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High-dose chemotherapy with autologous hematopoietic cell transplantation (AutoHCT) has long been an integral treatment modality for multiple myeloma and non-Hodgkin lymphoma. Over the past 25 years, numerous institutions have shifted this practice from requiring hospitalization to one that can be performed in an ambulatory setting, resulting in cost savings and improved quality of life for patients. The recent advent immune-effector cell (IEC) therapies and expansion of their indications is changing the treatment landscape for hematologic and non-hematologic malignancies. However, current financial models and reimbursement structures threaten the viability and sustainability of this treatment modality should it continue to require inpatient administration and management. This threat is leading institutions to develop outpatient IEC programs based off the outpatient AutoHCT templates. Integral to the success of both is a cohesive program with outpatient-specific standard operating protocols, highly-trained providers and staff with expertise specific in these treatment modalities, evidenced-based supportive care and prophylaxis plans, extensive caregiver vetting and education, and the infrastructure to support all individuals involved. In this policy and practice review we provide an overview of the guidelines and published academic experiences, give a perspective-based description of the roles and responsibilities of the individuals involved in this process at our institution, and highlight actionable recommendations that could allow for the dissemination and implementation of outpatient AutoHCT and IEC programs more broadly.

We report on a patient with ciltacabtagene autoleucel-induced movement and neurocognitive toxicity, which was refractory to immunosuppression but responsive to combination dopaminergic therapy (carbidopa/levodopa, ropinirole, amantadine). Response was seen upon both initial treatment and rechallenge after unintended withdrawal. This is the first report of a successful symptomatic treatment of this well-described neurotoxic syndrome.

IntroductionPatients with triple-class refractory (TCR) multiple myeloma (MM) often need cytoreductive chemotherapy for rapid disease control. Bendamustine is an outpatient-administered, bifunctional alkylator and isatuximab is an anti-CD38 monoclonal antibody with unique cytotoxicity characteristics. We hypothesized that isatuximab-bendamustine-prednisone would be well-tolerated regimen in TCR MM, and conducted single-center, phase Ib, investigator-initiated study.Patients/MethodsPatients had TCR MM and last daratumumab exposure ≥ 6 weeks. This study was conducted as a 3 + 3 design to establish the maximally tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Isatuximab 10 mg/kg IV was administered weekly (cycle 1), and every 2 weeks thereafter. Bendamustine was administered on days 1 and 2 at 3 dose levels (DL): 50, 75, and 100 mg/m2. Methylprednisolone was administered as 125 mg on day 1 and prednisone 60 mg days 2–4. Common definitions were used for DLTs, adverse events (CTCAE v 5.0), and disease response.ResultsFifteen patients were treated (3 DL1, 6 DL2, 6 DL3). Median age was 71, 53% had high-risk cytogenetics, and 34% had prior BCMA-targeting therapy. One DLT was observed at DL2 (Grade 3 thrombocytopenia plus bleeding). There were no Grade 5 treatment-related AEs. The MTD was not reached. The overall response rate was 20% (3/15) including one stringent complete response. The median PFS was 2.5 months (95% CI 0.9–4.1 months).ConclusionWe demonstrated the safety and tolerability of isatuximab-bendamustine-prednisone. Toxicities were mild and manageable with limited intervention. The study was discontinued due to slow accrual. However, we observed responses even among highly refractory patients.Clinical trial registrationThis study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019.

Multiple myeloma (MM) almost invariably progresses through novel therapies. Patients with quad-refractory MM (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) and penta-refractory MM (additional refractoriness to daratumumab) have few treatment options. Two chemotherapy regimens, bendamustine/prednisone (BP) and dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP), are often used in quad- and penta-refractory MM, but there are limited data on outcomes in this heavily pre-treated population. We conducted a single-center retrospective study to identify all patients who received DCEP and/or BP for quad- or penta-refractory MM. Disease response and refractoriness were defined by International Myeloma Working Group criteria. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and duration of response (DOR). We identified 27 patients who received BP for quad- or penta-refractory MM. The median number of prior lines of therapy was 6. The ORR for BP was 26%. The median PFS for BP was 1.4 months (95% CI 1.1–1.6) and median OS was 8.7 months (95% CI 2.3–15.0). Patients treated with cyclophosphamide had less response to BP. Thirty-one patients received DCEP for quad-refractory or penta-refractory MM. The median number of prior treatment regimens was 8. The ORR to DCEP was 35%. The median PFS was 2.7 months (95% CI 1.5–3.8) and median OS was 6.2 months (95% CI 4.4–7.8). DCEP and BP retain efficacy in quad- and penta-refractory MM. Our analysis supports prospective study of these regimens, possibly in combination or in comparison with other agents in this area of unmet need.

