RESUMO
BACKGROUND: The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. METHODS: In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. RESULTS: Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09). CONCLUSIONS: Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.
Assuntos
Anticorpos Biespecíficos/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Inotuzumab Ozogamicina/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Inotuzumab Ozogamicina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Suspensão de Tratamento/estatística & dados numéricos , Adulto JovemRESUMO
Blinatumomab, a bispecific T-cell engager (BiTE) associated with improved survival in relapsed or refractory acute lymphoblastic leukemia (ALL), was recently approved for treatment of minimal residual disease (MRD). MRD is an important predictor of survival in ALL, and recent studies suggest that achievement of MRD-negativity with blinatumomab improves outcomes in patients with ALL. However, further research is needed to determine how to optimally incorporate blinatumomab, and other novel therapies, into current therapies for ALL.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Humanos , Neoplasia Residual/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Terapia de Salvação/métodos , Terapia de Salvação/mortalidadeRESUMO
The mechanisms through which immune responses are generated against solid cancers are well characterized and knowledge of the immune evasion pathways exploited by these malignancies has grown considerably. However, for hematological cancers, which develop and disseminate quite differently than solid tumors, the pathways that regulate immune activation or tolerance are less clear. Growing evidence suggests that, while numerous immune escape pathways are shared between hematological and solid malignancies, several unique pathways are exploited by leukemia and lymphoma. Below we discuss immune evasion mechanisms in leukemia and lymphoma, highlighting key differences from solid tumors. A more complete characterization of the mechanisms of immune tolerance in hematological malignancies is critical to inform the development of future immunotherapeutic approaches.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Evasão da Resposta Imune , Tolerância Imunológica , Imunoterapia/métodos , Leucemia/imunologia , Linfoma/imunologia , Animais , Células Apresentadoras de Antígenos/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Regulação da Expressão Gênica , Humanos , Leucemia/genética , Leucemia/patologia , Leucemia/terapia , Linfoma/genética , Linfoma/patologia , Linfoma/terapia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/imunologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Issue: Health care sharing ministries (HCSMs) are a form of health coverage in which members--who typically share a religious belief--make monthly payments to cover expenses of other members. HCSMs do not have to comply with the consumer protections of the Affordable Care Act and may provide value for some individuals, but pose risks for others. Although HCSMs are not insurance and do not guarantee payment of claims, their features closely mimic traditional insurance products, possibly confusing consumers. Because they are largely unregulated and provide limited benefits, HCSMs may be disproportionately attractive to healthy individuals, causing the broader insurance market to become smaller, sicker, and more expensive. Goal: To understand state regulator perspectives on regulation of HCSMs and the impact of these arrangements on consumers and markets. Methods: Analysis of state laws governing HCSMs in all states; interviews with officials in 13 states; and review of the membership requirements and benefits of five HCSMs. Findings and Conclusions: State regulators voiced concerns regarding the potential risks of HCSMs to consumers and their individual markets. However, in the absence of reliable data describing HCSM enrollment, regulators cannot adequately assess harm. Though limited resources and political constraints have made oversight difficult, all states, regardless of their regulatory approach to HCSMs, should obtain data to better understand the role of HCSMs in their markets.
