatment emergent adverse event (TEAE) that was considered related to the study agent (TRAE). TRAE in >10% of pts were thrombocytopenia (52%), neutropenia (48%), anemia (19%), and dysgeusia (14%). Grade 3 or higher TRAE were reported for 57% of pts. Grade 3 or higher TRAE worsening from baseline in >1 pt were neutropenia (29%); anemia and thrombocytopenia (19.0% each); and diarrhea (9%). TEAEs contributed to treatment interruption, dose reduction, and treatment discontinuation in 57%, 14%, and 19% of pts, respectively. Anemia, thrombocytopenia, and neutropenia were the only TRAE leading to treatment modification in >1 pt. Hematologic toxicities were dose-dependent and reversible. Grade ≥3 thrombocytopenia and neutropenia were observed, respectively, in 67% and 50% of pts at 2 mg intermittent versus 0% and 31% at 0.5 mg QD. Serious AE considered possibly related to JNJ-64619178 by the investigator included 1 pt with Grade 3 anemia and 1 pt with Grade 1 atrial fibrillation, Grade 3 cardiac troponin I increase, and Grade 5 cardiac failure (>30 days from last dose). One other death of unknown cause was not considered related to treatment. Comparison of the multiple dose C trough across all dose levels suggests a dose-dependent increase in JNJ-64619178 plasma concentration. Robust target engagement, as measured by plasma symmetric dimethylarginine, was achieved at all dose levels. Serial analysis of variant allele frequency of clonal mutations in a subset of pts did not show significant reductions from baseline in peripheral blood or bone marrow. No pts experienced objective response or hematologic improvement according to International Working Group criteria, RBC transfusion independence, or meaningful reduction in transfusion requirements. Conclusion JNJ-64619178 demonstrated primarily hematologic toxicity in pts with transfusion-dependent lower-risk MDS, which was manageable at the selected expansion dose. Despite robust target engagement, clinical activity was not observed, and enrollment was stopped. The role of PRMT5 in MDS and the differential impact of PRMT5 inhibition on normal and malignant hematopoiesis require further study. Disclosures Platzbecker: Novartis: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria. Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Brunner: Agios: Consultancy; Keros Therapeutics: Consultancy; Aprea: Research Funding; AstraZeneca: Research Funding; GSK: Research Funding; Acceleron: Consultancy; Janssen: Research Funding; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Morillo: Janssen: Honoraria; Abbvie: Honoraria; Takeda: Honoraria. Patel: Acerta Pharma: Research Funding; Curis: Research Funding; Clovis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aileron Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Effector Therapeutics: Research Funding; Eli Lilly: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Millennium Pharmaceuticals: Research Funding; Mirati Therapeutics: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Stemline Therapeutics: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; TopAlliance: Research Funding; Vedanta: Research Funding; Verastem: Research Funding; Vigeo: Research Funding; Xencor: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Daiichi Sankyo: Research Funding; Cyteir Therapeutics: Research Funding; Ciclomed: Research Funding; Checkpoint Therapeutics: Research Funding; Calithera: Research Funding; Boehringer Ingelheim: Research Funding; Bicycle Therapeutics: Research Funding; AstraZeneca: Research Funding; Artios Pharma: Research Funding; Agenus: Research Funding; Florida Cancer Specialists: Research Funding; BioNTech: Research Funding; Incyte: Research Funding; Forma Therapeutics: Research Funding; Ignyta: Research Funding; Hutchinson MediPharma: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Hengrui: Research Funding; H3 Biomedicine: Research Funding; GlaxoSmithKline: Research Funding. Germing: Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Lavie: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Fees for lectures; Roche: Other: Fees for lectures; Novartis: Other: Fees for lectures; Takeda: Consultancy. Lauring: Janssen Research and Development: Current Employment; Johnson and Johnson: Current holder of stock options in a privately-held company. Mistry: Janssen: Current Employment, Current equity holder in publicly-traded company.

