Introduction

Clinical trials are the backbone of the development and advancement of therapeutic approaches. The pace of development of new agents, the regulatory overhead, the costs of data management, inclusion of quality-of-life assessments, radiologic assessments and central review, central pathology review, biospecimen acquisition, symptom-control assessments, and the evaluation of biologic correlates all present significant challenges for the future development of new therapeutic agents and regimens. As these therapeutic agents and approaches become increasingly targeted and the basic science, clinical risk factors, toxicities, and natural history of lymphomas broadens, the identification and assessment of relevant endpoints, be they clinical (e.g. physical examination, radiologic) or biologic (e.g. immunologic, genetic, metabolic, etc.), also becomes increasingly complex. In turn, the more complex the endpoints and the more targeted the regimens, the more challenges are presented when designing and conducting clinical trials and analyzing and interpreting the results. While this field of clinical trial design is too broad to give full discussion adequately in this chapter, the reader is referred to more extensive references on this area. Given the complexity of issues when designing, monitoring, interpreting, and analyzing data for a clinical trial, statistician input and collaboration is of paramount importance. This chapter will focus on the principles and details of clinical trials from the clinician perspective. As such, the fundamental considerations of clinical trial design as well as the types of trials conducted in clinical research will be reviewed.

The identification of a monoclonal protein in serum protein electrophoresis (SPEP) is a common event requiring medical consultation. A monoclonal protein may be the hallmark of a malignant disease, such as multiple myeloma or Waldenstrom's Macroglobulinemia (and less often of other lymphoproliferative disorders), of diseases associated with a malignant plasma cell clone, such as AL amyloidosis or other plasma cell related disorders, or, quite commonly may have no direct impact and belong to monoclonal gammopathies of undetermined significance (MGUS). Jan Waldenstrom introduced the term “essential hyperglobulinemia” in order to describe patients who had a small serum protein electrophoretic spike but no evidence of overt multiple myeloma (MM), Waldenstrom's macroglobulinemia (WM), primary amyloidosis (AL), or related disorders. The seminal work by Kyle indicated that some patients with this monoclonal gammopathy develop MM, or WM or AL or other lymphoproliferative malignancies, and introduced the term “monoclonal gammopathy of undetermined significance” (MGUS)[1]. Kyle also described patients with histologic and biochemical features of myeloma (bone marrow clonal plasma cells (BMPC) involvement of 10% or higher, presence of a serum M-protein value higher than 3 g/dl) that did not have lytic bone lesions, anemia, renal impairment or other clinical manifestations of myeloma who remained stable, with no need for chemotherapy, for several years[2]. Alexanian also presented data on “indolent myeloma”[3], that included patients who had no clinical features of overt myeloma such as anemia and renal dysfunction and had fewer than three lytic bone lesions. Among these patients, median time to initiation of chemotherapy was two years, but some patients remained stable for several years. Thus, the term “smoldering” MM or “asymptomatic” or “indolent” MM, entered the clinical practice. The definitions, however, were not strict among different groups. In 2003 a consensus paper defined MGUS and asymptomatic or smoldering myeloma (Table 10.1). MGUS requires that M-protein in serum is <30 g/l and that bone marrow clonal plasma cells are <10% with no evidence of other B cell proliferative disorders and no end organ damage (anemia, renal impairment, hypercalcemia, lytic bone lesions).

Introduction

Myeloma is primarily a disease of older age groups with the median age of diagnosis above 60 years. Although, in the past, the prognosis was poor, this has changed over the past decade with the advent of new therapies and the use of autologous stem cell transplantation. Whereas formerly the infective problems associated with myeloma were the consequence of the disease itself and were often the mode of presentation, now the disease can be viewed as more chronic and infections are more commonly related to either the therapies used or the longer term complications of myeloma itself. Nevertheless, infections still account for the majority of deaths in the first 120 days after diagnosis. This chapter will address the risk factors for infection in myeloma and will outline the more common infective complications and their management, as well as considering what preventive measures can be taken.

Risk factors for infection

Immunodeficiency

The hallmark of myeloma is B cell dysregulation, usually manifested by hypogammaglobulinemia. This leads to an increased risk of bacterial infections, particularly those due to encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. Other common bacterial infections that may present early on are Staphylococcus aureus and Eschericia coli[1]. However, there is ample evidence that the disease also affects cellular immunity with abnormalities of T lymphocytes, dendritic cells and NK cells. Although the cellular defects may be more subtle and do not normally manifest early in myeloma, they undoubtedly contribute to some of the complications of chemotherapy[2].