Assuntos
Custo Compartilhado de Seguro , Fundos de Seguro/economia , Seleção Tendenciosa de Seguro , Seguro Saúde , Religião , Regulamentação Governamental , Trocas de Seguro de Saúde , Humanos , Benefícios do Seguro , Cobertura do Seguro , Marketing de Serviços de Saúde , Patient Protection and Affordable Care Act , Governo Estadual , Estados UnidosRESUMO
At the intersection between children and older adults, the care of adolescent and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) poses unique challenges and issues beyond those faced by other age groups. Although the survival of AYA patients is inferior to younger children, growing evidence suggests that AYA patients have improved outcomes, with disease-free survival rates of 60% to 70%, when treated with pediatric-based approaches. A holistic approach, incorporating a multidisciplinary team, is a key component of successful treatment of these AYA patients. With the appropriate support and management of toxicities during and following treatment, these regimens are well tolerated in the AYA population. Even with the significant progress that has been made during the last decade, patients with persistence of minimal residual disease (MRD) during intensive therapy still have a poor prognosis. With new insights into disease pathogenesis in AYA ALL and the availability of disease-specific kinase inhibitors and novel targeted antibodies, future studies will focus on individualized therapy to eradicate MRD and result in further improvements in survival. This case-based review will discuss the biology, pharmacology, and psychosocial aspects of AYA patients with ALL, highlighting our current approach to the management of these unique patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Transplante de Medula Óssea , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transplante de Células-Tronco , Adulto JovemRESUMO
Issue: Policymakers have sought to improve the shopping experience on the Affordable Care Act's marketplaces by offering decision support tools that help consumers better understand and compare their health plan options. Cost estimators are one such tool. They are designed to provide consumers a personalized estimate of the total cost--premium, minus subsidy, plus cost-sharing--of their coverage options. Cost estimators were available in most states by the start of the fourth open enrollment period. Goal: To understand the experiences of marketplaces that offer a total cost estimator and the interests and concerns of policymakers from states that are not using them. Methods: Structured interviews with marketplace officials, consumer enrollment assisters, technology vendors, and subject matter experts; analysis of the total cost estimators available on the marketplaces as of October 2016. Key findings and conclusions: Informants strongly supported marketplace adoption of a total cost estimator. Marketplaces that offer an estimator faced a range of design choices and varied significantly in their approaches to resolving them. Interviews suggested a clear need for additional consumer testing and data analysis of tool usage and for sustained outreach to enrollment assisters to encourage greater use of the estimators.
Assuntos
Comportamento do Consumidor/economia , Técnicas de Apoio para a Decisão , Financiamento Pessoal/economia , Trocas de Seguro de Saúde/economia , Seguro Saúde/economia , Navegação de Pacientes/economia , Custo Compartilhado de Seguro/economia , Custos e Análise de Custo , Tomada de Decisões , Humanos , Patient Protection and Affordable Care Act , Estados UnidosRESUMO
Issue: Nearly 12.7 million individuals signed up for coverage in the Affordable Care Act's (ACA) health insurance marketplaces during the third open enrollment period, and by the end of March there were 11.1 million consumers with active coverage. States that operate their own marketplaces posted a year-to-year enrollment gain of 8.8 percent. To maintain membership and attract new consumers, the state-based marketplaces must sponsor enrollment assistance programs and conduct consumer outreach. These marketplaces relied heavily on such efforts during the third enrollment period, despite declining funding. Goal: To learn which outreach strategies, assistance programs, and other factors marketplace officials viewed as having exerted the greatest influence on enrollment. Methods: Survey of officials representing each of the 17 state-based marketplaces (15 responses). Key findings and conclusions: The cost of coverage and low health insurance literacy pose significant barriers to enrollment for many consumers. Marketplaces sought to overcome them by encouraging consumers to obtain in-person enrollment assistance from ACA-created assistance programs and from insurance brokers, and by partnering with community organizations for outreach activities. Many marketplaces also enhanced their web portals to make them easier to navigate and to give consumers better tools with which to evaluate their coverage options.
Assuntos
Relações Comunidade-Instituição/economia , Comportamento do Consumidor , Trocas de Seguro de Saúde/estatística & dados numéricos , Cobertura do Seguro/estatística & dados numéricos , Seguro Saúde/estatística & dados numéricos , Navegação de Pacientes , Financiamento Governamental , Reforma dos Serviços de Saúde , Letramento em Saúde , Humanos , Navegação de Pacientes/economia , Patient Protection and Affordable Care Act , Governo Estadual , Estados UnidosAssuntos
Anticorpos Biespecíficos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticorpos Biespecíficos/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia de SalvaçãoRESUMO
PURPOSE OF REVIEW: The phosphoinositide 3-kinase (PI3K) pathway, with downstream targets including Akt and mammalian target of rapamycin, has been implicated in numerous human cancers, including hematologic malignancies and lymphomas. The development and refinement of PI3K inhibitors directed toward this pathway show promising clinical efficacy. This review will discuss the emerging body of clinical data in lymphoid malignancies and present future directions for research utilizing these inhibitors. RECENT FINDINGS: The PI3Kδ inhibitor, idelalisib, has been most widely studied in lymphoma, and has shown promising results both as a single agent and in combination with other therapies. IPI-145, a dual inhibitor of PI3Kδ and PI3Kγ, has also shown efficacy and several clinical trials are underway. Other PI3K inhibitors are in active development, with several entering early phase clinical trials. SUMMARY: The PI3K pathway appears to be important in lymphoma and targeting this pathway shows promising clinical efficacy.