The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders. MDS patients often require red blood cell transfusions, resulting in iron overload (IOL). IOL increases production of reactive oxygen species (ROS), oxygen free radicals. We review and illustrate how IOL-induced ROS influence cellular activities relevant to MDS pathophysiology. ROS damage lipids, nucleic acids in mitochondrial and nuclear DNA, structural proteins, transcription factors and enzymes. Cellular consequences include decreased metabolism and tissue and organ dysfunction. In hematopoietic stem cells (HSC), consequences of ROS include decreased glycolysis, shifting the cell from anaerobic to aerobic metabolism and causing HSC to exit the quiescent state, leading to HSC exhaustion or senescence. ROS oxidizes DNA bases, resulting in accumulation of mutations. Membrane oxidation alters fluidity and permeability. In summary, evidence indicates that IOL-induced ROS alters cellular signaling pathways resulting in toxicity to organs and hematopoietic cells, in keeping with adverse clinical outcomes in MDS.

Referral to hematology for anemia is common. In paroxysmal nocturnal hemoglobinuria (PNH), cells deficient in the glycosylphosphatidyl inositol (GPI) anchor are lysed by complement. Eculizumab improves overall survival and quality of life while reducing hemolysis, transfusion requirements, and thrombosis. We evaluated the frequency of screening for PNH in patients with unexplained anemia. Key clinical features, laboratory data, and investigations were recorded for patients referred for anemia since 2010, without a specific cause found. PNH testing was done by flow cytometry. 540 patients had: anemia not yet diagnosed (NYD, n=318 (including unexplained iron deficiency, n=92; DAT-negative hemolysis, n=9)); anemia of chronic disease, n=173; and pancytopenia NYD, n=49. 82.4% had LDH testing done; 85.0% total bilirubin; 78.7% reticulocyte counts; and 40.6% haptoglobin level; 131 (24.2%) had possible hemolysis. PNH testing was done in 56 (10.4%). Those screened for PNH were more likely to have: younger age (P=0.04); a history of thrombosis (P

Background: In ‘real-life', the Nordic score guides ESA use in lower-risk MDS with predicted response rates of 25% or 74%. As new treatments emerge, a more discriminating score is needed. Objectives: To validate existing ESA predictive scores and develop a new score that identifies non-responders. Methods: ESA-treated patients were identified in 3 MDS registries in Italy and Canada (FISM 555, GROM 233, MDS-CAN 208). Clinical and disease-related variables were captured. Nordic, MDS-CAN and IPSS-R-based ESA scores were calculated and documented ESA responses compared. Results: 996 ESA-treated patients were identified. Overall response rate(ORR) was 59%. The database was randomly divided into balanced derivation (n=463) and validation (n=462) cohorts. By multivariate analysis, transfusion independence, erythropoietin level

Summary 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

Iron is an essential element for key cellular metabolic processes. However, transfusional iron overload (IOL) may result in significant cellular toxicity. IOL occurs in transfusion dependent hematologic malignancies (HM), may lead to pathological clinical outcomes, and IOL reduction may improve outcomes. In hematopoietic stem cell transplantation (SCT) for HM, IOL may have clinical importance; endpoints examined regarding an impact of IOL and IOL reduction include transplant-related mortality, organ function, infection, relapse risk, and survival. Here we review the clinical consequences of IOL and effects of IOL reduction before, during and following SCT for HM. IOL pathophysiology is discussed as well as available tests for IOL quantification including transfusion history, serum ferritin level, transferrin saturation, hepcidin, labile plasma iron and other parameters of iron-catalyzed oxygen free radicals, and organ IOL by imaging. Data-based recommendations for IOL measurement, monitoring and reduction before, during and following SCT for HM are made.

