Impact of Day 11 Methotrexate Dose Adjustments due to Mucositis on the Outcomes Following Allogeneic Stem Cell Transplant in the Setting of Anti Thymocyte Globulin (ATG) Based GVHD Prophylaxis.

Background: Dose adjustments of Day 11 Methotrexate (MTx) for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation (HCT) are common due to mucositis, renal injury, or other reasons. The impact of omitting or adjusting doses of MTx in the era of ATG-based GVHD prophylaxis remains unexplored.

Methods: We retrospectively analyzed the outcomes of all adult patients undergoing allogeneic HCT who received ATG-based GVHD prophylaxis at The Ottawa Hospital from January 2019 to December 2022.

Refractory myasthenia gravis treated with autologous hematopoietic stem cell transplantation.

Objectives: Patients with refractory myasthenia gravis (MG) have few treatment options. Autologous hematopoietic stem cell transplantation (HSCT) has been used to treat immune diseases; however, its use in the treatment of MG is not broadly considered. Our objective is to report on the efficacy and safety of HSCT in refractory MG.

Distance to CAR-T Treatment Center Does Not Impede Delivery.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable efficacy in relapsed or refractory large B cell lymphoma, but real-world evidence is needed to confirm safety and efficacy when facing the unique challenges of a wide geographical catchment area.

Methods: We reviewed patients treated with commercially available CAR-T at a medium-sized single center in Canada (The Ottawa Hospital) between December 2020 and July 2022 (Canadian implementation started in 2020).

Results: Fifty-one patients (59% male, median age 62) traveled a median distance of 655 km (range 3-3659) for treatment.

Phase-Based and Lifetime Health System Costs of Care for Patients Diagnosed with Leukemia and Lymphoma: A Population-Based Descriptive Study.

Hematologic cancers, notably leukemias and lymphomas, pose significant challenges to healthcare systems globally, due to rising incidence rates and increasing costs. This study aimed to estimate the phase and lifetime health system total costs (not net costs) of care for patients diagnosed with leukemia and lymphoma in Ontario, Canada. We conducted a population-based study of patients diagnosed between 2005 and 2019, using data from the Ontario Cancer Registry linked with health administrative databases.

Outcomes with low dose anti-thymocyte globulin based graft versus host disease prophylaxis after mismatched unrelated donor allogeneic hematopoietic cell transplantation.

Background: Anti-thymocyte globulin (ATG) based graft versus host disease (GVHD) prophylaxis is widely used for mismatched unrelated donor allogeneic hematopoietic cell transplantation (HCT) although optimal dose remains unclear. Although recent literature suggested improved outcomes with PTCy-based regimens when compared to ATG-based regimens these studies used doses of ATG ≥5 mg/kg. Thus, we analyzed outcomes of HLA 9/10 MMUD allogeneic HCTs using lower-dose ATG-based regimens at our center.

Economic Evaluations of Chimeric Antigen Receptor T-Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

Objectives: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer.

Methods: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included.

Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22.

A Discussion with Dr. Natasha Kekre, Hematologist and Clinician Scientist.

[Figure: see text] Dr. Natasha Kekre has been appointed to the Department of Medicine in the Division of Hematology, within the Transplant and Cellular Therapy Program at The Ottawa Hospital since 2015. She is also a scientist within the Ottawa Hospital Research Institute and an associate professor of medicine at the University of Ottawa.

The impact of feedback training on prediction of cancer clinical trial results.

Introduction: Funders must make difficult decisions about which squared treatments to prioritize for randomized trials. Earlier research suggests that experts have no ability to predict which treatments will vindicate their promise. We tested whether a brief training module could improve experts' trial predictions.

ASTCT Clinical Practice Recommendations for Transplantation and Cellular Therapies in Diffuse Large B Cell Lymphoma.

Autologous hematopoietic cell transplantation (auto-HCT) has long been the standard approach for patients with relapsed/refractory (R/R) chemosensitive diffuse large B cell lymphoma (DLBCL). However, the advent of chimeric antigen receptor (CAR) T cell therapy has caused a paradigm shift in the management of R/R DLBCL patients, especially with the recent approval of CD19-directed CAR-T therapy in the second-line setting in high-risk groups (primary refractory and early relapse [≤12 months]). Consensus on the contemporary role, optimal timing, and sequencing of HCT and cellular therapies in DLBCL is lacking; therefore, the American Society of Transplantation and Cellular Therapy (ASTCT) Committee on Practice Guidelines undertook this project to formulate consensus recommendations to address this unmet need.

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells.

Unlabelled: Chimeric antigen receptor (CAR) T-cells are an emerging therapy for the treatment of relapsed/refractory B-cell malignancies. While CD19 CAR-T cells have been FDA-approved, CAR T-cells targeting CD22, as well as dual-targeting CD19/CD22 CAR T-cells, are currently being evaluated in clinical trials. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of CD22-targeting CAR T-cell therapies.

