Search

This document provides a list of references to studies and articles related to CAR-T cell therapy for various types of lymphoma and multiple myeloma. The studies mentioned discuss the outcomes, safety, and efficacy of CAR-T cell therapies such as lisocabtagene maraleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, ciltacabtagene autoleucel, and idecabtagene vicleucel. The document also includes references to studies that discuss the potential risk of secondary malignancies and other long-term effects associated with CAR-T cell therapy. [Extracted from the article]

A letter to the editor is presented which discusses a three-arm prospective and non-randomized study of clinical efficiency of an early discharge model (EDM) and home-care (HC) treatment for multiple myeloma (MM) being treated with high dose melphalan (HDM) with hematopoietic progenitor cell (HPC).

Simple Summary: Available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CAR T therapy is safety. Cytokine release syndrome (CRS) and neurologic toxicity are well-described adverse effects. In MM trials, most CRS events tended to be grade 1 or 2. Another critical point is the extended timeline of the manufacturing process and that only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. Despite the improvement in survival outcomes, multiple myeloma (MM) remains an incurable disease. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) represents a new strategy for the treatment of relapsed/refractory MM (R/R). In this paper, we describe several recent advances in the field of anti-BCMA CAR T-cell therapy and MM. Currently, available data on anti-BCMA CART-cell therapy has demonstrated efficacy and manageable toxicity in heavily pretreated R/R MM patients. Despite this, the main issues remain to be addressed. First of all, a significant proportion of patients eventually relapse. The potential strategy to prevent relapse includes sequential or combined infusion with CAR T-cells against targets other than BCMA, CAR T-cells with novel dual-targeting vector design, and BCMA expression upregulation. Another dark side of CART therapy is safety. Cytokine release syndrome (CRS) andneurologic toxicity are well-described adverse effects. In the MM trials, most CRS events tended to be grade 1 or 2, with fewer patients experiencing grade 3 or higher. Another critical point is the extended timeline of the manufacturing process. Allo-CARs offers the potential for scalable manufacturing for on-demand treatment with shorter waiting days. Another issue is undoubtedly going to be access to this therapy. Currently, only a few academic centers can perform these procedures. Recognizing these issues, the excellent response with BCMA-targeted CAR T-cell therapy makes it a treatment strategy of great promise. [ABSTRACT FROM AUTHOR]

Not available.

Chimeric antigen receptor (CAR) T-cell therapy relies on T cells engineered to target specific tumor antigens such as CD-19 in B-cell malignancies. In this setting, the commercially available products have offered a potential long-term cure for both pediatric and adult patients. Yet manufacturing CAR T cells is a cumbersome, multistep process, the success of which strictly depends on the characteristics of the starting material, i.e., lymphocyte collection yield and composition. These, in turn, might be affected by patient factors such as age, performance status, comorbidities, and previous therapies. Ideally, CAR T-cell therapies are a one-off treatment; therefore, optimization and the possible standardization of the leukapheresis procedure is critical, also in view of the novel CAR T cells currently under investigation for hematological malignancies and solid tumors. The most recent Best Practice recommendations for the management of children and adults undergoing CAR T-cell therapy provide a comprehensive guide to their use. However, their application in local practice is not straightforward and some grey areas remain. An Italian Expert Panel of apheresis specialists and hematologists from the centers authorized to administer CAR T-cell therapy took part in a detailed discussion on the following: 1) pre-apheresis patient evaluation; 2) management of the leukapheresis procedure, also in special situations represented by low lymphocyte count, peripheral blastosis, pediatric population <25 kg, and the COVID-19 outbreak; and 3) release and cryopreservation of the apheresis unit. This article presents some of the important challenges that must be faced to optimize the leukapheresis procedure and offers suggestions as to how to improve it, some of which are specific to the Italian setting.

