Expedited evaluation of hereditary hematopoietic malignancies in the setting of stem cell transplantation.

Not available.

Multicenter analysis of immunosuppressive medications on the risk of malignancy following adult solid organ transplantation.

Objective: This study aimed to assess the risk of maintenance immunosuppression on the post-transplant risk of malignancy across all solid organ transplant types. Methods: This is a retrospective cohort study from a multicenter hospital system in the United States. The electronic health record was queried from 2000 to 2021 for cases of solid organ transplant, immunosuppressive medications, and post-transplant malignancy. Results: A total of 5,591 patients, 6,142 transplanted organs, and 517 post-transplant malignancies were identified. Skin cancer was the most common type of malignancy at 52.8%, whereas liver cancer was the first malignancy to present at a median time of 351 days post-transplant. Heart and lung transplant recipients had the highest rate of malignancy, but this finding was not significant upon adjusting for immunosuppressive medications (heart HR 0.96, 95% CI 0.72 - 1.3, p = 0.88; lung HR 1.01, 95% CI 0.77 - 1.33, p = 0.94). Random forest variable importance calculations and time-dependent multivariate cox proportional hazard analysis identified an increased risk of cancer in patients receiving immunosuppressive therapy with sirolimus (HR 1.41, 95% CI 1.05 - 1.9, p = 0.04), azathioprine (HR 2.1, 95% CI 1.58 - 2.79, p < 0.001), and cyclosporine (HR 1.59, 95% CI 1.17 - 2.17, p = 0.007), while tacrolimus (HR 0.59, 95% CI 0.44 - 0.81, p < 0.001) was associated with low rates of post-transplant neoplasia. Conclusion: Our results show varying risks of immunosuppressive medications associated with the development of post-transplant malignancy, demonstrating the importance of cancer detection and surveillance strategies in solid organ transplant recipients.

Clinical guideline variability in the diagnosis of hereditary hematopoietic malignancy syndromes.

A growing understanding of the complexities of hematopoietic malignancies necessitates the existence of clinical recommendations that are sufficiently comprehensive. Although hereditary hematopoietic malignancies (HHMs) are increasingly recognized for conferring risk of myeloid malignancy, frequently utilized clinical recommendations have never been appraised for the ability to reliably guide HHM evaluation. We assessed established society-level clinical guidelines for inclusion of critical HHM genes and graded the strength of testing recommendations. We uncovered a substantial lack of consistency of recommendations guiding HHM evaluation. Such heterogeneity in guidelines likely contributes to refusal by payers to support HHM testing, leading to underdiagnoses and lost opportunities for clinical surveillance.

Clinical considerations at the intersection of hematopoietic cell transplantation and hereditary hematopoietic malignancy.

In recent years, advances in genetics and the integration of clinical-grade next-generation sequencing (NGS) assays into patient care have facilitated broader recognition of hereditary hematopoietic malignancy (HHM) among clinicians, in addition to the identification and characterization of novel HHM syndromes. Studies on genetic risk distribution within affected families and unique considerations of HHM biology represent exciting areas of translational research. More recently, data are now emerging pertaining to unique aspects of clinical management of malignancies arising in the context of pathogenic germline mutations, with particular emphasis on chemotherapy responsiveness. In this article, we explore considerations surrounding allogeneic transplantation in the context of HHMs. We review pre- and post-transplant patient implications, including genetic testing donor selection and donor-derived malignancies. Additionally, we consider the limited data that exist regarding the use of transplantation in HHMs and safeguards that might be pursued to mitigate transplant-related toxicities.

Stagnation in quality of next-generation sequencing assays for the diagnosis of hereditary hematopoietic malignancies.

