Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major ...randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.
Although reduced-intensity conditioning (RIC) and non-myeloablative (NMA)-conditioning regimens have been used for over a decade, their relative efficacy vs myeloablative (MA) approaches to ...allogeneic hematopoietic cell transplantation in patients with AML and myelodysplasia (MDS) is unknown. We compared disease status, donor, graft and recipient characteristics with outcomes of 3731 MA with 1448 RIC/NMA procedures performed at 217 centers between 1997 and 2004. The 5-year univariate probabilities and multivariate relative risk outcomes of relapse, TRM, disease-free survival (DFS) and OS are reported. Adjusted OS at 5 years was 34, 33 and 26% for MA, RIC and NMA transplants, respectively. NMA conditioning resulted in inferior DFS and OS, but there was no difference in DFS and OS between RIC and MA regimens. Late TRM negates early decreases in toxicity with RIC and NMA regimens. Our data suggest that higher regimen intensity may contribute to optimal survival in patients with AML/MDS, suggesting roles for both regimen intensity and graft vs leukemia in these diseases. Prospective studies comparing regimens are needed to confirm this finding and determine the optimal approach to patients who are eligible for either MA or RIC/NMA conditioning.
Highlights • Risky and addicted free-to-play gamers show higher perceived stress and dysfunctional coping strategies than non-problematic free-to-play gamers. • Risky and addicted free-to-play gamers ...significantly spend more time and money on free-to-play games than non-problematic free-to-play gamers. • No age differences could be detected regarding risky and addicted free-to-play gaming in children and adolescents.
Disease relapse or progression is a major cause of death following umbilical cord blood (UCB) transplantation (UCBT) in patients with high-risk, relapsed or refractory acute lymphoblastic leukemia ...(ALL). Adoptive transfer of donor-derived T cells modified to express a tumor-targeted chimeric antigen receptor (CAR) may eradicate persistent disease after transplantation. Such therapy has not been available to UCBT recipients, however, due to the low numbers of available UCB T cells and the limited capacity for ex vivo expansion of cytolytic cells. We have developed a novel strategy to expand UCB T cells to clinically relevant numbers in the context of exogenous cytokines. UCB-derived T cells cultured with interleukin (IL)-12 and IL-15 generated >150-fold expansion with a unique central memory/effector phenotype. Moreover, UCB T cells were modified to both express the CD19-specific CAR, 1928z, and secrete IL-12. 1928z/IL-12 UCB T cells retained a central memory-effector phenotype and had increased antitumor efficacy in vitro. Furthermore, adoptive transfer of 1928z/IL-12 UCB T cells resulted in significantly enhanced survival of CD19(+) tumor-bearing SCID-Beige mice. Clinical translation of CAR-modified UCB T cells could augment the graft-versus-leukemia effect after UCBT and thus further improve disease-free survival of transplant patients with B-cell ALL.
Patients with acute myeloid leukemia (AML) who fail to achieve complete remission (CR) have a dismal prognosis. Although data suggest that durable remissions can be achieved in approximately 30% of ...patients with refractory or relapsed AML after allogeneic hematopoietic cell transplantation (HCT), only a small fraction of those patients are offered this therapeutic option. Importantly, patients with primary refractory AML have distinctly better outcomes following allogeneic HCT than those with refractory relapse. Access to suitable donors could be one of the main barriers in these situations. However, with recent developments in the field of allogeneic HCT, such as alternative donor sources, high-resolution HLA-typing, reduced intensity conditioning regimens and improvements in supportive care, this approach has the potential to offer long-term survival for patients with refractory and relapsed AML and should be considered as early after diagnosis as possible. Incorporating novel agents into the conditioning regimen or as post-transplant maintenance therapy could further improve outcomes and render older or medically infirm patients with refractory or relapsed AML eligible for allogeneic HCT. In this review, we summarize existing data on allogeneic HCT in patients with refractory or relapsed AML and explore novel approaches with the potential to improve outcomes in this patient population.
Ash emitted during explosive volcanic eruptions may disperse over vast areas of the globe posing a threat to human health and infrastructures and causing significant disruption to air traffic. In ...Antarctica, at least five volcanoes have reported historic activity. However, no attention has been paid to the potential socio-economic and environmental consequences of an ash-forming eruption occurring at high southern latitudes. This work shows how ash from Antarctic volcanoes may pose a higher threat than previously believed. As a case study, we evaluate the potential impacts of ash for a given eruption scenario from Deception Island, one of the most active volcanoes in Antarctica. Numerical simulations using the novel MMB-MONARCH-ASH model demonstrate that volcanic ash emitted from Antarctic volcanoes could potentially encircle the globe, leading to significant consequences for global aviation safety. Results obtained recall the need for performing proper hazard assessment on Antarctic volcanoes, and are crucial for understanding the patterns of ash distribution at high southern latitudes with strong implications for tephrostratigraphy, which is pivotal to synchronize palaeoclimatic records.
