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The NCCN Guidelines for Hematopoietic Cell Transplantation (HCT) provide an evidence- and consensus-based approach for the use of autologous and allogeneic HCT in the management of malignant diseases in adult patients. HCT is a potentially curative treatment option for patients with certain types of malignancies; however, recurrent malignancy and transplant-related complications often limit the long-term survival of HCT recipients. The purpose of these guidelines is to provide guidance regarding aspects of HCT, including pretransplant recipient evaluation, hematopoietic cell mobilization, and treatment of graft-versus-host disease—a major complication of allogeneic HCT—to enable the patient and clinician to assess management options in the context of an individual patient’s condition. These NCCN Guidelines Insights provide a summary of the important recent updates to the NCCN Guidelines for HCT, including the incorporation of a newly developed section on the Principles of Conditioning for HCT. more...

Managing double-expressor lymphomas (DEL) is controversial given the dearth of data and lack of standardized guidelines on this high-risk subset of lymphomas. No prospective and few retrospective studies limited by either their sample size or short follow-up address the question of initial treatment of choice for DEL. We performed the largest analysis to date exploring R-CHOP vs DA-EPOCH-R in DEL.Adults with DEL diagnosed from 6/2012-2/2021 at 4 unique sites were retrospectively analyzed. Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints include overall survival (OS), overall and complete response rates (ORR and CRR), cumulative incidence of relapse, and autologous hematopoietic cell transplantation (autoHCT) utilization.155 patients were included, 61 treated with R-CHOP and 94 with DA-EPOCH-R. 3-year PFS and OS were similar between R-CHOP and DA-EPOCH-R, 33.2% vs 57.2%,(P = .063), and 72.2% vs 71.6% (P = .43) after median follow-up times of 2.43 and 2.89 years, respectively. Patients65 had improved PFS with DA-EPOCH-R, hazard ratio 0.41 (P = .01). CRR and ORR rates were also similar. Relapse rates were not statistically different, 51.9% vs 28.6% (P = .069). AutoHCT utilization was higher with R-CHOP vs DA-EPOCH-R, 23.0% vs 8.5% (P = .017).Our findings do not support the use of DA-EPOCH-R over R-CHOP for DEL. Patients65 years may experience longer PFS with DA-EPOCH-R, but limitations to the analysis make this interpretation difficult. more...

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of aggressive B-cell lymphoma patients following CAR T-cell therapy failure. To more definitively define CPI therapy efficacy in this population, we retrospectively evaluated clinical outcomes in a large cohort of 96 patients with aggressive B-cell lymphomas receiving CPI therapy after CAR-T failure across 15 U.S. academic centers. Most patients (53%) had DLBCL, were treated with axicabtagene ciloleucel (53%), relapsed early (≤180 days) after CAR-T (83%), and received pembrolizumab (49%) or nivolumab (43%). CPI therapy was associated with an overall response rate of 19% and a complete response rate of 10%. Median duration of response was 221 days. Median progression-free survival (PFS) and overall survival (OS) were 54 and 159 days, respectively. Outcomes to CPI therapy were significantly improved in patients with primary mediastinal B-cell lymphoma. PFS (128 versus 51 days) and OS (387 versus 131 days) were significantly longer in patients with late (>180 days) versus early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of CPI-treated patients. Most patients (83%) died, commonly due to progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of aggressive B-cell lymphoma patients treated with CPI therapy after CAR-T relapse, our results reveal poor outcomes, particularly among those relapsing early after CAR-T. In conclusion, CPI therapy is not an effective salvage strategy for most patients after CAR-T, where alternative approaches are needed to improve post-CAR-T outcomes. more...

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels.Significance:Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial.This article is highlighted in the In This Issue feature, p. 517 more...

Representativeness of study participants

CART19/20 cell product characteristics. (A) % CD4+ among total T cells and CAR-expressing T cells. (B) Comparison of T-cell subtype frequency among CD4+ vs. CD8+ T cells in cryopreserved CART19/20 cell products. Te/exh: effector/exhausted T cells, CD45RA+/CD45RO–/CD62L–; Tem: effector-memory T cells, CD45RA–/CD45RO+/CD62L–; Tcm: central-memory T cells: CD45RA–/CD45RO+/CD62L+; naïve: CD45RA+/CD45RO–/CD62L+. (C) Phenotype of leukopak content prior to cell isolation. (D) Phenotype of cells obtained after isolation. (E) CD14 and CD25 expression patterns among CD62L+ cells in patient leukopak content prior to cell isolation. more...

To address antigen escape and loss of T-cell functionality, we report a phase I clinical trial (NCT04007029) evaluating autologous naive and memory T (TN/MEM) cells engineered to express a bispecific anti-CD19/CD20 chimeric antigen receptor (CAR; CART19/20) for patients with relapsed/refractory non-Hodgkin lymphoma (NHL), with safety as the primary endpoint. Ten patients were treated with 36 × 106 to 165 × 106 CART19/20 cells. No patient experienced neurotoxicity of any grade or over grade 1 cytokine release syndrome. One case of dose-limiting toxicity (persistent cytopenia) was observed. Nine of 10 patients achieved objective response [90% overall response rate (ORR)], with seven achieving complete remission [70% complete responses (CR) rate]. One patient relapsed after 18 months in CR but returned to CR after receiving a second dose of CART19/20 cells. Median progression-free survival was 18 months and median overall survival was not reached with a 17-month median follow-up. In conclusion, CART19/20 TN/MEM cells are safe and effective in patients with relapsed/refractory NHL, with durable responses achieved at low dosage levels.Significance:Autologous CD19/CD20 bispecific CAR-T cell therapy generated from TN/MEM cells for patients with NHL is safe (no neurotoxicity, maximum grade 1 cytokine release syndrome) and demonstrates strong efficacy (90% ORR, 70% CR rate) in a first-in-human, phase I dose-escalation trial.This article is highlighted in the In This Issue feature, p. 517 more...

