Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) ...therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .
Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes ...for pediatric and adult patients in a number of disease states, as ‘living drugs,’ their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients.
High-dose granulocyte transfusion therapy has been available for 20 years, yet its clinical efficacy has never been conclusively demonstrated. We report here the results of RING (Resolving Infection ...in Neutropenia with Granulocytes), a multicenter randomized controlled trial designed to address this question. Eligible subjects were those with neutropenia (absolute neutrophil count <500/μL) and proven/probable/presumed infection. Subjects were randomized to receive either (1) standard antimicrobial therapy or (2) standard antimicrobial therapy plus daily granulocyte transfusions from donors stimulated with granulocyte colony-stimulating factor (G-CSF) and dexamethasone. The primary end point was a composite of survival plus microbial response, at 42 days after randomization. Microbial response was determined by a blinded adjudication panel. Fifty-six subjects were randomized to the granulocyte arm and 58 to the control arm. Transfused subjects received a median of 5 transfusions. Mean transfusion dose was 54.9 × 109 granulocytes. Overall success rates were 42% and 43% for the granulocyte and control groups, respectively (P > .99), and 49% and 41%, respectively, for subjects who received their assigned treatments (P = .64). Success rates for granulocyte and control arms did not differ within any infection type. In a post hoc analysis, subjects who received an average dose per transfusion of ≥0.6 × 109 granulocytes per kilogram tended to have better outcomes than those receiving a lower dose. In conclusion, there was no overall effect of granulocyte transfusion on the primary outcome, but because enrollment was half that planned, power to detect a true beneficial effect was low. RING was registered at www.clinicaltrials.gov as #NCT00627393.
•Overall, no benefit of granulocyte transfusion therapy was observed, but the power of the study was reduced due to low accrual.•Post hoc secondary analysis suggested that patients receiving higher doses tended to have better outcomes than those receiving lower ones.
To develop an imaging method to characterize and map marrow composition in the entire skeletal system, and to simulate differential targeted marrow irradiation based on marrow composition.
Whole-body ...dual energy computed tomography (DECT) images of cadavers and leukemia patients were acquired, segmented to separate bone marrow components, namely, bone, red marrow (RM), and yellow marrow (YM). DECT-derived marrow fat fraction was validated using histology of lumbar vertebrae obtained from cadavers. The fractions of RM (RMF = RM/total marrow) and YMF were calculated in each skeletal region to assess the correlation of marrow composition with sites and ages. Treatment planning was simulated to target irradiation differentially at a higher dose (18 Gy) to either RM or YM and a lower dose (12 Gy) to the rest of the skeleton.
A significant correlation between fat fractions obtained from DECT and cadaver histology samples was observed (r=0.861, P<.0001, Pearson). The RMF decreased in the head, neck, and chest was significantly inversely correlated with age but did not show any significant age-related changes in the abdomen and pelvis regions. Conformity of radiation to targets (RM, YM) was significantly dependent on skeletal sites. The radiation exposure was significantly reduced (P<.05, t test) to organs at risk (OARs) in RM and YM irradiation compared with standard total marrow irradiation (TMI).
Whole-body DECT offers a new imaging technique to visualize and measure skeletal-wide marrow composition. The DECT-based treatment planning offers volumetric and site-specific precise radiation dosimetry of RM and YM, which varies with aging. Our proposed method could be used as a functional compartment of TMI for further targeted radiation to specific bone marrow environment, dose escalation, reduction of doses to OARs, or a combination of these factors.
