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Although chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with chemo-refractory B-cell lymphoma, a significant portion is refractory or relapse. Resistance is a major barrier to improving treatment efficacy and long-term survival in CAR T-cell therapy, and clinicians have very limited tools to discriminate a priori patients who will or will not respond to treatment. While CD19-negative relapses due to loss of target antigen is well described, it accounts for only about 30% of cases with treatment failure. Recent efforts have shed light on mechanisms of CD19-positive relapse due to tumor intrinsic resistance, T-cell quality/manufacturing, or CAR T-cell exhaustion mediated by hostile tumor microenvironment. Here, we review the latest updates of preclinical and clinical trials to investigate the mechanisms of resistance and relapse post CAR T-cell therapy in B cell lymphoma and discuss novel treatment strategies to overcome resistance as well as advances that are useful for a CAR T therapist to optimize and personalize CAR T-cell therapy.
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Linfoma de Células B , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/genética , Receptores de Antígenos de Linfocitos T/genética , Antígenos CD19 , Linfoma de Células B/terapia , Recurrencia , Tratamiento Basado en Trasplante de Células y Tejidos , Microambiente TumoralRESUMEN
BACKGROUND: Patients with multiple myeloma and high serum levels of circulating free light chains (FLC) have increased risk of acute kidney injury (AKI) secondary to cast nephropathy and is associated with poor survival. Despite removal of FLC by medium cutoff (MCO) dialyzer, the role of MCO hemodialysis (HD) in the treatment of cast nephropathy and its clinical benefits remain unknown. METHODS: A systematic review was conducted to establish the effectiveness of MCO dialyzer and clinical outcomes, compared to other forms of dialyzers in the removal of FLC, in myeloma patients with AKI. The primary outcome was effectiveness of MCO-HD in reducing serum FLC. The secondary outcomes were HD independence, estimated glomerular filtrate rate, mortality rates, length of hospitalization, rebound of serum FLC before the next dialysis, removal of other molecules during dialysis, and adverse events. RESULTS: We identified three case series, with a total of 17 patients. There were no randomized controlled trials (RCTs) or cohort studies. These case series showed that MCO dialyzer was effective in the removal of FLC and led to a reduction in FLC concentration post-dialysis. The majority of the case series did not have comparator arm and renal and/or other clinical outcomes. CONCLUSION: MCO dialyzer appeared to be effective in the removal of FLC based on the existing limited data. However, more data, particularly large-scale RCTs, are needed to assess the use of MCO dialyzer in reducing serum FLC and its effect on clinical outcomes in patients with multiple myeloma and AKI.
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Lesión Renal Aguda , Mieloma Múltiple , Humanos , Diálisis Renal/efectos adversos , Mieloma Múltiple/complicaciones , Mieloma Múltiple/terapia , Cadenas Ligeras de InmunoglobulinaRESUMEN
Site-specific modification of thiol-containing biomolecules has been recognized as a versatile and powerful strategy for probing our biological systems and discovering novel therapeutics. The addition of lipophilic silicon moiety opens up new avenues for multi-disciplinary research with broad applications in both the medicinal and material sciences. However, adhering to the strict biocompatibility requirements, and achieving the introduction of labile silicon handle and high chemo-selectivity have been formidable. In this paper, we report silicon-based conjugating reagents including ß-trialkylsilyl and silyl ether-tethered alkynones that selectively react with thiols under physiological conditions. The pH-neutral, metal-free and additive-free reaction yields stable products with broad substrate compatibility and full retention of silicon handles in most cases. Besides simple aliphatic and aromatic thiols, this approach is applicable in the labeling of thiols present in proteins, sugars and payloads, thereby expanding the toolbox of thiol conjugation.
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OBJECTIVES: Pregnancy-associated venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is associated with increased risk of maternal mortality and morbidity. This study aimed to assess potential risk factors for pregnancy-associated VTE. METHODS: In this case-control study, women with pregnancy-associated VTE were identified via International Classification of Diseases codes and included if they had been objectively diagnosed with VTE during pregnancy or within six weeks postpartum, from 2004 to 2016, at KK Women's and Children's Hospital or Singapore General Hospital in Singapore. Controls, i.e. pregnant women without VTE, were selected from a prospective longitudinal study. The odds ratio (OR) for VTE was computed for a range of maternal and obstetric factors. RESULTS AND CONCLUSIONS: From 2004 to 2016, 89 cases of pregnancy-associated VTE and 926 controls were identifed and analysed using logistic regression. The most significant risk factors for pregnancy-associated VTE were smoking (OR 5.44, p=0.0002) and preterm delivery (OR 5.06, p=0.023). Malay race, multiparity, non-O blood group and caesarean section, were also identified to be of higher risk. These risk factors should be useful in the development of thromboprophylaxis strategies for pregnancy and the postpartum period, especially in Singapore.