Introduction: Chimeric antigen receptor (CAR)-T-cell therapy is a new treatment for patients with hematologic malignancies in which other therapies have failed., Areas Covered: The review provides an overview for recognizing and managing the most acute toxicities related to CAR-T cells., Expert Opinion: The development of immune-mediated toxicities is a common challenge of CAR-T therapy. The mechanism that determines this toxicity is still unclear, although an unfavorable tumor microenvironment and a pro-inflammatory state put patients at risk. The monitoring, diagnosis, and treatment of post-CAR-T toxicities must be determined and based on international guidelines and internal clinical practice. It is urgent to identify biomarkers that can identify patients at greater risk of developing complications. The adoption of consistent grading criteria is necessary to improve toxicity management strategies continually. The first-line therapy consists of supportive care and treatment with tocilizumab or corticosteroids. An early start of cytokine blockade therapies could mitigate toxicity. The plan will include cytokine release prophylaxis, a risk-adapted treatment, prevention of on-target/off-tumor effect, and a switch on/off CAR-T approach.

Introduction: Autologous Stem Cell Transplantation (ASCT) represents the standard treatment in eligible "de-novo" multiple myeloma (MM) patients., Areas Covered: ASCT may be single or tandem, and a single ASCT can be followed by an allogeneic (Allo)-SCT. A systematic review has been conducted to examine the current evidence for the efficacy of using a tandem transplant strategy in MM., Expert Opinion: A tandem ASCT approach should be considered for all patients, although the benefit from the second ASCT in patients who are in complete remission or experience a very good partial response should be answered in a clinical trial. Recent results with the new induction regimens indicate that there is a role for tandem ASCT in the presence of adverse cytogenetic abnormalities. Planned AlloSCT after ASCT has not been found to be superior in the majority of studies and is not recommended outside of a clinical trial. However, single or tandem ASCT are both appropriate options and participation in prospective clinical trials should be encouraged to resolve the debate in the era of novel agents for MM.

Introduction: Autologous (auto) stem cell transplantation (SCT) and the development of new drugs have improved the survival of multiple myeloma (MM) patients. By contrast, though potentially curative, the use of allogeneic (allo)-SCT is controversial., Areas Covered: A review has been conducted to examine the current evidence for the use of allo-SCT in MM. We have examined novel cell therapies that may be exploited to induce myeloma-specific immune responses including the new promising frontier of chimeric antigen receptor (CAR)-T and -natural killer (NK) cells., Expert Opinion: One of the major controversies facing researchers in exploring the allo approach is the remarkable recent treatment improvement observed with second- and third-generation proteasome inhibitors and immunomodulatory drugs, monoclonal antibodies and deacetylase inhibitors. Despite these great advances, the disease remains to be incurable and allo-SCT may still play a role in the cure of MM. We think that allo-SCT conserves a role in MM and its curative potential in high-risk patients should be explored in the setting of control clinical trials. Novel cell therapies such as CAR technologies may open new avenues of research toward a potential cure. Data from currently ongoing prospective studies will be helpful to clarify pending clinical questions.

Introduction: Erythropoiesis-stimulating agents (ESAs) are used in treating cancer- and chemotherapy-induced anemia with the aim of accelerating the recovery of red blood cells (RBCs), reduce the risks associated with RBC transfusions and improve quality of life., Areas Covered: A systematic review has been conducted to examine the current evidence for the efficacy and safety of using ESAs in hematopoietic stem cell transplants (HSCTs)., Expert Opinion: Despite the international recommendations for the use of ESAs in treating different malignancies, there is a lack of guidelines for their use in patients undergoing HSCT. An evaluation of published clinical trials shows that there are no available powerful studies concerning the use of ESAs in this setting, with only heterogeneous and small numbers of patients reported so far. Nevertheless, the more robust and intriguing of these data suggest that the ESA's administration at an appropriate time after the infusion of stem cells may be effective both in autologous and allogeneic HSCTs. New guidelines are required, overseen by an expert in the in the field of stem cell transplantation.

