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BACKGROUND: Whole genome sequencing (WGS) has transformative potential for blood cancer management, but reimbursement is hindered by uncertain benefits relative to added costs. This study employed scenario planning and multi-criteria decision analysis (MCDA) to evaluate stakeholders' preferences for alternative reimbursement pathways, informing future health technology assessment (HTA) submission of WGS in blood cancer. METHODS: Key factors influencing WGS reimbursement in blood cancers were identified through a literature search. Hypothetical scenarios describing various evidential characteristics of WGS for HTA were developed using the morphological approach. An online survey, incorporating MCDA weights, was designed to gather stakeholder preferences (consumers/patients, clinicians/health professionals, industry representatives, health economists, and HTA committee members) for these scenarios. The survey assessed participants' approval of WGS reimbursement for each scenario, and scenario preferences were determined using the geometric mean method, applying an algorithm to improve reliability and precision by addressing inconsistent responses. RESULTS: Nineteen participants provided complete survey responses, primarily clinicians or health professionals (n = 6; 32â¯%), consumers/patients and industry representatives (both at n = 5; 26â¯%). "Clinical impact of WGS results on patient care" was the most critical criterion (criteria weight of 0.25), followed by "diagnostic accuracy of WGS" (0.21), "cost-effectiveness of WGS" (0.19), "availability of reimbursed treatment after WGS" (0.16), and "eligibility criteria for reimbursed treatment based on actionable WGS results" and "cost comparison of WGS" (both at 0.09). Participants preferred a scenario with substantial clinical evidence, high access to reimbursed targeted treatment, cost-effectiveness below $50,000 per quality-adjusted life year (QALY) gained, and affordability relative to standard molecular tests. Reimbursement was initially opposed until criteria such as equal cost to standard tests and better treatment accessibility were met. CONCLUSION: Payers commonly emphasize acceptable cost-effectiveness, but strong clinical evidence for many variants and comparable costs to standard tests are likely to drive positive reimbursement decisions for WGS.
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Whole genome and whole transcriptome sequencing (WGTS) can accurately distinguish B-cell acute lymphoblastic leukemia (B-ALL) genomic subtypes. However, whether this is economically viable remains unclear. This study compared the direct costs and molecular subtype classification yield using different testing strategies for WGTS in adolescent and young adult/adult patients with B-ALL. These approaches were: (1) combined BCR::ABL1 by fluorescence in situ hybridization (FISH) + WGTS for all patients; and (2) sequential BCR::ABL1 FISH + WGTS contingent on initial BCR::ABL1 FISH test outcome. The cost of routine diagnostic testing was estimated using Medicare or hospital fees, and the additional cost of WGTS was evaluated from the health care provider perspective using time-driven activity-based costing with resource identification elicited from experts. Molecular subtype classification yield data were derived from literature sources. Parameter uncertainty was assessed through deterministic sensitivity analysis; additional scenario analyses were performed. The total per patient cost of WGTS was $4319 (all costs reported in US dollars); consumables accounted for 74% of the overall cost, primarily driven by sequencing-related consumables. The incremental cost per additional patient categorized into molecular subtype was $8498 for combined BCR::ABL1 FISH + WGTS for all patients and $5656 for initial BCR::ABL1 FISH + WGTS for select patients compared with routine diagnostic testing. A reduction in the consumable costs of WGTS or an increase in the yield of molecular subtype classification is favorable.