Secondary acute myelogenous leukaemia (AML), as compared to de novo AML, occurs in the more elderly population, is independently more resistant to cytotoxic chemotherapy, has a higher relapse rate, and a worse prognosis. Secondary AML (sAML) is a heterogeneous disease, both biologically and clinically, even within the World Health Organization subgroups of sAML. Outcomes are the poorest in subgroups with sAML arising from an antecedent haematologic disorder which has been previously treated (ts-AML), and sAML in patients more...

PURPOSE: Pseudocirrhosis has been demonstrated to mimic cirrhosis radiographically, but studies evaluating the pathophysiology and clinical features are lacking. To better understand the incidence, risk factors, clinical course, and etiology of pseudocirrhosis, we performed a retrospective analysis of consecutively treated patients with metastatic breast cancer (MBC). METHODS: Of 374 patients treated for MBC from 2006-2012, 199 had imaging available for review. One radiologist evaluated computed tomography scans for evidence of pseudocirrhosis. Features of groups with and without pseudocirrhosis were compared by Kaplan-Meier product-limit survival estimates and log-rank tests. Wilcoxon Rank-Sum testing evaluated if patients more heavily treated were more likely to develop pseudocirrhosis. Univariate and multivariate Cox proportional hazard models investigated factors associated with mortality. RESULTS: Pseudocirrhosis developed in 37 of 199 patients (19%). Of the patients with liver metastases, 55% developed pseudocirrhosis. Liver metastases were demonstrated in 100% of patients with pseudocirrhosis. Survival in the subset with liver metastases favored those without pseudocirrhosis, 189 versus 69 months (p = 0.01). The number of systemic regimens received were higher in patients with pseudocirrhosis (p = 0.01). Ascites was demonstrated in 68%, portal hypertension in 11%, and splenomegaly in 8% of patients with pseudocirrhosis. CONCLUSIONS: Pseudocirrhosis does not occur in the absence of liver metastases, can manifest as hepatic decompensation, and appears to be associated with poorer survival amongst patients with hepatic metastases. Higher cumulative exposure to systemic therapy may be causative, instead of the previously held belief of pseudocirrhosis as an adverse effect of a particular systemic agent/class. more...

Highlights • Disease progression following anti-CD19 monoclonal antibody Tafasitamab treatment should not preclude subsequent anti-CD19 CART-cell therapy. • Previous studies have demonstrated sequential anti-CD19 to be effective. • Larger studies among R/R DLBCL patients across anti-CD19 modalities are needed to guide sequencing of therapies following initial anti-CD19 therapy., Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19. The L-MIND (NCT02399085) trial, an open-label, single-arm, phase II study of Tafasitamab (TAFA) plus lenalidomide (LEN), reported progression-free survival of 16 months in R/R DLBCL patients ineligible for autologous stem cell transplantation. Despite recent advances in anti-CD19 therapy, no clinical evidence exists to direct the sequencing of CAR T cell therapy following relapse after prior anti-CD19 therapy. We present the first published case of TAFA/LEN treatment followed by CAR T therapy with sustained remission. Disease progression following treatment with Tafasitamab may not preclude patients from CAR T cell therapy. more...

INTRODUCTION Prolonged cytopenias following Chimeric Antigen Receptor (CAR) T-cell therapy are common. The cytopenias are mainly due to the genotoxic effects of conditioning chemotherapy and systemic inflammatory insult to hematopoietic stem and progenitor cells from CAR T-cell activity. Tocilizumab, an anti-IL6 receptor antibody, reduces cytokine release syndrome (CRS), a clinical manifestation of CAR T inflammatory toxicity. We sought to determine if prophylactic tocilizumab can decrease the risk and/or severity of CRS. We secondarily hypothesized that decreasing the inflammatory injury to hematopoietic stem cells could improve bone marrow function after CAR T. Lastly, we analyzed the association between cytopenias and CAR T efficacy generally. METHODS In this single-institution, retrospective cohort study, we examined all patients who had received axicabtagene ciloleucel for relapsed/refractory diffuse large B cell lymphoma (DLBCL) between March 2018 and April 2021 (Table 1). Each patient was evaluated for prolonged cytopenias, defined as requiring granulocyte-colony stimulating factor (G-CSF), red blood cell or platelet transfusion beyond day 28 after CAR T infusion. After CAR T infusion, no patient was given any anti-lymphoma therapy prior to collection of blood count data. We compared response to CAR T 6 weeks post-infusion, progression-free survival (PFS), and overall survival (OS) for patients with and without prolonged cytopenias. A univariate regression analysis was performed, and between group differences were calculated using Chi-squared, Fisher's exact tests, and Cox Proportional hazard regression model. Kaplan-Meier and log-rank analyses were used to evaluate the PFS and OS. We also compared patients who did and did not receive prophylactic tocilizumab 36 hours after CAR T infusion for differences in prolonged cytopenias, PFS, OS, and development and severity of CRS and neurotoxicity. CRS and neurotoxicity were graded using the ASTCT consensus grading system. RESULTS The study included 54 patients, 31 (57.4%) met criteria for prolonged cytopenias. 1 (1.9%) patient died of progressive disease prior to day 28 and was excluded from analysis. All patients who died in this study did so on the basis of progressive lymphoma. Likelihood of no response to CAR T at 6 weeks was higher in patients who needed G-CSF support past day 28 (HR 2.20, p = 0.048), had a hemoglobin nadir less than 8 g/dL (HR 2.61, p = 0.031), were still requiring platelet transfusions after day 28 (HR 2.26, p = 0.038), or had a platelet nadir less than 25,000 per µl during the first 28 days (HR 4.01, p = 0.013, Table 2). For patients who had neutrophil counts below the median at day 28, the median PFS was 4.5 months vs. 17.9 months (HR 2.07, p = 0.035) compared to those above the median. In patients with a platelet nadir less than 25,000 per µl or below the median at day 28 (Figure 1), the median PFS was 4.5 months vs. not reached (HR 3.12, p = 0.003) and 3.9 months vs. not reached (HR 3.85, p = 0.0004) respectively. Median OS was 9.44 months in patients who required G-CSF support past day 28 (HR 2.79, p = 0.022) vs. not reached in those who didn't receive G-CSF past day 28. For patients with an ANC below the median on day 28, median OS was 19.87 months vs not reached (HR 2.65, p = 0.022). In patients with a platelet nadir less than 25,000 per µl or below the median at day 28, the median OS were 7.8 months vs not reached (HR 3.72, p = 0.006) and 7.79 months vs not reached (HR 3.39, p = 0.007) respectively. Among patients who received prophylactic tocilizumab, 12 (54.5%) had prolonged bone marrow failure compared to 19 (57.6%) among those who did not (p = 0.82). PFS, OS, and rates and severity of CRS and neurotoxicity did not differ between the prophylactic tocilizumab groups. CONCLUSIONS In this study of patients with relapsed/refractory aggressive B-cell lymphomas receiving a CD28 domain-containing CAR T product, severe short-term or prolonged cytopenias were associated with an increased risk of lymphoma progression and death. This effect was not ameliorated by administration of prophylactic tocilizumab, which also did not affect the development or severity of CAR T inflammatory toxicities. Further study is required to determine the mechanistic nature of the relationship between post-infusion cytopenias and CAR T efficacy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. more...

