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Last Modified, September 20, 2020
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Allogeneic Transplantation and Chimeric Antigen Receptor-Engineered T-Cell Therapy for Relapsed or Refractory Mantle Cell Lymphoma

Hematol Oncol Clin North Am

2020 Jordan Gauthier; David Maloney

Mantle cell lymphoma (MCL) accounts for fewer than 10% of non-Hodgkin lymphoma. There is a high initial response rate to chemotherapy and rituximab, but a nearly universal risk of relapse. Allogeneic hematopoietic cell transplantation (allo-HCT) provides one of the only curative options. We review the role of allo-HCT for relapsed and refractory (R/R) MCL and discuss a novel promising approach using autologous chimeric antigen receptor-engineered T (CAR-T) cells. We review preliminary safety and efficacy data of 2 pivotal trials investigating the use of CD19-targeted CAR-T cells for R/R MCL after ibrutinib failure and discuss potential timing of these approaches.

Purification of Human CD34+CD90+ HSCs Reduces Target Cell Population and Improves Lentiviral Transduction for Gene Therapy

Mol Ther Methods Clin Dev

2020 Yan-Yi Chan; Andrew Berger; Mark Enstrom; Thomas Eunson; Hans-Peter Kiem; Stefan Radtke; Anai Perez; Stefanie Schmuck; Margaret Cui; Jennifer Adair; Dnyanada Pande

Hematopoietic stem cell (HSC) gene therapy has the potential to cure many genetic, malignant, and infectious diseases. We have shown in a nonhuman primate gene therapy and transplantation model that the CD34+CD90+ cell fraction was exclusively responsible for multilineage engraftment and hematopoietic reconstitution. In this study, we show the translational potential of this HSC-enriched CD34 subset for lentivirus-mediated gene therapy. Alternative HSC enrichment strategies include the purification of CD133+ cells or CD38low/- subsets of CD34+ cells from human blood products. We directly compared these strategies to the isolation of CD90+ cells using a good manufacturing practice (GMP) grade flow-sorting protocol with clinical applicability. We show that CD90+ cell selection results in about 30-fold fewer target cells in comparison to CD133+ or CD38low/- CD34+ hematopoietic stem and progenitor cell (HSPC) subsets without compromising the engraftment potential in vivo. Single-cell RNA sequencing confirmed nearly complete depletion of lineage-committed progenitor cells in CD90+ fractions compared to alternative selections. Importantly, lentiviral transduction efficiency in purified CD90+ cells resulted in up to 3-fold higher levels of engrafted gene-modified blood cells. These studies should have important implications for the manufacturing of patient-specific HSC gene therapy and gene-engineered cell products.

Effectiveness and safety of rivaroxaban compared with low-molecular-weight heparin in cancer-associated thromboembolism

Blood Adv

2020 Gary Lyman

Guidelines provide differing recommendations regarding direct-acting oral anticoagulants vs low-molecular-weight heparin (LMWH) for treatment of cancer-associated thrombosis (CAT). This study was undertaken to evaluate the effectiveness and safety of rivaroxaban vs LMWH for treatment of CAT. Using US Surveillance, Epidemiology and End Results-Medicare-linked data from 2013 through 2016, we evaluated adults with active breast, lung, ovarian, or pancreatic cancer, who were admitted to the hospital or treated in the emergency department for CAT and were prescribed rivaroxaban or LMWH for outpatient anticoagulation. Patients with luminal gastrointestinal or genitourinary cancers were excluded. Rivaroxaban and LMWH users were 1:1 propensity score matched. Outcomes included the composite of recurrent thrombosis or major bleeding, each outcome separately, and mortality at 6 months, using an intent-to-treat approach. On-treatment analysis after 12 months was also performed. Proportional hazards models for the subdistribution of competing risk were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). We included 529 rivaroxaban- and 529 LMWH-treated patients with CAT. Rivaroxaban was not associated with differences in risk of the composite outcome (HR, 0.71; 95% CI, 0.41-1.22), major bleeding (HR, 1.01; 95% CI, 0.50-2.01), or mortality (HR, 0.87; 95% CI, 0.70-1.07) vs LMWH, but it reduced recurrent thrombosis (HR, 0.37; 95% CI, 0.15-0.95). On-treatment analysis at 12 months showed similar results. Rivaroxaban may be a reasonable alternative to LMWH for patients with CAT without gastrointestinal or genitourinary cancer.

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis

Blood

2020 Mary Redman; Daniel Sabath; David Garcia

Heparin-induced thrombocytopenia (HIT) is a life-threatening, pro-thrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays such as the Platelet Factor 4-Heparin ELISAs lack specificity, and the "gold standard" C14-labeled serotonin release assay (SRA) is of limited value for early patient management due to availability only through reference laboratories. Recent studies demonstrate that "pathogenic" HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin Expression Assay (PEA), may provide an option for rapid and conclusive results. Four hundred and nine consecutive adults suspected of HIT were classified as disease-positive, -negative or -indeterminate based upon predefined criteria that combined 4Ts scores and HIT ELISA results. Patients deemed "HIT-indeterminate" were considered disease-negative in the primary analysis and disease-positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (Area under the curve [AUC] of 0.94; 0.87-1.0, 95% CI) and similar to that of SRA (0.91; 0.82-1.0, 95% CI). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (0.78-0.98, 95% CI) and 0.86 (0.77-0.96, 95% CI), respectively. The PEA, a technically simple non-radioactive assay that uses ~20-fold fewer platelets compared to the SRA had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.

Two Steps Forward and One Step Back for Precision in Prostate Cancer Treatment

J Clin Oncol

2020 Robert Montgomery; Peter Nelson; Heather Cheng; Michael Schweizer

N/A

Corrigendum to 'Anti-ICOS Monoclonal Antibody Treatment of Canine Chronic GVHD' [Biology of Blood and Marrow Transplantation 24/1 (2018) 50-54]

Biol Blood Marrow Transplant

2020 Melissa Johnson; George Sale; Scott Graves; Maura Parker; Rainer Storb; Diane Stone; Smitha Pillai

N/A

Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis

N Engl J Med

2020 William Grady

BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P=0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology

J Natl Compr Canc Netw

2020 Rachel Salit; Vivian Oehler

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-Line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma

Clin Cancer Res

2020 Scott Tykodi

PURPOSE: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in patients with sRCC. PATIENTS AND METHODS: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology report. Patients were randomized 1:1 to receive NIVO (3 mg/kg) plus IPI (1 mg/kg) Q3W (four doses) then NIVO 3 mg/kg Q2W, or SUN 50 mg orally QD (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and IMDC intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. RESULTS: Of 1096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS (95% CI) favored NIVO+IPI (NR [25.2-NE]; n=74) versus SUN (14.2 months [9.3-22.9]; n=65) (HR 0.45 [95% CI, 0.3-0.7; P=0.0004]); PFS benefits with NIVO+IPI were similarly observed (median 26.5 vs 5.1 months; HR 0.54 [95% CI, 0.33-0.86; P=0.0093]). Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with SUN, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. CONCLUSIONS: NIVO+IPI showed unprecedented long-term survival, response and complete response benefits versus SUN in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.

Complexities of Next-Generation Sequencing in Solid Tumors: Case Studies

J Natl Compr Canc Netw

2020 Robert Montgomery; Brian Shirts; Bernardo Goulart; Alexandra Sokolova; Evan Yu; Heather Cheng; Colin Pritchard

With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.