Hereditary hematopoietic malignancies (HHMs) are inherited syndromes that confer the risk of blood cancer development. With the rapid acceleration of next-generation sequencing (NGS) into commercial biotechnology markets, HHMs are increasingly recognized by genetic counselors and clinicians. In 2020, it was demonstrated that most diagnostic test offerings for HHMs were insufficient for accurate diagnosis, failing to sequence the full spectrum of genetic events known to cause HHMs. We hypothesized the number of genes on commercially available HHM assay increased from 2020 to 2022, consistent with a more comprehensive sequencing approach. Here, we analyzed assays from eight commercial laboratories to determine the HHM-related genes sequenced by these assays. We compared these assays with panels from 2020 to determine trends in sequencing quality. Most HHM diagnostic assays did not change and remain insensitive for the detection of all HHM-related variants. Most (75%) HHM assays do not sequence CHEK2, the gene most frequently mutated in HHMs, and 25% of HHM assays does not sequence DDX41, the second most frequent HHM driver. The quality of HHM diagnostic assays stagnated despite the discovery of novel HHM-related genes and prior work demonstrating heterogeneity in the quality of HHM testing. Most commercially available HHM tests remain insufficient.

Contemporary Approach to Acute Myeloid Leukemia Therapy in 2022.

Recent advances in acute myeloid leukemia biology and drug development have transformed the therapeutic landscape for patients diagnosed with this disease. By harnessing insights from the study of the molecular pathogenesis of the disease, the acute myeloid leukemia treatment armamentarium now extends beyond conventional cytotoxic agents to include targeted therapies, and immunotherapeutics, with multiple novel modalities under investigation. During the past 5 years, recent drug approvals have also focused attention on disease scenarios and patient populations for whom newer therapies might be deployed. In this review, we highlight select acute myeloid leukemia therapies in the frontline setting through the lens of both disease and patient-related factors. Particular emphasis is placed on the assessment of patient fitness, as contemporary acute myeloid leukemia therapy decisions largely hinge on the determination of whether intensive chemotherapy is suitable for a patient. Additionally, we detail scenarios and areas of controversy wherein disease biology may inspire a reframing of traditional intensive treatment philosophies, regardless of patient fitness. Lastly, we provide an overview of emerging agents that are being investigated in the relapsed/refractory setting.

Application of Next-Generation Sequencing-Based Mutational Profiling in Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: Recent efforts to characterize hematologic cancers with genetic and molecular detail have largely relied on mutational profiling via next-generation sequencing (NGS). The application of NGS-guided disease prognostication and clinical decision making requires a basic understanding of sequencing advantages, pitfalls, and areas where clinical care might be enhanced by the knowledge generated. This article identifies avenues within the landscape of adult acute lymphoblastic leukemia (ALL) where mutational data hold the opportunity to enhance understanding of disease biology and patient care. RECENT FINDINGS: NGS-based assessment of measurable residual disease (MRD) after ALL treatment allows for a sensitive and specific molecular survey that is at least comparable, if not superior, to existing techniques. Mutational assessment by NGS has unraveled complex signaling networks that drive pathogenesis of T-cell ALL. Sequencing of patients with familial clustering of ALL has also identified novel germline mutations whose inheritance predisposes to disease development in successive generations. While NGS-based assessment of hematopoietic malignancies often provides actionable information to clinicians, patients with acute lymphoblastic leukemia are left underserved due to a lack of disease classification and prognostication schema that integrate molecular data. Ongoing research is positioned to enrich the molecular toolbox available to clinicians caring for adult ALL patients and deliver new insights to guide therapeutic selection, monitor clinical response, and detect relapse.

Targeted Therapies for the Evolving Molecular Landscape of Acute Myeloid Leukemia.

Despite considerable growth in our understanding of the heterogeneous biology and pathogenesis of acute myeloid leukemia (AML) in recent decades, for nearly forty years, little progress was gained in the realm of novel therapeutics. Since 2017, however, nine agents have been FDA-approved for patients with AML in both the upfront and relapsed/refractory (R/R) settings. Most of these compounds function as inhibitors of key cell cycle enzymatic pathways or mediators of leukemic proliferation and survival. They have been approved both as single agents and in combination with conventional or reduced-intensity conventional chemotherapeutics. In this article, we review the molecular landscape of de novo vs. R/R AML and highlight the potential translational impact of defined molecular disease subsets. We also highlight several recent agents that have entered the therapeutic armamentarium and where they fit in the AML treatment landscape, with a focus on FLT3 inhibitors, IDH1 and IDH2 inhibitors, and venetoclax. Finally, we close with a survey of two promising novel agents under investigation that are poised to enter the mainstream clinical arena in the near future.

