American Society of Clinical Oncology educational book / ASCO. American Society of Clinical Oncology. Meeting最新文献

At the time of writing, five anti-CD19 CAR T-cell products are approved by the U.S. Food and Drug Administration for seven different indications in lymphoid malignancies, including B-cell non-Hodgkin lymphoma, pediatric B-cell acute lymphoblastic leukemia, and multiple myeloma. CAR T cells for chronic lymphocytic leukemia, acute myeloid leukemia, and less common malignancies such as T-cell lymphomas and Hodgkin lymphoma are being tested in early-phase clinical trials worldwide. The purpose of this overview is to describe the current landscape of CAR T cells in hematologic malignancies, outline their outcomes and toxicities, and explain the outstanding questions that remain to be addressed.

Cancer immunotherapy tools include antibodies, vaccines, cytokines, oncolytic viruses, bispecific molecules, and cellular therapies. This review will focus on adoptive cellular therapy, which involves the isolation of a patient's own immune cells followed by their ex vivo expansion and reinfusion. The majority of adoptive cellular therapy strategies utilize T cells isolated from tumor or peripheral blood, but may utilize other immune cell subsets. T-cell therapies in the form of tumor-infiltrating lymphocytes, T-cell receptor T cells, and CAR T cells may act as "living drugs" as these infused cells expand, engraft, and persist in vivo, allowing adaptability over time and enabling durable remissions in subsets of patients. Adoptive cellular therapy has been less successful in the management of solid tumors because of poor homing, proliferation, and survival of transferred cells. Strategies are discussed, including expression of transgenes to address these hurdles. Additionally, advances in gene editing using CRISPR/Cas9 and similar technologies are described, which allow for clinically translatable gene-editing strategies to enhance the antitumor activity and to surmount the hostilities advanced by the host and the tumor. Finally, the common toxicities and approaches to mitigate these are reviewed.

Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPNs) are clonal diseases that differ in morphologic diagnostic criteria but share some common disease phenotypes that include cytopenias, propensity to acute myeloid leukemia evolution, and a substantially shortened patient survival. MDS/MPNs share many clinical and molecular features with MDS, including frequent mutations involving epigenetic modifier and/or spliceosome genes. Although the current 2016 World Health Organization classification incorporates some genetic features in its diagnostic criteria for MDS and MDS/MPNs, recent accumulation of data has underscored the importance of the mutation profiles on both disease classification and prognosis. Machine-learning algorithms have identified distinct molecular genetic signatures that help refine prognosis and notable associations of these genetic signatures with morphologic and clinical features. Combined geno-clinical models that incorporate mutation data seem to surpass the current prognostic schemes. Future MDS classification and prognostication schema will be based on the portfolio of genetic aberrations and traditional features, such as blast count and clinical factors. Arriving at these systems will require studies on large patient cohorts that incorporate advanced computational analysis. The current treatment algorithm in MDS is based on patient risk as derived from existing prognostic and disease classes. Luspatercept is newly approved for patients with MDS and ring sideroblasts who are transfusion dependent after erythropoietic-stimulating agent failure. Other agents that address red blood cell transfusion dependence in patients with lower-risk MDS and the failure of hypomethylating agents in higher-risk disease are in advanced testing. Finally, a plethora of novel targeted agents and immune checkpoint inhibitors are being evaluated in combination with a hypomethylating agent backbone to augment the depth and duration of response and, we hope, improve overall survival.

Avoidable differences in the care and outcomes of patients with cancer (i.e., cancer care disparities) emerge or worsen with discoveries of new, more effective approaches to cancer diagnosis and treatment. The rapidly expanding use of immunotherapy for many different cancers across the spectrum from late to early stages has, predictably, been followed by emerging evidence of disparities in access to these highly effective but expensive treatments. The danger that these new treatments will further widen preexisting cancer care and outcome disparities requires urgent corrective intervention. Using a multilevel etiologic framework that categorizes the targets of intervention at the individual, provider, health care system, and social policy levels, we discuss options for a comprehensive approach to prevent and, where necessary, eliminate disparities in access to the clinical trials that are defining the optimal use of immunotherapy for cancer, as well as its safe use in routine care among appropriately diverse populations. We make the case that, contrary to the traditional focus on the individual level in descriptive reports of health care disparities, there is sequentially greater leverage at the provider, health care system, and social policy levels to overcome the challenge of cancer care and outcomes disparities, including access to immunotherapy. We also cite examples of effective government-sponsored and policy-level interventions, such as the National Cancer Institute Minority-Underserved Community Oncology Research Program and the Affordable Care Act, that have expanded clinical trial access and access to high-quality cancer care in general.

Notable barriers exist in the delivery of equitable care for all patients with cancers. Social determinants of health at distal, intermediate, and proximal levels impact cancer care. Patient navigation is a patient-centered intervention that functions across these overlapping determinants to increase access to cancer services throughout the cancer care continuum. There is a need to standardize patient navigation training while remaining responsive to local contexts of care and a need to implement patient navigation programs with a health equity lens to address cancer care inequities.

Older adults comprise a considerable proportion of patients with cancer in the world. Across multiple cancer types, cancer treatment outcomes among older age groups are often inferior to those among younger adults. Cancer care for older individuals is complicated by the need to adapt treatment to baseline health, fitness, and frailty, all of which vary widely within this age group. Rates of social deprivation and socioeconomic disparities are also higher in older adults, with many living on reduced incomes, further compounding health inequality. It is important to recognize and avoid undertreatment and overtreatment of cancer in this age group; however, simply addressing this problem by mandating standard treatment of all would lead to harms resulting from treatment toxicity and futility. However, there is little high-quality evidence on which to base these decisions, because older adults are poorly represented in clinical trials. Clinicians must recognize that simple extrapolation of outcomes from younger age cohorts may not be appropriate because of variance in disease stage and biology, variation in fitness and treatment tolerance, and reduced life expectancy. Older patients may also have different life goals and priorities, with a greater focus on quality of life and less on length of life at any cost. Health care professionals struggle with treatment of older adults with cancer, with high rates of variability in practice between and within countries. This suggests that better national and international recommendations that more fully address the needs of this special patient population are required and that primary research focused on the older age group is urgently required to inform these guidelines.

