Epstein-Barr virus (EBV) is a ubiquitous herpes virus that infects the majority of the population worldwide. The virus can establish a lifelong latent infection in host B-lymphocytes. In the setting ...of immunocompromise as is the case post transplantation, the virus can reactivate and cause one of the deadliest complications post hematopoietic stem cell transplantation (HSCT), post-lymphoproliferative disease (PTLD), the incidence of which has been increasing. Multiple risk factors have been associated with the onset of PTLD such as age, reduced intensity conditioning, EBV serology mismatch and cytomegalovirus (CMV) reactivation. The rarity of clinical trials involving PTLD and the lack of approved treatment modalities renders the management of PTLD challenging. While the first-line treatment involves weekly administration of rituximab, there is no consensus when treating rituximab-refractory PTLD. There is a handful of clinical trials that investigate the role of EBV-specific cytotoxic T-lymphocytes (CTLs) and novel agents, such as bortezomib, lenalidomide, everolimus, panobinostat, and brentuximab. This article aims to explore the entity of EBV-PTLD in HSCT recipients, expanding on clinical presentation, risk factors, modes of monitoring and treatment, and so highlighting the gaps in knowledge that are needed in order to build a treatment paradigm suitable for all patients at risk.
BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of ...resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the ...secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease.
More than 30 years after its introduction, autologous stem cell transplantation (ASCT) remains the standard of care for young patients with newly diagnosed multiple myeloma. Not only did the arrival ...of novel agents such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PI) and monoclonal antibodies not replace ASCT, instead they solidified its central role as standard of care. Novel agent use is now inarguably essential in induction, maintenance, and possibly consolidation. In light of these new advancements, new challenges arise in deciding on optimal practice. Who is most suited to undergo ASCT? Is there an age threshold that should not be surpassed? Should transplantation be embarked on early or is it reasonable to delay it? What are the optimal induction, consolidation, and maintenance therapies? What is the role of tandem transplantation in the era of novel agents and where do patient-specific cytogenetics come into the equation when deciding on treatment? These are some of the questions addressed in this review which we will attempt to answer with the latest currently available data.
The optimal choice for graft-versus-host disease (GVHD) prophylaxis in haploidentical stem cell transplantation (haplo-SCT) remains debatable. Posttransplant cyclophosphamide (PTCy) and ...anti-thymocyte globulin (ATG) are two common strategies, but little is known about their combination.
Using the European Society for Blood and Marrow Transplantation (EBMT) registry, the authors identified 3649 adult patients with acute myeloid leukemia (AML) who underwent haplo-SCT in complete remission between 2007 and 2021 at 260 EBMT-participating centers who received either PTCy (n = 2999), ATG (n = 358), or combination prophylaxis (n = 292). Cord blood transplants, combined bone marrow and peripheral grafts, and transplants with ex vivo graft manipulation were excluded. Median follow-up was 31.8 months.
On multivariate analysis, adjusting for patient age and performance status, disease status at transplant, cytogenetic risk, conditioning intensity, stem cell source, female-to-male graft, and donor and patient CMV status, we present the following. Compared to PTCy, ATG had a higher risk of nonrelapse mortality (hazard ratio HR, 1.6; p = .003), worse leukemia-free survival (HR, 1.4; p = .002), overall survival (HR, 1.49; p = .0009), and GVHD-free and relapse-free survival (HR, 1.29; p = .012). The combination of PTCy and ATG, however, led to significantly reduced rates of grade 2-4 (HR, 0.51; p = .0003) and grade 3-4 (HR, 0.5; p = .018) acute GVHD and did not affect any transplant outcomes compared to PTCy without ATG.
The authors conclude that ATG alone is a less effective prophylaxis strategy compared to PTCy, however, the combination of PTCy and ATG is superior to either monotherapy. They propose that this combination could be considered a potential new standard of care for GVHD prophylaxis in haplo-SCT for AML.