A variety of lymphomas can involve the central nervous system (CNS) at different phases of their evolution, both in immunocompetent and immunocompromised individuals. They represent a heterogeneous group of malignancies, with variable clinical and behavioral characteristics, and require different therapeutic approaches. In this chapter, the therapeutic management of these malignancies will be analyzed separately in three main entities: primary CNS lymphomas (PCNSL), secondary CNS lymphomas (SCNSL), and other, less common, forms of CNS lymphomas.

Histopathology

Primary diffuse large B-cell lymphoma (DLBCL) of the CNS shows diffuse parenchymal growth with dense cuffing in perivascular spaces. The latter is best appreciated towards the periphery of the tumor. Large areas of necrosis may be present, especially in those treated with steroids prior to biopsy. Towards the periphery of the tumor the neoplastic cells are often admixed with astrocyte gliosis. Cytologically, the neoplastic cells resemble those of DLBCL encountered elsewhere. Similarly, the immunophenotype of primary CNS DLBCL is similar to those outside the CNS and is positive for B-cell markers (CD20, CD79a, and PAX-5). Strong IRF4/MUM1 staining is seen in 90% of cases. CD10 is expressed by a minority of cases, while many express BCL-6. BCL-2 is often expressed. As these lymphomas (by definition) occur in immunocompetent patients, Epstein–Barr virus (EBV) is generally absent.

Many lymphomas involving the CNS in immunocompromised patients are EBV-positive and show features of DLBCL, many with an immunoblastic morphology. Burkitt lymphoma, a common lymphoma in the immunocompromised patient, may involve the CNS.

Introduction

Immune dysfunction is an important feature of multiple myeloma and infection remains a major cause of morbidity and mortality. Numerous defects of the immune system occur in multiple myeloma and can also be observed in monoclonal gammopathy of uncertain significance. Indeed, evidence suggests that immune deficiency and infection may serve to promote progression to MM.

There has also been considerable interest in the identification of an autologous response against myeloma. Although cellular and humoral responses directed against myeloma-associated antigens have been described, it remains somewhat uncertain if the immune system plays a significant role in preventing or controlling myeloma cell growth. Despite this, there is an increasing interest in the potential role of immunotherapeutic approaches to treatment paraproteinemia although the immunologically hostile environment associated with multiple myeloma remains a major challenge.

An improved understanding of the mechanisms that mediate immune surveillance and tumor immunity in myeloma are important as a basis for improving patient outcome and are the subject of this review (Table 7.1).

Introduction

The interactions of clonal cells with the bone marrow begin with the initial establishment of transformed precursor MM cells in specialized niches, and their survival and persistence in such niches during the disease stage termed MGUS. During this stage, which can last for years, the bone marrow is gradually “re-modeled” to provide a permissive environment for the self-renewal of these (pre)malignant PC, with acquisition of (further) genetic lesions that trigger progression from MGUS to MM, accompanied by clonal expansion. Release of clonal cells into the circulation, and their homing to and establishment in other sites of hemopoietic bone marrow, with disruption of the bone homeostasis and angiogenesis, characterize the mature malignancy we call multiple myeloma (MM).

A multitude of players feature in these interactions (Table 6.1). Soluble factors direct migration and homing into bone marrow, upregulate anti-apoptotic pathways for drug resistance, modulate immune responses, act as mitogens to induce self-renewal and clonal expansion and function in many autocrine and paracrine loops to maintain survival, angiogenesis and bone destruction. Reciprocal interactions between MM cells and other cell types in the BM such as osteoblasts, osteoclasts, stromal cells and endothelial cells are mediated by some of these soluble factors, as well as by cell–cell contact dependent mechanisms such as adhesion molecules. Cell contact is also important for interactions with extracellular matrix proteins resulting in anti-apoptotic signaling and consequent drug resistance. This chapter will discuss these players in the context of each stage or component of disease pathogenesis, highlighting key players, and will consider in more detail the biochemical pathways that orchestrate survival and drug resistance of MM cells.

Why publish a book on lymphoma in 2007? Surely there are sufficient reviews, meetings and published educational symposia to make such a work redundant. Furthermore, doesn't instant access to online information make any work in print out of date before it appears?

The editors and authors of this work think not. We firmly believe that there is still a place for a clear summary of the diagnosis, staging and therapy of lymphoma in a single volume that reflect the advances in these areas which have taken place over the past five years. The problem with the plethora of information now available is that it is rarely set in a framework of understanding of the major challenges which still face those involved with the diagnosis and therapy of non-Hodgkin's and Hodgkin's lymphomas. We, and our patients, are confronted with many facts but little judgment. This work is our modest attempt to rectify this.

Accordingly the layout of the book should enable the reader to gain an understanding of patterns of disease, methods of staging, principles of new approaches to therapy, and interpretation of clinical trials and prognostic markers by reading the first part of the book. In the second part the reader will find separate succinct yet comprehensive reviews of the individual disease entities which make up the spectrum of diseases comprising the lymphomas.