Intro: Iron overload (IO) reflected by elevated serum ferritins is associated with increased mortality in patients with myelodysplastic syndromes (MDS) with a threshold effect seen above 1000 ug/ml (Malcovati, JCO 2005). Ferritin is elevated due to transfusions, inflammation and ineffective erythropoiesis but is an imperfect metric of true iron overload. Elevated levels of oxidatively damaging non-transferrin bound iron (NTBI) and labile plasma iron (LBI) are not easily measured but correlate with transferrin saturation (TSAT) >70% and >80% respectively (de Swart, Haematological 2018). The relationship of TSAT with ferritin and MDS-related clinical outcomes has not been well-characterized. Objectives: We aimed to describe temporal trends in TSAT according to transfusion dependence and to determine if elevated TSAT correlates with ferritin levels, and/or predicts for clinical outcomes such as survival, infectious death and cardiac death in patients with MDS. Methods: Adult patients enrolled in the Canadian national MDS registry over 11.5 years and 15 centers were evaluated retrospectively. Mean, median and ranges for ferritin and TSAT were calculated at six (+/- 3) month intervals. General linear mixed model analysis with repeated measures per subject was used to evaluate changes in ferritin and TSAT over time. Transfusion density (TD) was calculated at landmark year 1 and 2 and was defined as the total number of units transfused/months elapsed since commencing transfusion dependence, with TD-low and TD-high defined as above or below median. Log-rank tests were used to detect survival differences among three transfusion groups (transfusion independent [TI], TD-low and TD-high), among three TSAT groups (TSAT 80% at enrolment), and among three ferritin groups (≤500ug/mL, 501-1000ug/mL and >1000ug/mL at enrolment). Results: A total of 718 patients from the MDS-CAN registry were included in the analysis. Patient characteristics including demographics, clinical and laboratory characteristics are summarized in Table 1. With a median follow up of 2.1 years, actuarial OS was 2.4 years. 17% developed AML and 61% of patients have died. AML, progressive disease, infection, cardiac causes, bleeding accounted for 26%, 20%, 19%, 9.6% and 6.34% of known causes of death respectively. 56% experienced infections (median 2/patient), 7% experienced a cardiac event and 43% were hospitalized at least once. Ferritin and TSAT were moderately correlated over time (r=0.63, p < 0.0001) (Figure 1A) with only 39% of all ferritins >1000ug/mL associating with a TSAT of >80%. The relationship between the 2337 serum ferritins (recorded over 42 months) and TSAT is shown in Figure 1B. Among all patients, ferritin significantly increased from enrolment up to 42 months (p Conclusion: Among a cohort of predominantly low-intermediate risk MDS patients, TSAT correlated only moderately with serum ferritins. TD patients, and in particular high transfusion-burden TD patients have inferior clinical outcomes compared to TI or low-transfusion burden TD patients. Further analyses to probe these relationships are ongoing including the effect of TSAT and iron chelation therapy on infectious deaths, and a multivariate analysis adjusting for other covariates. Disclosures Geddes: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Keating:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees. Leber:Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shamy:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Storring:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nevill:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria. Delage:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Elemary:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chodirker:Hoffman Laroche: Honoraria. Leitch:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Exjade: Speakers Bureau. Buckstein:Astex: Honoraria; Celgene: Honoraria; Takeda: Research Funding; Celgene: Research Funding; Novartis: Honoraria.

The frailty index (FI) is based on the principle that the more deficits an individual has, the greater their risk of adverse outcomes. It is expressed as a ratio of the number of deficits present to the total number of deficits considered. We developed an MDS-specific FI using a prospective MDS registry and assessed its ability to add prognostic power to conventional prognostic scores in MDS. The 42 deficits included in this FI included measurements of physical performance, comorbidities, laboratory values, instrumental activities of daily living, quality of life and performance status. Of 644 patients, 440 were eligible for FI calculation. The median FI score was 0.25 (range 0.05-0.67), correlated with age and IPSS/IPSS-R risk scores and discriminated overall survival. With a follow-up of 20 months, survival was 27 months (95% CI 24-30.4). By multivariate analysis, age >70, FI, transfusion dependence, and IPSS were significant covariates associated with OS. The incremental discrimination improvement of the frailty index was 37%. We derived a prognostic score with five risk groups and distinct survivals ranging from 7.4 months to not yet reached. If externally validated, the MDS-FI could be used as a tool to refine the risk stratification of current clinical prognostication models.

