Chimeric Antigen Receptor T-cell Therapy for Multiple Myeloma

Relapsed/refractory multiple myeloma (MM) remains a significant clinical challenge, despite a wide array of approved therapeutic agents. Immunotherapy offers an advantage in this setting. Chimeric antigen receptor (CAR) modified T-cells have transformed care for patients with hematologic malignancies. CAR-T cells targeting CD-19 B-cell lymphoma cells have shown prominent activity in lymphoma and acute lymphoblastic leukemia. Recently, the CAR-T cell platform for MM demonstrated therapeutic benefit. Hence, it is rapidly progressing. The most commonly tested target for MM is the B-cell maturation antigen. Complexities involved in the generation and use of CAR-T cells for MM include the identification of appropriate target antigens that are specific, and tumor type restricted, in addition to the optimization of CAR constructs to mitigate toxicities including cytokine release syndrome. CAR-T cells hold immense promise as a therapeutic modality for the treatment of MM. In this article, we provide an updated review of clinical trials of MM-specific CAR-T cells.     

Chimeric Antigen Receptor T-Cell Therapy for Chronic Lymphocytic Leukemia: A Narrative Review

The treatment landscape for chronic lymphocytic leukemia (CLL) is changing rapidly. Novel targeted agents such as ibrutinib, venetoclax, and idelalisib have had a significant effect on first-line, relapsed/refractory, and high-risk disease. Despite these advances, there are continuous needs for new treatment options, especially for patients in whom these novel therapies fail or those who cannot tolerate these novel therapies. In 2011, Porter et al reported the first successful use of autologous chimeric antigen receptor T cells (CARTs) directed against cluster of differentiation (CD)19 in 3 refractory CLL patients. Several groups have since shown success with similar approaches in various settings of CLL, including failure of ibrutinib treatment and in patients who relapse after allogeneic stem cell transplantation. Although CD19-directed CART therapy holds great promise in CLL and other diseases, many challenges and questions remain including: optimization of the lymphodepletion regimen before CART infusion, optimal dosing of CART, a determination of the most effective CART product (T-cell subset[s]) as well as the optimal combinations and therapeutic sequences, and managing treatment-associated adverse events. Clinical trials addressing these challenges are in process. In this timely review, we analyze current state of CART therapy in CLL and attempt answering remaining questions.     

Fever Characteristics and Impact on Safety and Efficacy of Chimeric Antigen Receptor T-Cell Therapy

BackgroundFever is a hallmark symptom of cytokine release syndrome (CRS) after chimeric antigen receptor (CAR) T-cell therapy. Fever characteristics and the impact of fever on safety and efficacy post CAR T are not well understood. We sought to explore the impact of fever and its characteristics on safety and efficacy post CAR T-cell therapy.Patients and MethodsWe reviewed 40 patients with various hematologic malignancies (non-Hodgkin lymphoma, acute lymphoblastic leukemia, multiple myeloma) treated with CAR T-cell therapy between March 2019 and March 2022. We evaluated all patients who developed fever after CAR T infusion and analyzed the association of fever with toxicity (CRS and neurotoxicity) and efficacy (overall response (ORR) and complete response (CR) at day +90 post CAR T infusion). Fever was defined as per Lee criteria (equal to or greater than 38°C). CRS and immune-effector cell associated neurotoxicity syndrome (ICANS) were graded using American Society for Transplantation and Cellular Therapy grading system.ResultsFever occurred in 75% (30/40) of patients. Rates of all grade and grade 3+ CRS and ICANS were 75%, 2%, 33% and 10%, respectively. Fever occurred within 24 and 72 hours after CAR T infusion in 40% and 53% of patients, respectively. Fifty percent of patients received tocilizumab (toci) for CRS. After the first dose of toci, fever recurred in 38% of the patients, of which 67% had recurrence within 24 hours. Day +90 CR rates were 43% and 10% in patients with and without fever, respectively (Table 3).ConclusionWhile fever is common after CAR T-cell therapy, early-onset and higher magnitude do not appear to affect safety or efficacy of CAR T. Absence of fever may affect response to CAR T.     

Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy for Primary and Secondary Central Nervous System Lymphoma: A Systematic Review of Literature

Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.     

Clinical Analysis of Pediatric T-Cell Acute Lymphoblastic Leukemia Using the MRD-Oriented Strategy System

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) has historically been associated with a poor prognosis. However, prognostic indicators and methods of treatment used for T-ALL remain controversial. A total of 136 children newly diagnosed with T-ALL between 2005 and 2018 were consecutively enrolled in this study. We assessed the effect of different prognostic factors, such as clinical characteristics, minimal residual disease (MRD), and the role of transplantation in postremission treatment, as the outcomes. Compared with B-ALL patients, patients with T-ALL are generally older, more likely to be male and have a higher white blood cell count. The complete remission (CR) rate was 95.6%, while the 5-year overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) were 74.3 ± 3.7%, 71.3 ± 3.9%, and 24.4 ± 3.8%, respectively. In the multivariate analysis, day 33 MRD ≥0.1% and hyperleukocytosis were associated with a significantly worse prognosis in the whole group. Transplantation resulted in a significant survival advantage, compared with chemotherapy, for high-risk (HR) patients (5-year CIR: 15.6 ± 10.2% vs. 55.6 ± 11.7%, P = .029). The prognosis of children with T-ALL was poor, and the MRD on day 33 was found to be an important predictive factor of clinical outcome at our center.     

T-Cell Receptor α and δ Gene Assembly in B-Cell Precursor Acute Lymphoblastic Leukemia

The status of the TCR-s/δ genes in B-precursor ALL and the rearrangement patterns of these gene loci are discussed in this review. Although most of these rearrangements have been characterized, some still remain to be clarified. Almost all rearrangements of the TCRs in B-precursor ALL are incomplete and may reflect early recombinational steps during the TCR differentiation processes in normal T-lineage cells. In addition, even in T-cell malignancies, it is rarely possible to obtain clonal cell populations with TCR rearrangements arrested in very early recombinational steps. Therefore, studies of these as yet uncharacterized rearrangements may lead to the discovery of additional gene segments playing important roles in the TCR recombinational processes and may provide useful information for understanding the processes of T-cell differentiation.     

A Case of Adult T-Cell Leukemia Initiated with Central Nervous System Symptoms

We treated a 52-year-old Japanese woman with adult T-cell leukemia(ATL) initiated with central nervous system (CNS) symptoms.Her chief complaints were paraplegia and left facial palsy.CNS-ATL was diagnosed because of the following three features.1) Various sized lymphoid cells with marked nuclear convolutionwere numerous in her cerebrospinal fluid. 2) These cells werea monoclonal proliferation of T lymphocytes with OKT 4 marker.3) The patient's serum was positive for anti-ATL associatedantigen (ATLA). Although the neurological signs and symptomsimproved markedly after intrathecal administration of combinedchemotherapy (methotrexate, cytarabine and corti-costeroid),these ATL cells were highly resistant to radiation therapy.The abdominal mass which developed in the course of the diseasewas diagnosed as a tumor formed of ATL cells, and VEPA (vincristine,endoxan, prednisolone and adriamycin) was administered withmarked success.     

Shedding of CD9 Antigen in Acute Lymphoblastic Leukemia

A leukemia-associated CD9 glycoprotein antigen released into the extracellular milieu from acute lymphoblastic leukemia cells has been detected using a unique lectin-monoclonal antibody immunoassay. It has been demonstrated that the release of CD9 antigen is an active process and is associated with active cell growth. In addition, the difference of carbohydrate moiety, and hence glycosylation, in the CD9 antigen derived from lymphoblasts and neuroblasts was verified using lectin affinity chromatography. The lectin affinity of the carbohydrate moiety of lymphoblast CD9 antigen would indicate the presence of N-linked oligosaccharide chains having groups of N-acetyl glucosamine residues, a mannose core and a terminal D-galactose.

