Canadian Hematology Today

Mantle Cell Lymphoma: Evolving Frontline Treatment Strategies

Inna Y. Gong, MD, John Kuruvilla, MD, Michael Crump, MD — Thu, 27 Jun 2024 00:00:00 +0000

Mantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin lymphoma (NHL) that accounts for 3-10% of new NHL cases in Canada. The clinical course of MCL is heterogeneous, ranging from indolent behavior that does not require therapy for years, to highly aggressive disease with limited prognosis. As such, the 2022 International Consensus Classification (ICC) and World Health Organization (WHO) classifications subdivide MCL into two categories: 1) indolent MCL, which is characterized by blood involvement, splenomegaly without nodal involvement, or low-burden nodal involvement (mutated immunoglobulin heavy chain [IGHV], SOX11 negative, low Ki67 proliferative index); and 2) aggressive MCL, which is characterized by pleomorphic and blastoid morphologic appearance, TP53 aberrancy, high Ki67, and unmutated IGHV.

While traditionally, patients with MCL had a median overall survival (OS) of only 3 to 5 years, there has been significant improvement over the last two decades, owing to chemoimmunotherapy with rituximab, cytarabine-based induction regimens, addition of consolidative autologous stem cell transplant (ASCT), rituximab maintenance, and the advent of novel targeted therapies (including Bruton kinase inhibitors [BTKi], venetoclax, and lenalidomide) in the relapsed setting. Despite these advances, MCL remains incurable even with aggressive therapy, and most patients will invariably relapse. As such, prospective studies integrating novel therapies with either a chemotherapy backbone or evaluating chemotherapy-free regimens are ongoing, aiming to improve outcomes and reduce toxicities. This review summarizes the current understanding of disease prognostication, treatment options, and novel therapeutic strategies that will reshape the treatment paradigm of MCL in the near future.

Therapy for Myelodysplastic Syndromes Beyond the Front Line in 2024 in Canada

Rena Buckstein, MD, FRCPC — Thu, 27 Jun 2024 00:00:00 +0000

Management of anemia and/or transfusion dependence (TD) after failure of erythropoietic-stimulating agents (ESA) and therapeutic options after hypomethylating agent (HMA) failures remain the biggest challenges for physicians treating lower and higher-risk myelodysplastic syndromes (MDS), respectively. Fortunately, new therapies are available (or soon to be approved), and innovations in prognostic refinement using next-generation sequencing may also facilitate more precision medicine. This review highlights commercially available (or soon to be) options for the amelioration of anemia and transfusion dependence when ESA’s fail and the management of higher-risk MDS when hypomethylating agents fail or cease working. While not all of these agents are currently funded or approved in Canada, some are available for off-label access or purchase.

Management of Chronic Myeloid Leukemia that is Intolerant or Resistant to Front-Line Treatment

Lisa Bilston, MD, FRCPC, Kareem Jamani, MD, FRCPC — Thu, 27 Jun 2024 00:00:00 +0000

With advances in treatment for chronic myeloid leukemia (CML), the natural history of chronic phase (CP) CML has changed, with most individuals expected to live a normal life expectancy. The goal of therapy for most is to achieve a long-term deep molecular response (DMR) with the potential for medication discontinuation and treatment-free remission (TFR).1 Currently, six oral therapies have been approved for CP-CML in Canada: (1) imatinib, a first-generation tyrosine kinase inhibitor (TKI); (2) dasatinib, (3) nilotinib, and (4) bosutinib, the second-generation TKIs (2G-TKIs); (5) ponantinib, a third-generation TKI; and (6) asciminib, specifically targeting the ABL Myristoyl pocket (STAMP) inhibitor. Classically, treatment for CP-CML has consisted of front-line imatinib and switching to a 2G-TKI upon treatment resistance or intolerance. Increasingly, patients are being prescribed an upfront 2G-TKI with the goal of achieving quicker and deeper molecular remissions and a TFR.2 Challenges arise in CML when treatment with either two TKIs (imatinib + 2G-TKI) or one 2G-TKI fails, given the lack of evidence to inform clinical decision-making at this juncture. This paper aims to define TKI failure and help guide the selection of second-line treatment after failure of front-line therapy.

High-Risk Myeloma: Definitions and Treatments

Rintu Sharma, MD, Karla Alexandra Sánchez Hernández, MD, Guido Lancman, MD, MSc — Thu, 27 Jun 2024 00:00:00 +0000

Multiple myeloma is characterized by clonal proliferation of biologically heterogeneous plasma cells, leading to diverse clinical presentations and outcomes. Although outcomes have improved dramatically over the past decade with the rapid change in the treatment paradigm in standard-risk myeloma, a subset of patients remains who respond poorly to treatment and experience early relapses. These patients are considered high-risk and can be identified at the time of diagnosis based on several factors and their response to treatment (Table 1). Therefore, it is important to consider high-risk status as a dynamic assessment.

Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia After BTK Inhibitor and/or BCL-2 Inhibitor Failure

Sue Robinson, MD, FRCPC — Thu, 27 Jun 2024 00:00:00 +0000

The treatment landscape for first-line and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) has tremendously advanced with the introduction of Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL-2i). However, in this new era of targeted therapy for CLL, there is, unfortunately, no evidence yet to guide the optimal sequencing of these drugs. It remains unknown whether treating first-line with a BTKi and relapse with BCL-2i or BCL-2i at first-line followed by BTKi at relapse results in any difference in overall survival (OS). Ibrutinib (BTKi) was first introduced in 2014, and venetoclax (BCL-2i) in 2016, and currently, there are limited prospective data and treatment options for patients who have relapsed after one or both targeted therapies. This article will provide an overview of the approach to treatment for patients with CLL/SLL when BTKi and/or BCL-2i therapy has failed.

Before launching into the treatment of R/R CLL, it is worth noting that guidelines for risk assessment of CLL recommend determining the immunoglobulin heavy chain gene (IGHV) mutational status once, usually before the first treatment, and fluorescence in situ hybridization FISH for del(17p) and next-generation sequencing (NGS) before each treatment.1 Other than TP53, NGS-detected mutations are not routinely considered when choosing a therapy, but they may help predict the duration of remission and may become standard of care in the future.