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Secuenciación Completa del Genoma , Humanos , Secuenciación Completa del Genoma/economía , Secuenciación Completa del Genoma/métodos , Adolescente , Adulto , Hibridación Fluorescente in Situ/economía , Hibridación Fluorescente in Situ/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/economía , Proteínas de Fusión bcr-abl/genética , Transcriptoma , Adulto Joven , Técnicas de Diagnóstico Molecular/economía , Técnicas de Diagnóstico Molecular/métodos , Masculino , Pruebas Diagnósticas de Rutina/economía , Pruebas Diagnósticas de Rutina/métodos , Femenino , Análisis Costo-BeneficioRESUMEN
In the phase-2 clinical trial (AIM) of venetoclax-ibrutinib, 24 patients with mantle cell lymphoma (MCL; 23 with relapsed/refractory [R/R] disease) received ibrutinib 560mg and venetoclax 400mg both once daily. High complete remission (CR) and measurable residual disease negative (MRD-negative) CR rates were previously reported. With median survivor follow-up now exceeding 7 years, we report long-term results. Treatment was initially continuous, with elective treatment interruption (ETI) allowed after protocol amendment for patients in MRD-negative CR. For R/R MCL, the estimated 7-year progression-free survival (PFS) was 30% [95%CI: 14-49] (median 28 months [95%CI: 13-82]) and overall survival was 43% [95%CI: 23-62] (median 32 months [95%CI: 15-NE]). Eight patients in MRD-negative CR entered ETI for a median of 58 months (95%CI, 37-79), with four experiencing disease recurrence. Two of 3 re-attained CR on retreatment. Time-to-treatment-failure (TTF), which excluded progression in ETI for those reattaining response, was 39% overall and 68% at 7-years for responders. Beyond 56 weeks ï³Grade 3 and serious adverse events were uncommon. Newly emergent or increasing cardiovascular toxicity were not observed beyond 56 weeks. We demonstrate long-term durable responses and acceptable toxicity profile of venetoclax-ibrutinib in R/R MCL and show feasibility of treatment interruption while maintaining ongoing disease control. (NCT02471391).
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External quality assessment programs (EQAP) for molecular haematology generally only assess the analytical phase of laboratory testing or provide limited evaluation of post-analytical components. We incorporated comprehensive post-analytical evaluation into an existing national inter-laboratory sample exchange program for molecular haematology due to the increasing complexity of diagnostic molecular testing and interpretation. We report key findings from four years of longitudinal data using this approach. Eighteen participating laboratories enrolled in an annual reciprocal sample exchange program from 2019-2022, which covered conventional and next-generation sequencing (NGS) assays. Participants submitted results on their laboratory information system-generated reports which then underwent central review. Reports were assessed according to consensus values and relevant national and international reporting standards and guidelines. A total of 680 reports were received. Laboratories had high concordance in the analytical phase of testing, with incorrect variant detection observed in a total of six of 680 (0.9%) reports. In contrast, post-analytical concordance was much lower, with at least one discordance observed in 28.9-57.6% of all conventional reports and 33.3-100% NGS reports. The most frequent post-analytical discordances were: (1) not including key technical information on reports (total 41.9% conventional, 47.2% NGS); (2) not using standard gene and variant nomenclature (total 28.2% conventional, 25.6% NGS). NGS reports also demonstrated discrepancies in variant classification (total 20.4%) and interpretation (total 10.2%). The rate of discrepancies generally improved year-on-year. Inter-laboratory concordance for molecular haematology testing is high in the analytical phase, however opportunities exist for improvement in the post-analytical phase. Given that result interpretation is crucial for clinical decision-making and that molecular testing is a complex and evolving field, we suggest that EQAPs should comprehensively evaluate both analytical and post-analytical components of laboratory performance in order to harmonise reporting and to support the accurate interpretation of molecular haematology tests.
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Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Laboratorios Clínicos , Hematología/normas , Garantía de la Calidad de Atención de Salud , Técnicas de Diagnóstico MolecularRESUMEN
ABSTRACT: CD19-directed chimeric antigen receptor T cells (CAR-T) achieve high response rates in patients with relapsed/refractory mantle cell lymphoma (MCL). However, their use is associated with significant toxicity, relapse concern, and unclear broad tractability. Preclinical and clinical data support a beneficial synergistic effect of ibrutinib on apheresis product fitness, CAR-T expansion, and toxicity. We evaluated the combination of time-limited ibrutinib and CTL019 CAR-T in 20 patients with MCL in the phase 2 TARMAC study. Ibrutinib commenced before leukapheresis and continued through CAR-T manufacture for a minimum of 6 months after CAR-T administration. The median prior lines of therapy was 2; 50% of patients were previously exposed to a Bruton tyrosine kinase inhibitor (BTKi). The primary end point was 4-month postinfusion complete response (CR) rate, and secondary end points included safety and subgroup analysis based on TP53 aberrancy. The primary end point was met; 80% of patients demonstrated CR, with 70% and 40% demonstrating measurable residual disease negativity by flow cytometry and molecular methods, respectively. At 13-month median follow-up, the estimated 12-month progression-free survival was 75% and overall survival 100%. Fifteen patients (75%) developed cytokine release syndrome; 12 (55%) with grade 1 to 2 and 3 (20%) with grade 3. Reversible grade 1 to 2 neurotoxicity was observed in 2 patients (10%). Efficacy was preserved irrespective of prior BTKi exposure or TP53 mutation. Deep responses correlated with robust CAR-T expansion and a less exhausted baseline T-cell phenotype. Overall, the safety and efficacy of the combination of BTKi and T-cell redirecting immunotherapy appears promising and merits further exploration. This trial was registered at www.ClinicalTrials.gov as #NCT04234061.