The soluble CD9 antigen is specifically detected in plasma from ALL patients at the time of diagnosis, in cerebrospinal fluid from patients with central nervous system involvement, and spent medium from CD9-positive leukemic blasts obtained at the time of diagnosis. Interestingly when bone marrow cells taken from patients in complete remission were studied, a distinct amount of CD9 antigen was released into spent medium in some of the cases. All of these patients have subsequently developed hematological relapse. The present data suggest that shedding of CD9 antigen by leukemic cells may enable the clinical monitoring of residual leukemic cell burden.     

T-Cell Acute Lymphoblastic Leukemia with t(11;14) in Children

We review and update our examination of the clinical and biologic findings in 19 cases of acute lymphoblastic leukemia (ALL) with the t(11;14) and discuss the literature relevant to the clinical, biologic, and molecular aspects of these translocations. In nine consecutively diagnosed cases at St. Jude Children's Research Hospital and 10 cases reported by other institutions, clinical features did not differ among T-cell ALL patients with and without the t(11;14), although leukemic cells with this translocation were more likely to coexpress CD4 and CD8 antigens. The t(11;14)(p13;q11) appears to occur exclusively in T-cell malignancies of intermediate- or late-stage thymocyte differentiation; further studies will be needed to determine whether it has prognostic significance.     

小儿急性淋巴细胞白血病IgH及TCRγ基因重排研究

应用ＰＣＲ对３３例小儿急性淋巴细胞白血病（ＡＬＬ）进行免疫球蛋白重链（ＩｇＨ）及Ｔ细胞受体γ（ＴＣＲγ）基因重排研究,以探讨该２种重排在小儿ＡＬＬ的发生规律及与免疫分型的关系。结果显示：ＩｇＨ阳性１９例（５７．６％）,ＴＣＲγ阳性１０例（３０．３％）。有７例ＩｇＨ及ＴＣＲγ均呈阳性,其中５例来自Ｂ系或Ｔ系分化早期的淋巴细胞白血病,提示在儿童初发淋巴细胞白血病中,ＩｇＨ基因重排的发生率明显高于ＴＣＲγ基因重排,且在免疫表型为分化早期的Ｔ或Ｂ淋巴细胞白血病中,并存上述２种基因重排的可能性很大。     

Cerebrospinal Fluid Neopterin Levels in Children with Central Nervous System Leukemia

Cerebrospinal fluid (CSF) neopterin levels were determined by high-pressure liquid chromatography in 48 normal children and in 15 children with meningeal relapse of hematologic malignancies (13 acute lymphoblastic leukemia and 2 high-grade lymphomas). When meningeal relapse was diagnosed, all patients had CSF neopterin levels higher than mean normal value + 2 standard deviations. No significant correlation between the blast count in the CSF and neopterin levels was observed. CSF data before relapse were available in 10 children: the neopterin values at relapse were significantly higher than values observed at diagnosis. In 3 patients, elevated neopterin levels preceeded the occurrence of neurologic signs and the detection of blast cells in CSF by 15 to 30 days. In the absence of infection, the rise of CSF neopterin levels in patients with hematologic malignancies indicates an active phase of the disease. This could reflect a cell-mediated immunologic process induced by malignant cells. The measurement of CSF neopterin should be helpful in the monitoring of patients to detect early meningeal relapse.     

Month-of-Birth and Incidence of Acute Lymphoblastic Leukemia in Children

As a means of examining the virus-relatedness of acute lymphoblastic leukemia (ALL) in children, we investigated the association between month-of-birth and the occurrence of ALL in 1487 children aged 0-15 years at the time of diagnosis. Our hypothesis being that evidence of seasonal variation in births of ALL cases would suggest exposure to a transmissible etiologic agent during the perinatal period. The data were obtained Surveillance, Epidemiology, and End Results (SEER) Program and consisted of children diagnosed during the years 1973-1986. Aggregate monthly incidence rates of ALL stratified by month-of-birth, for each SEER site, all sites combined, and for broad geographic regions were calculated. No evidence for an association between month-of-birth and childhood ALL was found.     

