High-Risk Multiple Myeloma in 2026: Evolving Definitions and Therapeutic Options
Multiple myeloma (MM) is a plasma cell malignancy characterized by osteolytic bone disease, anemia, kidney disease, and hypercalcemia, resulting in significant morbidity compared to age-matched controls. Treatment has advanced considerably over the past 20 years; the current standard of care involves treatment with quadruplet regimens combining a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and dexamethasone, with a CD38 monoclonal antibody. Eligible and fit patients will proceed with autologous stem cell transplantation (ASCT), and, following initial therapy, all patients receive maintenance therapy, typically lenalidomide and a CD38 monoclonal antibody. For elderly or frail patients, regimens such as daratumumab plus lenalidomide, or lenalidomide plus bortezomib, with or without dexamethasone, may be considered, but most patients will tolerate four drug regimens well. These treatment combinations have resulted in dramatic improvements in both progression‑free survival (PFS) and overall survival (OS); the phase III PERSEUS trial reported a 2-year PFS of 84.3%. Even with the use of older triplet regimens and ASCT, real-world data document a median OS of ~10 years. However, not all patients will achieve these outcomes. A subset of patients with MM has poorer outcomes even with state-of-the-art treatment with quadruplet regimens, which is broadly defined as high-risk multiple myeloma (HRMM). Patients with HRMM have earlier relapses, more aggressive disease biology, and shorter remissions with standard-of-care treatments. They can also be more prone to the development of aggressive presentations, such as extramedullary plasmacytomas (EMP), anaplastic morphology, and secondary plasma cell leukemia. The hallmark of all these subtypes is treatment refractoriness—defined as a lack of durable responses to standard effective treatments. Herein, we review the definition of HRMM, outcomes with standard treatment, and preferred treatment approaches for a patient with de novo or functional HRMM in the Canadian treatment landscape.
Copyright (c) 2026 Canadian Hematology Today https://creativecommons.org/licenses/by-nc-nd/4.0
Is Continuous Therapy Becoming Finite? The Evolving Landscape of CLL Treatment in 2026
The front-line treatment landscape for chronic lymphocytic leukemia (CLL) is rapidly evolving, with several new therapeutic options emerging. Traditionally, chemoimmunotherapy (CIT) formed the foundation of front-line treatment. However, over the past decade, targeted therapies have transformed the management of CLL, replacing CIT as the backbone of front-line treatment. Table 1 summarizes pivotal trials that have advanced CLL treatment. As a result of these advances, clinicians now have multiple highly effective frontline options. The challenge is no longer selecting the most efficacious regimen but rather selecting the optimal strategy for each individual patient. To address this evolving landscape, this review highlights current evidence and key practical considerations shaping frontline CLL management in Canada.
Upfront Therapy for Non‑transplantable Multiple Myeloma in 2026: Decision‑making in an Increasingly Complex Therapeutic Landscape
Multiple myeloma (MM) is an age-related disease with a median age at diagnosis of approximately 70 years. While quadruplet regimens, such as daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-VRd), followed by autologous hematopoietic stem cell transplantation (HSCT), as demonstrated in the Perseus trial, have recently become a standard for transplant-eligible patients, optimal first-line therapy remains challenging in older, frail individuals with comorbidities and reduced functional reserve. This challenge is driven less by biological differences in the disease and more by heterogeneity in treatment tolerance, comorbidity burden, and real-world care conditions. Historically, non‑transplant‑eligible patients were treated with doublets, such as melphalan/prednisone or lenalidomide/dexamethasone (Rd). With the introduction of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), triplet regimens, including VRd and later DRd (daratumumab, lenalidomide, dexamethasone), became the new standard of therapy. A major advance was the incorporation of monoclonal CD38 antibodies. Network meta‑analyses have shown that anti-CD38 monoclonal antibody-based combinations significantly improve progression-free survival (PFS) and response rates compared with regimens lacking anti-CD38 therapy. However, increasing efficacy has also led to greater treatment complexity and toxicity, which is particularly relevant for older and frail patients. For this population, first-line therapy must balance effective disease control with minimizing treatment-related morbidity and preserving quality of life. In addition, regional differences in access to modern therapies—especially to anti‑CD38 monoclonal antibodies and quadruplet combinations—further widen the gap between evidence-based recommendations and real‑world practice. This review provides practical guidance on selecting first-line therapy for patients with MM who are not eligible for transplantation, focusing on efficacy, toxicity profiles, and key clinical decision factors.