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Adenina/análogos & derivados , Linfoma de Células del Manto , Piperidinas , Receptores Quiméricos de Antígenos , Adulto , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Receptores Quiméricos de Antígenos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Linfocitos T , Inmunoterapia Adoptiva/métodos , Antígenos CD19RESUMEN
BACKGROUND: Clinical indications for ibrutinib reimbursement in Australia should consider the inclusion of patients with chronic lymphocytic leukemia (CLL) harboring prognostically unfavorable TP53/IGHV genomic aberrations. This study assessed the cost effectiveness of five first-line treatment strategies in CLL for young (aged ≤ 65 years), fit patients without significant comorbidities: (1) no testing (fludarabine, cyclophosphamide and rituximab [FCR] for all), (2) test for del(17p) only, (3) test for TP53 gene mutation status, (4) test for TP53 and IGHV gene mutation status and (5) no testing (ibrutinib for all). METHOD: A decision analytic model (decision tree and partitioned survival model) was developed from the Australian healthcare system perspective with a lifetime horizon. Comparative treatment effects were estimated from indirect treatment comparisons and survival analysis using several studies. Costs, utility and adverse events were derived from public literature sources. Deterministic and probabilistic sensitivity analyses explored the impact of modeling uncertainties on outcomes. RESULTS: Strategy 1 was associated with 5.69 quality-adjusted life-years (QALYs) and cost 458,836 Australian dollars (AUD). All other strategies had greater effectiveness but were more expensive than Strategy 1. At the willingness-to-pay (WTP) threshold of 100,000 AUD per QALY gained, Strategy 1 was most cost effective with an estimated probability of 68.8%. Strategy 4 was cost effective between thresholds 155,000-432,300 AUD per QALY gained, and Strategy 5 >432,300 AUD per QALY gained. CONCLUSION: Population targeting using mutation testing for TP53 and IGHV when performed with del(17p) testing specifically in the context of frontline ibrutinib choice does not make a cost-ineffective treatment into a cost-effective treatment.
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Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Análisis de Costo-Efectividad , Análisis Costo-Beneficio , Australia , Algoritmos , Años de Vida Ajustados por Calidad de VidaRESUMEN
Flow cytometry (FC) incorporating the T-cell receptor ß constant chain-1 (TRBC1) has been recently proposed as a new standard in T-cell clonality assessment. While early studies demonstrated high sensitivity in samples with conspicuous tumour burden, performance in real-world samples, including those with low tumour burden and correlation with molecular methods has been limited. We evaluated TRBC1-FC performance and correlated the results with high-throughput TRB sequencing and a targeted next-generation sequencing gene panel. Our cohort consisted of 90 evaluable samples from 57 patients. TRBC1-FC confirmed T-cell clonality in 37 out of 38 samples (97%) that were involved in a mature T-cell neoplasm (MTCN). T-cell clonality was also identified in nine samples from patients lacking a current or prior diagnosis of MTCN, consistent with the emerging entity T-cell clonality of uncertain significance. TRBC-FC was polyclonal in all samples and negative for disease involvement by standard pathology assessment. However, correlation with TRB sequencing in 17 of these samples identified two cases that harboured the known clonal sequence from index testing, indicating the presence of measurable residual disease not otherwise detected. Our study provides real-world correlative validation of TRBC1-FC, highlighting the strengths and limitations pertinent to its increasing implementation by general diagnostic laboratories.