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Complicaciones Cardiovasculares del Embarazo/epidemiología , Tromboembolia Venosa/epidemiología , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Factores de Riesgo , Singapur/epidemiología , Adulto JovenRESUMEN
ABSTRACT: The identification and targeting of B-cell maturation antigen (BCMA) through immunotherapeutic strategies such as antibody-drug conjugates, chimeric antigen receptor T cells, and T-cell engagers have revolutionized the care of patients with multiple myeloma (MM). These treatment modalities have improved the survival outcomes of patients with relapsed and/or refractory MM compared with previously established strategies and are moving into earlier lines of therapy. Despite their efficacy, the majority of patients eventually relapse, necessitating additional therapeutic targets for salvage. G-protein-coupled receptor class 5 member D, Fc receptor-homolog 5, and SLAMF7 are some examples of novel targets in development. This expanding armamentarium of immunotherapeutic agents will be crucial to address the unmet need for relapses after BCMA-targeting therapies, particularly antigen-negative relapses. The utilization of sequential T-cell redirective therapies including agents targeting different tumor-associated antigens and combination therapies appears feasible, paving the way for effective chemotherapy-free regimes. Deliberate consideration of treatment timing, preserving T-cell health, overcoming antigenic loss, and comprehension of the complex tumor microenvironment would be key to maximizing therapeutic benefits and minimizing adverse effects. This review summarizes novel targets in development for myeloma beyond BCMA, presenting pivotal safety and efficacy data derived from clinical trials when available and the considerations vital for navigating this expanding landscape of immunotherapeutic options.
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Antígeno de Maduración de Linfocitos B , Mieloma Múltiple , Mieloma Múltiple/terapia , Mieloma Múltiple/inmunología , Humanos , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Antígeno de Maduración de Linfocitos B/inmunología , Inmunoterapia/métodos , Terapia Molecular Dirigida , Linfocitos T/inmunología , Linfocitos T/metabolismo , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/antagonistas & inhibidores , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismoRESUMEN
BACKGROUND: The incidence of mismatch repair deficiency in colorectal cancer (CRC) in young people remains unknown in Asians. The present study assessed the clinicopathological features and efficacy of immunohistochemistry screening for Lynch syndrome in young Asian CRC patients. MATERIAL AND METHODS: This was a retrospective review conducted in Singapore General Hospital between January 2006 and December 2010 of 240 unrelated patients under the age of 50. All patients had immunohistochemical (IHC) staining for mismatch repair proteins in resected CRC specimen data retrieved from a prospective computerized database. RESULTS: A total of 21 % (n = 51) of the patients had abnormal IHC staining. Loss of staining for MLH1, MSH2, MSH6, and PMS2 proteins was observed in 10, 4, 6, and 13 % of tumors, respectively. Of the 22 patients who had abnormal staining of MLH1, 13 had concomitant abnormal staining for PMS2. One tumor specimen had abnormal staining in all four proteins. If the Amsterdam criteria alone were to be used, 86 % (n = 44) of the cohort would have not been detected for mismatch repair gene defects. CONCLUSIONS: The overall burden of germline mismatch repair deficiency in the Singapore population may be as high as 21 %. The Amsterdam criteria alone are inadequate to detect Lynch syndrome patients. The use of IHC staining of at least four mismatch repair proteins is a useful screening strategy for Lynch syndrome diagnosis. Routine screening of mismatch repair deficiency may be recommended for all young Asian CRC patients.
