Understanding Telomere Biology in Hematopoietic Cell Transplantation: A Dynamical Systems Perspective.

Background: T cell proliferation and repertoire reconstitution is a hallmark of successful hematopoietic cell transplantation (HCT). This process may be modeled as a dynamical system and in such a system, precise telomere length (TL) measurement may reflect the proliferative capacity of donor T cells. TL for different chromosomes span a few orders of magnitude, and different blood cell populations including T cell clones display variable TL; these differences across the cell populations are not represented when examining average leukocyte TL.

Understanding Telomere Biology in Hematopoietic Cell Transplantation: A Dynamical Systems Perspective.

Background: T cell proliferation and repertoire reconstitution is a hallmark of successful hematopoietic cell transplantation (HCT). This process may be modeled as a dynamical system and in such a system, precise telomere length (TL) measurement may reflect the proliferative capacity of donor T cells. TL for different chromosomes span a few orders of magnitude, and different T cell clones will display variable TL; these differences across the population are not represented when examining average TL.

SARS-CoV-2 Vaccination in the First Year After Hematopoietic Cell Transplant or Chimeric Antigen Receptor T-Cell Therapy: A Prospective, Multicenter, Observational Study.

Background: The optimal timing of vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy.

Methods: We conducted a multicenter, prospective, observational study at 30 cancer centers in the United States.

Defining and Grading Infections in Clinical Trials Involving Hematopoietic Cell Transplantation: A Report From the BMT CTN Infectious Disease Technical Committee.

The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) was established in 2001 to conduct large multi-institutional clinical trials addressing important issues towards improving the outcomes of HCT and other cellular therapies. Trials conducted by the network investigating new advances in HCT and cellular therapy not only assess efficacy but require careful capturing and severity assessment of adverse events and toxicities. Adverse infectious events in cancer clinical trials are typically graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE).

SARS-CoV-2 vaccination in the first year after hematopoietic cell transplant or chimeric antigen receptor T cell therapy: A prospective, multicenter, observational study (BMT CTN 2101).

Background: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood.

Objective: To describe humoral and cellular responses after SARS-CoV-2 vaccination initiated <4 months versus 4-12 months after cellular therapy.

Design: Multicenter prospective observational study.

SARS-CoV-2 vaccination in the first year after allogeneic hematopoietic cell transplant: a prospective, multicentre, observational study.

Background: The optimal timing for SARS-CoV-2 vaccines within the first year after allogeneic hematopoietic cell transplant (HCT) is poorly understood.

Methods: We conducted a prospective, multicentre, observational study of allogeneic HCT recipients who initiated SARS-CoV-2 vaccinations within 12 months of HCT. Participants were enrolled at 22 academic cancer centers across the United States.

Cell-free next-generation sequencing impacts diagnosis and antimicrobial therapy in immunocompromised hosts: A retrospective study.

Background: Cell-free next-generation sequencing (cfNGS) may have a unique role in the diagnosis of infectious complications in immunocompromised hosts. The rapid turnaround time and non-invasive nature make it a promising supplement to standard of care.

Methods: This retrospective, observational single-center study at a tertiary care medical center in Virginia investigated the use of cfNGS in clinical practice.

Engraftment syndrome after allogeneic stem cell transplantation: a systematic review and meta-analysis.

Engraftment syndrome (ES) is associated with neutrophil recovery after stem cell transplantation (SCT). It is associated with autologous and allogeneic SCT. However, a literature review has shown that allogeneic SCT (allo-SCT) is associated with ES without conclusive data on risk factors or effects on outcomes.

Transient left ventricular dysfunction following chimeric antigen receptor T-cell-mediated encephalopathy: A form of stress cardiomyopathy.

Chimeric antigen receptor (CAR) T-cell therapy represents a new strategy in treating lymphoid malignancies, such as relapsed-refractory diffuse large B-cell lymphoma (DLBCL). Several toxicities including cytokine release syndrome (CRS), neurotoxicity, and cardiovascular toxicity have been linked to CAR T-cell therapy. Transient impairment in left ventricular systolic function is described after CAR-T, however, the mechanism remains poorly understood.

High dose valacyclovir for cytomegalovirus prophylaxis following allogeneic hematopoietic cell transplantation.

Introduction: Cytomegalovirus (CMV) is one of the most common and clinically significant viral infections following allogeneic hematopoietic cell transplantation (HCT). Currently available options for CMV prophylaxis and treatment present challenges related to side effects and cost.

Methods: In this retrospective medical record review, the incidence of clinically significant CMV infection (CMV disease or reactivation requiring preemptive treatment) following allogeneic HCT was compared in patients receiving valacyclovir 1 g three times daily versus acyclovir 400 mg every 12 h for viral prophylaxis.

What is the minimum adequate busulfan dose for patients with sickle cell disease undergoing reduced intensity conditioning with fludarabine, busulfan, and anti-thymocyte globulin?

Fludarabine busulfan anti-thymocyte globulin is a common conditioning chemotherapy with reduced toxicity used for transplantation in sickle cell disease (SCD). The dose of busulfan used in this protocol is variable across studies and centers. The minimum dose that maintains long-term donor chimerism is not well established.