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Linfoma , Linfocitos T , Humanos , Linfocitos T/patología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Citometría de Flujo/métodos , Receptores de Antígenos de Linfocitos T , Linfoma/patologíaAsunto(s)
Arsenicales , Leucemia Promielocítica Aguda , Humanos , Trióxido de Arsénico/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoina/farmacología , Tretinoina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Óxidos/farmacología , Óxidos/uso terapéutico , Proteínas de Fusión Oncogénica/genética , Arsenicales/uso terapéutico , Receptor alfa de Ácido Retinoico , Proteínas RepresorasRESUMEN
OPINION STATEMENT: Mantle cell lymphoma (MCL) treatment advances have significantly improved disease-free remission, with greater focus in clinical trials being placed on measurable residual disease (MRD) as a marker of subclinical disease assessment. While this concept is used extensively in other haematological neoplasms, there is yet to be a consensus on the threshold for MRD in MCL that demonstrates prognostic and therapeutic significance, and in this context has yet to reach routine clinical practice. The historical long-term method for MCL MRD assessment has been real-time quantitative polymerase chain reaction (PCR), targeting the clonal immunoglobulin heavy locus (IGH) rearrangement or the IGH::CCND1 translocation rearrangement. A significant problem at present relates to identifying alternative assays for patients who do not have a suitable molecular target by this method. This article reviews existing techniques used in MRD assessment for MCL and describes novel methods which may overcome existing limitations, including next-generation sequencing modalities. The use of circulating tumour DNA is explored, with techniques such as CAPP-Seq and PhasED-Seq demonstrating promise in B-lymphoproliferative disorders, though application in MCL requires further study. The other aspect of practice using MRD is identifying therapeutic options which can address a subclinical molecular relapse. Developing suitable interventions that can alter the disease trajectory based on longitudinal MRD kinetics are needed to justify its incorporation into standard care.
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Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/diagnóstico , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/terapia , Recurrencia Local de Neoplasia/genética , Translocación Genética , Pronóstico , Neoplasia Residual/diagnóstico , Neoplasia Residual/genéticaRESUMEN
Undetectable measurable residual disease (MRD) is associated with favourable clinical outcomes in chronic lymphocytic leukaemia (CLL). While assessment is commonly performed using multiparameter flow cytometry (MFC), this approach is associated with limitations including user bias and expertise that may not be widely available. Implementation of unsupervised clustering algorithms in the laboratory can address these limitations and have not been previously reported in a systematic quantitative manner. We developed a computational pipeline to assess CLL MRD using FlowSOM. In the training step, a self-organising map was generated with nodes representing the full breadth of normal immature and mature B cells along with disease immunophenotypes. This map was used to detect MRD in multiple validation cohorts containing a total of 456 samples. This included an evaluation of atypical CLL cases and samples collected from two different laboratories. Computational MRD showed high correlation with expert analysis (Pearson's r > 0.99 for typical CLL). Binary classification of typical CLL samples as either MRD positive or negative demonstrated high concordance (>98%). Interestingly, computational MRD detected disease in a small number of atypical CLL cases in which MRD was not detected by expert analysis. These results demonstrate the feasibility and value of automated MFC analysis in a diagnostic laboratory.
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Leucemia Linfocítica Crónica de Células B , Neoplasia Residual , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Citometría de Flujo , Inmunofenotipificación , Humanos , Aprendizaje AutomáticoRESUMEN
In laboratory medicine, a misidentified patient sample can lead to an incorrect tissue diagnosis, a potentially fatal blood transfusion error or other serious adverse events. Although well characterised in routine patient care, the overall impacts of misidentification errors in the clinical research setting are less conspicuous but potentially greater, with downstream effects that may extend beyond care at an individual level. When data discrepancies or queries arise in clinical trial data then a data clarification form (DCF) is issued to the researcher by the overseeing trial coordinator or sponsor. Higher rates of DCF's are sometimes used as a crude surrogate marker of poorer trial quality. However, data is scarce on misidentification rates in clinical trials. In five clinical trials involving 822 histology or blood specimens analysed by our pathology department, DCF's were issued for 21% (174) of specimens. Amongst these 67% (117 / 174) were related to sample identification. Although these errors were recognised before data was compromised or an adverse event occurred, they highlight an alarming lack of stringency of use of patient identifiers in the research setting. We therefore propose the use of an appropriate number of de-identified data points and a formalised specimen accession process as employed in routine care to mitigate misidentification errors and their impact in clinical research. Increased recognition in the research community of the likely effect of truncating or reducing the number of patient identifiers is needed to minimise misidentification errors in the research setting.
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Investigación Biomédica , Errores Médicos , Humanos , Privacidad , LaboratoriosRESUMEN
Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p = .426) or overall survival (OS) (p = .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p = ·005) and OS (p = .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.