Assuntos
Linfoma/tratamento farmacológico , Linfoma/enzimologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Humanos , Linfoma/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/químicaRESUMO
PURPOSE: Individuals diagnosed with cancer between 15 and 39 years (adolescent and young adult [AYA]) face unique vulnerability. Detail is lacking about care delivery for these patients, especially those with ALL. We address these knowledge gaps by describing AYA ALL care delivery details at National Cancer Institute Community Oncology Research Program (NCORP) (sub)affiliates by model of care. METHODS: Participating institutions treated at least one AYA with ALL from 2012 to 2016. Study-specific criteria were used to determine the number of unique clinical facilities (CFs) per NCORP and their model of care (adult/internal medicine [IM], pediatric, mixed [both]). Surveys completed by NCORPs for each CF by model of care captured size, resources, services, and communication. RESULTS: Among 84 participating CFs (adult/IM, n=47; pediatric, n=15; mixed, n=24), 34% treated 5-10 AYAs with ALL annually; adult/IM CFs more often treated <5 (adult/IM, 60%; pediatric, 40%; mixed, 29%). Referral decisions were commonly driven by an age/diagnosis combination (58%), with frequent ALL-specific age minimums (87%) or maximums (80%). Medical, navigational, and social work services were similar across models while psychology was available at more pediatric CFs (pediatric, 80%; adult/IM, 40%; mixed, 46%-54%). More pediatric or mixed CFs reported oncologists interacting with pediatric/adult counterparts via tumor boards (pediatric, 93%; adult/IM, 26%; mixed, 96%) or initiating contact (pediatric, 100%; adult/IM, 77%; mixed 96%); more pediatric CFs reported an affiliated counterpart (pediatric, 53%; adult, 19%). Most CFs reported no AYA-specific resources (79%) or meetings (83%-98%). CONCLUSION: System-level aspects of AYA ALL care delivery have not been examined previously. At NCORPs, these characteristics differ by models of care. Additional work is ongoing to investigate the impact of these facility-level factors on guideline-concordant care in this population. Together, these findings can inform a system-level intervention for diverse practice settings.
Assuntos
Neoplasias , Oncologistas , Humanos , Adolescente , Adulto Jovem , Criança , Neoplasias/epidemiologia , Neoplasias/terapia , Neoplasias/diagnóstico , Atenção à Saúde , Inquéritos e QuestionáriosRESUMO
Acute myeloid leukemia (AML) is a fatal disease characterized by the accumulation of undifferentiated myeloblasts, and agents that promote differentiation have been effective in this disease but are not curative. Dihydroorotate dehydrogenase inhibitors (DHODHi) have the ability to promote AML differentiation and target aberrant malignant myelopoiesis. We introduce HOSU-53, a DHODHi with significant monotherapy activity, which is further enhanced when combined with other standard-of-care therapeutics. We further discovered that DHODHi modulated surface expression of CD38 and CD47, prompting the evaluation of HOSU-53 combined with anti-CD38 and anti-CD47 therapies, where we identified a compelling curative potential in an aggressive AML model with CD47 targeting. Finally, we explored using plasma dihydroorotate (DHO) levels to monitor HOSU-53 safety and found that the level of DHO accumulation could predict HOSU-53 intolerability, suggesting the clinical use of plasma DHO to determine safe DHODHi doses. Collectively, our data support the clinical translation of HOSU-53 in AML, particularly to augment immune therapies. Potent DHODHi to date have been limited by their therapeutic index; however, we introduce pharmacodynamic monitoring to predict tolerability while preserving antitumor activity. We additionally suggest that DHODHi is effective at lower doses with select immune therapies, widening the therapeutic index.