Introduction: Aggressive non-Hodgkin's lymphoma (aNHL) with secondary central nervous system (sCNS) involvement has a poor prognosis. Studies have reported a response to induction treatment as low as 35%, leaving less than half of patients eligible for autologous stem cell transplant (ASCT). Outcomes of patients in these clinical scenarios are dismal and treatment is ill-defined. Small case series suggest chimeric antigen receptor (CAR)-T cell therapy may play a role in the management of relapsed/refractory (R/R) B-cell lymphoma (BCL) with sCNS involvement, but follow-up is limited and response duration is uncertain. Allogeneic hematopoietic stem cell transplant (alloHCT) offers a durable remission for a subset of patients with R/R systemic aNHL primarily mediated through a graft versus lymphoma (GVL) effect, but it is unclear if GVL properties include the immune-privileged CNS. The present study aims to describe outcomes of a cohort of patients with R/R aggressive B- and T-cell NHL with sCNS involvement who underwent alloHCT at a single academic institution. Methods: This is a retrospective analysis that includes all patients with R/R aNHL with sCNS involvement who underwent alloHCT at the University of California, Los Angeles from 2005-2020. The UCLA Institutional Board Review approved this study. Relevant clinical data was extracted from medical records. Hematopoietic cell transplantation comorbidity index (HCT-CI) and time to neutrophil and platelet engraftment were measured according to Center for International Blood and Marrow Transplant Research criteria. Results: Ten patients were included (3 females, 7 males). Histologic subtypes included anaplastic BCL (1), mantle cell lymphoma (1), blastic natural killer-cell lymphoma (1), peripheral T-cell lymphoma, not otherwise specified (1), primary mediastinal BCL (1), and diffuse large B-cell lymphoma (DLBCL) (non-germinal center=3, germinal center-like=2). Two DLBCL patients had histologic transformed lymphoma (follicular lymphoma =1, chronic lymphocytic lymphoma = 1). Four patients had sCNS involvement at the time of initial diagnosis or during frontline treatment; the remaining 6 patients developed sCNS lymphoma at relapse. sCNS lymphoma was identified in the parenchymal (n=4), leptomeningeal (n=3), or both (n=3) compartments. The median age at the time of alloHCT was 49.5 (range 28-68), and 1 patient was ˃ 60. At the time of alloHCT, 1 patient had residual disease in the CNS and the remaining 9 patients were in a complete remission. Eight patients received ˃ 3 prior lines of therapy, and 3 patients failed prior ASCT. HCT-CI scores were 0 (n=1), 1 (n=2), 2 (n=3), 3 (n=1), and unknown (n = 3). Donor types included 10/10 matched related (3), 10/10 matched unrelated (4), 9/10 mismatched related (1), and double umbilical cord blood (2). Graft source was peripheral blood in 8 patients and cord blood in 2 patients. Conditioning regimens included myeloablative, reduced intensity and non-myeloablative in 6, 3 and 1 patient(s), respectively. Six patients received total body irradiation-containing conditioning. The average time to neutrophil engraftment was 18 days (range 11-29), and the average time to platelet engraftment was 26.5 days (range 18-59). One patient had primary graft failure. Of the 6 patients with day 100 disease reassessment (CR at time of alloHCT=5, PR in CNS at time of alloHCT=1), all were in CR. With a median follow-up of 341 days, 2 patients relapsed (CNS=1 and systemic = 1), and 6 patients died. Cause of death included infection (n=3), lymphoma (n=1), primary graft failure (n=1), and organizing pneumonia (n=1). Six patients developed acute graft versus host disease (GVHD) (grade 1-2, n=1; grade 3, n=5), and 4 patients developed chronic GVHD (score 1-2, n= 2; score 3, n=2). The median overall and progression-free survival for the entire cohort was 341 days (range 23-4825) and 268.5 days (range 23-4825), respectively. Conclusions: AlloHCT in patients with R/R aNHL with sCNS involvement is feasible and may provide a durable response in a subset of patients. Four patients remained alive and free of disease one year post-alloHCT and one patient converted from a PR to a CR in the CNS 100 days post-alloHCT, suggesting effective donor immune surveillance within the CNS. Transplant-related morbidity and mortality limits the widespread application of this therapeutic modality and less toxic approaches are urgently needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. more...