Most patients with relapsed/refractory multiple myeloma (RRMM) have been treated with drug combinations including a proteasome inhibitor (PI) and/or an immunomodulatory drug (IMiD). The goal of ...therapy for such patients is therefore to achieve disease control with acceptable toxicity and patient-defined decent quality of life. Physicians face a difficult task not only deciding who to treat, but also when to treat and how to treat, utilizing knowledge of previously administered therapies, patient comorbidities, potential adverse events, and patient wishes to make such a critical decision. New drugs and combination regimens are continuously underway thus broadening the options for therapy and giving way to a more individualized approach for patients with RRMM. The integration of novel agents into the treatment paradigm has shifted the perception of multiple myeloma (MM) from an incurable, fatal disease to a manageable, chronic one. This comprehensive review addresses the results and challenges posed by many of the newer agents for the treatment of RRMM. It attempts to propose a universal strategy for optimal therapy decision-making thus answering three simple fundamental questions-when to treat, how to treat, and how long to treat for.
The current standard of care model for newly diagnosed fit multiple myeloma (NDMM) patients is the sequential treatment of induction, high dose melphalan, autologous stem cell transplantation (ASCT), ...and maintenance. Adequate induction is required to achieve good disease control and induce deep response rates while minimizing toxicity as a bridge to transplant. Doublet induction regimens have greatly fallen out of favor, with current international guidelines favoring triplet or quadruplet induction regimens built around the backbone of the proteasome inhibitor bortezomib and dexamethasone (Vd). In fact, the updated 2021 European Haematology Association (EHA) and European Society for Medical Oncology (ESMO) clinical practice guidelines recommend the use of either lenalidomide-Vd (VRd), or daratumumab-thalidomide-Vd (Dara-VTd) as first-line options for transplant-eligible NDMM patients, and when not available, thalidomide-Vd (VTd) or cyclophosphamide-Vd (VCd) as acceptable alternatives. Quadruplet regimens featuring anti-CD38 monoclonal antibodies are extremely promising and remain heavily investigated, as is the incorporation of more recent proteasome inhibitors such as carfilzomib. This review will focus on induction therapies prior to ASCT examining the latest data and guidelines on triplet and quadruplet regimens.
Hodgkin lymphoma is a highly curable disease. Although most patients achieve complete response following frontline therapy, key unmet clinical needs remain including relapsed/refractory disease, ...treatment-related morbidity, impaired quality of life and poor outcome in patients older than 60 years. The incorporation of novel therapies, including check point inhibitors and antibody-drug conjugates, into the frontline setting, sequential approaches, and further individualized treatment intensity may address these needs. We summarize the current treatment options for patients with classical Hodgkin lymphoma from frontline therapy to allogeneic hematopoietic stem cell transplantation and describe novel trials in the field.
Summary
Myelofibrosis (MF) is a clonal stem cell neoplasm with heterogeneous clinical phenotypes and well‐established molecular drivers. Allogeneic haematopoietic stem cell transplantation (HSCT) ...offers an important curative treatment option for primary MF and post‐essential thrombocythaemia/polycythaemia vera MF or secondary MF. With a disease course that varies from indolent to highly progressive, we are now able to stratify risk of mortality through various tools including patient‐related clinical characteristics as well as molecular genetic profile. Owing to the high risk of mortality and morbidity associated with HSCT for patients with myelofibrosis, it is important to improve patient selection for transplant. Our primary goal is to comprehensively define our understanding of current practices including the role of Janus Kinase (JAK) inhibitors, to present the data behind transplantation before and after leukaemic transformation, and to introduce novel personalization of MF treatment with a proposed clinical‐molecular prognostic model to help elucidate a timepoint optimal for consideration of HSCT.
Iron overload (IOL) due to increased intestinal iron absorption constitutes a major clinical problem in patients with non-transfusion-dependent thalassemia (NTDT), which is a cumulative process with ...advancing age. Current models for iron metabolism in patients with NTDT suggest that suppression of serum hepcidin leads to an increase in iron absorption and subsequent release of iron from the reticuloendothelial system, leading to depletion of macrophage iron, relatively low levels of serum ferritin, and liver iron loading. The consequences of IOL in patients with NTDT are multiple and multifactorial. Accurate and reliable methods of diagnosis and monitoring of body iron levels are essential, and the method of choice for measuring iron accumulation will depend on the patient's needs and on the available facilities. Iron chelation therapy (ICT) remains the backbone of NTDT management and is one of the most effective and practical ways of decreasing morbidity and mortality. The aim of this review is to describe the mechanism of IOL in NTDT, and the clinical complications that can develop as a result, in addition to the current and future therapeutic options available for the management of IOL in NTDT.
PDF