Assuntos
Leucemia Mieloide Aguda , Pirimidinas , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Humanos , Pirimidinas/uso terapêutico , Camundongos , Animais , Di-Hidro-Orotato Desidrogenase , Imunoterapia/métodos , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , FemininoRESUMO
While the 2022 European LeukemiaNet (ELN) acute myeloid leukemia (AML) risk classification reliably predicts outcomes in younger patients treated with intensive chemotherapy, it is unclear whether it applies to adults ≥ 60 years treated with lower-intensity treatment (LIT). We aimed to test the prognostic impact of ELN risk in patients with newly diagnosed (ND) AML ≥ 60 years given LIT and to further refine risk stratification for these patients. A total of 595 patients were included: 11% had favorable-risk, 11% had intermediate-risk, and 78% had adverse-risk AML as defined by ELN. ELN risk was prognostic for overall survival (OS) (P<0.001) but did not stratify favorable-risk from intermediate-risk (P=0.71). Within adverse-risk AML, the impact of additional molecular abnormalities was further evaluated. Multivariable analysis was performed on a training set (N=316) and identified IDH2 mutation as an independent favorable prognostic factor, and KRAS, MLL2, and TP53 mutations as unfavorable (P<0.05). A "mutation-score" was calculated for each combination of these mutations, assigning adverse-risk patients into two risk groups: -1 to 0 points ("Beat-AML-intermediate") vs 1+ points ("Beat-AML-adverse"). In the final refined risk classification, the ELN favorable- and intermediate-risk groups were combined into a newly defined "Beat-AML-favorable-risk", in addition to mutation scoring within the ELN adverse-risk. This approach redefines risk for older ND AML and proposes refined Beat-AML-favorable- (22%), Beat-AML-intermediate- (41%), and Beat-AML-adverse-risk (37%) groups with improved discrimination for OS (2-year OS: 48% vs 33% vs 11%, respectively, P<0.001; C-index: 0.60 vs 0.55 for ELN), providing patients and providers additional information for treatment decision-making.
RESUMO
Despite improvements in survival among pediatric patients with acute lymphoblastic leukemia (ALL), survival outcomes for adolescents and young adults (AYAs) with ALL have lagged. The reasons for the inferior outcomes among AYAs are multifactorial, each presenting unique challenges and requiring novel solutions. First, adverse disease biology is more common among AYAs with ALL. Ongoing trials are investigating novel approaches to treatment, such as incorporating JAK inhibitors for Philadelphia chromosome-like ALL, menin inhibitors for KMT2A-rearranged ALL, and BCL2/BCLXL inhibition for T-cell ALL. Poorer adherence to therapy also impedes improvements in survival outcomes for AYAs with ALL, but early data suggest that technology, both for monitoring and interventions, may be useful in increasing adherence among this population. Finally, better access to clinical trials and collaboration between pediatric and adult centers is critical in advancing the care of AYAs with ALL. Significant improvements have been made over the past decade, but recognizing, understanding, and addressing each of these unique challenges provides hope that the outcomes for AYAs will continue to improve even further.
Assuntos
Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Humanos , Adulto Jovem , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
INTRODUCTION: Asparaginase is essential to chemotherapy regimens for acute lymphoblastic leukemia (ALL). Survival of patients with ALL has improved since incorporating asparaginase into chemotherapy backbones. Hispanic patients have a higher incidence of ALL than other ethnicities and suffer inferior outcomes. The inferior outcome of Hispanics is due to several factors, including the increased incidence of high-risk genetic subtypes and susceptibility to treatment-related toxicity. AREAS COVERED: We summarize the current knowledge of asparaginase-related toxicity by comparing their incidence between Hispanic and non-Hispanic patients. These toxicities include hypersensitivity, hepatotoxicity, pancreatitis, thrombosis, and hypertriglyceridemia. The PubMed database and Google Scholar were used to search for this review from October 2022 to June 2023. EXPERT OPINION: Except for hepatotoxicity and hypertriglyceridemia secondary to asparaginase-based treatments, which may develop more frequently among Hispanic patients with ALL, other toxicities were comparable between Hispanic and non-Hispanic patients. Nevertheless, studies with larger cohorts and more accurate capturing of Hispanic ethnicity should be conducted to fill the gaps in the current knowledge.