BACKGROUND GVHD and non-relapse mortality (NRM) remain frequent complications of HLA-matched HSCT despite the use of standard immunosuppression like tacrolimus and methotrexate. Alternative GVHD prophylaxis (PPX) strategies like T-cell depletion and post-transplant cyclophosphamide negatively impact relapse, infection, and organ toxicity, and no strategy has yet demonstrated a clear benefit for GVHD-free survival. Orca-T is an investigational cellular product comprising stem and immune cells that leverages highly purified donor regulatory T cells to control alloreactive immune responses. Unlike point-of-care graft engineering approaches, Orca-T is produced in a central GMP laboratory and has been successfully distributed to multiple centers across in the U.S. Early clinical trials using Orca-T showed a good safety profile, promising GVHD control, and potentially improved immune reconstitution. Here, we present trial results from both a single-institution Phase 1/2 trial that has completed enrollment and an ongoing multicenter Phase 1b trial. METHODS As of 28 July 2021, 113 patients aged 18-72 have received Orca-T for AML, ALL, MDS, lymphoma, or myelofibrosis. We present here data from 80 patients that have ≥90 days follow-up. 28 and 52 patients, respectively, received Orca-T followed by single-agent GVHD prophylaxis on a single-center Phase 2 study (NCT01660607) and a multicenter Phase Ib (NCT04013685). Orca-T products were derived from HLA-matched related (n=46) or unrelated (n=34) donors. Patients received a variety of myeloablative conditioning regimens (e.g., non-TBI, n=66; TBI-based, n=14) followed by single-agent PPX with either tacrolimus (n=73) or sirolimus (n=7). Median follow-up for these patients is 541 days (single-center) and 248 days (multicenter). We identified a contemporaneous SOC cohort, and we reported on their clinical outcomes at Stanford (n=95) with both matched related (n=52) and unrelated (n=43) transplant recipients who received unmanipulated PBSC products (median f/u 546) and methotrexate plus tacrolimus prophylaxis. RESULTS The Orca-T investigational cell therapy was manufactured reliably, delivered in less than 72 hours for all patients, and every patient enrolled received Orca-T. The Treg drug product was characterized by high Treg purity of 93.8% +/- 3.1% and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between trials). An Orca-T product was produced and infused for all patients, and there were no logistics failures or infusion reactions. All patients engrafted and Orca-T patients showed earlier neutrophil (median of 12 days vs. 14 days, p On the single-center, Phase 2 clinical trial study at Stanford there is evidence of improved 1-year GVHD and relapse-free survival (GRFS) which was 77% (CI 51-88%) for Orca-T patients vs 34% (CI 25-44%) with SOC (Figure 1A). We observed improved rates of >grade 2 acute GVHD at Day +180 (aGVHD, 14% versus 33%), moderate-to-severe chronic GVHD at 1 year (4% versus 42%) and NRM at 1 year (0% versus 13%). Relapse-free (RFS) and overall survival (OS) trended upwards for Orca-T. Severe infectious complications were rare. Key clinical results from both Orca-T trials are summarized in Table 1; 23 of 80 patients had ≥1 year follow-up. Consistent with findings from the single-institution study, on the multicenter study, rates of moderate-to-severe cGVHD and non-relapse mortality were low at 1-year post-transplant at 3% and 4%, respectively. For all patients who received Orca-T across both studies, we observed GRFS of 72% (Figure 1B), RFS of 78%, and OS of 91% at 1 year. These survival rates compare favorably to the contemporaneous SOC control (33%, 71% and 78%, respectively). Immune reconstitution in Orca-T patients with single agent tacrolimus appears similar to SOC except for observable differences in the IL-2 pathway. CONCLUSIONS Manufacture of high precision Orca-T investigational cell therapy drug products was scaled in a central GMP with reliable distribution to centers. Patients that received Orca-T and single-agent PPX showed significantly reduced aGVHD, cGVHD and NRM. Orca-T shows promise to improve GRFS and other transplant outcomes. Orca-T has been granted Regenerative Medicine Advanced Therapy status by the FDA, and a phase 3 prospectively, randomized study is planned. Figure 1 Figure 1. Disclosures Gandhi: Gamida Cell: Consultancy, Membership on an entity's Board of Directors or advisory committees; CareDx Inc: Honoraria. Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Shiraz: Kite Pharma-Gilead: Research Funding. Mehta: Kadmon: Research Funding; Incyte: Research Funding; CSLBehring: Research Funding; Syndax: Research Funding. McGuirk: Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Bellicum Pharmaceuticals: Research Funding; Pluristem Therapeutics: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Novartis: Research Funding. Waller: Verastem Oncology: Consultancy, Research Funding; Cambium Oncology: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Arai: Magenta Therapeutics: Research Funding. Rezvani: US Department of Justice: Consultancy; Nohla Therapeutics: Other: One-time scientific advisory board; Pharmacyclics-Abbvie: Research Funding; Kaleido: Other: One-time scientific advisory board. Weng: Kite Pharma: Research Funding. Miklos: Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties. Frank: Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Allogene Therapeutics: Research Funding. Fernhoff: Orca Bio: Current Employment. Putnam: Orca Bio: Current Employment. McClellan: Orca Bio: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Abedi: Seattle Genetics: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau. Meyer: Triursus Therapeutics: Current holder of stock options in a privately-held company; GigaImmune: Current holder of stock options in a privately-held company; Orca Biosystems: Research Funding; Indee, Jura: Consultancy. more...

Context/Objective: Blinatumomab, a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule, is an effective treatment for patients with MRD+ BCP-ALL.1 Blinatumomab is infused continuously (cIV) 28 days/cycle. Severe adverse events (AEs), e.g., cytokine release syndrome (CRS) and neurologic toxicity (NT), may occur; thus, hospitalization is recommended for cycle 1: days 1–3 (C1:D1–3) and C2:D1–2. However, the incidence of severe AEs is low (CRS: 2%, NT: 13%).1 We believe that with digital monitoring, blinatumomab can be safely administered as an outpatient. Design: Adult patients (n=45) with BCP-ALL in complete remission and MRD+ (≥0.1% blasts) are being enrolled at ≤25 sites, with endpoint: grade ≥3 AE (Amgen NCT04506086). Patient suitability and outpatient monitoring are established. Patients receive 2–4 blinatumomab cycles. Cycles are initiated in the outpatient setting, and digital monitoring devices are activated/attached. Once home, patients set up the home hub and real-time data transfer to the healthcare provider (HCP) begins. The devices are worn continuously, 24 hours/day, for C1:D1–3 and C2:D1–2 only. Devices: Current Health’s Wearable Monitoring System (CHWMS) is an FDA-cleared platform for wireless wearable health monitoring at home. The CHWMS provides continuous oxygen saturation, respiratory rates, and heart rates; an axillary sensor provides continuous temperature. Patients manually measure blood pressure every 3–6 hours around the clock. Patients have an integrated tablet to contact the HCP if needed. HCP/designee has a smartphone and receives vital signs constantly. The CHWMS platform generates a loud alert based on pre-specified vital sign thresholds or for data transfer interruption. Regardless of whether there is an alert, HCP may initiate direct audio/video contact with the patient, assess the patient’s condition, and make appropriate interventions. Patients are required to have a caregiver present during monitoring. Patients have a full set of replacement devices and a 24/7 support hotline. Trial enrollment is underway. This study may generate feasibility data on the effectiveness of home monitoring during blinatumomab infusion in patients with MRD+ BCP-ALL. 1Gokbuget, Blood, 2018. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved. more...