Aberrant DNA methylation is a key pathological mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and provides rationale for the clinical development of hypomethylating agents (HMAs) for the treatment of these diseases. One HMA, azacitidine (Vidaza®, Celgene Corp.), has demonstrated improved survival versus conventional care regimens in patients with intermediate-2/high-risk MDS and AML (20-30% blasts) and has a favorable tolerability profile. Emerging evidence indicates that azacitidine can have an immunomodulatory effect by, for example, increasing functional regulatory T-cell (Treg) numbers and killer-cell-immunoglobulin-like receptor expression. Allogeneic hematopoietic progenitor cell transplantation (allo HPCT) is the only potentially curative treatment approach in patients with advanced MDS or AML. Unfortunately, allo HPCT in these settings is limited because most patients are ineligible due to age/comorbidities, or are at a high risk of treatment failure due to disease relapse. Recent studies have shown that azacitidine after allo HPCT increases Treg numbers while inducing a cytotoxic CD8+ T-cell response, suggesting a potential mechanism for augmenting the graft-versus-leukemia (GvL) effect without increasing graft-versushost- disease (GVHD). In patients at a high risk of relapse following allo HPCT, pre-emptive azacitidine may help prevent/delay relapse. For patients who have relapsed following allo HPCT, azacitidine may be a salvage therapy option, either as monotherapy or in combination with donor lymphocyte infusions (DLI). In this mini-review, we discuss these emerging clinical data for HMAs in the post-allo HPCT regimens and highlight the possible future role of azacitidine in this setting.

Introduction: Advanced-stage Hodgkin's lymphoma (HL) has become a curable disease in the majority of patients. Despite this, about 20% of these patients relapsed or are primary refractory to the first-line treatment and high-dose chemotherapy (HDC) and autologous (Auto) hematopoietic progenitor cells transplantation (HPCT) are considered a therapeutic option., Areas Covered: The authors reviewed HDC and HPCT treatment strategies in recurrent or refractory HL patients, with the goal of providing an overview of this approach., Expert Opinion: Patients younger than 60-65 years with relapsed disease or refractory to first-line therapy should receive a second-line chemotherapy, followed by HDC and Auto-HPCT. Progression-free and overall survival results are significantly better when a second remission or a minimal disease status is achieved before Auto-HPCT, and demonstrate that this strategy is able to cure more than half of the advanced HL patients. Myeloablative allogeneic HPCT (Allo-HPCT) has been employed in advanced phases of the disease, but there have been significant concerns due to treatment-related mortality (TRM). The safety of allogeneic transplantation has improved with the use of reduced-intensity allogeneic (RIC-Allo) HPCT strategies. Despite early favorable results, mature results of RIC-Allo available in the literature are consistent in demonstrating a lack of long-term disease control.

Introduction: The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (auto-HPCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. Administration of high-dose melphalan (HDM) is considered the standard conditioning regimen. Nevertheless, several attempts have recently been made to improve the conditioning phase of the HDC procedure., Areas Covered: We reviewed all the reported experiences and illustrated current knowledge in the field of conditioning regimens., Expert Opinion: For fit MM patients, HDC followed by auto-HPCT remains the standard of care. The available data confirm that melphalan (MEL) 200 mg/m(2) should continue to be considered the gold standard conditioning regimen, with dose reduction based on age and renal function. Targeting exposure to MEL by using area under the curve is a particularly appealing approach that could be explored to maximize efficacy and minimize toxicity of this drug. Other strategies are currently being evaluated in different trials, and the most interesting areas of research involve the incorporation of newer agents like bortezomib (BOR) into conditioning regimens. Moreover, intravenous busulfan has become available and this formulation may reduce toxicity and result in greater efficacy in association with MEL-based conditioning.

