Expert Review of Hematology最新文献

Introduction: Inotuzumab ozogamicin (InO) is indicated for the treatment of adults with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL). This systematic literature review (CRD42022330496) assessed outcomes by baseline characteristics for patients with R/R ALL treated with InO to identify which patients may benefit most.

Methods: In adherence with PRISMA guidelines, searches were run in Embase and MEDLINE. Inclusion criteria were real-world evidence, observational studies, and phase 2-4 trials. The Cochrane Risk of Bias tool and Newcastle-Ottawa instrument assessed quality.

Results: 34 publications were included; 11 described the phase 3 INO-VATE trial. Patients treated with InO who were CD22-positive, in first salvage, and eligible for subsequent hematopoietic stem cell transplant (HSCT) had improved outcomes. Reduced incidence of veno-occlusive disease was observed in patients with normal transaminase levels and bilirubin, no prior liver disease, and who did not receive dual alkylators.

Conclusions: The ideal patient for InO treatment has CD22-positive disease (≥20% leukemic blasts), normal liver function, no history of liver disease, is in first salvage, has not previously received HSCT, prefers outpatient treatment, or has high disease burden. Limitations included potentially missing publications that were non-English, not identified in the searches, or available after the date the searches were conducted.

Registration: This systematic review was registered on the Prospective Register of Systematic Reviews (PROSPERO), registration number: CRD42022330496.

Introduction: T cells engineered to express antigen-specific T cell receptors (TCR; TCR-T) are a promising class of immunotherapeutic for patients with hematologic malignancies. Like chimeric antigen receptor-engineered T cells (CAR-T), TCR-T are cell products with defined specificity and composition. Unlike CAR-T, TCR-T can recognize targets arising both from intracellular and cell surface proteins and leverage the sensitivity of natural TCR signaling machinery. A growing number of TCR-T targeting various antigens in different hematologic malignancies are in early-phase clinical trials, and more are in preclinical development.

Areas covered: This review covers results from early-phase TCR-T clinical trials for hematologic malignancies. Challenges in the field are reviewed, including identifying optimal targets, engaging CD4⁺ help for CD8⁺ T cells, and overcoming tumor-induced suppression; recent innovations to overcome these challenges are also highlighted.

Expert opinion: In the future, TCR-T's promise for hematologic malignancies will be borne out in later-phase clinical trials and approvals for clinical use. Improved antigen discovery methods will help build the toolbox of targets needed for broadly applicable TCR-T. Rationally designed TCR-T modifications including incorporation of accessory receptors and gene editing will enhance TCR-T function. New hybrid receptors combining features of TCR and CAR will enter the clinic.

Introduction: Spontaneous regression (SR) is observed in some patients with mature T-cell non-Hodgkin lymphoma (MTCL), including adult T-cell leukemia/lymphoma (ATL), although the incidence is rare.

Area covered: We extracted 31 cases with MTCL who experienced SR based on a literature search and summarized the patient characteristics and clinical outcomes.

Expert opinion: MTCL with SR included various subtypes, the most common being ATL (n = 17). Five of 24 cases (21%) maintained SR for more than 5 years, and the median duration of SR was 2 years. Sixteen of 31 cases (52%) experienced tumor relapse after SR. Two retrospective studies including ATL cases showed SR rates of 18% and 4%, respectively. Representative triggers are infection and surgical biopsies, and possible mechanisms include immunological mechanisms such as cross-reactivity of virus-specific T cells with tumor antigens. The diagnostic criteria for SR are not standardized among reports, and the clinical outcomes are not fully described. Practically, observation is the only accepted strategy after SR was achieved. In the era of molecular targeted therapy or immunotherapy, new strategies including maintenance therapy after SR could be discussed, although clinical data are lacking.

Introduction: Cyclooxygenase-2 (COX-2) inhibitors (COXIBS) are considered a suitable option for the treatment of hemophilic arthropathy.

Areas covered: The role of traditional non-steroidal anti-inflammatory drugs; (NSAIDS) and COXIBS in people with hemophilia (PWH) and in the non-hemophiliac population has been reviewed in order to know which of them is more advisable in PWH and whether they should be used as the first or second therapeutic step for the treatment of musculoskeletal pain (since there is a discrepancy between what is advised by the WFH and the WHO).