50% of patients with relapsed/refractory (R/R) B-cell lymphomas (BCL) who initially respond to CD19 CAR T therapy will relapse either due to poor CAR-T persistence or CD19 antigen escape. Preclinical data demonstrate that engineering of bispecific anti-CD19/CD20 CAR in naïve/memory T-cells (TN/MEM) via lentiviral transduction effectively targets tumor cells, overcomes antigen escape and enhances CART persistence (Zah E et al., Cancer Immunol Res, 2016). We conducted a first-in-human phase 1 clinical trial with bispecific CD19/CD20 CAR T-cells for patients with R/R BCL (NCT04007029). Patients with measurable disease after 2 or more lines of therapy for DLBCL and PMBCL, and 3 or more lines of therapy for MCL, FL and CLL were included. Autologous leukocytes obtained by leukapheresis were sorted for CD14-/CD25-/CD62L+ TN/MEM cells, followed by lentiviral transduction of the bispecific CD19/CD20 CAR. Following Cy-Flu lymphodepletion, patients are infused with CD19/CD20 CAR TN/MEM cells, at doses ranging from 5 x 107 and 2 x 108 CAR positive cells. 5 patients are included in the analysis, 4 in the first cohort and 1 in the second cohort. All patients had CD19/CD20+ B cell malignancy on tissue biopsy prior to CAR-T. Patients had previously received a median of 4 prior lines of therapy, and 4 received bridging therapy. Infusions were well tolerated, and no dose limiting toxicities were identified. All patients had grade 1 CRS, with median onset 8 days (range 7-11) after infusion. No patient had immune effector cell-associated neurotoxicity syndrome (ICANS). Peak expansion was noted on day 14. Median follow up is 11.1 months (95% CI 2.1-14.8), with 4 of patients in ongoing complete remission. The 1 patient who did not respond had early disease progression, with CD19 and CD20 negative mediastinal lymphoma at day 14 after CAR infusion. Median progression-free survival (PFS) and overall survival (OS) were not reached and all responders demonstrate ongoing CAR T-cell persistence and B-cell aplasia by data cutoff. Bispecific CD19/CD20 CAR in naïve/memory T-cells are safe and effective in patients with R/R BCL. To our knowledge, this is the first study that potentially obviates the challenges of the commonest causes of relapse after CAR T-cell therapy, poor CAR-T persistence and antigen escape mechanisms, by means of modifying naïve/memory T cells and dual antigen targeting, respectively. Patient and Treatment CharacteristicsID12345DiagnosisMCLFLPMBCLFLFLSexMMFMFAge6058296235Prior lines of therapy44343Stage44442EECOG01100Bridging therapy?YesYesYesYesNoDosage, x 106 CART50505050200Max CRS/ICANS gradeGrade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Grade 1 CRS. No ICANS.Required treatment for CRS/ICANS?NoNoNoNoNoBest Response to CARTCRCRNone; refractoryCRCRPFS (months)14.811.10.54.82.1OS (months)14.811.16.24.82.1Subsequent Follow-upAlive, ongoing remissionAlive, ongoing remissionNo response to CART; died from infectious complications after subsequent therapy with nivolumab and brentuximab.Alive, ongoing remissionAlive, ongoing remission Citation Format: Sanaz Noelle Ghafouri, Christopher Walthers, Mobina Roshandell, Brenda Ji, Jacqueline Trent, Jia Ming Chen, Jacob Naparstek, Caitlin Harris, Thomas Schweppe, Karla K. Nawaly, Monica Mead, Sven de Vos, Patricia Young, Caspian Oliai, Gary Schiller, John M. Timmerman, Yvonne Y. Chen, Sarah Larson. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T-cells for the treatment of relapsed or refractory B-cell lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT007. more...

7566 Background: Progress in chimeric antigen receptor (CAR) T-cell therapy has included reduction in life-threatening toxicity. Rates of severe cytokine release syndrome (CRS) have declined from 50% in early trials to 7% in the most recent real-world experience. However, rates of severe immune effector cell-associated neurotoxicity (ICANS) associated with axicabtagene ciloleucel (Axicel) remain unchanged. IL-1 is a major driver of ICANS pathophysiology that is produced upstream of IL-6. The IL-1 receptor antagonist, Anakinra, can prevent neurotoxicity in animal models when given at fever onset. We present our early experience of the first 13 participants enrolled into a phase II trial evaluating Anakinra to prevent severe ICANS (NCT4205838). Methods: This investigator-sponsored trial included adults eligible for standard-of-care Axicel for large B-cell lymphoma after ≥2 lines of intensive chemoimmunotherapy. Participants received Anakinra 100 mg SQ q6h x 12-36 doses until ICANS returned to grade ≤1. The trigger to initiate Anakinra was any grade ICANS or grade ≥3 CRS in the absence of ICANS. A protocol modification, made after the first 3 participants were treated, changed the trigger for Anakinra to grade ≥2 CRS. In addition to Anakinra, all participants received standard-of-care interventions for CRS and ICANS. The primary objective is to estimate the efficacy of Anakinra in preventing severe ICANS (grade ≥3) according to ASTCT 2018 consensus grading. Results: To date, 13 participants have been enrolled, and 7 met criteria to initiate Anakinra and received the first dose prior to severe ICANS. Median age was 56 years (range, 23-84 years). Of the 7 participants whom received Anakinra prior to severe ICANS, only 1 of 7 (14%) developed grade 3 ICANS. The most common adverse event was injection site reaction, which peaked at grade 2. There were no unexpected toxicities. Once the protocol was amended to initiate Anakinra for grade ≥2 CRS (N = 4), no participant developed severe ICANS, and only one participant met the institutional standard to receive corticosteroids (Table). Conclusions: Anakinra is feasible to initiate in the non-prophylactic setting in patients at increased risk for severe ICANS. These early results demonstrate potential to reduce severe ICANS associated with Axicel to a rate similar to other CAR T-cell products, and to reduce corticosteroid use. Further enrollment to the pre-planned sample size of N=36 is required to demonstrate statistical efficacy. Serum IL-1 analysis is also ongoing. Clinical trial information: NCT4205838. [Table: see text] more...