Introduction: There are considerable concerns regarding the appropriate use of health care resources to reduce costs and waiting lists associated with autologous hematopoietic progenitor cell transplantation (AHPCT). One of the strategies to reach this goal is outpatient-based (OpB) AHPCT., Areas Covered: We reviewed all the reported experiences in this field and illustrated the various models of OpB AHPCT., Expert Opinion: The role of high-dose melphalan (HDM) followed by AHPCT in the treatment of Multiple Myeloma (MM) continues to evolve in the novel agent era and the International Myeloma Working Group recommends that AHPCT should be offered at some point in the course of the treatment program for a medically fit patient. The relatively short neutropenia and the limited extra-marrow toxicity after HDM support the hypothesis that MM patients are the most suitable for outpatient transplant programs. Various models have shown that the procedure is feasible and safe and may highly contribute to shorten waiting lists and to considerably cut health costs, with an improvement of quality of life. Ideal candidates may be those who are asymptomatic and fully active, who have a full-time caregiver and who can reside within easy reach from the transplant center.

Introduction: Extracorporeal photopheresis (ECP) has been extensively used for the treatment of immune-mediated diseases for over 20 years and has a consistent and predictable safety profile with long-term use. Documenting the efficacy of ECP as therapeutic treatment has long been a matter of importance for physicians., Areas Covered: The authors reviewed publications in this field with the goal of providing an overview of this therapeutic approach., Expert Opinion: ECP is efficacious in a high percentage of those cutaneous T-cell lymphoma patients who have circulating malignant T cells in the context of a still-near-normal immune competence. From the side of graft-versus-host disease (GVHD), the use of ECP showed a clinical benefit in patients with steroid-refractory acute GVHD (aGVHD) and it is believed that ECP deserves to be evaluated as part of a combination strategy in first-line therapy of aGVHD. In chronic GHVD, the published data show that ECP can be effective in extensive and long-standing disease even when treatment is initiated at an advanced stage after conventional immunosuppressive and corticosteroid therapy has failed. ECP should be considered most beneficial for patients with predominantly mucocutaneous chronic GVHD. The fields of application of the procedure could be vast, and could also include autoimmune and metabolic diseases. The most important methodological issues which affect ECP evaluation is that the large majority of data about ECP result from single-arm observational series and the significant efficacy is mainly based on small and retrospective studies. ECP has never been proved to offer any survival advantage in a context of a randomized trial and the above-mentioned limitation also affects the accuracy of many biological modifications observed during ECP. Starting from these considerations, the need of a prospective randomized study becomes increasingly urgent.

Background: Different factors influence the clinical outcome of allogeneic transplants, the foremost being good immune recovery., Materials and Methods: The purpose of this study was to evaluate the influence of different factors, such as stem cell source, type of donor, conditioning regimen and acute graft-versus-host disease, on early lymphocyte recovery after transplantation. We then analyzed the impact of early CD4+ cell count on overall survival, transplant-related mortality and disease-related mortality., Results: Univariate analysis with Spearman's rho showed a significant correlation between early CD4+ cell recovery and overall survival, transplant-related mortality, stem cell source and type of donor. In multivariate analysis CD4+ cell count was significantly associated with (i) stem cell source, being higher in patients whose haematopoietic progenitor cells were obtained by apheresis than in those whose source of grafted cells was bone marrow, and (ii) type of donor, being higher in patients transplanted from sibling donors than in those whose graft was from an alternative donor. The ROC curve of CD4+ cell count indicated that a cut-off of 115 CD4+ cells/mL could differentiate groups with different outcomes. At 2 years follow-up, patients achieving this CD4+ cell count had significantly lower cumulative transplant-related mortality compared to patients who did not have this count (10%±4% versus 40%±8%, p=0.0026). At the 5-year follow-up, the overall survival rates were 77.5%±0.6% and 36%±7% (p=0.000) in patients with a CD4+ cell count ≥115/mL and in patients with CD4+ cell count ≤ 115/mL, respectively., Conclusion: Early CD4+ cell recovery after allogeneic transplantation has a relevant impact on overall survival and transplant-related mortality and is influenced by two factors: stem cell source and type of donor.