Expert opinion: For the treatment of chronic musculoskeletal pain related to hemophilic arthropathy, it is reasonable to use as a first step a combination of oral paracetamol (650 mg per every 6 h) or metamizole (575 mg per every 6 h), one of the COXIBS (e.g. celecoxib 200 mg per once a day) and a proton pump inhibitor (e.g. omeprazole 20 mg per once a day). The possible side effects of COXIBS should never be forgotten. For the treatment of hemophilic arthropathy pain, the risk/benefit ratio of COXIBS should be carefully assessed on an individual basis, although they are more advisable than traditional NSAIDS.

Introduction: Leukemic stem cells (LSC) are the source of relapse in acute myeloid leukemia (AML). Thus, eliminating LSC is one of the overarching goals of AML research. Radioimmunotherapy is an immunotherapeutic approach which utilizes radioactive isotopes as effector molecules based on the proven ability of ionizing radiation (IR) to kill LSC.It has the potential to eliminate target-antigen negative LSC.

Areas covered: LSC biology, radiobiological principles of RIT, an overview of published and unpublished clinical results of RIT in AML. Issues of practical implementation of RIT in clinical trials.

Expert opinion: RIT for AML isat a critical juncture. Its ability to target antigen negative LSC gives it an advantage compared with other forms of immunotherapy. In order to compete with other forms of targeted therapy the procedure has to be simplified.

Introduction: COVID-19 is a continuing challenge for immunocompromised patients with hematological malignancies. Such patients are at increased risk for complications, including hospitalization, respiratory failure, delayed anti-cancer therapies, and even death. In addition to non-pharmacologic interventions, the main strategies for prevention in such patients are vaccination and pre-exposure prophylaxis.

Areas covered: In this narrative review, which relied on a review of the PubMed and bioRxiv databases (starting 1 November 2019), we summarize the epidemiology of COVID-19 and vaccine responses in patients with hematological malignancies and the use of antiviral agents as prophylaxis. A limitation to vaccination is suboptimal immune responses in immunocompromised patients, particularly those with abnormalities in lymphocyte count and function. A limitation to prophylaxis, which has only been proven effective for antiviral monoclonal antibodies (mAbs), is the emergence of resistant strains in the general population.

Expert opinion: For immunocompromised patients with hematological malignancies, we recommend vaccinations as guided by evolving US Centers for Disease Control and Prevention (CDC) recommendations, consideration of pre-exposure prophylaxis with antiviral mAbs, providing that they are effective against circulating viral strains, and rapid diagnostic testing linked to early therapy for the prevention of severe complications of COVID-19 in those who have broken through the prevention strategies.

Introduction: Transfusion-related acute lung injury (TRALI) remains a leading cause of blood transfusion associated mortality, particularly in the intensive care unit. TRALI is underrecognized, underreported and lacks specific biomarkers and clinical therapies.

Areas covered: In this review, the focus will be on the key pathophysiological features of TRALI. This will include the latest insights into the critical importance of complement (in contrast to Fcγ-receptors; FcγRs) as a driver of TRALI, and the role of recipient immune cells such as neutrophils and macrophages, and also the contribution of the pulmonary endothelium.

Expert opinion: Increased efforts are needed to stimulate active reporting of TRALI cases. More research into the immuno-cellular pathophysiology of TRALI is required, including the role of the pulmonary endothelium. Heterogeneity in the underlying clinical condition and the different transfusion triggers should be taken into consideration. This will aid in the search for novel biomarkers and therapeutic modalities. At the moment, the most promising potential therapeutic strategies appear to be administration of interleukin (IL)-10, inhibition of complement activation and blockade of Osteopontin (OPN). Follow-up investigations are, however, highly warranted which should pave the way for multicenter international clinical trials, in order to battle the mortality due to TRALI.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells, characterized by somatic mutations of the Phosphatidylinositol Glycan Class A Gene, resulting in increased hemolysis. The advent of complement inhibitors has since changed the way clinicians approach treating PNH. Pegcetacoplan is a C3 inhibitor that has shown promise in this field and improved outcomes for patients who have been diagnosed with PNH.

Areas covered: This review article will aim to examine the pathophysiology of PNH and the current treatments available, with a focus on pegcetacoplan. It will focus on the pharmacodynamics, pharmocokinetics and evidence in the use of pegcetacoplan in PNH. Electronic sources including PubMed, MEDLINE, were utilized with studies in the last 5 years prioritized, especially the phase 3 Prince and Pegasus studies.

Expert opinion: The results from phase 3 studies for pegcetacoplan have been promising, showing good efficacy and improvements in patients' conditions. More research is required to evaluate the use of pegcetacoplan, especially in combination with existing treatment in patients who are having suboptimal results. Nonetheless, with more results on the way and new agents to treat PNH in the vicinity, this remains a very exciting time for both clinicians and patients.