Abstract Background Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness. Methods We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis. Results Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%–88%) compared to 62% (95% CI, 32%–86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22–1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines. Conclusions In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation. Clinical Trials Registration NCT04372602. Duvelisib, a PI3Kδγ inhibitor, had comparable efficacy and safety to placebo in treatment of severe COVID-19. Duvelisib led to significant downregulation of proinflammatory cytokines associated with COVID-19/acute respiratory distress syndrome without worsening viral replication.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect “B cell-featured” plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options. Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.

Rain recharges soil water storages and either percolates downward into aquifers and streams or is returned to the atmosphere through evapotranspiration. Although it is commonly assumed that summer rainfall recharges plant-available water during the growing season, the seasonal origins of water used by plants have not been systematically explored. We characterize the seasonal origins of waters in soils and trees by comparing their midsummer isotopic signatures (δ2H) to seasonal isotopic cycles in precipitation, using a new seasonal origin index. Across 182 Swiss forest sites, xylem water isotopic signatures show that summer rain was not the predominant water source for midsummer transpiration in any of the three sampled tree species. Beech and oak mostly used winter precipitation, whereas spruce used water of more diverse seasonal origins. Even in the same plots, beech consistently used more winter precipitation than spruce, demonstrating consistent niche partitioning in the rhizosphere. All three species' xylem water isotopes indicate that trees used more winter precipitation in drier regions, potentially mitigating their vulnerability to summer droughts. The widespread occurrence of winter isotopic signatures in midsummer xylem implies that growing-season rainfall may have minimally recharged the soil water storages that supply tree growth, even across diverse humid climates (690–2068 mm annual precipitation). These results challenge common assumptions concerning how water flows through soils and is accessed by trees. Beyond these ecological and hydrological implications, our findings also imply that stable isotopes of δ18O and δ2H in plant tissues, which are often used in climate reconstructions, may not reflect water from growing-season climates.

The critical temperature beyond which photosynthetic machinery in tropical trees begins to fail averages approximately 46.7 °C (Tcrit)1. However, it remains unclear whether leaf temperatures experienced by tropical vegetation approach this threshold or soon will under climate change. Here we found that pantropical canopy temperatures independently triangulated from individual leaf thermocouples, pyrgeometers and remote sensing (ECOSTRESS) have midday peak temperatures of approximately 34 °C during dry periods, with a long high-temperature tail that can exceed 40 °C. Leaf thermocouple data from multiple sites across the tropics suggest that even within pixels of moderate temperatures, upper canopy leaves exceed Tcrit 0.01% of the time. Furthermore, upper canopy leaf warming experiments (+2, 3 and 4 °C in Brazil, Puerto Rico and Australia, respectively) increased leaf temperatures non-linearly, with peak leaf temperatures exceeding Tcrit 1.3% of the time (11% for more than 43.5 °C, and 0.3% for more than 49.9 °C). Using an empirical model incorporating these dynamics (validated with warming experiment data), we found that tropical forests can withstand up to a 3.9 ± 0.5 °C increase in air temperatures before a potential tipping point in metabolic function, but remaining uncertainty in the plasticity and range of Tcrit in tropical trees and the effect of leaf death on tree death could drastically change this prediction. The 4.0 °C estimate is within the ‘worst-case scenario’ (representative concentration pathway (RCP) 8.5) of climate change predictions2 for tropical forests and therefore it is still within our power to decide (for example, by not taking the RCP 6.0 or 8.5 route) the fate of these critical realms of carbon, water and biodiversity3,4.

Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects. This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ 0thalassaemia, were aged 9–18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2–4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400. 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m 2, p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia. On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia. The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.