Abstract Background and purpose Total body irradiation (TBI) is a common component of hematopoietic cell transplantation (HCT) conditioning regimens. Preclinical studies suggest prolonged bone marrow ...(BM) injury after TBI could contribute to impaired engraftment and poor hematopoietic function. Materials and methods We studied the longitudinal changes in the marrow environment in patients receiving allogeneic HCT with myeloablative (MA, n = 42) and reduced intensity (RIC, n = 56) doses of TBI from 2003–2013, including BM cellularity, histologic features of injury and repair, hematologic and immunologic recovery. Results Following MA conditioning, a 30% decrease in the marrow cellularity persisted at 1 year post-transplant ( p = 0.03). RIC HCT marrow cellularity transiently decreased but returned to baseline by 6 months even though the RIC group received mostly umbilical cord blood (UCB) grafts (82%, vs. 17% in the MA cohort, p < 0.01). There was no evidence of persistent marrow vascular damage or inflammation. Recipients of more intensive conditioning did not show more persistent cytopenias with the exception of a tendency for minimal thrombocytopenia. Immune recovery was similar between MA and RIC. Conclusions These findings suggest that TBI associated with MA conditioning leads to prolonged reductions in marrow cellularity, but does not show additional histological evidence of long-term injury, which is further supported by similar peripheral counts and immunologic recovery.
Introduction
Peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) is a rare, highly heterogeneous group of mature T‐cell neoplasms that historically has been associated with poor outcomes. ...We sought to investigate the influence of primary disease site on PTCL‐NOS outcomes using a large national cancer registry.
Methods
Baseline clinical and demographic data including primary organ of involvement and Ann Arbor disease stage were extracted from the SEER database. Patients were grouped into nine organ system groups and compared to nodal disease acting as a control. Cox regression models were utilized for adjusted survival analyses.
Results
A total of 3095 patients were identified in the SEER database and included in the final analysis. The median age was 61 and a majority of patients were male (60%) and identified as non‐Hispanic white (68%). A plurality of patients had stage IV disease (32%). Lymph nodes and spleen were the most common primary disease sites (67%), while central nervous system was the least common (1%). Patients with early‐stage PTCL‐NOS of the gastrointestinal/genitourinary systems had worse overall survival HR = 1.97 (1.50–2.59); p < 0.001 and lymphoma‐specific survival HR = 1.74 (1.26–2.40); p < 0.001 which was statistically significant even after adjusting for other variables. Early‐stage PTCL‐NOS of the central nervous system also had worse overall survival HR = 1.90 (1.11–3.27); p = 0.020 and lymphoma‐specific survival HR = 2.11 (1.17–3.80); p = 0.013. Early‐stage PTCL‐NOS of the skin had better overall survival HR = 0.54 (0.42–0.68); p < 0.001 and lymphoma‐specific survival HR = 0.388 (0.28–0.53); p < 0.001 which was statistically significant even after adjustments.
Conclusion
Our findings suggest an association between primary organ involved by PTCL‐NOS and both overall and lymphoma‐specific survival even after adjusting for common variables. These results warrant validation in future prospective studies.
Background and Objectives
Graft failure (GF) after cord blood transplant (CBT) has decreased with improved supportive care and cord selection strategies. We aimed to evaluate cord blood selection and ...factors associated with retransplantation on the incidence of GF, determine risk factors for GF including host antibodies to Kell antigen and evaluate survival after GF.
Materials and Methods
We retrospectively reviewed 84 patients who underwent CBT at the University of Oklahoma between 2000 and 2016 and compared outcomes in patients with/without engraftment by Day 28. The nonengraftment cohort was further divided into patients who underwent retransplantation. Kaplan–Meier curves with log‐rank tests were calculated to assess the association between mortality and engraftment.
Results
Engraftment following CBT was high at 81%, with 52% engrafting by Day 28 and an additional 29% engrafting by a median of 36 days. Retransplantation led to 88% engraftment at a median of 53 days. Overall, 75% of the 40 patients who did not engraft by Day 28 died. Female sex and total nucleated cell count < 3.5/kg were significantly associated with lack of engraftment and higher mortality. Antibodies to Kell fetal antigen were not identified. Retransplantation by Day 28 for primary GF conferred a survival advantage.