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Quimioterapia de Inducción , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Adulto , Citometría de Flujo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Pronóstico , Neoplasia Residual/diagnósticoRESUMEN
OBJECTIVES: Molecular biomarker tests can inform the clinical management of genomic heterogeneous hematological malignancies, yet their availability in routine care largely depends on the supporting health economic evidence. This study aims to systematically review the economic evidence for recent molecular biomarker tests in hematological malignancies. METHODS: We conducted a systematic search in five electronic databases for studies published between January 2010 and October 2020. Publications were independently screened by two reviewers. Clinical study characteristics, economic methodology, and results were extracted, and reporting quality was assessed. RESULTS: Fourteen studies were identified, of which half (n = 7; 50%) were full economic evaluations examining both health and economic outcomes. Studies were predominantly conducted in a first-line treatment setting (n = 7; 50%) and adopted a non-lifetime time horizon to measure health outcomes and costs (n = 7; 50%). Five studies reported that companion diagnostics for associated therapies were likely cost-effective for acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, and multiple myeloma. Four studies suggested molecular biomarker tests for treatment monitoring in chronic myeloid leukemia were likely cost-saving. CONCLUSIONS: Although there is initial confirmation of the promising health economic results, the present research for molecular biomarker tests in hematological malignancies is sparse with many applications of technological advances yet to be evaluated.
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Neoplasias Hematológicas , Leucemia Mielógena Crónica BCR-ABL Positiva , Biomarcadores , Análisis Costo-Beneficio , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , HumanosRESUMEN
The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each individual disease context.
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Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Linfoma de Células del Manto , Adulto , Antineoplásicos/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células del Manto/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas c-bcl-2/genéticaRESUMEN
The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes , Neoplasias Hematológicas , Leucemia Linfocítica Crónica de Células B , Mutación , Mielopoyesis/efectos de los fármacos , Trastornos Mieloproliferativos , Neoplasias Primarias Secundarias , Sulfonamidas , Proteína X Asociada a bcl-2 , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Femenino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/metabolismo , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados , Proteína X Asociada a bcl-2/antagonistas & inhibidores , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: Measurable residual disease (MRD) monitoring in acute lymphoblastic leukemia (ALL) is an important predictive factor for patient outcome and treatment intensification. Molecular monitoring, particularly with quantitative polymerase chain reaction (qPCR) to measure immunoglobin heavy or kappa chain (Ig) or T-cell receptor (TCR) gene rearrangements, offers high sensitivity but accessibility is limited by expertise, cost, and turnaround time. Flow cytometric assays are cheaper and more widely available, and sensitivity is improved with multi-parameter flow cytometry at eight or more colors. METHODS: We developed a 10-color single tube flow cytometry assay. Samples were subject to bulk ammonium chloride lysis to maximize cell yields with a target of 1 × 106 events. Once normal maturation patterns were established, patient samples were analyzed in parallel to standard molecular monitoring. RESULTS: Flow cytometry was performed on 114 samples. An informative immunophenotype was identifiable in all 22 patients who had a diagnostic sample. MRD analysis was performed on 87 samples. The median lower limits of detection and quantification were 0.004% (range 0.0005%-0.028%) and 0.01% (range 0.001%-0.07%) respectively. Sixty-five samples had concurrent molecular MRD testing, with good correlation (r = 0.83, p < 0.001). Results were concordant in 52 samples, and discordant in 13 samples, including one case where impending relapse was detected by flow cytometry but not Ig/TCR qPCR. CONCLUSIONS: Our 10-color flow cytometric MRD assay provided adequate sensitivity and good correlation with molecular assays. This technique offers rapid and affordable testing in B-ALL patients, including cases where a suitable molecular assay cannot be developed or has reduced sensitivity.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Enfermedad Aguda , Adulto , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Antígenos de Linfocitos TRESUMEN
Covalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.
Asunto(s)
Antineoplásicos , Leucemia Linfocítica Crónica de Células B , Linfoma de Células B Grandes Difuso , Antineoplásicos/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Estudios RetrospectivosRESUMEN
Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B-cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin-fixed, paraffin-embedded biopsies of RS (n = 19), de novo diffuse large B-cell lymphoma (DLBCL; n = 58), transformed indolent lymphomas (follicular [tFL], n = 16; marginal zone [tMZL], n = 24) and non-transformed small lymphocytic lymphoma (SLL; n = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next-generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD-1 was performed. LAG3 gene expression was higher in RS compared to DLBCL (P = 0·0002, log2FC 1·96), tFL (P < 0·0001, log2FC 2·61), tMZL (P = 0·0004, log2FC 1·79) and SLL (P = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour-infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti-tumour responses in RS.