TPS7051 Background: The prognosis for adults with relapsed or refractory BCP-ALL is poor. MRD+ is the strongest predictor of relapse. Blinatumomab, a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule, is an effective treatment for patients with MRD+.1 Blinatumomab is administered as a continuous intravenous infusion (cIV) 28 days per cycle. Severe adverse events (AEs) such as cytokine release syndrome (CRS) and neurologic toxicity (NT) may occur; thus, hospitalization is recommended for the first 3 days of cycle 1 and the first 2 days of cycle 2 for MRD+ patients. However, the incidence of severe AEs is low in MRD+ BCP-ALL patients (CRS: 2%, NT: 13%).1 We believe that with the use of effective digital monitoring devices, blinatumomab can be safely administered for the entire 28-day cIV cycle as an outpatient. Methods: Adult patients (n = 45) with BCP-ALL in complete remission and MRD+ (≥0.1% blasts) are being enrolled at 25 planned treatment sites, endpoint: grade ≥3 AE during monitoring (Amgen NCT04506086). Patient suitability for blinatumomab and outpatient monitoring is established. Patients will receive 2-4 cycles of blinatumomab. Cycles are initiated in the outpatient setting, digital monitoring devices activated and attached, and patients sent home. Once home, patients set up the home hub and real-time remote data transfer to the healthcare professional (HCP) begins. The devices are worn continuously, 24 hours a day for the first 3 days of cycle 1 and the first 2 days of cycle 2 only. Devices: Current Health’s Wearable Monitoring System (CHWMS) is an FDA-cleared platform for wireless and wearable health monitoring of patients at home. The CHWMS provides continuous oxygen saturation, respiratory rate, and heart rate; an axillary temperature sensor is worn and provides continuous temperature. Patients manually measure blood pressure every 3-6 hours around the clock. Patients have an integrated mobile device (tablet) to initiate contact with the HCP if needed. HCP/designee has a mobile device (smart phone) and receives vital signs as a constant live feed transmitted from the CHWMS device. The CHWMS platform generates a loud audible alert based on pre-specified vital sign alarming thresholds or if there is an interruption in data transfer. HCP may initiate direct audio and video contact with the patient, assess the patient’s condition, and make an appropriate intervention. HCP may also initiate patient contact in the absence of an alert. Patients are required to have a caregiver present during the entire period of outpatient monitoring. Patients have a full set of replacement devices as well as a 24/7 hotline for device support. Trial enrollment is underway. This study may generate feasibility data on the effectiveness of home monitoring during blinatumomab infusion in patients with MRD+ BCP-ALL. 1Gökbuget, Blood, 2018. Clinical trial information: NCT04506086. more...

Introduction Older adults with AML are often ineligible for high intensity chemotherapy and potentially curative allogeneic hematopoietic cell transplantation (HCT) due to poor performance status at presentation, comorbidities, and/or adverse genetic features associated with refractory disease and chemoresistance. Recently, the lower intensity combination of a hypomethylating agent and venetoclax (HMA/Ven) was shown to achieve durable responses in patients with AML. Despite this combination having been studied primarily in older, transplant-ineligible adults, a small subset of patients on the Phase 1b trial were successfully bridged to HCT (Pratz et al, 2019). We conducted a multi-center analysis assessing patient characteristics and clinical outcomes of patients treated with HMA/Ven who subsequently proceeded to HCT. Methods We retrospectively identified 51 adults who received HMA/Ven in either the front-line or relapsed/refractory (R/R) setting and underwent subsequent HCT between 2017 - 2019 at Stanford University, the University of California, San Francisco, and the University of California, Los Angeles. Patients received either azacitidine or decitabine in combination with venetoclax. Patients were evaluated for efficacy endpoints including: best response prior to HCT (complete remission [CR], CR with incomplete hematologic recovery [CRi], morphologic leukemia-free state [MLFS]), measurable residual disease (MRD) prior to HCT by flow cytometry (sensitivity threshold ≤1x10-4), and post-HCT relapse and survival. Results The median age at HCT was 65.5 years (24 - 76). Fifty-three percent of patients had a KPS of ≤ 80, and 29% had an HCT-CI of ³ 3. Fifty-seven percent had adverse-risk disease by 2017 European Leukemia Net criteria. The majority (63%) received decitabine; 23 (45%) received HMA/Ven as front-line induction and 28 (55%) for R/R disease. Compared to patients with R/R disease, patients who received front-line HMA/Ven were more likely to be older (67 vs 54 years, p = 0.003) and have a KPS ≤ 80 (65% vs 47%, p = 0.03). Patients with R/R disease had a median of 2 (1 - 4) lines of therapy prior to receiving HMA/Ven and 2 patients had undergone prior HCT. The number of HMA/Ven cycles prior to HCT varied considerably, with a median of 3 (1 - 11). The majority (78%) of patients achieved a complete remission prior to HCT. Of the patients who received front-line HMA/Ven, 83% achieved CR, 13% CRi, and 4% MLFS; 17 (74%) patients had a pre-HCT MRD assessment, of which 71% were MRD-negative. Of the patients who received HMA/Ven for R/R disease, 41% achieved CR, 22% CRi, 33% MLFS, and 4% had refractory disease; 24 (86%) of patients had a pre-HCT MRD assessment, of which 54% were MRD-negative. Across the full cohort, 49% of patients received non-myeloablative, 35% myeloablative, and 16% reduced intensity conditioning. The majority (94%) of patients received peripheral blood stem cell grafts; donor sources were 35% HLA-matched related, 43% HLA-matched unrelated, and 22% haploidentical. Following HCT, 100-day non-relapse mortality was 4%, 6-month overall survival (OS) was 85% and 6-month relapse-free survival (RFS) was 63%. Among patients who received front-line HMA/Ven, 6-month OS was 88% and 6-month RFS was 80%; among patients with R/R disease, 6-month OS was 81% and 6-month RFS was 51%. Patients who were MRD-negative had a 6-month OS of 87% and RFS of 75%; MRD-positive patients had 6-month OS of 73% and RFS of 46%. Among the 27 patients transplanted prior to July 1, 2019, 1-year OS and RFS were 78% and 59% for the entire cohort, 90% and 80% for the 10 patients receiving frontline HMA/Ven, and 71% and 47% for the 17 patients with R/R disease. Conclusion In patients with AML, an HMA in combination with venetoclax can achieve complete remissions-MRD-negative in many cases-thus providing a viable pathway to potentially curative HCT. This treatment pathway is especially important in older/unfit patients receiving front-line HMA/Ven due to ineligibility for high intensity induction chemotherapy, as well as those with relapsed/refractory and previously chemoresistant disease. Following HCT, patients treated in both settings had low NRM and favorable rates of disease response. Prospective studies are warranted to further explore the optimal use of HMA/Ven therapy as a bridge to successful transplant outcomes. Disclosures Muffly: Amgen: Consultancy; Adaptive: Research Funding; Servier: Research Funding. Logan:Abbvie: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Amphivena: Research Funding; Autolus: Research Funding; Jazz: Research Funding; Kadmon: Research Funding; Kite: Research Funding; Pharmacyclics: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding. more...

