Measurable residual disease conversion rate with consolidation chemotherapy in acute myeloid leukemia.

The rate of MRD clearance in AML with standard consolidation chemotherapy is not well defined. A multi-institution retrospective analysis was performed on 107 consecutively treated AML patients in morphologic complete remission with detectable MRD post-induction therapy who received standard chemotherapy consolidation. In response to standard intermediate/high-dose cytarabine consolidation therapy, 26 of 60 patients (43.3%) with MRD threshold of detection of at least 0.1% converted to MRD-negative status (undetectable with assay used), and 6 of 47 patients (12.8%) with MRD threshold of detection > 0.1% converted to MRD-negative status. Multivariable logistic regression for patients with MRD threshold of detection of at least 0.1% showed that, when controlling for age, ELN risk category, dose of cytarabine, and use of a combination agent, treatment with 1 cycle of consolidation cytarabine versus ≥2 cycles decreased the odds of conversion of AML to MRD-negative (OR = 0.24, 95% CI 0.07-0.85, p = 0.03).

Transient SARS-CoV-2 RNA-Dependent RNA Polymerase Mutations after Remdesivir Treatment for Chronic COVID-19 in Two Transplant Recipients: Case Report and Intra-Host Viral Genomic Investigation.

Remdesivir is the first FDA-approved drug for treating severe SARS-CoV-2 infection and targets RNA-dependent RNA polymerase (RdRp) that is required for viral replication. To monitor for the development of mutations that may result in remdesivir resistance during prolonged treatment, we sequenced SARS-CoV-2 specimens collected at different treatment time points in two transplant patients with severe COVID-19. In the first patient, an allogeneic hematopoietic stem cell transplant recipient, a transient RdRp catalytic subunit mutation (nsp12:A449V) was observed that has not previously been associated with remdesivir resistance. As no in vitro study had been conducted to elucidate the phenotypic effect of nsp12:A449V, its clinical significance is unclear. In the second patient, two other transient RdRp mutations were detected: one in the catalytic subunit (nsp12:V166A) and the other in an accessory subunit important for processivity (nsp7:D67N). This is the first case report for a potential link between the nsp12:V166A mutation and remdesivir resistance in vivo, which had only been previously described by in vitro studies. The nsp7:D67N mutation has not previously been associated with remdesivir resistance, and whether it has a phenotypic effect is unknown. Our study revealed SARS-CoV-2 genetic dynamics during remdesivir treatment in transplant recipients that involved mutations in the RdRp complex (nsp7 and nsp12), which may be the result of selective pressure. These results suggest that close monitoring for potential resistance during the course of remdesivir treatment in highly vulnerable patient populations may be beneficial. Development and utilization of diagnostic RdRp genotyping tests may be a future direction for improving the management of chronic COVID-19.

Efficacy of checkpoint inhibition after CAR-T failure in aggressive B-cell lymphomas: outcomes from 15 US institutions.

Checkpoint inhibitor (CPI) therapy with anti-PD-1 antibodies has been associated with mixed outcomes in small cohorts of patients with relapsed aggressive B-cell lymphomas after CAR-T failure. To define CPI therapy efficacy more definitively 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 US academic centers. Most patients (53%) had diffuse large B-cell lymphoma, 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 vs 51 days) and OS (387 vs 131 days) were significantly longer in patients with late (>180 days) vs early (≤180 days) relapse after CAR-T. Grade ≥3 adverse events occurred in 19% of patients treated with CPI. Most patients (83%) died, commonly because of progressive disease. Only 5% had durable responses to CPI therapy. In the largest cohort of patients with aggressive B-cell lymphoma 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.

Patient Characteristics and Outcomes of Outpatient Tisagenlecleucel Recipients for B Cell Non-Hodgkin Lymphoma.

