Autoimmune syndromes presenting as a paraneoplastic manifestation of myelodysplastic syndromes: clinical features, course, treatment and outcome

Autoimmune manifestations (AIM) are reported in up to 10-30% of myelodysplastic syndromes (MDS) patients; this association is not well defined. We present herein a retrospective chart review of single center MDS patients for AIM, a case discussion and a literature review. Of 252 MDS patients examined, 11 (4.4%) had AIM around MDS diagnosis. International Prognostic Scoring System scores were: low or intermediate (int)-1 (n=7); int-2 or high (n=4). AIM were: culture negative sepsis (n=7); inflammatory arthritis (n=3); vasculitis (n=4); sweats; pericarditis; polymyalgia rheumatica (n=2 each); mouth ulcers; pulmonary infiltrates; suspicion for Behcet’s; polychondritis and undifferentiated (n=1 each). AIM treatment and outcome were: prednisone +/- steroid sparing agents, n=8, ongoing symptoms in 5; azacitidine (n=3), 2 resolved; and observation, n=1, ongoing symptoms. At a median follow up of 13 months, seven patients are alive. In summary, 4.4% of MDS patients presented with concomitant AIM. MDS should remain on the differential diagnosis of patients with inflammatory symptoms

Clinical Features, Treatment, and Outcome of HIV-Associated Immune Thrombocytopenia in the HAART Era

The characteristics of HIV-associated ITP were documented prior to the HAART era, and the optimal treatment beyond HAART is unknown. We performed a review of patients with HIV-associated ITP and at least one platelet count <20 × 109/L since January 1996. Of 5290 patients in the BC Centre for Excellence in HIV/AIDS database, 31 (0.6%) had an ITP diagnosis and platelet count <20 × 109/L. Initial ITP treatment included IVIG, n = 12; steroids, n = 10; anti-RhD, n = 8; HAART, n = 3. Sixteen patients achieved response and nine patients achieved complete response according to the International Working Group criteria. Median time to response was 14 days. Platelet response was not significantly associated with treatment received, but complete response was lower in patients with a history of injection drug use. Complications of ITP treatment occurred in two patients and there were four unrelated deaths. At a median followup of 48 months, 22 patients (71%) required secondary ITP treatment. This is to our knowledge the largest series of severe HIV-associated ITP reported in the HAART era. Although most patients achieved a safe platelet count with primary ITP treatment, nearly all required retreatment for ITP recurrence. New approaches to the treatment of severe ITP in this population are needed

Analysis of predictors of response to ruxolitinib in patients with myelofibrosis in the phase 3b expanded-access JUMP study.

Data from the large, prospective, multinational, phase 3b JUMP study were analyzed to identify factors predictive of spleen and symptom responses in myelofibrosis patients receiving ruxolitinib. Factors associated with higher spleen response rates included International Prognostic Scoring System (IPSS) low/intermediate-1 risk vs intermediate-2/high risk (43.1% vs 30.6%; adjusted OR [aOR] 0.65 [95% CI 0.44-0.95]), ruxolitinib as first- vs second- or later-line therapy (40.2% vs 31.5%; aOR 0.53 [95% CI 0.38-0.75]), and a ruxolitinib total daily dose at Week 12 of20 mg/day vs ≤20 mg/day (41.3% vs 30.4%; aOR 0.47 [95% CI 0.33-0.68]). No association was seen between baseline characteristics or total daily dose at Week 12 and symptom response. Ruxolitinib led to higher spleen response rates in patients with lower IPSS risk, and when used earlier in treatment. Higher doses of ruxolitinib were associated with higher spleen response rates, but not with symptom improvement.Trial registrationINC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis (JUMP).2010-024473-39; NCT01493414Date of registration: 16 December 2011https://www.clinicaltrialsregister.eu/ctr-search/search?query=2010-024473-39https://clinicaltrials.gov/ct2/show/NCT01493414

Safety and efficacy of ruxolitinib in an open-label, multicenter, single-arm phase 3b expanded-access study in patients with myelofibrosis: A snapshot of 1144 patients in the JUMP trial

JUMP is a phase 3b expanded-access trial for patients without access to ruxolitinib outside of a clinical study; it is the largest clinical trial to date in patients with myelofibrosis who have been treated with ruxolitinib. Here, we present safety and efficacy findings from an analysis of 1144 patients with intermediate- or high-risk myelofibrosis, as well as a separate analysis of 163 patients with intermediate-1-risk myelofibrosis – a population of patients not included in the phase 3 COMFORT studies. Consistent with ruxolitinib’s mechanism of action, the most common hematologic adverse events were anemia and thrombocytopenia, but these led to treatment discontinuation in only a few cases. The most common non-hematologic adverse events were primarily grade 1/2 and included diarrhea, pyrexia, fatigue, and asthenia. The rates of infections were low and primarily grade 1/2, and no new or unexpected infections were observed. The majority of patients achieved a ≥50% reduction from baseline in palpable spleen length. Improvements in symptoms were rapid, with approximately half of all patients experiencing clinically significant improvements, as assessed by various quality-of-life questionnaires. The safety and efficacy profile in intermediate-1-risk patients was consistent with that in the overall JUMP population and with that previously reported in intermediate-2- and high-risk patients. Overall, ruxolitinib provided clinically meaningful reductions in spleen length and symptoms in patients with myelofibrosis, including those with intermediate-1-risk disease, with a safety and efficacy profile consistent with that observed in the phase 3 COMFORT studies. This trial was registered as NCT01493414 at ClinicalTrials.gov

Symptomatic benefit of momelotinib in patients with myelofibrosis: results from the SIMPLIFY phase III studies

Background: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy. Methods: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data. Results: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as “improved” or “stable” compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm. Conclusions: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings

The somatic genomic landscape of glioblastoma

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer