Navigating Sequencing in Relapsed/Refractory Multiple Myeloma: Canadian Experts Discuss the Evidence and the Evolving Options
Relapsed and refractory (R/R) multiple myeloma presents increasingly complex therapeutic decisions. Clinicians must not only weigh efficacy and tolerability but consider how today’s treatment decisions will affect future options. In a roundtable discussion, myeloma experts discuss practical approaches to sequencing therapies across diverse patient scenarios.
Copyright (c) 2026 Canadian Hematology Today https://creativecommons.org/licenses/by-nc-nd/4.0
New Developments in the Front‑line Treatment of Advanced Stage Classic Hodgkin Lymphoma: A Canadian Perspective
Classic Hodgkin lymphoma (cHL) is highly curable, with excellent outcomes achieved through decades of treatment refinement. Recent years have witnessed a paradigm shift in the management of patients with advanced stage disease, driven by the integration of novel therapies into front-line treatment. Minimizing long-term complications remains an important objective, especially for patients in the adolescent/young adult (AYA) age group. Herein, we summarize the latest developments in the treatment of advanced stage cHL through a Canadian lens, focusing on recent clinical trials that have reshaped the therapeutic landscape.
Copyright (c) 2025 Canadian Hematology Today https://creativecommons.org/licenses/by-nc-nd/4.0
Practical Management of Aggressive B-Cell Lymphomas with CD20×CD3 Bispecific Antibodies
CD20×CD3 bispecific antibodies (BsAbs) have transformed the therapeutic landscape of relapsed or refractory large B-cell lymphoma (LBCL). By redirecting T cells to target CD20-expressing lymphoma cells, these off-the-shelf agents offer high response rates and durable remissions in patients who previously had limited options, including those who relapse after chimeric antigen receptor T-cell therapy. In Canada, epcoritamab and glofitamab are now approved for patients with LBCL after at least two prior lines of treatment. The combination of glofitamab, gemcitabine, and oxaliplatin has been recently approved for patients with relapsed/refractory diffuse large B-cell lymphoma not otherwise specified LBCL after at least 1 line of therapy and who are ineligible for autologous hematopoietic stem cell transplant. This review provides a practical framework for Canadian hematologists: identifying eligible patients, implementing pretreatment evaluation, safely delivering therapy in inpatient and outpatient settings, and managing toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. We will also discuss infection prophylaxis, sequencing with cellular therapies, and future directions for BsAbs in earlier treatment lines.
Unique Toxicities of Novel Myeloma Therapies: Focus on Belantamab Mafodotin, Talquetamab, and Selinexor
Recent survival improvements in patients with multiple myeloma are attributable largely to the introduction of three main drug classes, immunomodulatory drugs (IMIDs), proteasome inhibitors, and anti-CD38 monoclonal antibodies. However, the majority of patients will inevitably develop resistance to all three drug classes, and survival in this setting has been historically poor. Several novel therapeutic classes exploiting new mechanisms of action (e.g., chimeric antigen receptor (CAR)-T cell therapy, bispecific antibodies, antibody-drug conjugates (ADC), and selective inhibitors of nuclear export) have shown high levels of activity in relapsed myeloma and promise to transform the treatment landscape. However, these therapies have been associated with distinct toxicity profiles, with adverse effects that are uncommonly observed with conventional antimyeloma therapies. Given improvements in long-term disease control and survival with current therapies, treatment-related toxicity represents an increasingly important health burden in patients with myeloma, and the development of effective toxicity management strategies is required to minimize complications and ensure preserved quality of life.
Rational Use of Immunoglobulin in Adult Patients with Secondary Hypogammaglobulinemia in the Setting of Hematologic Malignancy: A Canadian Perspective
Hypogammaglobulinemia is identified by the detection of low serum immunoglobulin (Ig) levels. Secondary hypogammaglobulinemia (SHG) is an acquired state in which circulating Ig levels are reduced due to suppressed antibody production or increased antibody loss. Specifically, SHG most commonly refers to low circulating total IgG levels. In contrast, primary hypogammaglobulinemia (PHG) is due to an underlying inborn error of immunity contributing to low or defective Ig production and frequent and/or severe infections. In patients with hematologic malignancies, it is important to evaluate baseline Ig (IgG, IgM, IgA) levels at the time of diagnosis. However, it may be challenging to distinguish whether low Ig levels are attributable to PHG or SHG, if antibody defects are identified in the context of hematologic malignancies (including chronic lymphocytic leukemia [CLL], lymphoma, and multiple myeloma), even before initiation of immunosuppressive treatment, PHG should be considered, especially in younger patients presenting with a hematologic malignancy who have a history of recurrent, severe infections. Treatment of several hematologic malignancies includes anti-CD20 B cell‑depleting therapy, which is known to cause the development of SHG. Advancements in lymphoma and myeloma management now incorporate bispecific antibody therapies and chimeric antigen receptor T-cell (CAR T-cell) therapies, which have revolutionized care for patients with disease refractory to conventional treatments. However, the risk of SHG is significant, with rates of ≥70% with bispecific antibody treatments and 20–46% with CAR T-cell therapies. Thus, patients with hematologic malignancies have a high rate of SHG attributable to both the underlying disease and associated treatment.
Double-Exposed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Clinical Approach and Management
Managing patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have been treated with both a covalent Bruton’s tyrosine kinase (BTK) and BCL2 inhibitor represents an increasingly common and complex clinical challenge. While some patients may be candidates for retreatment with a covalent BTK and/or BCL2 inhibitor, those who are refractory to both classes have limited therapeutic options beyond phosphoinositide 3-kinase (PI3K) inhibitors or allogeneic hematopoietic stem cell transplantation, which is typically feasible only for highly selected individuals. In this context, enrollment in clinical trials or compassionate access programs provides the best opportunity to access promising novel therapies, including next-generation BTK inhibitors and T-cell–directed immunotherapy approaches. This review provides a practical approach for assessing and managing double-exposed CLL/SLL in the current Canadian context.
Front-line Treatment for Chronic Lymphocytic Leukemia in 2025: Finite Duration Versus Continuous Treatment
Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative disorder and is the most common hematologic malignancy in Western populations. In Canada, an estimated 2,000 or more new cases are diagnosed each year. Improvements in diagnostic techniques, enhanced prognostication methods, and the development of targeted treatments have revolutionized the management of CLL over the past decade. Despite an ever-expanding therapeutic landscape (Figure 1), the decision to initiate treatment continues to be guided by the International Workshop on CLL criteria. For patients who require treatment, we now have a choice of two treatment approaches based on current Health Canada approvals: fixed‑duration therapy (e.g., chemoimmunotherapy, venetoclax‑obinutuzumab [VO], or ibrutinib‑venetoclax [IV]) versus continuous treatment until disease progression or toxicity (i.e., Bruton’s tyrosine kinase inhibitors [BTKi]). In this review, we will summarize the evidence for these two approaches and provide our views on factors that may influence treatment selection.
Cellular Therapy and Follicular Lymphoma: Where Do We Stand in 2025?
Patients with low-risk follicular lymphoma (FL) have a median overall survival (OS) exceeding 20 years. Whereas those with adverse features, such as a high Follicular Lymphoma International Prognostic Index (FLIPI) score or progression of disease within 24 months of front-line treatment (POD24) have inferior outcomes. Standardized treatment in the second line and beyond is not firmly established and largely depends on patient fitness and medication access. The duration of response decreases with each line of therapy. In this review, we evaluate the evidence for T-cell‑redirecting therapies in FL.
Intensive Versus Non-intensive Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)
Newly approved treatments have increased the options available for patients with acute myeloid leukemia (AML), but have also generated questions concerning the selection of the most appropriate therapy for a given individual (Tables 1 & 2). The trials leading to the approval of these therapies were based on limited genetic data (e.g., cytogenetics, FMS-like tyrosine kinase-3 [FLT3] status) and clinical parameters (e.g., age, comorbidities, therapy, or secondary AML). Data concerning effectiveness or lack of efficacy of a drug or drug regimen in specific AML subgroups is often determined after drug approval. For example, venetoclax (VEN) + azacitidine (AZA) lower intensity therapy (LIT), which is approved for the treatment of patients with newly diagnosed AML deemed ineligible for intensive chemotherapy (IC) or aged >75 years, was found to have limited efficacy in patients with mutated TP53. Despite the regulatory approved indications for VEN‑based LIT, some older and younger patients can be selected for either LIT or IC. Furthermore, with the availability of maintenance therapy after IC16, several important questions have emerged regarding the role of IC in older patients. No published prospective studies have compared IC with LIT in “fit” patients with newly diagnosed AML to inform treatment choice. Two retrospective propensity score matched real‑world data analyses of outcomes in patients with newly diagnosed AML (irrespective of the genetic profile) who received induction with VEN + AZA or IC, indicated no difference in overall survival (OS). However, one study showed improved complete remission (CR) and/or allogeneic hematopoietic stem cell transplant (alloHCT) rates in favour of IC (60.9% vs. 44.2%, P = 0.006 and 18.1% vs. 8.0%, P = 0.012, respectively). Other single‑centre retrospective studies comparing VEN + AZA with IC have yielded conflicting results. None of these studies provided information concerning the use of oral AZA maintenance therapy. The studies did suggest that outcomes may be dependent on specific genetic abnormalities and/or clinical factors. Currently, several Phase 2 trials are comparing VEN + AZA with IC in adult patients with newly diagnosed AML (NCT04801797, NCT05904106, NCT05554406, NCT05554393). Here, two case scenarios will be discussed to highlight issues surrounding treatment choice: a) fit individuals who are ≥75 years with newly diagnosed European LeukemiaNet (ELN)-defined favourable-risk AML and b) IC eligible persons who are ≥18 years with newly diagnosed ELN‑defined poor-risk AML, who require alloHCT in first complete remission (CR1) with curative intent.
Concise Review of Chronic Myelomonocytic Leukemia in Canada in 2025
Chronic myelomonocytic leukemia (CMML) is a clonal myelodysplastic syndrome/myeloproliferative overlap neoplasm characterized by prominent monocytosis, with a very heterogeneous clinical presentation and an inherent risk of transforming to acute myeloid leukemia (AML). It is relatively rare, and the incidence is poorly defined. A Canadian analysis of a period of 20 years identified 1,440 cases and reported an incidence of 2.45 cases per 1,000,000. Given that it often presents at an advanced age, with a median age of 70–76 years, aggressive therapeutic approaches are limited.
Management of Newly Diagnosed Primary Central Nervous System Lymphoma
The last decade has witnessed significant progress in the clinical management of patients with newly diagnosed primary central nervous system (CNS) diffuse large B-cell lymphoma (PCNS-DLBCL, hereafter referred to as PCNSL). Data from several clinical trials have demonstrated the potential for long-term remission in a proportion of patients, particularly those eligible for intensive multi-agent chemotherapy approaches. High-dose methotrexate (HD‑MTX)‑based induction regimens remain standard-of-care globally for both younger and older patients with newly diagnosed PCNSL. However, with clinical trial data demonstrating the efficacy of multiple regimens (differing in partner chemotherapy agents, hematological toxicity, and MTX dose density), but with few randomized comparisons, the optimal induction regimen remains unclear. Consolidation therapy is key to survival outcomes in PCNSL. Thiotepa-based autologous stem cell transplantation (TT-ASCT) has been widely adopted as the consolidation therapy of choice for patients ≤70 years. However, it is increasingly recognized that appropriately selected patients older than 70 years can also benefit from TT-ASCT consolidation. In parallel, declining rates of whole-brain radiotherapy (WBRT) have been observed due to significant risk of neurotoxicity, particularly in patients aged ≥60 years. This review summarises the contemporary clinical management of patients with newly diagnosed PCNSL. We focus on key diagnostic considerations, the landscape of evidence-based first-line treatments, and practical guidance for treatment selection and delivery. We also briefly discuss specific scenarios, including human immunodeficiency virus (HIV)-associated PCNSL and vitreoretinal involvement in the context of PCNSL.
Diagnosis and Management of Small Lymphocytic Lymphoma (SLL)Versus Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are recognized as a single disease entity with distinct phenotypic manifestations, characterized by predominant peripheral blood (PB) involvement in CLL and nodal and/or splenic disease in SLL1-3. This article explores the historically divergent approaches taken to treat CLL and SLL, highlights recent advances in understanding their shared biology, and advocates for a unified approach to real-world management and clinical trial eligibility for both conditions.
Expert Discussion: Building Unique Networks and Partnerships to Bring Novel Therapies to Remote Patients
Novel, highly effective therapies for multiple myeloma are raising hopes, while also adding complexity to treatment decisions and care management. Recently, Canadian Hematology Today sat down with two Canadian experts and discussed what the availability of novel therapies means for patients, and how clinical leaders are coordinating care to improve access for patients in Northern Ontario.
Advancing BTK Inhibition: Non‑Covalent Bruton Tyrosine Kinase Inhibitors and Their Emerging Role in Canadian Practice
The B-cell receptor (BCR) signaling pathway is a key driver in the development of B-cell malignancies, such as chronic lymphocytic leukemia (CLL), Waldenstrom’s macroglobulinemia (WM), mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), by promoting abnormal proliferation and survival. Antigen binding to the BCR triggers activation of Bruton’s tyrosine kinase (BTK), which in turn leads to activation of the nuclear factor kappa-B (NFκB) pathway, leading to nuclear translocation of NF-κB transcription factors. The essential role of BTK activation in BCR signaling highlights the rationale for BTK inhibition as a targeted therapeutic intervention in B-cell malignancies, effectively suppressing BCR signaling and limiting B-cell proliferation and survival.
Hypertension as a Cardiovascular Toxicity of Bruton’s Tyrosine Kinase Inhibitors for Chronic Lymphocytic Leukemia
In 2014, ibrutinib, a covalent Bruton’s tyrosine kinase inhibitor (BTKi), became available as a treatment for chronic lymphocytic leukemia (CLL) in Canada. It was welcomed with enthusiasm given its oral administration, lower rate of neutropenia and infections, and efficacy in heavily pretreated and high-risk del17p subtypes, at a time when only chemotherapy and monoclonal antibodies were available. Soon adverse events (AE) due to off-target effects emerged; particularly concerning were cardiac arrhythmias, bleeding, and hypertension (HTN). Second-generation BTKis were designed to target BTK more directly, and fortunately, clinical trials reported a lower rate of cardiac AEs. Less attention has been given to HTN despite it being an important modifiable risk factor for subsequent cardiac AEs. This is particularly relevant for CLL, given that the predominantly elderly patient population with CLL tend to survive as long as age-matched peers. This review focuses on HTN as an adverse effect of BTKis, and recommending a management approach. Many contemporary CLL studies with BTKi define HTN as an AE using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0, and typically consider severe HTN to be grade 3-5 (Table 1). HTN is generally defined as a disorder characterized by a pathological increase in blood pressure (BP), which is defined as a repeated elevation in the BP exceeding 140 over 90 mm Hg. It is clinically relevant even at a grade 2 level from a global perspective for most patients.
Richter Transformation in the Canadian Landscape: Clinical Perspectives and Emerging Trends
Over the past decade, the treatment landscape for chronic lymphocytic leukemia (CLL) and its lymphoma counterpart, small lymphocytic lymphoma (SLL), has evolved significantly. The shift from chemoimmunotherapy (CIT) to the increased use of targeted agents, such as Bruton’s tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL2i), has led to marked improvements in patient outcomes. Despite these advancements, some patients still experience disease transformation to a more aggressive histology known as Richter Transformation (RT), and the clinical outcomes with this histology remain dismal, with median overall survival (OS) typically shorter than one year. Therefore, RT represents a significant unmet need for patients with CLL/SLL. This review describes recent advances in the understanding and management of RT within the Canadian landscape, focusing on transformation to diffuse large B-cell lymphoma (DLBCL).
Central Nervous System Relapse of Aggressive B-cell Lymphoma: Insights Into Current Treatment Approaches
Central nervous system (CNS) relapse of lymphoma, also known as relapse with secondary CNS lymphoma (SCNSL), is a rare but devastating complication that confers poor survival outcomes and treatment decision challenges. Diffuse large B-cell lymphoma (DLBCL) accounts for most cases with an incidence of 4-6% and commonly occurs within 1 year of diagnosis (median of 5 months). However, CNS relapse is also seen in the context of other aggressive B-cell lymphoma histological subtypes, such as Burkitt lymphoma and mantle cell lymphoma, with an incidence of 20% and 4%, respectively. Identifying patients at risk of CNS relapse has been limited by the low sensitivity of diagnostic variables and scores. More recently, the use of CNS prophylaxis with high-dose methotrexate (HD-MTX) in DLBCL has also been challenged. CNS involvement can be parenchymal (40-50%), leptomeningeal (30-40%), or both (10-15%). Clinical presentation can occur with a range of neurological symptoms depending on the location of CNS involvement (e.g. motor deficits, symptoms related to increased intracranial pressure, cognitive/personality changes, visual disturbance) together with possible systemic symptoms in the presence of concurrent systemic disease involvement. For ease of making treatment decisions and understanding various approaches to management, SCNSL can be divided into 3 distinct clinical scenarios: 1) treatment-naïve-SCNSL, in which CNS involvement of lymphoma occurs concurrently with systemic disease at diagnosis; 2) relapsed isolated-SCNSL, in which relapse of previously treated systemic disease occurs isolated to the CNS; and 3) relapsed concurrent-SCNSL, in which relapse of previously treated systemic disease occurs both within the CNS and systemically. This review will focus on treatment approaches for SCNSL in the relapsed setting, both relapsed isolated-SCNSL and relapsed concurrent-SCNSL, confined to DLBCL.
Front-line Treatment of B-cell Acute Lymphoblastic Leukemia in Canada: Current Strategies and Evolving Paradigms
The treatment landscape for adults with B-cell acute lymphoblastic leukemia (B-ALL) has evolved considerably, with pediatric-inspired regimens, targeted therapies, and measurable residual disease (MRD)-guided approaches improving outcomes. However, treatment strategies in the clinic remain highly variable due to heterogeneity in prospective trials, a lack of randomized comparative data, and the continued evolution of therapies—particularly with the increasing use of targeted agents and immunotherapies in the front-line setting. The absence of national standardization further contributes to variability in clinical practice. This review provides an overview of current front-line treatment strategies for B-ALL in Canada, highlighting key therapeutic approaches and recent advancements in optimizing care.
Hemophagocytic Lymphohistiocytosis and Other Cytokine Storm Syndromes in Adults
Hemophagocytic lymphohistiocytosis (HLH) is a rare and highly fatal syndrome of pathological immune activation leading to excessive inflammation, hypercytokinemia, and multi-organ failure. HLH is broadly divided into primary HLH, driven mainly by genetic defects in cytotoxicity and secondary HLH, a heterogeneous group of disorders with similar clinical and laboratory features to primary HLH, but characterized by hyperinflammation rather than defective cytotoxicity. Primary HLH occurs nearly exclusively in children. Most adult HLH is secondary, often in the context of immunomodulatory therapy, infection, malignancy, autoimmune/autoinflammatory diseases, or immunodeficiency. HLH falls under the umbrella concept of cytokine storm syndrome (CSS). In 2020, the coronavirus disease 2019 (COVID-19) pandemic greatly amplified clinical interest and research in CSS, and specifically the concept of a maladaptive immune response to infection. Early on, COVID-19-CSS was compared to HLH. However, HLH is mainly driven by the interferon-γ (IFN-γ)-chemokine ligand 9 (CXCL-9) axis, resulting in profound T cell and macrophage activation, and is characterized by very high ferritin and soluble CD25 (sCD25, synonymous with the alpha chain of the soluble interleukin (IL)-2 receptor), often with only modestly elevated C-reactive protein (CRP). In contrast, COVID-19-CSS is characterized by defective type I/type III interferon responses leading to excessive IL-6 signaling and very high CRP, which can be ameliorated by IL-6 inhibition. The increased interest in CSS spurred by COVID-19 has coincided with significant recent advances in our understanding of other CSS, such as thrombocytopenia, anasarca, fever/(reticulin) fibrosis, organomegaly, renal dysfunction (TAFRO) syndrome (typically associated with idiopathic multicentric Castleman disease, iMCD-TAFRO) and severe or catastrophic Still’s disease. This review will provide practical guidance for clinicians in diagnosing adult HLH, differentiating it from TAFRO syndrome and Still’s disease. Specifically, in section 3 and Table 2, we propose a heuristic (problem-solving strategy or shortcut) to decrease cognitive load when faced with an acutely ill patient with evolving CSS, with a focus on simple and readily available inflammatory markers (CRP, ferritin, sCD25). This heuristic can help clinicians make diagnostic and therapeutic decisions in real time.
Momelotinib Usage Within Our Current Canadian Myelofibrosis Armamentarium
Myelofibrosis (MF) can be categorized as primary MF (PMF), or secondary MF, which comprises post-polycythemia MF (PPV) and post-essential thrombocythemia (PET). Activating mutations in JAK2, CALR, or MPL are the main driver mutations resulting in abnormal signalling that promotes cell proliferation and survival, leading to secretion of inflammatory cytokines causing myeloproliferation, bone marrow fibrosis, and extramedullary hematopoiesis in MF. The current treatment landscape for MF consists of strategies to reduce spleen volume and improve MF-related symptoms with less effective results in improving cytopenias. Mainstay therapies have included hydroxyurea (HU) and Janus kinase inhibitors (JAKi), as well as curative allogeneic stem cell transplant (ASCT), though fewer patients are eligible for this treatment. Several JAKi have been approved in Canada for first-line treatment, including ruxolitinib, fedratinib, and most recently, momelotinib. Approximately 40% of patients with MF have anemia at diagnosis, and nearly 25% are red blood cell (RBC) transfusion-dependent (TD). Many patients with MF struggle with symptoms related to chronic anemia, and anemia often progresses with time, leading to transfusion dependence for many patients. Anemia of any severity negatively impacts MF survival and is highlighted as a negative prognostic factor among most validated MF scoring systems. Anemia results in increased patient fatigue and lower quality of life (QoL), which results in increased healthcare utilization. Severe anemia results in a 2-fold increased healthcare resource utilization compared to mild anemia. This review focuses on the current treatment approaches for MF, with particular focus on MF-related anemia and the targeted role of newer JAKi, such as momelotinib.
Practical Considerations for Early Relapsed/Refractory Multiple Myeloma in the Canadian Landscape in 2025
Multiple-class drug combinations have long been integral to the management of multiple myeloma (MM). This has led to significant advances in myeloma survival with agents such as lenalidomide and daratumumab moving to frontline therapy. Therefore, relapse therapy requires rational sequencing strategies to prioritize effective regimens with each treatment line without compromising access to subsequent lines. At first relapse, most transplant-eligible patients would have undergone RVd (lenalidomide, bortezomib, dexamethasone) induction with subsequent consolidative high-dose therapy with autologous stem cell rescue and Len (lenalidomide) maintenance. For transplantineligible patients, frontline therapy with DRd (daratumumab, lenalidomide, dexamethasone) has become the standard of care until myeloma progression or drug intolerance. With the increasing adoption of quadruple therapy in frontline treatment, a significant proportion of patients will soon be multi-class exposed or refractory at early relapse, including exposure to daratumumab, lenalidomide, and bortezomib. This shift necessitates careful consideration of treatment sequences based on available regimens, which include previous treatment responses, cytogenetic and molecular risk profiles (e.g., high-risk versus standard-risk disease), disease kinetics at relapse, and the potential benefit of therapies with novel mechanisms of action. Achieving and maintaining sustained minimal residual disease (MRD) negativity is also critical, as patients in this category consistently experience better outcomes, regardless of cytogenetic risk or line of therapy.
Relapsed or Refractory Mantle Cell Lymphoma: Available and Emerging Therapies
Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma (NHL) that accounts for 5–7% of all NHL. In most cases, it is characterized by t(11;14) leading to cyclin D1 overexpression. MCL displays a heterogeneous clinical behavior, ranging from a very indolent to a very aggressive clinical course. Biological features associated with aggressive disease include morphology (pleomorphic or blastoid), high proliferation index (Ki67 >30%), adverse clinical scores (Mantle Cell Lymphoma International Prognostic Index [MIPIb])3, and TP53 mutation status. Patients who relapse within 24 months of initial treatment (POD24) have a poor prognosis with median overall survival (OS) of approximately 12 months. Most patients achieve long-term disease control with first-line treatment, which currently involves induction rituximab-containing chemotherapy with or without autologous stem cell transplantation, followed by maintenance rituximab. Trials assessing Bruton tyrosine kinase inhibitors (BTKi) and other novel agents in the first-line setting have been recently published or are ongoing. These options are currently not available in Canada outside of clinical trials but may become standard of care in the future. Relapse after first-line therapy is inevitable, and curability outside the context of allogeneic stem cell transplant (alloSCT) remains unclear, with most patients eventually requiring second and subsequent lines of therapy. In the last decade, new therapies have changed the treatment landscape of relapsed/refractory (R/R) MCL, and their optimal sequencing or combination remain unclear. Treatment options will be described herein, with a proposed treatment algorithm for R/R MCL (Figure 1).
Copyright (c) 2024 Canadian Hematology Today https://creativecommons.org/licenses/by-nc-nd/4.0
Treatment of Philadelphia Chromosome-negative Myeloproliferative Neoplasms in 2024: A Concise Review
In 1951, William Dameshek coined the term myeloproliferative disorders (MPDs) for diseases characterized by abnormal proliferation of one or more terminally differentiated myeloid cell lines in the peripheral blood.1,2 In 2008, the World Health Organization (WHO) renamed these disorders as myeloproliferative neoplasms (MPNs) in recognition of their clonal nature. There are currently two classification system for MPNs: WHO and International Consensus Classification (ICC), 2022.3,4 This review will focus on the Philadelphia chromosome-negative MPNs, which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).
Front-line Treatment of Older Patients with Hodgkin Lymphoma
The evolution of treatment for classical Hodgkin lymphoma (cHL) represents a great success in oncology, with disease outcomes evolving from universally fatal to vastly curable. However, not all patients benefit equally from modern therapies, which include response‑adapted regimens and the addition of novel, targeted agents to the front-line setting. Although patients older than 60 years account for the later peak in cHL’s characteristic bimodal age distribution and represent approximately 20–25% of all patients with cHL, their outcomes remain inferior compared to younger patients. A retrospective study including 401 patients >60 years treated in British Columbia between 2000 and 2019 revealed modest progression‑free survival (PFS) and disease-specific survival rates of 50% and 63%, respectively, with a median follow-up of nine years. While these outcomes have improved relative to cohorts treated prior to 2000, they nevertheless fall short of those experienced by younger patients. Furthermore, the gap in outcomes between young and older patients progressively worsens with each increasing age decile, with patients >70 years having a particularly poor prognosis. This shortfall has been attributed in part to patient-specific factors such as comorbidities and frailty, which may limit treatment tolerance, but also to differing disease biology, with negative prognostic features including advanced stage disease, Epstein-Barr virus positivity, and mixed cellularity histology often present in those with older age. Adding to the challenges in treating older patients is the fact that this group is frequently underrepresented in clinical trials, or excluded altogether, making their optimal treatment ill-defined.
The Evolving Landscape of DLBCL Treatment Beyond the First Line in 2024
The landscape for treating relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in 2024 is rapidly evolving, with various treatment options emerging. Traditionally, salvage chemotherapy followed by autologous stem cell transplant (ASCT) has been the primary treatment for young, fit patients with R/R DLBCL, and only limited options exist for those ineligible for transplant. However, recent research and regulatory approvals, such as chimeric antigen receptor (CAR) T-cell and bispecific antibody therapies, have significantly improved our ability to treat patients previously considered palliative for R/R DLBCL. Moreover, further research has demonstrated that these advanced technologies are not only effective in the transplant setting but also in individuals who are not traditionally eligible for ASCT and those with comorbid conditions. One anticipated development has been the provincial approvals of bispecific T-cell engagers (BiTEs), such as epcoritamab and glofitamab, which target CD20 and CD3. BiTE therapy holds promise as an off-the-shelf treatment option, potentially offering wider availability to patients compared to CAR T-celll therapy or even post‑CAR T-cell failure.
Minimal Residual Disease in Myeloma in 2024: Where We are Today
Minimal residual disease (MRD) refers to a small population of cancer cells that persists in the body after treatment. Often undetectable using traditional diagnostic methods, these cells can eventually cause relapse in patients who appear to have achieved a complete response (CR) to treatment. For that reason, MRD has become a vital parameter in evaluating the effectiveness of cancer therapies, particularly in hematological malignancies, such as multiple myeloma (MM), and certain solid tumours. Detection of MRD represents a challenge, as the disease may not cause symptoms or be detected through traditional methods (i.e., visible under a microscope). Nevertheless, these cells are often responsible for disease relapse; alternatively, sustained absence of these cells may portend a prolonged remission and presumably be required for disease cure. Therefore, monitoring and detecting MRD are increasingly recognized as essential for long-term patient care and treatment planning.
Safety and tolerability of Bruton's tyrosine kinase inhibitors in the treatment of Waldenström macroglobulinemia
Waldenström macroglobulinemia (WM) is an indolent B-cell non-Hodgkin lymphoma (NHL) characterized by malignant B cells that produce IgM monoclonal protein. Like other indolent B-cell NHLs, treatment is indicated when patients are symptomatic with lymphadenopathy, splenomegaly or have detrimental cytopenias, but uniquely hyperviscosity and other complications related to gammopathy may present a need for treatment. Currently in Canada chemoimmunotherapy using bendamustine and rituximab (BR) is the favored therapeutic combination for treatment-naïve patients with WM due to a superior efficacy and toxicity profile compared to rituximab plus CHOP and a fixed duration schedule. The availability of Bruton’s tyrosine kinase inhibitors (BTKi) have transformed the treatment landscape for patients with WM, particularly in the relapsed setting. Ibrutinib, a once-daily BTKi, was approved by Health Canada (HC) for WM in 2016 based on two non-randomized studies showing high response rates in heavily pretreated rituximab-refractory patients with sustained efficacy (86% progression-free survival (PFS) at 18 months) and acceptable tolerability. Ibrutinib forms an irreversible covalent bond to the cysteine residue (C481) at the active binding site of BTK. Patients with mutated MYD88 (MYD88MUT), who represent over 90% of patients with WM, have a higher rate of response with ibrutinib than those without (MYD88WT). Aside from its impressive efficacy, its oral administration offers a major advantage in terms of convenience for patients and lower administrative costs for publicly funded health care systems such as in Canada. The toxicity of ibrutinib has become of greater concern with the ongoing emergence of trial data and real-world clinical experience with the drug. The indefinite duration of treatment results in extended exposure of a primarily elderly patient population to toxicities such as increased bleeding risk, atrial fibrillation, hypertension, and infection. Discontinuation of ibrutinib due to adverse events occurs at a higher rate in the real-world compared to clinical trials and has been associated with an inferior overall survival in WM. Fortunately, several BTKis have recently emerged. Both acalabrutinib and zanubrutinib also bind irreversibly to BTK at C481, but both have more selectivity for targeting BTK than ibrutinib. Data has demonstrated that tighter and more selective binding of BTK does translate into fewer adverse effects for patients. The most informative study to date in this regard is the randomized phase 3 clinical trial comparing ibrutinib to zanubrutinib, the ASPEN study. ASPEN is the largest multicentre phase 3 trial to date randomizing 201 patients with MYD88MUT WM to receive ibrutinib at 420 mg daily (n=99) vs. zanubrutinib 160 mg twice daily (n=102), with 37 patients being treatment-naïve and 164 being relapsed or refractory (R/R) with a median of 1 prior line of therapy (range 1-8). The median age at enrolment was 70 however more patients randomized to zanubrutinib than to ibrutinib were >75 years old (33% vs 22%, respectively). Although not statistically significant, a higher rate of complete response (CR)/very good partial response (VGPR) was observed for zanubrutinib vs ibrutinib (28% vs 19%, respectively). With a median follow up of 19.4 months the major response rates (77% vs. 78%) and PFS (85% vs. 84% at 18 months) were also not statistically different in patients receiving zanubrutinib vs. ibrutinib, respectively. However, zanubrutinib was associated with a trend towards less toxicity. In particular, the incidences of all grade atrial fibrillation, diarrhea, bruising, muscle spasms, peripheral edema, and pneumonia were over 10% higher among ibrutinib-treated patients. The incidence of neutropenia was higher for zanubrutinib-treated patients (> 10% difference), although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). Further, more ibrutinib-treated patients required dose reductions (23% vs. 14%) and discontinued treatment (9% vs. 4%) due to adverse events. An analysis of quality of life (QoL) instruments demonstrated a trend towards greater improvement in the zanubrutinib arm, particularly in the subgroup of patients who achieved VGPR. These QoL improvements were most notable in validated instrument subscales encompassing appetite, dyspnea, fatigue, physical functioning and role functioning. The ASPEN trial formed the basis for recent approval of zanubrutinib for WM by HC. Although provincial funding is not yet in place, clinicians in Quebec can access zanubrutinib through the Patient d’exception mechanism. As Canadian hematologists will be able to choose a BTKi for their patient with R/R WM, it is important to review the toxicities reported in trials. Toxicities of BTKis and their management will be discussed in this article.
Copyright (c) 2022 Canadian Hematology Today https://creativecommons.org/licenses/by-nc-nd/4.0
Expert clinical framework report: Management of adverse events related to novel therapies for relapsed/refractory multiple myeloma (RRMM)
Multiple Myeloma (MM) is a malignancy of the plasma cells accumulating in the bone marrow. MM develops stepwise from the premalignant conditions, monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). The Canadian Cancer Society estimates that in 2022 4,000 Canadians will be diagnosed, and 1,650 will die from MM. Survival rates have improved over the years with the development of novel treatment strategies, including proteasome inhibitors (PI), immunomodulatory drugs (IMiDs), targeted antibody and cellular therapies, and a selective inhibitor of nuclear export (SINE), as well as with the use of combinations of drugs. Although a number of patients will have a durable response following high-dose chemotherapy and autologous stem cell transplant (ASCT), MM remains an incurable malignancy with the majority of patients relapsing and eventually developing refractory disease (RRMM). Collaborative environments, in which pharmacists work with hematologists/oncologists, nurse practitioners, and supportive care teams, have been shown to improve adherence to the treatment plan. Prescription of appropriate prophylaxis in combination with various treatment strategies may reduce the number and duration of treatment delays. Intensified clinical and pharmaceutical care, including medication management and structured patient counseling for patients on oral anticancer drugs, has been shown to reduce the number of medication errors and severe side effects while improving the patient’s treatment experience. Nurses play a vital role in the management of toxicities as they educate, support, and advocate for patients. This report discusses the management of adverse events (AEs) related to both established agents and novel therapies for the optimal management of patients with RRMM. Established and novel therapies are often used in combination, which presents the potential for overlapping toxicities. The optimal combination therapies including the sequencing of various regimens are yet to be determined. Basic research and clinical trials with investigational agents are ongoing in an effort to improve both the depth and duration of response in newly diagnosed patients and those with RRMM with the aim of finding the best treatment options for every patient.
Bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy for indolent lymphoma
Classic follicular (FL) and marginal zone (MZL) lymphomas are the primary indolent non-Hodgkin lymphomas (iNHL). Once first-line therapy is initiated, the majority of patients eventually experience treatment failure and face progressively shorter disease-free periods following subsequent lines of conventional chemotherapy. Patients with progressive disease within 24 months of first-line therapy (POD24) represent a significant unmet need. The five-year overall survival (OS) for patients with FL and POD24 is only 50% vs 90% for those without POD24. The three-year OS for patients with MZL is 53% and 95% respectively.
Copyright (c) 2023 Canadian Hematology Today https://creativecommons.org/licenses/by-nc-nd/4.0
The role of FDG-PET scanning and PET-adapted therapy in the primary treatment of Hodgkin lymphoma: A primer for clinicians
The evolving treatment paradigm for classical Hodgkin lymphoma (cHL) remains focused on maintaining high rates of progression-free survival (PFS) and overall survival (OS), while seeking to reduce both short-term and late toxicities from chemotherapy and radiation. Functional imaging with fluoro-deoxyglucose (FDG)‑positron emission tomography (PET) combined with computed tomography (CT) is recognized as standard for staging and response evaluation of Hodgkin lymphoma (HL). Recent randomized controlled trials evaluating FDG-PET-guided therapy for patients with limited stage and advanced stage Hodgkin lymphoma provide clinicians and patients with meaningful data upon which to base individualized treatment approaches. FDG‑PET scanning after two cycles of therapy (interim PET or PET2) represents the most important determinant of further appropriate treatment and subsequent outcomes, and is now the cornerstone of risk-adapted therapy for all patients receiving curative-intent initial therapy for Hodgkin lymphoma. For patients with limited stage cHL, post-chemotherapy assessment (after two or four cycles of treatment depending on the regimen used) is also a key determinant of the need for the addition of involved site or nodal radiation as part of combined modality therapy. This review summarizes the important role of interim and end of chemotherapy FDG-PET scanning to guide individualized initial therapy for patients to achieve optimal treatment outcomes.