Safety and efficacy of autologous cell vaccines in solid tumors: a systematic review and meta-analysis of randomized control trials.

We conducted a systematic review and meta-analysis of randomized control trials to formally assess the safety and efficacy of autologous whole cell vaccines as immunotherapies for solid tumors. Our primary safety outcome was number, and grade of adverse events. Our primary efficacy outcome was clinical responses.

Identifying effect modifiers of CAR-T cell therapeutic efficacy: a systematic review and individual patient data meta-analysis protocol.

Background: Chimeric antigen receptor T cell therapy (CAR-T) represents a promising and exciting new therapy for hematologic malignancies, where prognosis for relapsed/refractory patients remains poor. Encouraging results from clinical trials have often been tempered by heterogeneity in response to treatment among patients, as well as safety concerns including cytokine release syndrome. The identification of specific patient or treatment-specific factors underlying this heterogeneity may provide the key to the long-term sustainability of this complex and expensive therapy.

CLIC-01: Manufacture and distribution of non-cryopreserved CAR-T cells for patients with CD19 positive hematologic malignancies.

Unlabelled: Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada's publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies.

Engaging Patients and Caregivers in an Early Health Economic Evaluation: Discerning Treatment Value Based on Lived Experience.

Background: Traditionally, economic evaluations have engaged clinicians and policymakers; however, patients and their caregivers have insight that can ensure that the economic evaluation process appropriately reflects disease consequences and adequately addresses their priorities related to treatment.

Objective: We aimed to identify patient priorities to inform an early economic evaluation of chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

Methods: We conducted two online group discussions of four participants each, involving patients with experience of hematological cancer and a caregiver.

Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma.

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion.

Current challenges in the manufacture of clinical-grade autologous whole cell vaccines for hematological malignancies.

Autologous whole cell vaccines use a patient's own tumor cells as a source of antigen to elicit an anti-tumor immune response in vivo. Recently, the authors conducted a systematic review of clinical trials employing these products in hematological cancers that showed a favorable safety profile and trend toward efficacy. However, it was noted that manufacturing challenges limit both the efficacy and clinical implementation of these vaccine products.

Building a Platform for Meaningful Patient Partnership to Accelerate "Bench-to-Bedside" Translation of Promising New Therapies.

Engaging patients as partners in the design and execution of early-phase clinical trials offers a unique opportunity to ensure patient perspectives are considered. Here we describe our experience partnering with four individuals with lived experience of blood cancer to co-develop documents and services to support participants of an early-phase trial. Through regular team meetings, patient partners co-developed a visual informed consent document and a non-technical summary of the informed consent document to facilitate participant understanding of trial procedures.

Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial.

High-risk large B-cell lymphoma (LBCL) has poor outcomes with standard first-line chemoimmunotherapy. In the phase 2, multicenter, single-arm ZUMA-12 study (ClinicalTrials.gov NCT03761056) we evaluated axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, as part of first-line treatment in 40 patients with high-risk LBCL.

Optimal Timing of Allogeneic Stem Cell Transplantation for Primary Myelofibrosis.

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by cytopenias, splenomegaly, and risk of leukemic transformation. In light of newer therapies, such as ruxolitinib, that are not curative but improve quality of life, the timing of transplantation needs more in-depth analysis to determine which patients would benefit from an early versus a delayed transplantation strategy. Because prospective clinical trials are impractical for diseases with only one curative option, such as PMF, we developed a Markov cohort model to simulate the long-term disease trajectory in patients with PMF and predict the optimal timing of transplantation stratified by Dynamic International Prognostic Scoring System (DIPSS) risk.

Use of CRISPR/Cas9 gene editing to improve chimeric antigen-receptor T cell therapy: A systematic review and meta-analysis of preclinical studies.

Background: Chimeric antigen-receptor T (CAR-T) cells represent great promise in cancer treatment. CRISPR/Cas9 gene editing in preclinical studies has enabled the development of enhanced CAR-T products with improved function and reduced toxicity.

Methods: A systematic review of preclinical animal studies was conducted to determine the efficacy and safety of this approach.

Histomorphometric and microarchitectural analysis of bone in metastatic breast cancer patients.

Background: Despite widespread use of repeated doses of potent bone-targeting agents (BTA) in oncology patients, relatively little is known about their in vivo effects on bone homeostasis, bone quality, and bone architecture. Traditionally bone quality has been assessed using a trans-iliac bone biopsy with a 7 mm "Bordier" core needle. We examined the feasibility of using a 2 mm "Jamshidi™" core needle as a more practical and less invasive technique.