Approach to Patients with Acute Myeloid Leukemia in First Relapse: A Practical Guide for Canadian Hematologists
Acute myeloid leukemia (AML) is an aggressive and heterogeneous type of blood cancer associated with significant morbidity and mortality. Despite major improvements in the treatment of AML over the last decade, many patients unfortunately present with relapsed or refractory (R/R) disease after first-line standard treatment. With traditional high-intensity induction chemotherapy (IC) for AML, such as the 7+3 regimen, complete remission (CR) rates are about 75–80%, and in those who achieve remission, the relapse rate is approximately 40–50%. With less intensive regimens, such as azacitidine plus venetoclax (Aza-Ven), composite CR rates are about 65–70%, and in those who respond, about half will relapse within 2 years.3 Relapses mainly result from the survival of leukemia stem cells (LSCs), which may acquire additional mutations under the selective pressure of therapy and expand to drive disease recurrence.4 The majority of patients with R/R AML present with adverse-risk genetic features, which are associated with a lower median overall survival (OS) of less than 6 months. With second-line therapy for R/R AML, the overall response rates (ORRs) ranged between 20%–45%,5 underscoring the unmet need regarding the best therapeutic approach for these patients. This review aims to help the reader quickly identify the most common current standard salvage chemotherapy regimens and targeted agents used in the first relapse setting of AML and discuss the ongoing challenges in treating this patient population.
Current Management of Relapsed or Refractory Classic Hodgkin Lymphoma in Canada
Classic Hodgkin lymphoma (HL) is a rare B-cell malignancy with approximately 1,150 new cases diagnosed annually in Canada. Outcomes have improved substantially over the past several decades, with HL-related mortality declining by 2.2–3.0% annually since 1984, reflecting advances in both first-line and salvage therapies. Despite this progress, 10–30% of patients develop primary refractory or relapsed (R/R) disease, with risk influenced by stage, treatment regimen, and clinical features. Relapse rates are further decreasing with contemporary first-line regimens such as nivolumab, doxorubicin, vinblastine, and dacarbazine (nivolumab-AVD) and brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), and are now estimated at 5–10% in advanced-stage disease. Key adverse prognostic factors at relapse include primary refractory disease, relapse within 12 months, and advanced-stage disease. The introduction of novel targeted therapies, including the anti-CD30 antibody-drug conjugate brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors nivolumab and pembrolizumab, has led to improved outcomes in R/R HL. However, in Canada, access to targeted therapies has been constrained by delays in funding and restrictive approval criteria. In this review, we address common challenges and outline our approach to the treatment of adults with R/R HL within the contemporary Canadian context.
Not All Bruton's Tyrosine Kinase Inhibitors are Created Equal: Pharmacologic Insights into the Efficacy, Resistance, and Safety of Covalent and Non-covalent BTK Inhibitors
As the therapeutic landscape for B-cell malignancies continues to evolve, understanding the pharmacologic nuances of BTK inhibition has become increasingly important. In this interview, Rohit Khanna, publisher of Canadian Hematology Today, speaks with Giorgio Minotti, Professor of Pharmacology at the Università Campus Bio-Medico in Rome about the mechanistic differences between covalent and noncovalent BTK inhibitors, and the clinical implications for BTK inhibitor efficacy, resistance, and safety.
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.
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.
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.
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.
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.
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.
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.
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.