Assuntos
Antineoplásicos , Doença Hepática Induzida por Substâncias e Drogas , Hipertrigliceridemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Adulto , Asparaginase/efeitos adversos , Antineoplásicos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológicoRESUMO
A failed graft-versus-tumor (GVT) effect is a common mechanism of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Although targeting the PD-1/PD-L1 axis may restore GVT effects, PD-1 blockade exacerbates graft-versus-host disease (GVHD) in murine models, and severe GVHD can occur in patients treated with anti-PD-1 therapy after alloHCT. Therefore, we developed a prospective study to assess the safety and efficacy of pembrolizumab in patients relapsing after alloHCT. Eligible patients received pembrolizumab (200 mg every 3 weeks) for up to 2 years. Twelve patients were enrolled (8 patients with acute myeloid leukemia, 1 patient with myelodysplastic syndrome, 1 patient with classical Hodgkin lymphoma, and 2 patients with diffuse large B-cell lymphoma [DLBCL]). All participants received reduced-intensity preparative regimens with in vivo T-cell depletion. The median time from alloHCT to enrollment was 587 days (range, 101-4211). Three participants (25%) experienced grade 3 to 4 immune-related adverse events (irAE) (pneumonitis, 2 patients; hyperthyroidism, 1 patient), all occurring after 1 to 2 cycles, and resolving after pembrolizumab discontinuation and corticosteroid treatment. irAEs of any grade occurred in 5 patients (42%). No treatment-emergent GVHD was observed. Overall and complete response (CR) rates were 22% (2/9). Both patients achieving CRs had PD-L1 gene-amplified lymphomas and diffuse PD-L1 expression on pretreatment biopsies. An acquired EZH2 mutation was identified at relapse in a patient with DLBCL who achieved an initial CR to pembrolizumab, which was associated with downregulated HLA expression on malignant B cells, implicating EZH2 mutations as a potential immune escape mechanism after PD-1-blockade therapy. In conclusion, after alloHCT, treatment with pembrolizumab is feasible and associated with objective responses in relapsed lymphoid malignancies but can induce severe irAEs, requiring vigilant monitoring. This trial was registered at www.clinicaltrials.gov as #NCT02981914.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Humanos , Animais , Camundongos , Antígeno B7-H1 , Estudos Prospectivos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Recidiva , Doença de Hodgkin/etiologiaRESUMO
Adults compose nearly half of all patients diagnosed with acute lymphoblastic leukemia (ALL) and historically have had poor survival compared with pediatric patients. Recently approved therapies, such as monoclonal antibodies, CAR T-cell constructs, and next-generation tyrosine kinase inhibitors, have improved survival in relapsed and refractory ALL, and studies are now examining incorporating these treatments and others into the upfront setting. In adolescent and young adult patients, use of pediatric-based regimens has already improved survival compared with historical controls, and the addition of monoclonal antibodies, such as inotuzumab ozogamicin and blinatumomab, may further enhance this survival benefit. In older adults, approaches have centered on minimizing conventional chemotherapy to decrease toxicity by incorporating monoclonal antibodies and other novel therapies to increase efficacy. With the addition of tyrosine kinase inhibitors to chemotherapy for patients with Philadelphia chromosome-positive ALL, survival of this once poor-prognosis ALL subtype now approaches or exceeds outcomes of other subtypes of adult ALL. Further refinements in the backbone treatment regimen and optimal consolidation approaches will likely improve survival further. Although allogeneic hematopoietic stem cell transplant was previously routinely used as consolidation for adults with ALL, incorporation of measurable residual disease and other risk stratification strategies has enabled better identification of patients who will benefit from allogeneic hematopoietic stem cell transplant. Ongoing clinical trials investigating these approaches will continue the evolution of treatment approaches for adults with ALL, with further improvement in outcomes anticipated.
Assuntos
Antineoplásicos Imunológicos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Criança , Humanos , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto JovemRESUMO
Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase, and the Cochrane Library for prospective interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥18 years. Risk of bias was assessed with a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean complete remission (CR) rate was 81% and the measurable residual disease (MRD)-negative remission rate was 81% at 4 weeks after CAR-T infusion. With median follow-up across studies of 24 months, the cumulative 12-month probabilities of progression-free survival (PFS) and overall survival (OS) were 37% (95% CI, 26-48) and 57% (95% CI, 49-65), respectively. Relapse occurred in 40.3% of cases; target antigen was retained in 73.2% of relapses. Across studies, any grade of cytokine release syndrome (CRS) occurred in 82% of patients (95% CI, 61-95) and grade 3 or higher CRS in 27% (95% CI, 18-36). Neurotoxicity of any grade occurred in 34% of patients (95% CI, 24-47) and grade 3 or higher in 14% (95% CI, 1-25). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.