Tisagenlecleucel (tisa-cel) is an approved CD19-directed chimeric antigen receptor T cell (CAR-T) therapy for relapsed/refractory B cell malignancies. Given potentially life-threatening toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, inpatient tisa-cel infusion and toxicity monitoring are often considered; however, the toxicity profile of tisa-cel may be conducive to outpatient administration. Here we review the characteristics and outcomes of tisa-cel recipients treated in the outpatient setting. Patients age ≥18 years with B cell non-Hodgkin lymphoma who received tisa-cel between June 25, 2018, and January 22, 2021, at 9 US academic medical centers were included in a retrospective analysis. Six of the 9 representative centers (75%) had an outpatient program in place. A total of 157 patients were evaluable, including 93 (57%) in the outpatient treatment group and 64 (43%) in the inpatient treatment group. Baseline characteristics, toxicity and efficacy, and resource utilization were summarized. The most common lymphodepletion (LD) regimen was bendamustine in the outpatient group (65%) and fludarabine/cyclophosphamide (91%) in the inpatient group. The outpatient group had more patients with a Charlson Comorbidity Index of 0 (51% versus 15%; P < .001), fewer patients with an elevated lactate dehydrogenase (LDH) level above the normal range at the time of LD (32% versus 57%, P = .003) compared to the inpatient group, and a lower Endothelial Activation and Stress Index score (.57 versus 1.4; P < .001). Any-grade CRS and ICANS were lower in the outpatient group (29% versus 56% [P < .001] and 10% versus 16% [P = .051], respectively). Forty-two outpatient tisa-cel recipients (45%) required an unplanned admission, with a median length of stay of 5 days (range, 1 to 27 days), compared to 13 days (range, 4 to 38 days) in the inpatient group. The median number of tocilizumab doses administered was similar in the 2 groups as were the rate of intensive care unit (ICU) transfer (5% versus 8%; P = .5) and median length of ICU stay (6 days versus 5 days; P = .7). There were no toxicity-related deaths in the 30 days post-CAR-T infusion in either group. Progression-free survival and overall survival were similar in the 2 groups. With careful patient selection, outpatient tisa-cel administration is feasible and associated with similar efficacy outcomes as inpatient treatment. Outpatient toxicity monitoring and management may help optimize healthcare resource utilization.

NCCN Guidelines® Insights: Hematopoietic Cell Transplantation, Version 3.2022.

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.

CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma.

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.

R-CHOP Vs DA-EPOCH-R for Double-Expressor Lymphoma: A University of California Hematologic Malignancies Consortium Retrospective Analysis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. Patients <65 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). CONCLUSIONS: Our findings do not support the use of DA-EPOCH-R over R-CHOP for DEL. Patients <65 years may experience longer PFS with DA-EPOCH-R, but limitations to the analysis make this interpretation difficult.

Anti-CD19 CAR T-cell therapy remission despite prior anti-CD19 antibody Tafasitamab in relapsed/refractory DLBCL.

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.

How to address second and therapy-related acute myelogenous leukaemia.

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 <55 years of age. This review describes the suboptimal outcomes of contemporary therapy, to support the notion of an unmet need for innovative treatment strategies in sAML. Despite the recent approval of CPX-351, long-term outcomes for this high-risk disease remain dismal. Resistance mechanisms to intensive chemotherapy contribute to relapse. Targeted immune therapy may avoid multidrug resistance mechanisms, but are unlikely to provide long-term remission due to a complex and rapidly evolving clonal disease profile. Advances for sAML will likely be accomplished by CAR T cell therapy or bispecific antibodies providing a bridge to allogeneic stem cell transplantation. Therefore, focus should be placed on novel strategies that can augment the untargeted effector function of allogeneic grafts.

Clinical features of pseudocirrhosis in metastatic breast cancer.

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 to 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.

Liposomal Cytarabine-Daunorubicin (CPX-351) Extravasation: Case Report and Literature Review.

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.

Allogeneic Hematopoietic Stem Cell Transplantation for Older Patients With Acute Myeloid Leukemia.

OPINION STATEMENT: 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.

Propensity score matched comparison of SBRT versus IMRT for the treatment of localized prostate cancer.