The High Arctic plays a vital role in Earth's climate system, and its ecosystems are highly sensitive to global climate change. High Arctic lakes are valuable sentinels of climate change, as their ...sediments integrate long-term natural climatic fluctuations and anthropogenic influences. Here, we present a high-resolution ∼5000 year-reconstruction of NE Greenland climate variability from Aucella Lake (74°N, 20°E) based on physical, chemical, and biological properties of lake sediments. We use CT-scans, hyperspectral imaging, organic matter, XRD, and diatom analyses to show that changing air temperatures were controlled by a mix of regional climatic changes and local landscape feedbacks. The latest Mid-Holocene (∼5.0–3.8 cal. ka BP) was characterized by relatively warmer conditions, while the onset of the Late-Holocene was marked by abrupt temperature decreases that coincided with the beginning of glacial advances elsewhere (∼3.8–3.4 cal. ka BP). From ∼3.4–2.4 cal. ka BP, the sedimentary record indicated progressive warming, with temperature peaking during the Medieval Climate Anomaly, although temperature rises were punctuated by abrupt, short-lived cold periods. From ∼1.1–0.05 cal. ka BP, the influence of landscape factors over the system diminished. Sedimentary indicators suggested a transition towards a colder, more humid climate, coinciding with the beginning of the Little Ice Age, that was characterized by a marked decrease in air temperature that reached minimum values at the end of this period. The last 50 years at Aucella Lake were marked by abrupt temperature rises, consistent with recently observed anthropogenic global warming. Our results illustrate the importance of high-resolution multiproxy studies for accurately characterizing lake linkages to their environment and climate.
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•Arctic lakes are climate change sentinels. Their sediments show natural climatic fluctuations and anthropogenic influences.•High-resolution climate variability from NE Greenland based on lake sediments properties.•Changing air temperatures were controlled by a mix of regional climatic changes and local landscape feedbacks.
The extant literature documents burden among caregivers of patients undergoing a hematopoietic stem cell transplantation (HSCT), but little is known about the burden of caregivers of patients ...receiving outpatient and homebound HSCTs. This scoping study sought to evaluate what is known about the burden of the increasing number of adult caregivers of patients receiving outpatient HSCTs and to create practice guidelines for how to best support this vulnerable group. Online databases were searched for studies that evaluated caregiver burden in adult caregivers of HSCT patients since 2010 (the publication date of the most recent systematic review on HSCT caregiver burden). Of the 1271 articles retrieved, 12 met the inclusion criteria, though none specifically examined outpatient or homebound caregivers. Overall, studies corroborated existing literature on the experience of significant burden among HSCT caregivers across the HSCT trajectory, and highlighted the emotional costs of outpatient transplants on caregivers and the need to identify caregivers at high risk for burden early in the transplant process. Future studies of outpatient caregivers should include a comprehensive assessment of burden and seek to identify points along the transplant trajectory at which caregivers are at particular risk for negative outcomes and when intervention is most appropriate.
PR1, an HLA-A2-restricted peptide derived from both proteinase 3 and neutrophil elastase, is recognized on myeloid leukemia cells by cytotoxic T lymphocytes (CTLs) that preferentially kill leukemia ...and contribute to cytogenetic remission. To evaluate safety, immunogenicity and clinical activity of PR1 vaccination, a phase I/II trial was conducted. Sixty-six HLA-A2+ patients with acute myeloid leukemia (AML: 42), chronic myeloid leukemia (CML: 13) or myelodysplastic syndrome (MDS: 11) received three to six PR1 peptide vaccinations, administered subcutaneously every 3 weeks at dose levels of 0.25, 0.5 or 1.0 mg. Patients were randomized to the three dose levels after establishing the safety of the highest dose level. Primary end points were safety and immune response, assessed by doubling of PR1/HLA-A2 tetramer-specific CTL, and the secondary end point was clinical response. Immune responses were noted in 35 of 66 (53%) patients. Of the 53 evaluable patients with active disease, 12 (24%) had objective clinical responses (complete: 8; partial: 1 and hematological improvement: 3). PR1-specific immune response was seen in 9 of 25 clinical responders versus 3 of 28 clinical non-responders (P=0.03). In conclusion, PR1 peptide vaccine induces specific immunity that correlates with clinical responses, including molecular remission, in AML, CML and MDS patients.
Allogeneic hematopoietic SCT is an effective treatment in accelerated (AP) or blast phase (BP) CML. Imatinib (IM) has transient but significant activity in advanced phases of CML, which may permit ...early allografting for responding patients. To identify prognostic factors in allograft recipients previously treated with IM, we analyzed 449 allogeneic hematopoietic SCTs performed from 1999 to 2004 in advanced-phase CML, using the data reported to the Center for International Blood and Marrow Transplant Research. CML patients in second chronic phase (CP2, n=184), AP (n=185) and BP (n=80) received HLA-identical sibling (27%), related (3%), or matched or mismatched unrelated donor (70%), peripheral blood (47%) or BM (53%) hematopoietic SCT after myeloablative (78%) or non-myeloablative (22%) conditioning. In all, 52% in CP2, 49% in AP and 46% in BP received IM before hematopoietic SCT. Disease-free survival was 35-40% for CP2, 26-27% for AP and 8-11% for BP. Cumulative incidence of acute and chronic GVHD and TRM were not affected by the stages of CML or pre-hematopoietic SCT IM exposure. Multivariate analyses showed that conventional prognostic indicators remain the strongest determinants of transplant outcomes. In conclusion, there are no new prognostic indicators of the outcomes of allogeneic hematopoietic SCT for advanced-phase CML in the IM era.
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