Assuntos
Linfoma de Burkitt , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Doença Aguda , Adulto , Antígenos CD19 , Terapia Baseada em Transplante de Células e Tecidos , Criança , Síndrome da Liberação de Citocina , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Prospectivos , RecidivaRESUMO
Safety and efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) consolidation after blinatumomab is largely undetermined. To address this issue, we assembled multi-center data of relapsed refractory (RR) acute lymphocytic leukemia (ALL) patients who received alloHCT after blinatumomab. From December 2014 to May 2019, 223 patients who received blinatumomab for RR ALL outside clinical trials were identified. Among them, 106 (47%) patients transplanted post blinatumomab were evaluated for response and toxicity. Ninety-two (87%) patients received alloHCT after achieving CR, while remaining received subsequent salvage prior to undergoing alloHCT. Progression free survival (PFS) and overall survival (OS) at 2 years post alloHCT was 48% (95% CI: 36-59%) and 58% (95% CI: 45-69%), respectively. The cumulative incidence of GIII-IV aGVHD at 3 months was 9.9% (95% CI: 5.0-16.6%). Similarly, cumulative incidence of moderate to severe cGVHD at 2 years was 34.4% (95% CI: 23.7-45.3%). The overall survival at 2 years was not significantly different in patient who achieved CR with MRD negative (68.4% [95% CI: 28.5-89.1%]) compared to CR with MRD positive (63.4% [95% CI: 47.8-75.4%]) prior to alloHCT (p = 0.8). Our real-world analysis suggests that alloHCT is feasible and effective post blinatumomab in patients with RR ALL.
Assuntos
Anticorpos Biespecíficos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anticorpos Biespecíficos/uso terapêutico , Linfócitos B , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapiaRESUMO
Recent approval of several novel agents has dramatically improved outcomes for patients with relapsed and refractory (R/R) B-cell acute lymphoblastic leukemia. Blinatumomab, a bi-specific T-cell engager targeted to CD3 and CD19, inotuzumab ozogamicin (InO), an antibody-drug conjugate to CD22, and tisagenlecleucel, a CD19 chimeric antigen receptor T-cell with a 4-1BB costimulatory domain, have all demonstrated impressive response rates in R/R B-ALL as compared to historic controls. However, important considerations when choosing among these novel agents include clinical features that may impact efficacy, such as relative disease burden, antigen expression, and T-cell function, as well as patient and disease characteristics that may contribute to risk of toxicity. In addition, suitability of the patient for hematopoietic stem cell transplant (HSCT) as well as patient preference must also be considered. This review will focus on factors to weigh when choosing an agent in the setting of R/R disease and important challenges moving forward.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia Adotiva/métodos , Inotuzumab Ozogamicina/uso terapêutico , Anticorpos Biespecíficos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Humanos , Inotuzumab Ozogamicina/farmacologia , RecidivaRESUMO
Incorporation of asparaginase (ASNase) and pegylated asparaginase (PEG-ASP) into pediatric-inspired regimens for adults with acute lymphoblastic leukemia (ALL) has led to improved treatment outcomes albeit with increased toxicities. This study compared the efficacy and safety of the Children's Oncology Group standard PEG-ASP (SD) dosing (>1000, median 2500 IU/m2/dose) in adult Philadelphia chromosome-negative ALL patients receiving multiagent chemotherapy vs reduced dose PEG-ASP (RED) (≤1000, median 500 IU/m2/dose) during induction. 51 patients were included, 26 in RED and 25 in SD (median age 49 vs 37 years, p = .027). Median day 7 ASNase activity level for RED was 0.16 IU/mL. All 11 patients who received PEG-ASP 1000 IU/m2 and 9/11 patients who received 500 IU/m2 achieved an ASNase level ≥0.1 IU/mL. Patients receiving RED experienced fewer total grade 3/4 toxicities during induction compared to SD (p = .02) while still attaining therapeutic ASNase levels. RED permits safer ASNase use in adults with ALL and should be tested in a larger cohort prospectively.