Black men have a higher prevalence of and mortality rate from prostate cancer compared with White men and have been shown to present with more aggressive and later-stage disease. How prostate cancer treatment affects these racial disparities is still unclear. Several studies have shown that Black men who receive treatment have a more pronounced decrease in prostate cancer-specific death; however, there remains a large disparity in all-cause mortality. This disparity may be in part related to a higher risk of death resulting from comorbidities, given the higher rates of cardiovascular disease and diabetes in Black men, both of which are complicated by the use of androgen-deprivation therapy. To further understand these disparities, it is important that we analyze the racial differences in adverse event rates and severity. Increasing the percentage of Black men in clinical trials will improve the understanding of the biologic drivers of racial disparities in prostate cancer. To evaluate the potential differences in adverse event reporting and demonstrate the feasibility of enrolling equal numbers of Black and White men in trials, we performed a prospective, multicenter study of abiraterone plus prednisone with androgen-deprivation therapy in men with metastatic castration-resistant prostate cancer, stratified by race. Racial differences in prostate-specific antigen kinetics and toxicity profile were demonstrated. Higher rates and severity of adverse events related to adrenal hormone suppression, including hypertension, hypokalemia, and hypomagnesemia, were seen in the Black cohort, not previously reported. Increased enrollment of Black men in prostate cancer clinical trials is imperative to further understand the impact of race on clinical outcomes and treatment tolerability.

Advances in the treatment of brain tumors have led to an increase in the number of survivors of this disease. Consequently, the long-term complications associated with past and current treatments are becoming more apparent. Of relevance to patients who receive treatment of brain tumors are the potential neuroendocrine complications that develop either acutely or several years following treatment. Presentation may differ between adults and children (e.g., short stature or adult growth hormone deficiency) but in both settings can complicate treatment and impact quality of life. The risk for the development of these complications depends on the location of the tumor (proximity to the pituitary/hypothalamus) and/or the treatment delivered (chemotherapy/surgery/radiation). Given the potential overlap in symptoms attributable to the underlying brain tumor and neuroendocrine dysfunction, a high level of suspicion, appropriate investigation, and administration of treatment may reduce morbidity and mortality for patients with brain tumors experiencing neuroendocrine dysfunction.

Supportive care aims to prevent and manage adverse effects of cancer and its treatment across the entire disease continuum. Research and clinical experience in dedicated centers have demonstrated that early appropriate supportive care interventions improve symptoms, quality of life, and overall survival in a cost-effective manner. The challenge is to assess symptoms and needs with validated tools regularly and, ideally, between clinic appointments; electronic patient-reported outcome measures and dedicated easily accessible supportive care units can help. As management of certain problems improves, others come to the fore. Cancer-related fatigue and malnutrition are very frequent and need regular screening, assessment of treatable causes, and early intervention to improve. Pharmacologic agents and phytopharmaceuticals are of little use, but other interventions are valuable: physical exercise, counseling on fatigue, and cognitive behavioral therapy/mind-body interventions (e.g., for fatigue). Nutrition should be oral, rich in proteins, and accompanied by muscle training adapted to the patient's condition. Psychological and societal counseling is often useful; nausea or other problems such as gastrointestinal dysmotility or metabolic derangements must be tackled. Chemotherapy-induced peripheral neuropathy frequently worsens quality of life and has no established prevention strategy (notwithstanding current interest in cryotherapy and compression therapy) and thus requires careful assessment of patient predisposition to develop it with the consideration of feasible dose and treatment alternatives. When painful, duloxetine helps. Nonpharmacologic strategies, including acupuncture, physical exercise, cryotherapy/compression, and scrambler therapy, are promising but require large phase III trials to become the accepted standard. Personalization of chemotherapy, dependent on realistic goals, is key.

With the aging of the population, the number of older adults with hematologic malignancies is growing, and treatment paradigms for these patients are rapidly evolving. Use of allogeneic stem cell transplant has been expanding to include septuagenarians but remains a potentially morbid procedure, creating an opportunity for a geriatric-focused evaluation to improve assessment of the individual's risk in undergoing the procedure. Although age alone should not be the sole determinant for transplant eligibility, geriatric assessment often identifies vulnerabilities that are not captured in assessing performance status and comorbidities alone. Those vulnerabilities may be optimized in an approach employing three sequential steps: characterize resiliency, bolster resilience, and harmonize with patient goals. Data are emerging that show that this approach is associated with lower nonrelapse mortality, shorter length of stay, and better survival after transplant. In older adults with myeloma, treatment recommendations also aim to balance the expected efficacy and toxicity profile and incorporate the patient's goals and preferences. Assessment of frailty allows for more personalized estimates of risk of toxicity. Currently, the European Myeloma Network currently recommends using the International Myeloma Working Group frailty scale as a standard approach to defining frail or at-risk populations with myeloma. In addition to treatment selection, the care of older adults with myeloma must include consideration of other issues, including reducing early mortality with antibiotic prophylaxis, polypharmacy, depression, cognition, and falls. Overall, appreciation of the aging-associated vulnerabilities will allow for the ultimate personalized care and treatment of older adults with hematologic malignancies.