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Biomarcadores de Tumor/deficiencia , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Enzimas Reparadoras del ADN/deficiencia , Detección Precoz del Cáncer/métodos , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Adenosina Trifosfatasas/deficiencia , Adulto , Factores de Edad , Pueblo Asiatico , Neoplasias Colorrectales Hereditarias sin Poliposis/enzimología , Neoplasias Colorrectales Hereditarias sin Poliposis/etnología , Proteínas de Unión al ADN/deficiencia , Femenino , Humanos , Inmunohistoquímica , Modelos Logísticos , Masculino , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto , Homólogo 1 de la Proteína MutL , Proteína 2 Homóloga a MutS/deficiencia , Proteínas Nucleares/deficiencia , Estudios Retrospectivos , SingapurRESUMEN
PURPOSE: Treatment options for myeloma and indolent lymphoma are increasing exponentially, with distinct efficacy, side effects, and cost. We aim to determine the factors influencing patient and caregiver treatment preferences. METHODS: Patients and caregivers of patients with myeloma and indolent lymphoma were recruited from two cancer centers in Singapore. Preferences were elicited using a discrete choice experiment. Attributes and levels were selected based on a previous qualitative study. The relative preference for levels within each attribute (part worth utility values) and the extent to which an attribute would influence decision making (relative importance) were calculated. Patient and caregiver participation in the treatment plan selection process were assessed using the Control Preference Scale. RESULTS: One hundred ninety-nine patients and 169 caregivers were recruited. Patients placed the highest importance on out-of-pocket costs (relative importance = 35%), followed by efficacy (25%), persistent side effects (19%), administration route (8%), treatment duration (7%), and short-term side effects (5%). Caregivers ranked efficacy (27%) as the most important attribute, over out-of-pocket costs (24%). Most patients preferred a collaborative role in the shared decision-making process, while similar proportions of caregivers favored active and collaborative roles. CONCLUSION: Our study demonstrates that both patients and caregivers consider cost seriously when making treatment decisions. Furthermore, as patient and caregiver preferences may differ, there are implications for treatment selection and counseling, especially in cultures where caregivers have more prominent roles in treatment planning.
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Linfoma , Mieloma Múltiple , Humanos , Mieloma Múltiple/terapia , Cuidadores/psicología , Gastos en Salud , Linfoma/terapia , SingapurRESUMEN
AL amyloidosis is the most common form of systemic amyloidosis. However, the non-specific nature of presenting symptoms requires the need for a heightened clinical suspicion to detect unexplained manifestations in the appropriate clinical setting. Early detection and treatment are crucial as the degree of cardiac involvement emerges as a primary prognostic predictor of survival in a patient with AL amyloidosis. Following the diagnosis of AL amyloidosis with appropriate tissue biopsies, prompt treatment with a bortezomib, cyclophosphamide and dexamethasone-based first-line induction with or without daratumumab should be initiated. The goal of treatment is to achieve the best haematologic response possible, ideally with involved free light chain <20 mg/L, as it offers the best chance of organ function improvement. Treatment should be changed if patients do not achieve a partial response within 2 cycles of treatment or very good partial response after 4 cycles or after autologous stem cell transplant, as achievement of profound and prolonged clonal responses translates to better organ response and long-term outcomes. Early involvement of multidisciplinary subspecialists such as renal physicians, cardiologists, neurologists, and gastroenterologists for optimal maintenance and support of involved organs is recommended for optimal management of patients with AL amyloidosis.
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Dexametasona , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Dexametasona/uso terapéutico , Dexametasona/administración & dosificación , Singapur , Bortezomib/uso terapéutico , Bortezomib/administración & dosificación , Ciclofosfamida/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Consenso , Anticuerpos Monoclonales/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células MadreRESUMEN
Recent advances in treatment modalities have led to improved survival in patients with multiple myeloma (MM). However, despite these, MM remains an incurable disease. Many MM patients relapse through and become refractory to current treatment strategies or are intolerant due to toxicities arising from therapy. As such, novel strategies addressing new targets are crucial in improving care for MM patients. BCMA has emerged as a rationale therapeutic target for treatment of MM as it is preferentially expressed in mature B-lymphocytes and plasma cells with the overexpression and activation of BCMA via its ligands associated with the disease progression in multiple myeloma. Given the high expression of BCMA in malignant Plasma cells compared to those from normal healthy volunteers, targeting BCMA should reduce risks of on-target off-tumor toxicities. The main BCMA-targeting approaches currently used for treatment of MM include: 1) chimeric antigen receptor (CAR) T-cell therapy; 2) bi- and multi- specific antibodies; and 3) monoclonal antibodies and their drug conjugates. This review will outline these therapeutic agents and present their emerging clinical data.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno de Maduración de Linfocitos B/antagonistas & inhibidores , Inmunoterapia Adoptiva , Mieloma Múltiple/terapia , Células Plasmáticas/efectos de los fármacos , Linfocitos T/trasplante , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antígeno de Maduración de Linfocitos B/metabolismo , Quimioterapia de Consolidación , Humanos , Inmunoterapia Adoptiva/efectos adversos , Terapia Molecular Dirigida , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/inmunología , Mieloma Múltiple/metabolismo , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.1% compared to 14.6% (P = 0.032) in those who did not. However, neither concomitant CNS-systemic relapse rates, systemic relapse rates, nor three-year PFS and OS were significantly different between treatment groups in multivariable analysis. Among propensity score-matched patients (N = 102), HDMTX was also associated with significantly lower isolated CNS relapse rates (HR 0.06, 95% CI 0.004-0.946, P = 0.046). HDMTX was well tolerated with manageable toxicities when given at a dose of 3 g/m2 by day 3 of RCHOP chemotherapy. Using propensity score matching and multivariable regression to yield treatment groups with well-balanced covariates, we showed that prophylactic HDMTX improved isolated CNS relapse rates but did not decrease concomitant CNS-systemic relapse rates, systemic relapse rates, or improve survival outcomes.