Conclusion
This study demonstrates that failure to engraft by 28 days was associated with increased mortality, and risk was mitigated with early retransplantation. Female sex and low total cell dose were associated with increased mortality. Early identification of GF coupled with early retransplantation can reduce mortality in CBT.
Background
Evans syndrome is a rare condition manifested by combined autoimmune hemolytic anemia (AIHA) and thrombocytopenia or neutropenia. It is often associated with other autoimmune disorders, ...immunodeficiencies, and non‐Hodgkin's lymphoma.
Case Report
We describe a patient with Evans syndrome that may have been related to exposure to a polyethylene‐based intrauterine contraceptive device (IUD). A 26‐year‐old white female presented with severe, symptomatic AIHA and subsequently developed severe thrombocytopenia. She had a refractory course resistant to multiple treatments including corticosteroids, intravenous immune globulin, rituximab, splenectomy, cyclophosphamide, cyclosporine, eculizumab, and plasma exchange. It was then noticed that her serum autoantibody agglutinated red blood cells (RBCs) in the presence of polyethylene glycol (PEG) but not in the absence of PEG nor when an alternative agglutination enhancing technique, low‐ionic‐strength solution, was used. Therefore, her polyethylene‐containing IUD, which was a polyethylene frame with a levonorgestrel‐releasing device, was removed. Norgestrel‐dependent, platelet (PLT)‐reactive antibodies were not identified by either flow cytometry or in vivo in a NOD/SCID mouse. Testing for PEG‐dependent antibodies was not possible. Remission, with no requirement for RBC or PLT transfusions and return of her hemoglobin and PLT counts to normal, followed removal of the IUD.
Conclusion
The patient's recovery after removal of the IUD and the PEG dependence of RBC agglutination suggested a possibility that the IUD may have been a contributing factor to the etiology of Evans syndrome in this patient.
Since November 2018, Blood Advances has published American Society of Hematology (ASH) clinical practice guidelines on venous thromboembolism, immune thrombocytopenia, and sickle cell disease. More ...ASH guidelines on these and other topics are forthcoming. These guidelines have been developed using consistent processes, methods, terminology, and presentation formats. In this article, we describe how patients, clinicians, policymakers, researchers, and others may use ASH guidelines and the many related derivates by describing how to interpret information and how to apply it to clinical decision-making. Also, by exploring how these documents are developed, we aim to clarify their limitations and possible inappropriate usage.
Clinical tools for measuring tumor vascular hemodynamics, such as dynamic contrast-enhanced MRI, are clinically important to assess tumor properties. Here we explored the use of multispectral ...optoacoustic tomography (MSOT), which has a high spatial and temporal resolution, to measure the intratumoral pharmacokinetics of a near-infrared-dye-labeled 2-Deoxyglucose, 2-DG-800, in orthotropic 2-LMP breast tumors in mice. As uptake of 2-DG-800 is dependent on both vascular properties, and glucose transporter activity – a widely-used surrogate for metabolism, we evaluate hemodynamics of 2-DG-MP by fitting the dynamic MSOT signal of 2-DG-800 into two-compartment models including the extended Tofts model (ETM) and reference region model (RRM). We showed that dynamic 2-DG-enhanced MSOT (DGE-MSOT) is powerful in acquiring hemodynamic rate constants, including Ktrans and Kep, via systemically injecting a low dose of 2-DG-800 (0.5 µmol/kg b.w.). In our study, both ETM and RRM are efficient in deriving hemodynamic parameters in the tumor. Area-under-curve (AUC) values (which correlate to metabolism), and Ktrans and Kep values, can effectively distinguish tumor from muscle. Hemodynamic parameters also demonstrated correlations to hemoglobin, oxyhemoglobin, and blood oxygen level (SO2) measurements by spectral unmixing of the MSOT data. Together, our study for the first time demonstrated the capability of DGE-MSOT in assessing vascular hemodynamics of tumors.
PDF