Immunodeficient patients are at higher risk for developing lymphoproliferative disorders (LPDs), above all non-Hodgkin lymphomas (NHLs). Even though the association between primary immunodeiciency diseases (i.e. X-linked lymphoproliferative syndrome, common variable immunodeiciency, ataxia telangiectasia, and Wiskott-Aldrich syndrome) and LPDs, on the one hand, and between LPDs and autoimmune diseases, on the other, is well known, the leading causes of immunosuppression are, at present, organ transplantation and human immunodeiciency virus (HIV) infection. Lymphomas in the immunocompromised host have been traditionally regarded as having a more aggressive course, including extranodal involvement, a more rapid clinical course, poorer response to conventional therapies, and poorer outcome, but this has been called into question both in post-transplant lymphoproliferative disorders (PTLD) following solid organ transplant (SOT) and HIV-related lymphoma by more recent publications.

Tumors following solid organ transplantation (PTLD)

PTLDs are well recognized and potentially life-threatening complications after SOT. PTLD is seen in up to 10% of all SOT recipients. It is the most common form of post-transplant malignancy in children and in adults it is the second most common malignancy after skin cancer. In both children and adults it is the most common cause of cancer-related mortality after SOT, with the reported overall mortality for PTLD exceeding 50%. Up to 85% of PTLDs are of B-cell lineage and most of these (over 80%) are associated with Epstein-Barr virus (EBV) infection. Around 10-15% of PTLDs are of T-cell lineage, around 30% of which are associated with EBV.

Introduction and presentation

Burkitt (BL) and lymphoblastic lymphomas (LBL) are highly aggressive diseases with distinct natural histories and clinical presentations. BL mostly occurs in the first two decades of life and accounts for 1–2% of all lymphomas. Three clinical variants are recognized: (1) endemic BL, which is primarily found in equatorial Africa; (2) sporadic BL, which presents worldwide but is the most common type in western countries; and (3) immunodeficiency-associated BL, which is associated with HIV infection. There are important clinical differences in these variants (Table 11.1), with endemic BL involving the jaw, orbit, and paraspinal regions in half of the cases as well as the mesentery and gonads, while sporadic BL mostly involves the distal ileum, cecum, and/or mesentery, and rarely the jaw. When bulky or disseminated disease is present, extranodal involvement of the ovaries, kidney, breasts, and/or CNS may be seen. Clinical presentation in a Berlin–Frankfurt–Munster Group (BFM) series of 152 pediatric patients included advanced stage (III/IV) disease in 38%, bone marrow involvement in 33%, and central nervous system (CNS) disease in 4%. Of the patients in this series, 27% presented as acute leukemia, referred to as the L3 subtype of acute lymphoblastic leukemia (ALL) within the French-American-British (FAB) classification, or B-ALL. BL infrequently presents in adults, but does occur with increased frequency in patients with HIV infection.

LBL is most commonly a malignancy of T-cell precursor cells, and, as such, it is identical to T-cell acute lymphoblastic leukemia (T-ALL).

Introduction

Lymphomas are tumors that have largely benefited from the introduction of cytotoxic chemotherapy. Treatment strategies based on intensive chemotherapy have also demonstrated improved survival of patients with relapsed lymphomas. It is necessary to identify selected populations with adverse prognostic factors that would justify such a strategy. Prognostic indices have been developed both to define therapeutic strategies and compare results of clinical trials. Such indices are usually based on retrospective studies that highlight methodological problems in prospective studies in the monoclonal antibody era. The recent development of technologies analyzing gene expression profiling also gives us new tools for both more accurate diagnosis and prognostic implications. We are also beginning to see the development of indices based on lymphoma-specific biological risk factors. Positron emission tomography using 18F-fluorodeoxyglucose should also improve assessment of tumor response and introduce new prognostic measures.

Methodology for building prognostic indices

The goals of a prognostic index (PI) are as follows:

1. (i) for a single patient at the time of diagnosis, to help the physician to predict the probable course of the disease and propose an individualized treatment, and to give the patient and his or her family accurate information;

2. (ii) to compare the results ofclinical trials to ascertain whether groups of patients share the same prognosis;

3. (iii) to design clinical trials in homogeneous subgroups of patients.

A good PI must fulfill several qualities.

It must be accurate

1. (i) It must include patients with the same lymphoma subtype.

2. […]

Introduction

Atypical lymphoproliferative, histiocytic, and dendritic cell disorders often mimic their more common benign or malignant counterparts, and thus can easily be misdiagnosed. Although it may be challenging to identify these unusual disease entities precisely, doing so may significantly alter further evaluation, prognosis, and management of the patient. Multidisciplinary collaboration between clinicians and pathologists is often required to arrive at a definitive diagnosis. Critical to this process is obtaining adequate tissue, ideally through excisional lymph node biopsy. Although core-needle biopsy may sometimes yield a diagnosis, for many of these entities it will be inadequate. Fine needle aspiration has been demonstrated to be of little value in the diagnosis of lymphoproliferative disorders, as it does not provide an adequate assessment of tissue architecture. In cases where a biopsy is equivocal, additional biopsies may be necessary to establish a firm diagnosis.

In this chapter, we will summarize the pathophysiology, presentation, diagnosis, prognosis, and treatment of atypical lymphoproliferative, histiocytic, and dendritic cell disorders. Three main categories of these disorders have been defined (Table 17.1). Benign conditions, such as Kikuchi's disease, often behave indolently and can usually be managed with observation. Histiocytic disorders exhibit a wide range of behavior, and may require more aggressive therapies. Atypical lymphoproliferative disorders can be polyclonal, such as Castleman'sdisease, or malignant, such as lymphomatoid granulomatosis, and are treated in a variety of different ways.

Introduction

Modern treatment of newly diagnosed MM has led to improved responses and markedly improved survival[1,2]. However, despite excellent responses and disease control most patients will eventually relapse and require further therapy. Management of relapsed disease is therefore a critical aspect of overall care. This chapter provides a comprehensive overview of the determinants of and general approaches to therapy as well as a review of specific treatment regimens.

Definition of relapsed and relapsed/refractory MM

The European Group for Blood and Marrow Transplantation (EBMT)[3] criteria and International Myeloma Working Group (IMWG) uniform criteria[4] define progressive disease as ≥25% increase (or reappearance from complete response) in the measurable biochemical component (serum monoclonal protein, urine Bence Jones protein or Serum Free Light chain), an increase in bone marrow plasma cells to >10% or the development of new lytic bone lesions/soft tissue plasmacytomas. Clinical relapse is defined as the development of progressive disease and/or myeloma associated end organ dysfunction (CRAB criteria). Primary refractory myeloma refers to disease that fails to achieve at least a minimal response (MR) with initial therapy whilst relapsed and refractory MM is defined as disease that is non-responsive to salvage therapy, or progresses within 60 days of last treatment in patients who previously achieved at least a minimal response (MR).

Introduction

Myeloma bone disease is a major cause of morbidity in patients, the clinical manifestations of which include pain, cord compression, loss of mobility and deformity. The clinical features of myeloma bone disease are due to osteoporosis, or focal lytic lesions leading to pathological fractures, vertebral collapse and hypercalcemia (Figure 8.1). Neurological sequelae secondary to bone disease are commonly caused by compression of nerves by damaged and displaced bone and most dramatically include spinal cord compression, which often presents as a neurosurgical emergency occurring in up to 5% of patients with myeloma (Figure 8.2)[1]. Indeed, consequences of osteolytic bone disease are often the presenting features of myeloma. Approximately 67% of patients with myeloma present with bone pain and up to 90% of patients with myeloma exhibit features of myeloma bone disease at some stage of the disease course[2,3].

The bone marrow micro-environment has long been recognized as a hospitable locale for the growth and rapid expansion of myeloma and other hematological malignancies as well as the metastatic spread of solid tumors including breast and prostate cancers. However, myeloma is uniquely associated with an aggressive and destructive osteolytic bone disease, which not only causes substantial morbidity as a direct result of bone destruction but, owing to the destruction of boney barriers, enables rapid tumor expansion and spread to extra-medullary sites. Once myeloma has escaped from the bone marrow micro-environment, disease enters a leukemic phase and is rapidly fatal.

Since the first edition we have seen a number of important changes in the diagnosis, staging and therapy for many lymphoma subtypes. We are beginning to observe how molecular and cytogenetic characteristics can profoundly influence prognosis and that such tools should now be as much a part of our diagnostic armamentarium as histology and immunophenotyping.

In the near future we expect that “next generation” sequencing will also have a considerable impact not only on our understanding of the pathogenesis of lymphoma, but also on our selection of therapy. We can also envisage how such techniques will themselves also lead to less toxic and more targeted therapies.

We have seen the steady increase in the incorporation of PET and PET CT into staging, risk-adapted therapy, and reassessment such that the presence of a PET/CT scanner and radiologic expertise should now be an essential in every major Lymphoma centre. The promise and precautions for this important tool are summarized within this edition.

In terms of therapy, the steady progress in both the use of monoclonal antibodies and new treatment regimens is reflected in the updated chapters. Lymphoma specialists are also beginning to see the incorporation of agents that block intra-cellular signaling pathways into clinical practice, notably ibrutinib in CLL/SLL and mantle cell lymphoma, and idelalisib in indolent B-cell lymphoproliferative disorders. These specifically targeted therapies give us hope that, in the very near future, the management of lymphoma will be both more effective and less toxic.