Low participation rates and disparities in participation in interventional clinical trials for myelodysplastic syndromes.

BACKGROUND: The development of novel therapies for the myelodysplastic syndromes (MDS) is hampered by inadequate trial recruitment. Factors contributing to low trial accrual are incompletely understood. METHODS: This study analyzed a pooled patient database from institutions of the US MDS Clinical Research Consortium to compare the characteristics of participants in interventional trials with those of patients who did not enroll in a trial. RESULTS: Data were identified for 1919 patients with MDS, and 449 of these patients (23%) participated in an interventional clinical trial. The median age of all patients was 68 years, and 64% were male. Patients who participated in trials were significantly younger than nonparticipants (P = .014), and men were more likely to participate in a trial (71% of trial participants were male, whereas 61% of nonparticipants were; P < .001). Race and ethnicity were not associated with trial enrollment. Patients in more affluent ZIP codes had a higher participation rate (P < .001). Patients with intermediate- and high-risk disease according to the revised International Prognostic Scoring System were overrepresented (P = .004), and trial participants less frequently had treatment-related disease (P < .001). In multivariable analyses, participation in a clinical trial was associated with a reduced hazard of death (P = .004). Even at large referral centers, only a minority of patients with MDS enrolled in interventional trials. CONCLUSIONS: Restrictive trial eligibility criteria that exclude patients with MDS on account of age, comorbidities, or a history of another cancer are limit enrollment of MDS patients to clinical trials. Gaining insight into the barriers to trial accrual may help investigators and study sponsors to design trials that will accrue more rapidly and augment treatment options for patients with MDS.

Single-cell sequencing in hematology.

PURPOSE OF REVIEW: In this review, we highlight key recent insights into hematopoiesis and hematological malignancies through the application of novel single-cell approaches. We particularly focus on biological insights made through the study of stem/progenitors cells in myeloid malignancy at single-cell resolution. RECENT FINDINGS: Bulk molecular profiling of hematological malignancies by next generation sequencing techniques has provided major insights into the molecular pathogenesis of blood cancers. This technology is now routinely implemented in advanced clinical diagnostics, leading to the development of novel targeted therapies. However, bulk genetic analysis can obscure key aspects of intratumoral heterogeneity which underlies critical disease events, such as treatment resistance and clonal evolution. The past few years have seen an explosion of novel techniques to analyze RNA, DNA, and protein expression at the single-cell level, providing unprecedented insight into cellular heterogeneity. SUMMARY: Given the ease of accessibility of liquid tumor biopsies, hematology is well positioned to move novel single-cell techniques towards routine application in the clinic. The present review sets out to discuss current and potential future applications for this technology in the management of patients with hematological cancers.

Impact of graft-versus-lymphoma effect on outcomes after reduced intensity conditioned-alemtuzumab allogeneic haematopoietic stem cell transplantation for patients with mature lymphoid malignancies.

Allogeneic haematopoietic stem cell transplant (allo-HSCT) offers potentially curative therapy for patients with relapsed/refractory lymphoid malignancies. Reduced-intensity conditioning (RIC) with Alemtuzumab reduces transplant-related mortality and graft-versus-host disease (GvHD), but may be associated with increased risk of relapse. With the aim of studying the effect of GVHD and donor lymphocyte infusions (DLI) on relapse, we performed a retrospective study of 288 patients (57% non-Hodgkin lymphoma, 24% Hodgkin lymphoma and 19% chronic lymphocytic leukaemia; 58% were relapsed/refractory) who underwent RIC-Alemtuzumab-HSCT between 2000 and 2012. Median follow-up time for survivors was 64 months. Five-year overall survival, relapse incidence, GvHD/relapse-free survival and non-relapse mortality were 47%, 33%, 37% and 28% respectively. Cumulative incidence of grade II-IV acute and extensive chronic GvHD was 22% and 21% at 100 days and 5 years respectively. On multivariate analysis, presence of GvHD (P = 0·03) and unrelated donor type (P = 0·03) were protective of relapse. 62/288 patients received DLI for either mixed donor chimerism (prophylactic DLI, n = 37) or clinical relapse (therapeutic DLI, n = 25). Prophylactic and therapeutic DLI successfully converted the patient to full or stable mixed donor chimerism in 78% and 56% of patients respectively. These data demonstrate good long-term outcomes and support the concept of the graft-vs-lymphoma effect as a key protective factor against relapse following RIC-Alemtuzumab allo-HSCT for patients with mature lymphoid malignancies.

Autoimmune cytopenias and thrombotic thrombocytopenic purpura.

The autoimmune cytopenias are a group of disorders resulting primarily from autoantibody-mediated destruction of blood cells, with variable clinical sequelae depending on the severity and lineage affected. Disease presentation ranges from an asymptomatic finding on a routine full blood count to an acutely unwell patient suffering the clinical consequences of severe anaemia, neutropenia or thrombocytopenia. The cytopenia may be primary or secondary to underlying infectious, immune or malignant processes. Thrombotic thrombocytopenic purpura (TTP) is a distinct, rare but potentially life-threatening entity that classically but not invariably presents with a pentad of acute onset haemolytic anaemia, thrombocytopenia, neurological symptoms, renal impairment and fevers. Autoimmune cytopenias have formed a recognised diagnostic entity for over 150 years yet continue to present a challenge in medical practice due to heterogeneity in clinical presentation and triggering factors, an incomplete understanding of underlying pathophysiology and a lack of evidence-based therapeutic approaches.

Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation.