OBJECTIVE: Stereotactic body radiation therapy (SBRT) is an attractive option for prostate cancer due to its short treatment duration and cost. In this report, we compare the efficacy and toxicity outcomes of prostate cancer patients treated with SBRT to those who received intensity-modulated radiation therapy (IMRT). METHODS: Two hundred sixty-three patients with localized prostate adenocarcinoma were included, ranging from clinically very low- to high-risk groups. We retrospectively compare consecutive patients treated with SBRT with consecutive patients treated with conventionally fractionated IMRT. For most patients, SBRT was delivered to a total dose of 36.25 Gy in five fractions and IMRT to 75.6 Gy in 42 fractions. To minimize selection bias, we perform propensity score analyses. RESULTS: The treatment groups became similar after propensity matching with absolute standard bias reduced to ≤0.19. For the first analysis, 5-year actuarial survival was 90.8 and 88.1 % in SBRT and IMRT groups, respectively (p = 0.7260), while FFBF was 88.7 and 95.5 %, respectively (p = 0.1720). For the second analysis (accounting for risk group), actuarial 5-year survival was 96.7 and 87.1 % in the SBRT and IMRT groups, respectively (p = 0.3025), while FFBF was 89.7 and 90.3 %, respectively (p = 0.6446). Toxicity did not exceed grade 3 in any of the studied patients. The highest recorded genitourinary toxicity at the time of latest follow-up was grade 2. CONCLUSION: Our data support the hypothesis that SBRT has non-inferior efficacy and toxicity rates as IMRT. Given the lower cost and convenience for patients, SBRT may be considered as an alternative treatment for localized prostate cancer.

SBRT for the Primary Treatment of Localized Prostate Cancer: The Effect of Gleason Score, Dose and Heterogeneity of Intermediate Risk on Outcome Utilizing 2.2014 NCCN Risk Stratification Guidelines.

PURPOSE: To report an update of our previous experience using stereotactic body radiation therapy (SBRT) for the primary treatment of prostate cancer, risk stratified by the updated National Comprehensive Cancer Network (NCCN) version 2.2014, reporting efficacy and toxicity in a community hospital setting. METHODS: From 2007 to 2012, 142 localized prostate cancer patients were treated with SBRT using CyberKnife. NCCN guidelines Version 2.2014 risk groups analyzed included very low (20%), low (23%), intermediate (35%), and high (22%) risk. To further explore group heterogeneity and to comply with new guidelines, we separated our prior intermediate risk group into favorable intermediate and unfavorable intermediate groups depending on how many intermediate risk factors were present (one vs. > one). The unfavorable intermediate group was further analyzed in combination with the high risk group as per NCCN guidelines Version 2.2014. Various dose levels were used over the years of treatment, and have been categorized into low dose (35 Gy, n = 5 or 36.25 Gy, n = 107) and high dose (37.5 Gy, n = 30). All treatments were delivered in five fractions. Toxicity was assessed using radiation therapy oncology group criteria. RESULTS: Five-year actuarial freedom from biochemical failure (FFBF) was 100, 91.7, 95.2, 90.0, and 86.7% for very low, low, intermediate and high risk patients, respectively. A significant difference in 5 year FFBF was noted for patients with Gleason score (GS) ≥8 vs. 7 vs. 5/6 (p = 0.03) and low vs. high dose (p = 0.05). T-stage, pretreatment PSA, age, risk stratification group, and use of ADT did not affect 5-year FFBF. Multivariate analysis revealed GS and dose to be the most predictive factors for 5-year FFBF. CONCLUSION: Our experience with SBRT for the primary treatment of localized prostate cancer demonstrates favorable efficacy and toxicity comparable to the results reported for IMRT in literature. GS remains the single most important pretreatment predictor of outcome.

Radioprotectants to reduce the risk of radiation-induced carcinogenesis.

PURPOSE: 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. RESULTS/CONCLUSIONS: 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.