Inherited Susceptibility to Hematopoietic Malignancies in the Era of Precision Oncology.

As germline predisposition to hematopoietic malignancies has gained increased recognition and attention in the field of oncology, it is important for clinicians to use a systematic framework for the identification, management, and surveillance of patients with hereditary hematopoietic malignancies (HHMs). In this article, we discuss strategies for identifying individuals who warrant diagnostic evaluation and describe considerations pertaining to molecular testing. Although a paucity of prospective data is available to guide clinical monitoring of individuals harboring pathogenic variants, we provide recommendations for clinical surveillance based on consensus opinion and highlight current advances regarding the risk of progression to overt malignancy in HHM variant carriers. We also discuss the prognosis of HHMs and considerations surrounding the utility of allogeneic stem-cell transplantation in these individuals. We close with an overview of contemporary issues at the intersection of HHMs and precision oncology.

Assessment of technical heterogeneity among diagnostic tests to detect germline risk variants for hematopoietic malignancies.

PURPOSE: To determine the degree of testing consistency among commercially available diagnostic assays for hereditary hematopoietic malignancies (HHMs). METHODS: Next-generation sequencing assays designed for the diagnosis of HHMs were studied to determine which genes were sequenced, their ability to detect variant types relevant for HHMs, and clinical-grade characteristics such as price, turnaround time, and tissue types accepted. RESULTS: Commercial assays varied in price (USD 250-4702), number of genes sequenced (12-73), and average turnaround time (14-42 days). A number of nongermline tissue types were accepted despite the tests being designed for germline diagnostic purposes. Multiple genes with well-characterized roles in HHM pathogenesis were omitted from more than one-third of panels intended for the evaluation of HHMs. Only 4 of 82 genes were consistently covered across all HHM diagnostic panels. The assays were highly variable in their sensitivity for structural alterations relevant to HHMs, such as copy-number variants. CONCLUSION: A high degree of diagnostic heterogeneity exists among commercially available HHM diagnostic assays. Many of these assays are incapable of detecting the full spectrum of HHM-associated variants, leaving patients vulnerable to the consequences of underdiagnosis, missed opportunities for screening, and the potential for donor-derived malignancies.

Targeted RNA-sequencing for the quantification of measurable residual disease in acute myeloid leukemia.

Great effort is spent on developing therapies to improve the dire outcomes of those diagnosed with acute myeloid leukemia. The methods for quantifying response to therapeutic intervention have however lacked sensitivity. Patients achieving a complete remission as defined by conventional cytomorphological methods therefore remain at risk of subsequent relapse due to disease persistence. Improved risk stratification is possible based on tests designed to detect this residual leukemic burden (measurable residual disease). However, acute myeloid leukemia is a genetically diverse set of diseases, which has made it difficult to develop a single, highly reproducible, and sensitive assay for measurable residual disease. Here we present the development of a digital targeted RNA-sequencing-based approach designed to overcome these limitations by detecting all newly approved European LeukemiaNet molecular targets for measurable residual disease in acute myeloid leukemia in a single standardized assay. Iterative modifications and novel bioinformatics approaches resulted in a greater than 100-fold increase in performance compared with commercially available targeted RNA-sequencing approaches and a limit of detection as low as one leukemic cell in 100,000 cells measured, which is comparable to quantitative polymerase chain reaction analysis, the current gold standard for the detection of measurable residual disease. This assay, which can be customized and expanded, is the first demonstrated use of high-sensitivity RNA-sequencing for measurable residual disease detection in acute myeloid leukemia and could serve as a broadly applicable standardized tool.

When to obtain genomic data in acute myeloid leukemia (AML) and which mutations matter.