BACKGROUND AND AIMS: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with severe, treatment-refractory Crohn's disease [CD]. The evidence base for AHSCT for CD is limited, with one randomised trial [ASTIC] suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe, outside the ASTIC trial. METHODS: We identified 99 patients in the European Society for Blood and Marrow Transplantation [EBMT] registry, who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in seven countries. RESULTS: Median patient age was 30 years [range 20-65]. Patients had failed or been intolerant to a median of six lines of drug therapy; 61/82 [74%] had had surgery. Following AHSCT, 53/78 [68%] experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months [range 6-174]; 22/82 [27%] required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at latest follow-up, 57% [24/42] achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at 1 year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% confidence interval [CI] 1.14-4.83, p = 0.02). One patient died due to infectious complications [cytomegalovirus disease] at Day +56. CONCLUSIONS: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.

Targeting Splicing in the Treatment of Myelodysplastic Syndromes and Other Myeloid Neoplasms.

Genome sequencing of primary cells from patients with myelodysplastic syndromes (MDS) led to the identification of recurrent heterozygous mutations in gene encoding components of the spliceosome, the cellular machinery which processes pre-messenger RNA (mRNA) to mature mRNA during gene transcription. Splicing mutations are mutually exclusive with one another and collectively represent the most common mutation class in MDS, occurring in approximately 60 % of patients overall and more than 80 % of those with ring sideroblasts. Evidence from animal models suggests that homozygous splicing mutations are lethal, and that in heterozygously mutated models, any further disruption of splicing triggers apoptosis and cell death. MDS cells with spliceosome mutations are thus uniquely vulnerable to therapies targeting splicing, which may be tolerated by healthy cells. The spliceosome is emerging as a novel therapeutic target in MDS and related myeloid neoplasms, with the first clinical trial of a splicing modulator opening in 2016.

Allogeneic stem cell transplantation in myelodysplastic syndromes: does pretransplant clonal burden matter?

PURPOSE OF REVIEW: Currently, the only potential curative therapy for myelodysplastic syndromes (MDS) is allogeneic hematopoietic stem cell transplantation (alloSCT). As alloSCT confers both a short-term mortality risk compared with conservative management, and a longer-term risk of chronic health burden from graft-versus-host disease and other complications, careful patient selection for alloSCT is essential. Here, we review data on disease burden and transplant outcomes in MDS, describing which patients stand to benefit most (and least) from alloSCT. Evidence for timing of alloSCT and modifying tumor burden prior to transplant is also discussed. RECENT FINDINGS: Although patients who undergo alloSCT with excess blasts have poorer outcomes than those transplanted with fewer blasts, the effect of clone size in patients with MDS without increased blast proportion is poorly studied, and it is also not yet known whether posttransplant outcomes can be modified with pretransplant therapy such as intensive induction chemotherapy or hypomethylating agent treatment. Randomized data are lacking. Most hematopoietic cells in patients with MDS are clonal, even in cases without increased marrow blast proportion. Certain high-risk point mutations such as TP53 seem to be associated with a worse outcome even when subclonal. SUMMARY: Patients with more than 10% blasts should be considered for cytoreductive therapy before transplant, especially if reduced intensity conditioning (alloSCT) is planned. Patients with less than 10% blasts who are appropriate candidates for transplant can proceed straight to transplant, though it appears better to delay transplant for those with lower-risk disease. Hypomethylating agent therapy may be useful as a bridge to transplant. Randomized data are eagerly awaited.

Thrombopoiesis-stimulating agents and myelodysplastic syndromes.

Thrombocytopenia in patients with myelodysplastic syndromes (MDS) is a frequent cause of haemorrhage-related morbidity and mortality, and is associated with increased risk of leukaemic transformation and reduced overall survival. In addition, thrombocytopenia in MDS limits the tolerability and therapeutic efficacy of disease-modifying therapies, such as azacitidine or lenalidomide. The recombinant human erythropoietin (rHuEPO) erythropoiesis-stimulating agents, epoetin and darbepoetin, are an established component of anaemia management in lower-risk MDS. Their success has, in turn, driven the development of haematopoietic growth factors targeting thrombocytopenia. While recombinant thrombopoietin (THPO) proved too immunogenic for clinical use, novel thrombopoiesis-stimulating agents (TSAs) have the potential to reduce bleeding events, decrease dependency on platelet transfusions and extend exposure to disease-modifying therapies. Two TSAs, eltrombopag and romiplostim, have demonstrated benefit in chronic immune thrombocytopenia purpura (ITP) and safety and efficacy data for use of these agents in MDS is growing. However, important safety concerns remain, such as the potential for stimulation of neoplastic myeloid clones by THPO agonists. In this narrative review, we discuss the rationale and biological mechanism for TSAs in MDS, describe the agents currently available and their mechanism of action, and present current clinical data relating to TSA safety and efficacy in the context of MDS.

Healthcare access and health beliefs of the indigenous peoples in remote Amazonian Peru.

Little is published about the health issues of traditional communities in the remote Peruvian Amazon. This study assessed healthcare access, health perceptions, and beliefs of the indigenous population along the Ampiyacu and Yaguasyacu rivers in north-eastern Peru. One hundred and seventy-nine adult inhabitants of 10 remote settlements attending health clinics were interviewed during a medical services trip in April 2012. Demographics, health status, access to healthcare, health education, sanitation, alcohol use, and smoke exposure were recorded. Our findings indicate that poverty, household overcrowding, and poor sanitation remain commonplace in this group. Furthermore, there are poor levels of health education and on-going barriers to accessing healthcare. Healthcare access and health education remain poor in the remote Peruvian Amazon. This combined with poverty and its sequelae render this population vulnerable to disease.