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Antimetabolitos Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/prevención & control , Neoplasias del Sistema Nervioso Central/secundario , Linfoma de Células B Grandes Difuso/prevención & control , Metotrexato/uso terapéutico , Recurrencia Local de Neoplasia/prevención & control , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
While the outcome of patients with multiple myeloma has significantly improved over the last two decades, the disease remains incurable for the majority of patients. With the advent of novel agents, there has been a shift towards prolonged therapy as opposed to fixed-duration therapy, aimed at improving progression-free survival and overall survival. Evidence favoring continuous therapy has emerged over the last 2 decades and in the context of maintenance after proteasome inhibitor plus immunomodulatory drug induction followed by high dose melphalan and stem cell transplantation, this leads to >80% overall survival at 5 years. Maintenance therapy specifically has been demonstrated to correlate with increasing depth of disease response with a significant proportion of patients who remain minimal residual disease positive at the end of induction therapy achieving minimal residual disease negativity with maintenance therapy both in clinical trials and selected real world populations. As the survival improves, it is crucial to identify patients who are projected to have better survival and spare them toxicities arising from indefinite maintenance therapy. The role of minimal residual disease in this context is being investigated in numerous clinical trials and in the next few years the goal should be to use this in a rational way to achieve the ability to identify patients who would require continuation or escalation of therapy to improve their projected survival as well as to identify the group of patients in whom maintenance therapy could perhaps be time-limited without compromising their survival. Here we review the evidence for maintenance therapy from the key trials in the past years, present an overview of the current landscape and our perspective of maintenance therapy in the future.
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Antineoplásicos/uso terapéutico , Quimioterapia de Mantención , Mieloma Múltiple/tratamiento farmacológico , Antineoplásicos/efectos adversos , Humanos , Quimioterapia de Mantención/efectos adversos , Quimioterapia de Mantención/mortalidad , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Neoplasia Residual , Factores de Tiempo , Resultado del TratamientoRESUMEN
INTRODUCTION: The number of treatment options for myeloma and indolent lymphoma are expanding at an exponential rate, with few direct head-to-head comparisons on which to base efficacy measures. We sought to understand how patients, their caregivers and physicians weigh treatment characteristics in order to come to a decision on which treatment option to pursue. METHODS: Patients, their caregivers and physicians were recruited and interviewed until data saturation was reached. A qualitative, thematic analysis was done to identify themes important to each stakeholder. RESULTS: We found that, while all three groups valued efficacy the most, the consideration of other secondary characteristics of the treatment, such as cost, toxicity and logistical issues all differed subtly between the different groups. Patients valued minimising cost and toxicity, even at small trade-offs in efficacy. Caregivers and physicians valued efficacy foremost. CONCLUSION: Acknowledging and managing these differences is paramount because they influence shared decision-making and may affect patient outcomes in the short term, as well as their more general well-being in the long term.
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INTRODUCTION: Communication between patients and physicians is crucial in the disclosure of cancer diagnosis. Although westernisation of Asian societies has resulted in increased awareness of patient autonomy, the family continues to play an important influencing role in the disclosure process. Therefore, in this study, we aimed to characterise the experience of physicians with the disclosure of cancer diagnosis in a westernised Asian population. METHODS: Oncologists at a tertiary hospital were approached to participate in this study. Information pertaining to the extent and approach to disclosure was collated. Logistic regression analysis was performed to characterise factors pertaining to the willingness of physicians to fully disclose a diagnosis of cancer. RESULTS: In all, 25 oncologists (mean age 38 years; 72% men) responded to the survey. A majority of oncologists disclosed a cancer diagnosis directly to the patient over the first few visits. The main reason behind partial or non-disclosure was family objection. Ordinal logistic regression analysis showed that family resistance was the only significant predictor of reluctance to disclose a cancer diagnosis (p = 0.01). CONCLUSION: In this pilot study, contrary to previous reports, we found that oncologists were more likely to disclose a diagnosis of cancer to the patient first, that they do not accede fully to the family's request for non-disclosure and that family resistance was the only significant predictor of reluctance to disclose a diagnosis of cancer.