Background Liposomal formulation of anthracyclines provide better systemic and organ-specific tolerance, with potential for less local tissue damage during extravasation. Several small series have reported that most liposomal anthracycline extravasations are consistent with irritant injury without tissue necrosis. There have been no reports published regarding the clinical effects of extravasation of liposomal cytarabine-daunorubicin (CPX-351). Case report The patient received CPX-351 for relapsed acute myelogenous leukemia via a left chest wall port-a-catheter. The catheter became dislodged. Once symptoms developed, the infusion was discontinued, with observations demonstrating an 8-cm region of edema, warmth, no erythema, and no drainage. Limited supportive management was performed. Physical examination the following day demonstrated no evidence of necrosis, and erythema resolved completely without additional intervention. Conclusion CPX-351 extravasation behaving as an irritant is consistent with the reports of other liposomal anthracyclines. more...

Acute myelogenous leukemia (AML) in the elderly is complex and has a poor prognosis, often characterized by higher risk cytogenetic and molecular features compared to that in younger patients. Rates of transplant have been limited by concern related to non-relapse mortality, as older patients have historically been considered medically unfit for the transplantation process. Reduced-intensity conditioning (RIC) for hematopoietic stem cell transplantation (HSCT) has been shown to provide similar efficacy to myeloablative methods, with decreased non-relapse mortality in the elderly and improved efficacy over non-transplant approaches with cytotoxic chemotherapy alone. Targeted non-cytotoxic and modified cytotoxic agents have emerged to further improve transplant outcomes for older AML patients. Validated comorbidity indices are useful tools to assess an individual's fitness for undergoing HSCT rather than chronological age alone. We believe HSCT is the primary curative treatment approach for many older AML patients, taking into account risk and comorbidities, particularly given the tendency of leukemia in this population to harbor an unfavorable disease profile. We use RIC and advocate for the addition of targeted agents if applicable. With continuing data in support of transplant for older AML patients, we anticipate that transplant rates in this population will continue to rise. more...

Introduction: Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that targets CD19. L-MIND (NCT02399085) is an ongoing, open-label, single-arm, phase II study of Tafasitamab (TAFA) plus lenalidomide (LEN) in patients with relapsed/refractory (R/R) DLBCL ineligible for autologous stem cell transplantation (ASCT). A durable progression-free survival of 16 months in a poor-risk subgroup of patients treated with TAFA plus LEN was recently presented (Salles et al., 2019 ICML Meeting. Abstract 124). Treatment with CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown promising results for patients with R/R DLBCL after failure on ≥ 2 lines of systemic therapy (Neelapu S, et al. N Engl J Med 2017). Despite recent advances in anti-CD19 therapy, relapse remains frequent after each treatment modality. There is no clinical evidence to direct the sequencing of CAR T cell therapy after anti-CD19 therapy. Here, we present the first published case of an outcome after anti-CD19 antibody treatment TAFA/LEN as part of the L-MIND trial, followed by anti-CD19 CAR T therapy. Case Presentation: The patient is a 58 year old female who initially presented in March 2013 with an 8 cm mesenteric mass, workup revealed stage III germinal center B cell-like (GCB) DLBCL arising from follicular lymphoma, Ki-67 proliferation index 80%, and IGH/BCL2 fusion. The patient received 6 cycles of dose-adjusted R-EPOCH. Despite achieving a complete remission (CR) to this frontline therapy, the patient experienced disease relapse within two years. Subsequently, the patient received rituximab plus ifosfamide, carboplatin, and etoposide (RICE) chemotherapy, to which a second CR was achieved. The patient declined ASCT. Second relapse occurred approximately two years later. After meeting eligibility criteria, she was enrolled in the L-MIND trial in October 2017 and received TAFA plus LEN for 6 cycles (1 cycle = 28 days; TAFA 12mg/kg intravenously, weekly x 3 cycles, biweekly thereafter; LEN 25mg daily on days 1-21 of each cycle). TAFA/LEN was well tolerated. Stable disease was achieved with this investigational regimen, followed by progression in April 2018. Fourth-line treatment consisted of rituximab, gemcitabine, oxaliplatin, (R-GEM-OX) for 4 cycles, to which the patient had a partial response. Shortly thereafter, the patient received anti-CD19 CAR T therapy (axicabtagene ciloleucel [Yescarta]) in September 2018 (Figure 1). Treatment course was complicated by grade 2 cytokine release syndrome. A complete response was achieved one month after treatment, and has been sustained since then. As of this report (July 2019), patient remains without clinical evidence of relapse. Discussion: An important question to address in the era of targeted cellular therapy is: can the same tumor antigen be targeted with a different cancer immune therapy modality after disease progression following a previous therapy against that same antigen? In such a clinical scenario, there is concern for sustained antigen blockade from the prior line of therapy. In addition, there is concern for the selective pressures of prior therapy targeted against a specific antigen allowing for progression of a clone that does not express that antigen, rendering subsequent therapy against the same target ineffective (antigen escape). The half-life of TAFA is approximately 16 days, suggesting that it was eliminated prior to CAR T-cell infusion five months later. Although a biopsy was not done upon progression after TAFA, we assume that CD19 antigen escape did not account for the relapse, since the patient has achieved sustained remission with subsequent anti-CD19 CAR T cell therapy. Therefore, disease progression following treatment with anti-CD19 monoclonal antibody Tafasitamab may not preclude patients from anti-CD19 CAR T cell therapy, despite previously targeting the same antigen. Figure 1 Disclosures de Vos: Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. more...