GGLG-08方案联合伊马替尼治疗儿童Ph阳性急性淋巴细胞白血病的疗效与安全性分析

目的 研究GGLG-08方案联合伊马替尼治疗儿童Ph阳性急性淋巴细胞白血病的效果与安全性.方法 回顾性分析51例儿童Ph+急性淋巴细胞白血病患儿的临床资料,给予对照组患儿CCLG-ALL2008化疗方案,治疗组患儿采用伊马替尼联合CCLG-ALL2008化疗方案,比较2组患儿的治疗疗效及不良反应,同时分析影响患儿诱导缓解后5年生存率的主要因素.结果 对照组患儿诱导治疗后完全缓解(CR)率为92.86％,治疗组患儿CR率为95.65％;治疗组患儿1年无事件生存率(EFS)为91.30％,3年无事件生存率(EFS)为69.57％,5年无事件生存率(EFS)为65.22％.与对照组比较,治疗组未增加化疗相关毒性.导致患儿诱导缓解后5年生存率降低的独立风险因素为:患儿对糖皮质激素诱导不敏感、治疗依从性差、治疗中复发以及首次诱导缓解失败.结论 GGLG-08方案与伊马替尼联合使用治疗儿童Ph阳性急性淋巴细胞白血病的临床疗效明显,安全性良好.     

Treatment of Testicular Relapse of B-cell Acute Lymphoblastic Leukemia With CD19-specific Chimeric Antigen Receptor T Cells

BackgroundIrradiation has been a standard treatment for testicular relapse but is associated with severe hypogonadism. Because CD19-specific chimeric antigen receptor T (CAR-T) cells can eradicate leukemic blasts in cerebrospinal fluid, a pharmacologic sanctuary site, we tested the efficacy of this therapy in 7 boys with isolated testicular relapse of B-cell acute lymphoblastic leukemia.Patients and MethodsCD19-specific CAR-T cells were generated with the use of autologous T cells transduced with a lentiviral vector to express a CAR molecule containing anti-CD19 scFv derived from the HI19α murine monoclonal antibody, human CD8α hinge, and human 4-1BB (CD137) and CD3ζ costimulatory signaling transmembrane domains. After the conditioning regimen, which consisted of intravenous fludarabine and intravenous cyclophosphamide, 7 patients with a median age of 9 years (range, 2-10 years) with isolated testicular relapse received a single infusion of CD19 CAR-T cells at a total dose of 5 × 10⁶ all T cells per kilogram.ResultsAll 7 patients achieved complete remission with normal testes. Six patients remained in second remission for 5 to 23 months (median, 14 months), and 1 patient subsequently relapsed in the bone marrow. The probability of event-free survival for all patients at 12 months of follow-up was 83.3% ± 15.2% (standard error). The treatment was well-tolerated, with grade 1 cytokine-release syndrome developing in 5 patients.ConclusionThese results suggest that CAR-T cell therapy is a treatment option for patients with testicular relapse.     

Survival Time and Season-of-Treatment Initiation in Children with Acute Lymphoblastic Leukemia

We examined survival in childhood acute lymphoblastic leukemia (ALL) as a function of season-of-treatment initiation. Survival for 1797 children aged 15 and under from the Surveillance, Epidemiology, and End Results (SEER) cancer registry, diagnosed and treated from 1973-1986 was obtained. There was no significant seasonal pattern for survival by season-of-treatment initiation. Neither age, gender, nor treatment type served as effect modifiers or confounders in this relationship. Female gender, age between one and ten years, and certain broad categories of treatment type were significant predictors of survival in separate univariate analyses, however. The nonsignificance of the results do not support the concept that season-of-treatment initiation is a prognostic factor in survival from ALL in children.     

大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的安全性观察

目的 观察大剂最甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)的毒副反应.方法 全组35例缓解期ALL患儿累计给予HD-MTX治疗210例次,治疗结束后观察并记录毒副反应的发生情况及处理措施.结果 HD-MTX常见的毒副反应为骨髓抑制、胃肠道反应、口腔黏膜溃疡、肝功能损害及肾功能损害等,多为轻度.全组毒副...