Transfused MDS patients are at risk for iron overload (IOL). IOL may exacerbate congestive heart failure (CHF), coronary artery disease (CAD) and arrythmias (ARR). We retrospectively examined cardiac events (CE) in red blood cell (RBC) transfusion dependent (TD) lower IPSS risk MDS patients. Patients were censored at death or MDS progression. 151 MDS patients were lower IPSS risk and RBC TD. Median number of cardiac risk factors (RF) per patient was 1 (1–4). CE following RBC TD occurred in 48 (32%) and were: CHF, n = 20; CAD, n = 15; ARR, n = 11. In univariate analysis factors significant for time to (TT) CE were: age at 1st RBC transfusion; number of RBCU transfused while lower IPSS risk; received iron chelation therapy (ICT); MDS treatment received; and number of cardiac RF/patient (p ≤ 0.02). Receiving ICT remained significant for TTCE in multivariate analysis (p = 0.03). Median TTCE in patients not receiving and receiving ICT was 7.0 (0.1–65.0) and 20.0 (0.1–148.6) months, respectively (p = 0.02). For lower IPSS risk RBC transfusion dependent MDS patients, time to first cardiac event following RBC TD was significantly longer in patients receiving ICT. These results suggest ICT may delay cardiac events in transfused patients. The results should be confirmed in larger numbers in prospective analyses.

Background Myelodysplastic syndrome (mds) is characterized by peripheral blood cytopenias, with most patients developing significant anemia and dependence on red blood cell (rbc) transfusion. In paroxysmal nocturnal hemoglobinuria (pnh), mutations in the PIGA gene lead to lack of cell-surface glycosylphosphatidylinositol, allowing complement-mediated lysis to occur. Paroxysmal nocturnal hemoglobinuria results in direct antiglobulin test–negative hemolysis and cytopenias, and up to 50% of patients with mds test positive for pnh cells. We wanted to determine whether pnh is considered to be a contributor to anemia in mds. Methods Patients with a diagnosis of mds confirmed by bone-marrow biopsy since 2009 were reviewed. Highresolution pnh testing by flow cytometry examined flaer (fluorescein-labeled proaerolysin) binding and expression of CD14, CD15, CD24, CD45, CD59, CD64, and CD235 on neutrophils, monocytes, and rbcs. Results In 152 patients with mds diagnosed in 2009 or later, the mds diagnosis included subtypes associated with pnh positivity (refractory anemia, n = 7, and hypoplastic mds, n = 4). Of 11 patients who underwent pnh testing, 1 was positive (9.0%). Reasons for pnh testing were anemia ( n = 3), new mds diagnosis ( n = 2), hypoplastic mds ( n = 2), decreased haptoglobin ( n = 1), increased rbc transfusion requirement ( n = 1), and unexplained iron deficiency ( n = 1). Conclusions Testing for pnh was infrequent in mds patients, and the criteria for testing were heterogeneous. Clinical indicators prompted pnh testing in 6 of 11 patients. Given that effective treatment is now available for pnh and that patients with pnh-positive mds can respond to immunosuppressive therapy, pnh testing in mds should be considered. Prospective analyses to clarify the clinical significance of pnh positivity in mds are warranted.in clinical practice, with manageable toxicity.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

An increased incidence of infections and infectious mortality has been reported in myelodysplastic syndromes (MDS) patients receiving red blood cell (RBC) transfusions.We examined incidence of infections requiring antibiotics, antifungal or antiviral medications in transfused lower International Prognostic Scoring System (IPSS) risk MDS patients and whether this differed with iron chelation therapy (ICT).138 transfused MDS patients were lower IPSS risk. 59 received ICT; median duration was 13 months. There was no significant difference between groups in neutrophil count at first RBC transfusion or first infection. Infections included: bacterial, n = 88; viral; fungal; and mycobacterial; n = 2 each. In ICT and non-ICT patients, respectively, infections were (number [%]): patients, 23 (40.0%) and 22 (27.8%); episodes (median [range]), 2 (1-6) and 2 (1-5); hospitalizations, 16 (27.1%) and 8 (10.1%); and deaths, 0 (0%) and 1 (1.3%), p = NS for all. Median overall survival (OS) from first RBC transfusion was superior in ICT patients, p = 0.01, and remained significant in a multivariate analysis (MVA), p = 0.003. Median time to first infection (TTI) was 27 and 7.8 months, respectively, p 0.0001, and ICT remained significant for TTI in an MVA, p = 0.02, hazard ratio 0.3. For ICT patients with blast count5%, TTI was significantly superior (p = 0.004).In this retrospective analysis, for lower IPSS risk MDS patients receiving RBC transfusions, though number and type of infections were similar between groups and despite similar neutrophil counts, time to first infection was significantly longer in ICT patients (p 0.0001). These results should be confirmed in larger, prospective analyses.