Development of radioprotective agents has focused primarily on cytoprotection from relatively high doses of therapeutic radiation and nuclear disasters. Epidemiological studies and radiobiological models report the potential for stochastic effects from relatively low-dose radiation exposure. Diagnostic studies like computed tomography (CT) expose the patient to a small but significant amount of radiation, which has been reported to increase the risk for carcinogenesis. Young patients expected to undergo multiple CT studies may benefit from a protective agent given prior to CT. This review includes published data of agents that have been shown to protect against radiation-induced carcinogenesis. A discussion follows regarding the data that describes the extent of radiation exposure during CT, as well as technical modifications, which also reduce radiation exposure.Most experiments have used in vivo animal models or in vitro cell lines. Ethical barriers prevent large-scale human studies, although, there are two prospective human studies from the Chernobyl nuclear accident. Collectively, all of these studies provide evidence of statistically significant reductions in radiation-induced carcinogenesis. Protection is achieved by several mechanisms, which include free radical scavenging, caloric restriction, non-steroidal anti-inflammatory agents, humoral factors, and an oxidative agent. Enhanced efficacy is achieved when targeting multiple mechanisms. The data presented provides the scientific foundation for future development of a radioprotectant that may reduce the risk of carcinogenesis from low-dose exposure when certain at-risk populations undergo diagnostic studies like CT. more...

Purpose To provide a retrospective analysis of the efficacy of hyperbaric oxygen therapy (HBOT) for treating hemorrhagic cystitis (HC) and proctitis secondary to pelvic- and prostate-only radiotherapy. Methods and Materials Nineteen patients were treated with HBOT for radiation-induced HC and proctitis. The median age at treatment was 66 years (range, 15–84 years). The range of external-beam radiation delivered was 50.0–75.6 Gy. Bleeding must have been refractory to other therapies. Patients received 100% oxygen at 2.0 atmospheres absolute pressure for 90–120 min per treatment in a monoplace chamber. Symptoms were retrospectively scored according to the Late Effects of Normal Tissues—Subjective, Objective, Management, Analytic (LENT-SOMA) scale to evaluate short-term efficacy. Recurrence of hematuria/hematochezia was used to assess long-term efficacy. Results Four of the 19 patients were lost to follow-up. Fifteen patients were evaluated and received a mean of 29.8 dives: 11 developed HC and 4 proctitis. All patients experienced a reduction in their LENT-SOMA score. After completion of HBOT, the mean LENT-SOMA score was reduced from 0.78 to 0.20 in patients with HC and from 0.66 to 0.26 in patients with proctitis. Median follow-up was 39 months (range, 7–70 months). No cases of hematuria were refractory to HBOT. Complete resolution of hematuria was seen in 81% ( n = 9) and partial response in 18% ( n = 2). Recurrence of hematuria occurred in 36% ( n = 4) after a median of 10 months. Complete resolution of hematochezia was seen in 50% ( n = 2), partial response in 25% ( n = 1), and refractory bleeding in 25% ( n = 1). Conclusions Hyperbaric oxygen therapy is appropriate for radiation-induced HC once less time-consuming therapies have failed to resolve the bleeding. In these conditions, HBOT is efficacious in the short and long term, with minimal side effects. more...

Objective The low alpha/beta ratio of prostate cancer suggests that hypofractionated schemes of dose-escalated radiotherapy should be advantageous. We report our experience using stereotactic body radiation therapy (SBRT) for the primary treatment of prostate cancer to assess efficacy and toxicity. Methods From 2007 to 2010, 70 patients (51 % low risk, 31 % intermediate risk, and 17 % high risk) with localized prostate cancer were treated with SBRT using the CyberKnife system. One-third of patients received androgen deprivation therapy. Doses of 37.5 Gy (n = 29), 36.25 Gy (n = 36), and 35 Gy (n = 5) were administered in five fractions and analyzed as high dose (37.5 Gy) vs. low dose (36.25 and 35 Gy). Results At a median 27 and 37 months follow-up, the low and high dose groups' median PSA nadir to date was 0.3 and 0.2 ng/ml, respectively. The 3-year freedom from biochemical failure (FFBF) was 100 %, 95.0 % and 77.1 % for the low-, intermediate- and high-risk patients. A dose response was observed in intermediate- and high-risk patients with 72 % vs. 100 % 3-year FFBF for the low and high dose groups, respectively (p = 0.0363). Grade III genitourinary toxicities included 4 % acute and 3 % late (all high dose). Potency was preserved in 83 % of hormone naïve patients. Conclusion CyberKnife dose escalated SBRT for low-, intermediate- and high-risk prostate cancer exhibits favorable efficacy with acceptable toxicity. more...

On the basis of an Early Breast Cancer Trialists' Collaborative Group meta-analysis, it has been suggested that the controversy over post-mastectomy radiotherapy (PMRT) for women with 1–3 involved lymph nodes should end. However, the meta-analysis lacks appropriate sample size, stratification, and uses outdated systemic regimens. Thus, the debate should continue. more...