Mutational profiling has fundamentally changed our approach to patients with acute myeloid leukemia (AML). Patients with AML are routinely profiled for the presence of mutations in FLT3, NPM1, CEBPA, and, more recently, TP53 In this chapter, we review the role of mutational profiling to help define disease biology in AML, particularly among patients with putatively intermediate-risk disease. We describe the body of evidence supporting the utility of mutational profiling when performed at the time of diagnosis (to identify prognostic and targetable mutations), at the time of complete remission (to assess minimal residual disease as a marker for relapse), and at the time of relapse (to identify therapeutic targets and eligibility for clinical trials). We further identify particular mutations that have been shown to affect prognosis across the established European LeukemiaNet risk categories and discuss which mutational events might be used to alter the approach to patient care at various time points during the disease course. We also review the evidence in support of molecular profiling for assessment of minimal/measurable residual disease and describe the current landscape of studies designed to validate this approach.

When to obtain genomic data in acute myeloid leukemia (AML) and which mutations matter.

Mutational profiling has fundamentally changed our approach to patients with acute myeloid leukemia (AML). Patients with AML are routinely profiled for the presence of mutations in FLT3, NPM1, CEBPA, and, more recently, TP53 In this chapter, we review the role of mutational profiling to help define disease biology in AML, particularly among patients with putatively intermediate-risk disease. We describe the body of evidence supporting the utility of mutational profiling when performed at the time of diagnosis (to identify prognostic and targetable mutations), at the time of complete remission (to assess minimal residual disease as a marker for relapse), and at the time of relapse (to identify therapeutic targets and eligibility for clinical trials). We further identify particular mutations that have been shown to affect prognosis across the established European LeukemiaNet risk categories and discuss which mutational events might be used to alter the approach to patient care at various time points during the disease course. We also review the evidence in support of molecular profiling for assessment of minimal/measurable residual disease and describe the current landscape of studies designed to validate this approach.

Molecular Measurable Residual Disease Testing of Blood During AML Cytotoxic Therapy for Early Prediction of Clinical Response.

Measurable residual disease (MRD) testing after initial chemotherapy treatment can predict relapse and survival in acute myeloid leukemia (AML). However, it has not been established if repeat molecular or genetic testing during chemotherapy can offer information regarding the chemotherapy sensitivity of the leukemic clone. Blood from 45 adult AML patients at day 1 and 4 of induction (n = 35) or salvage (n = 10) cytotoxic chemotherapy was collected for both quantitative real-time PCR (qPCR) assessment (WT1) and next generation sequencing (>500 × depth) of 49 gene regions recurrently mutated in MDS/AML. The median age of subjects was 62 (23-78); 42% achieved a complete response. WT1 was overexpressed in most patients tested but was uninformative for very early MRD assessment. A median of 4 non-synonymous variants (range 0-7) were detected by DNA sequencing of blood on day 1 of therapy [median variant allele frequency (VAF): 29%]. Only two patients had no variants detectable. All mutations remained detectable in blood on day 4 of intensive chemotherapy and remarkably the ratio of mutated to wild-type sequence was often maintained. This phenomenon was not limited to variants in DNMT3A, TET2, and ASXL1. The kinetics of NPM1 and TP53 variant burden early during chemotherapy appeared to be exceptions and exhibited consistent trends in this cohort. In summary, molecular testing of blood on day 4 of chemotherapy is not predictive of clinical response to cytotoxic induction therapy in AML. The observed stability in variant allele frequency suggests that cytotoxic therapy may have a limited therapeutic index for clones circulating in blood containing these mutations. Further validation is required to confirm the utility of monitoring NPM1 and TP53 kinetics in blood during cytotoxic therapy.

NY-ESO-1 Vaccination in Combination with Decitabine Induces Antigen-Specific T-lymphocyte Responses in Patients with Myelodysplastic Syndrome.