A Preliminary Investigation towards the Risk Stratification of Allogeneic Stem Cell Recipients with Respect to the Potential for Development of GVHD via Their Pre-Transplant Plasma Lipid and Metabolic Signature.

The clinical outcome of allogeneic hematopoietic stem cell transplantation (SCT) may be influenced by the metabolic status of the recipient following conditioning, which in turn may enable risk stratification with respect to the development of transplant-associated complications such as graft vs. host disease (GVHD). To better understand the impact of the metabolic profile of transplant recipients on post-transplant alloreactivity, we investigated the metabolic signature of 14 patients undergoing myeloablative conditioning followed by either human leukocyte antigen (HLA)-matched related or unrelated donor SCT, or autologous SCT.

Hematopoietic stem cell mobilization following PD-1 blockade: Cytokine release syndrome after transplantation managed with ascorbic acid.

Checkpoint inhibitor therapy is effective in the treatment of relapsed classical Hodgkin's Lymphoma. Here, we report a patient with relapsed Hodgkin's Lymphoma who received nivolumab prior to autologous stem cell mobilization. She went on to develop cytokine storm shortly following transplantation, with marked T-cell proliferation coincident with myeloid engraftment.

T Cell Repertoire Evolution after Allogeneic Bone Marrow Transplantation: An Organizational Perspective.

High-throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire, which makes it difficult to correlate T cell reconstitution with clinical outcomes. The associations identified thus far are of a broadly statistical nature, precluding precise modeling of outcomes based on T cell repertoire development following bone marrow transplantation (BMT). Previous work has demonstrated an inherent, mathematically definable order observed in the T cells from a diverse group of donors, which is perturbed in recipients following BMT.

Determining the Quantitative Principles of T Cell Response to Antigenic Disparity in Stem Cell Transplantation.

Alloreactivity compromising clinical outcomes in stem cell transplantation is observed despite HLA matching of donors and recipients. This has its origin in the variation between the exomes of the two, which provides the basis for minor histocompatibility antigens (mHA). The mHA presented on the HLA class I and II molecules and the ensuing T cell response to these antigens results in graft vs.

A dynamical systems perspective on chimeric antigen receptor T-cell dosing.

Chimeric antigen receptor T cells (CAR T cells) are dosed similarly to donor lymphocyte infusions following hematopoietic cell transplantation. However, the mechanism driving proliferation in CAR T cells is distinct from conventional T cells. As such there are quantitative differences in the antigen response of these engineered cells when compared with conventional T cells.

The influence of lymphoid reconstitution kinetics on clinical outcomes in allogeneic stem cell transplantation.

Lymphoid recovery following myeloablative stem cell transplantation (SCT) displays a logistic pattern of exponential growth followed by a plateau. Within this logistic framework, lymphoid recovery is characterized by the parameters R (slope of ascent), a (time of maximal rate of ascent) and K (plateau), the 'steady-state' lymphocyte count. A retrospective analysis of allogeneic SCT performed from 2008 to 2013 was undertaken to compare lymphoid recovery and clinical outcomes in 131 patients with acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndromes.

Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies.

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age.

Reconstituting donor T cells increase their biomass following hematopoietic stem cell transplantation.

In this study, we used a rapid, highly-sensitive, single-cell biomass measurement method, Live Cell Interferometry (LCI), to measure biomass in populations of CD3 + T cells isolated from hematopoietic stem cell transplant (SCT) patients at various times pre- and post-transplant (days 0-100). CD3 + T cell 'mass spectra' were obtained from five autologous and 20 allogenic transplant recipients. We found a pronounced rise in median T cell biomass (+25%; p <0.

Conditioning neoadjuvant therapies for improved immunotherapy of cancer.

Recent advances in the treatment of melanoma and non-small cell lung cancer (NSCLC) by combining conventional therapies with anti-PD1/PD-L1 immunotherapies, have renewed interests in immunotherapy of cancer. The emerging concept of conventional cancer therapies combined with immunotherapy differs from the classical concept in that it is not simply taking advantage of their additive anti-tumor effects, but it is to use certain therapeutic regimens to condition the tumor microenvironment for optimal response to immunotherapy. To this end, low dose immunogenic chemotherapies, epigenetic modulators and inhibitors of cell cycle progression are potential candidates for rendering tumors highly responsive to immunotherapy.

Sequence homology between HLA-bound cytomegalovirus and human peptides: A potential trigger for alloreactivity.

Human cytomegalovirus (hCMV) reactivation may often coincide with the development of graft-versus-host-disease (GVHD) in stem cell transplantation (SCT). Seventy seven SCT donor-recipient pairs (DRP) (HLA matched unrelated donor (MUD), n = 50; matched related donor (MRD), n = 27) underwent whole exome sequencing to identify single nucleotide polymorphisms (SNPs) generating alloreactive peptide libraries for each DRP (9-mer peptide-HLA complexes); Human CMV CROSS (Cross-Reactive Open Source Sequence) database was compiled from NCBI; HLA class I binding affinity for each DRPs HLA was calculated by NetMHCpan 2.8 and hCMV- derived 9-mers algorithmically compared to the alloreactive peptide-HLA complex libraries.