Fast Facts: CAR T-Cell Therapy in Diffuse Large B-Cell Lymphoma: A practical resource for nurses

By R.J. Buka and D. Moloney

Diffuse large B-cell lymphoma (DLBCL) is the most common form of high-grade non-Hodgkin lymphoma. While treatment with immunochemotherapy has generally shown good outcomes, specific subgroups of patients with high-risk disease have an unfavorable prognosis. Extensive efforts have been made to improve outcomes in these patients. As such, CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become the new standard of care for patients with relapsed or refractory DLBCL after at least two prior lines of therapy. It is an exciting new therapeutic intervention that is integral to the concept of personalized medicine. Table of Contents: • DLBCL: an overview • CAR T cells • CAR T-cell products • Delivering CAR T-cell therapy and managing patient expectations • CAR T-cell therapy-related toxicities

• Language: English
• Publisher: S. Karger
• Release date: Sep 30, 2021
• ISBN: 9783318069358

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Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common form of high-grade non-Hodgkin lymphoma. While treatment with immunochemotherapy has generally shown good outcomes, specific subgroups of patients with high-risk disease have an unfavorable prognosis. Extensive efforts have been made to improve outcomes in these patients. As such, CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become the new standard of care for patients with relapsed or refractory DLBCL after at least two prior lines of therapy. It is an exciting new therapeutic intervention that is integral to the concept of personalized medicine.

Here, as well as providing an overview of how CAR T cells work, current and emerging products and the results of clinical trials, we look at the key role of nurses in the education of, and communication with, patients and caregivers and the multidisciplinary delivery and coordination of CAR T-cell therapy. Clear and accurate patient education and good communication and coordination between the treatment center and the referring center, leading up to and following CAR T-cell therapy, is essential for successful outcomes in eligible patients.

In particular, we look at the nurse’s role in managing the frequent short-term toxicities associated with CAR T-cell therapy and longer-term monitoring, as well as how to manage patients’ treatment expectations. We hope this will be a valuable resource for all nurses caring for patients and the needs of their family members, as well as other members of the multidisciplinary team.

Hematopoiesis is the highly controlled process by which blood cells are made and mature. It can go wrong at any point, by virtue of numerous genetic faults, resulting in distinctly different diseases. Lymphomas are cancers that originate from lymphoid cells – T lymphocytes (T cells), B lymphocytes (B cells), natural killer cells – and their progenitors (Figure 1.1). As the name suggests, diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells.

Epidemiology and classification

Simplistically, lymphomas can be categorized as Hodgkin lymphoma and non-Hodgkin lymphoma (NHL), with the latter further subcategorized as high-grade (aggressive disease) or low-grade (slow-growing, indolent disease) NHL. Through the course of the disease, low-grade lymphoma can transform into high-grade lymphoma. This is important for CAR T-cell approvals, which are discussed later. NHL makes up around 4% of all cancer cases in both the UK and USA.¹,² DLBCL not otherwise specified (NOS) is the most common high-grade lymphoma, comprising 30–40% of all NHL.³,⁴ It is an aggressive cancer with a median age of onset of about 70 years and has a slight male predominance.

Figure 1.1 Development of lymphoid cells from hematopoietic stem cells (HSC) to terminally differentiated cells through intermediate progenitors.

Subclassification. Gene expression profiling (GEP) can be used to subclassify DLBCL NOS into two principal molecular subtypes.⁵

•The germinal center B-cell-like (GCB) subtype is derived from B cells in the germinal center of secondary lymphoid organs.

•The activated B-cell-like (ABC) subtype is derived from a more mature stage in the B-cell life cycle after it has traversed the germinal center.

Defining these two DLBCL subtypes has prognostic relevance, as GCB-DLBCL has a significantly better prognosis than ABC-DLBCL.⁶,⁷ As GEP is not in mainstream clinical use, analysis of immunohistochemical staining patterns can be used to assign the subtype.⁸

Finally, there are a number of lymphomas that are closely related to DLBCL, including primary mediastinal B-cell lymphoma, primary CNS lymphoma and testicular lymphoma. The distinctions are beyond the scope of this book but are important, as they may require specific treatments and may or may not be eligible for CAR T-cell therapy.

Diagnosis

Clinical presentation. DLBCL may present with enlarged lymph nodes and/or symptoms that include fever, weight loss or night sweats, otherwise known as ‘B symptoms’.⁹

Many conditions can mimic lymphoma, including infectious diseases such as Epstein–Barr virus (EBV), tuberculosis and syphilis, autoimmune diseases such as sarcoidosis, and benign self-limiting conditions such as Kikuchi lymphadenitis.

Although DLBCL is often confined to the lymph nodes (‘nodal’ disease), as lymphocytes reside in other tissues it can also involve extranodal sites, including the gastrointestinal tract, lungs, skin, kidneys, adrenal glands, brain, bones and other soft tissues, and can thus present in many different ways.

Work-up should include a detailed history and examination, extensive blood work-up and cross-sectional imaging. Formal diagnosis requires histological assessment of affected tissue. A surgical excisional lymph-node biopsy is the gold standard investigation because it usually provides ample tissue to allow thorough histological assessment of the nodal architecture.¹⁰,¹¹ However, a core-needle biopsy is frequently performed as it is straightforward to arrange and can often yield a diagnosis.

Figure 1.2 Hematoxylin–eosin-stained section of DLBCL showing sheets of large pleomorphic malignant lymphoid cells.

Immunohistopathological examination is the key to diagnosis; DLBCL is characterized by diffuse infiltration and effacement of the normal architecture of affected lymph nodes by sheets of large lymphomatous B cells (Figure 1.2), which stain positive for B-cell markers, including CD19, CD20, CD79a and surface immunoglobulin (Ig) M.

Staging

DLBCL is staged from the results of imaging and biopsy.

•Stage I: involvement of one lymph node region (a node or group of adjacent nodes) or localized involvement of a single extralymphatic site (stage IE).

•Stage II: involvement of two or more lymph nodes on the same side of the diaphragm or localized involvement of a single extralymphatic site and one or more lymph nodes on the same side of the diaphragm (stage IIE).

•Stage III: involvement of lymph nodes on both sides of the diaphragm.

•Stage IV: widespread disease with involvement of one or more extralymphatic organs with or without lymph-node involvement.

Estimating prognosis

The revised International Prognostic Index (R-IPI) is a widely used five-parameter prognostic scoring system that predicts outcomes in patients with DLBCL treated with R-CHOP immunochemotherapy (discussed below).¹² A more recent iteration of the score, the National Comprehensive Cancer Network IPI (NCCN-IPI), uses the same parameters but with more categories and different weighting, thereby better distinguishing clinically important risk groups (Table 1.1).¹³

Knowing the cell of origin and the molecular features of the disease can further refine prognosis when used in conjunction with the NCCN-IPI score.¹⁴ As discussed above, GCB-DLBCL has a more favorable prognosis than the ABC subtype. Rearrangements or amplifications of the genes MYC, BCL2 or BCL6 may lead to their increased expression, conferring a survival advantage on the tumor cells. In around 10% of cases of DLBCL, the MYC gene is rearranged in combination with either or both of the BCL2 or BCL6 genes, forming double- or triple-hit lymphomas, which have a poorer prognosis.¹⁵ Chromosomal translocations involving MYC, BCL2 and/or BCL6 lead to high overexpression in lymphoma cells, endowing them with a