Purpose: Treatment options are limited for patients with high-risk myelodysplastic syndrome (MDS). The azanucleosides, azacitidine and decitabine, are first-line therapy for MDS that induce promoter demethylation and gene expression of the highly immunogenic tumor antigen NY-ESO-1. We demonstrated that patients with acute myeloid leukemia (AML) receiving decitabine exhibit induction of NY-ESO-1 expression in circulating blasts. We hypothesized that vaccinating against NY-ESO-1 in patients with MDS receiving decitabine would capitalize upon induced NY-ESO-1 expression in malignant myeloid cells to provoke an NY-ESO-1-specific MDS-directed cytotoxic T-cell immune response.Experimental Design: In a phase I study, 9 patients with MDS received an HLA-unrestricted NY-ESO-1 vaccine (CDX-1401 + poly-ICLC) in a nonoverlapping schedule every four weeks with standard-dose decitabine.Results: Analysis of samples serially obtained from the 7 patients who reached the end of the study demonstrated induction of NY-ESO-1 expression in 7 of 7 patients and NY-ESO-1-specific CD4+ and CD8+ T-lymphocyte responses in 6 of 7 and 4 of 7 of the vaccinated patients, respectively. Myeloid cells expressing NY-ESO-1, isolated from a patient at different time points during decitabine therapy, were capable of activating a cytotoxic response from autologous NY-ESO-1-specific T lymphocytes. Vaccine responses were associated with a detectable population of CD141Hi conventional dendritic cells, which are critical for the uptake of NY-ESO-1 vaccine and have a recognized role in antitumor immune responses.Conclusions: These data indicate that vaccination against induced NY-ESO-1 expression can produce an antigen-specific immune response in a relatively nonimmunogenic myeloid cancer and highlight the potential for induced antigen-directed immunotherapy in a group of patients with limited options. Clin Cancer Res; 24(5); 1019-29. ©2017 AACRSee related commentary by Fuchs, p. 991.

Technical Advances in the Measurement of Residual Disease in Acute Myeloid Leukemia.

Outcomes for those diagnosed with acute myeloid leukemia (AML) remain poor. It has been widely established that persistent residual leukemic burden, often referred to as measurable or minimal residual disease (MRD), after induction therapy or at the time of hematopoietic stem cell transplant (HSCT) is highly predictive for adverse clinical outcomes and can be used to identify patients likely to experience clinically evident relapse. As a result of inherent genetic and molecular heterogeneity in AML, there is no uniform method or protocol for MRD measurement to encompass all cases. Several techniques focusing on identifying recurrent molecular and cytogenetic aberrations or leukemia-associated immunophenotypes have been described, each with their own strengths and weaknesses. Modern technologies enabling the digital quantification and tracking of individual DNA or RNA molecules, next-generation sequencing (NGS) platforms, and high-resolution imaging capabilities are among several new avenues under development to supplement or replace the current standard of flow cytometry. In this review, we outline emerging modalities positioned to enhance MRD detection and discuss factors surrounding their integration into clinical practice.

Colon cancer metastasis to the thyroid gland: report of a case with unique molecular profile.

A high index of suspicion is needed when a patient presents with thyroid mass in the settings of an advanced CRC. Secondary thyroid malignancy should be considered unless proven otherwise. reatment should be determined considering extent of CRC metastasis, patient's general condition, and presence of local symptoms.

Tissue-of-origin-specific gene repositioning in breast and prostate cancer.

Genes have preferential non-random spatial positions within the cell nucleus. The nuclear position of a subset of genes differ between cell types and some genes undergo repositioning events in disease, including cancer. It is currently unclear whether the propensity of a gene to reposition reflects an intrinsic property of the locus or the tissue. Using quantitative FISH analysis of a set of genes which reposition in cancer, we test here the tissue specificity of gene repositioning in normal and malignant breast or prostate tissues. We find tissue-specific organization of the genome in normal breast and prostate with 40 % of genes occupying differential positions between the two tissue types. While we demonstrate limited overlap between gene sets that repositioned in breast and prostate cancer, we identify two genes that undergo disease-related gene repositioning in both cancer types. Our findings indicate that gene repositioning in cancer is tissue-of-origin specific.