Iron overload (IOL) portends inferior outcome in myelodysplastic syndromes (MDS). Erythropoiesis-stimulating agents (ESA) may reduce red blood cell transfusion requirements. MDS patients receiving ESA were reviewed for characteristics, response to ESA by International Working Group 2006 criteria and ferritin levels. Forty-nine patients received an ESA, had ferritin levels available, and were not receiving iron chelation therapy. Baseline characteristics were not significantly different between ESA responders (ER) and non-responders (ENR; P = NS). The median ESA treatment duration was 6.7 (1.5–85.9) months. Twenty-one (43 %) patients had an ESA response. Median ferritin level in ER was pre-ESA, 473 (range 91–2727) and post-ESA, 801 (130–11,164) ng/mL (P = 0.01), and in ENR pre-ESA, 672 (76–3285) and post-ESA, 1423 (431–6593) ng/mL (P

Background. Hematologic improvement (HI) occurs in some patients with acquired anemias and transfusional iron overload receiving iron chelation therapy (ICT) but there is little information on transfusion status after stopping chelation.Case Report. A patient with low IPSS risk RARS-T evolved to myelofibrosis developed a regular red blood cell (RBC) transfusion requirement. There was no response to a six-month course of study medication or to erythropoietin for three months. At 27 months of transfusion dependence, she started deferasirox and within 6 weeks became RBC transfusion independent, with the hemoglobin normalizing by 10 weeks of chelation. After 12 months of chelation, deferasirox was stopped; she remains RBC transfusion independent with a normal hemoglobin 17 months later. We report the patient’s course in detail and review the literature on HI with chelation.Discussion. There are reports of transfusion independence with ICT, but that transfusion independence may be sustained long term after stopping chelation deserves emphasis. This observation suggests that reduction of iron overload may have a lasting favorable effect on bone marrow failure in at least some patients with acquired anemias.

Chemoimmunotherapy with rituximab improves survival in clinical trials in upfront chronic lymphocytic leukemia (CLL) treatment. This study compared clinical outcomes with and without rituximab added to first-line chemotherapy in a provincial cohort of CLL patients. Between 1973 and 2014, 1345 patients received CLL treatment: 48% with rituximab, 52% chemotherapy alone. Median overall survival (OS) and treatment-free survival (TFS) were significantly longer with rituximab: OS 8.9 vs. 6.2 years, p

Lymphoproliferative disorders are prevalent in HIV-positive patients and the majority are aggressive [1]. The success of highly active antiretroviral therapy (HAART) has resulted in a substantial i...

Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int − 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level

Human immunodeficiency virus (HIV)-associated multicentric Castleman disease (MCD) is a lymphoproliferation associated with human herpes virus-8 (HHV-8). Optimal treatment in patients not responding to antiretroviral therapy (ART) is undefined. We report 12 patients with ART refractory HIV-MCD. Patients with HIV-MCD were identified and baseline characteristics, treatment and outcome considered. Median CD4 count at HIV-MCD diagnosis was 295 (60-950) cells/mL. All patients had waxing and waning systemic symptoms, lymphadenopathy and/or splenomegaly, with non-Hodgkin lymphoma (NHL) in three. Treatment included: anti-HHV-8 therapy, n = 8; alone, n = 4; with systemic chemotherapy (CT) ± immunotherapy (IT), n = 4; CT ± IT only, n = 2. Initial median HHV-8 viral load (VL) was 7 × 10(4) copies/mL and at follow-up40 in 6/7 survivors; and 403-7.2 × 10(6) in 4/5 who died. One patient developed NHL despite an HHV-8 VL40. HIV-MCD is challenging to treat. Suppression of plasma HHV-8 VL did not prevent development of NHL. Anti-HHV-8 therapy should probably be considered adjunctive to cytotoxic therapies.