Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. ...Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.
GPRC5D-Targeted CAR T Cells for Myeloma Mailankody, Sham; Devlin, Sean M; Landa, Jonathan ...
The New England journal of medicine,
09/2022, Letnik:
387, Številka:
13
Journal Article
Recenzirano
Odprti dostop
B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled ...receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model.
In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy.
A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×10
CAR T cells. At the 450×10
CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×10
to 150×10
cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×10
to 150×10
cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×10
to 150×10
cells.
The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).
In recent literature, the human microbiome has been shown to have a major influence on human health. To investigate this impact, scientists study the composition and abundance of bacterial species, ...commonly using 16S rRNA gene sequencing, among patients with and without a disease or condition. Methods for such investigations to date have focused on the association between individual bacterium and an outcome, and higher-order pairwise relationships or interactions among bacteria are often avoided due to the substantial increase in dimension and the potential for spurious correlations. However, overlooking such relationships ignores the environment of the microbiome, where there is dynamic cooperation and competition among bacteria. We present a method for identifying and ranking pairs of bacteria that have a differential dichotomized relationship across outcomes. Our approach, implemented in an R package PairSeek, uses the stability selection framework with data-driven dichotomized forms of the pairwise relationships. We illustrate the properties of the proposed method using a published oral cancer data set and a simulation study.
Clonal hematopoiesis (CH), as evidenced by recurrent somatic mutations in leukemia-associated genes, commonly occurs among aging human hematopoietic stem cells. We analyzed deep-coverage, targeted, ...next-generation sequencing (NGS) data of paired tumor and blood samples from 8,810 individuals to assess the frequency and clinical relevance of CH in patients with non-hematologic malignancies. We identified CH in 25% of cancer patients, with 4.5% harboring presumptive leukemia driver mutations (CH-PD). CH was associated with increased age, prior radiation therapy, and tobacco use. PPM1D and TP53 mutations were associated with prior exposure to chemotherapy. CH and CH-PD led to an increased incidence of subsequent hematologic cancers, and CH-PD was associated with shorter patient survival. These data suggest that CH occurs in an age-dependent manner and that specific perturbations can enhance fitness of clonal hematopoietic stem cells, which can impact outcome through progression to hematologic malignancies and through cell-non-autonomous effects on solid tumor biology.
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•Deep sequencing shows clonal hematopoiesis (CH) is common in solid tumor patients•CH is associated with increasing age, tobacco use, and prior radiation therapy•CH is associated with an increased risk of hematologic cancers•The presence of CH adversely impacts survival from non-hematologic cancers
Coombs et al. examined a large cohort of solid tumor patients who underwent deep-coverage, paired tumor/blood sequencing and demonstrated that clonal hematopoiesis is common and associated with increasing age, tobacco use, and prior radiation therapy and that it predicts an increased risk of hematologic cancers and shorter survival.
Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that ...alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio HR, 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.
In studies of survival and its association with treatment and other prognostic variables, elapsed time alone will often show itself to be among the strongest, if not the strongest, of the predictor ...variables. Kaplan-Meier curves will show the overall survival of each group and the general differences between groups due to treatment. However, the time-dependent nature of treatment effects is not always immediately transparent from these curves. More sophisticated tools are needed to spotlight the treatment effects. An important tool in this context is the treatment effect process. This tool can be potent in revealing the complex myriad of ways in which treatment can affect survival time. We look at a recently published study in which the outcome was relapse-free survival, and we illustrate how the use of the treatment effect process can provide a much deeper understanding of the relationship between time and treatment in this trial.
Tracking of clonal immunoglobulin V(D)J rearrangement sequences by next generation sequencing is highly sensitive for minimal residual disease in multiple myeloma. However, previous studies have ...found variable rates of V(D)J sequence identification at baseline, which could limit tracking. Here, we aimed to define the factors influencing the identification of clonal V(D)J sequences. Bone marrow mononuclear cells from 177 myeloma patients underwent V(D)J sequencing by the LymphoTrack assays (Invivoscribe). As a molecular control for tumor cell content, we sequenced the samples using our in-house myeloma panel myTYPE. V(D)J sequence clonality was identified in 81% of samples overall, as compared with 95% in samples where tumor-derived DNA was detectable by myTYPE. Clonality was detected more frequently in patients with lambda-restricted disease, mainly because of increased detection of kappa gene rearrangements. Finally, we describe how the tumor cell content of bone marrow aspirates decrease gradually in sequential pulls because of hemodilution: From the initial pull used for aspirate smear, to the final pull that is commonly used for research. In conclusion, baseline clonality detection rates of 95% or higher are feasible in multiple myeloma. Optimal performance depends on the use of good quality aspirates and/or subsequent tumor cell enrichment.
The performance of time-to-event models is frequently assessed in part by estimating the concordance probability, which evaluates the probabilistic pairwise ordering of the model-based risk scores ...and survival times. The standard definition of this probability conditions on any survival time pair ordering, irrespective of whether the times are meaningfully separated. Inclusion of survival times that would be deemed clinically similar attenuates the concordance and moves the estimate away from the contrast-of-interest: comparing the risk scores between individuals with disparate survival times. In this manuscript, we propose a concordance definition and corresponding method to estimate the probability conditional on survival times being separated by at least a minimum difference. The proposed estimate requires direct input from the analyst to identify a separable survival region and, in doing so, is analogous to the clinically defined subgroups used for binary outcome area under the curve estimates. The method is illustrated in two cancer examples: a prognostic score in clear cell renal cell carcinoma and two biomarkers in metastatic prostate cancer.
High-dose chemotherapy (HDT) plus autologous stem cell transplantation (ASCT) is the standard of care for chemosensitive relapsed and refractory diffuse large B-cell lymphoma (rel/ref DLBCL). Interim ...restaging with functional imaging by positron emission tomography using 18F-deoxyglucose (FDG-PET) has not been established after salvage chemotherapy (ST) and before HDT-ASCT by modern criteria. Herein, we evaluated 129 patients with rel/ref DLBCL proceeding to HDT-ASCT, with ST response assessment by FDG-PET according to the contemporary Deauville 5-point scale. At 3 years, patients achieving a Deauville response of 1 to 3 to ST experienced superior progression-free survival (PFS) and overall survival (OS) rates of 77% and 86%, respectively, compared with patients achieving Deauville 4 (49% and 54%, respectively) (P < .001). No other pre-HDT-ASCT risk factors significantly impacted PFS or OS. Despite achieving remission to ST, patients with Deauville 4 should be the focus of risk-adapted investigational therapies.
•FDG-PET–assessed response to ST according to Deauville criteria predicts outcome post-ASCT for rel/ref DLBCL.
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