Transforming Acute Myeloid Leukemia Treatment Through Next-Generation Sequencing: A Single-Center Experience.

In the last decade, advancements in understanding the genetic and molecular mechanisms of acute myeloid leukemia (AML) have significantly improved treatment options. Techniques such as immunophenotyping, cytogenetics, and next-generation sequence (NGS) testing are now standard practices for patient assessments, allowing for personalized therapies based on individual patient needs. Our study aimed to evaluate the impact of cytogenetics and NGS on initial treatment decisions for AML at our institution. We analyzed the frequency of alternative therapy choices that could have been made with complete molecular and cytogenetic information and compared overall survival rates between patient groups. We also analyzed the turnaround time for result generation. Our retrospective study evaluated 39 AML patients treated at our university hospital from June 2020 to June 2022, excluding classic acute promyelocytic leukemia cases. Patients with incomplete data or concurrent hematological malignancies were excluded. We collected data on admission blood counts, European LeukemiaNet (ELN) risk stratification, Charlson score, treatment type, and timing of cytogenetics and NGS results. Patients were categorized into 'standard' or 'other therapy' groups based on their molecular and cytogenetic profiles in accordance with NCCN guidelines. Our main goal was to determine how often NGS and cytogenetics results could have influenced induction therapy choices. Secondary objectives included comparing overall survival rates and analyzing report turnaround times for NGS and cytogenetics. Our study found that out of the 39 AML patients, 17 were in the "standard" group, and 22 were in the "other therapy" group. The standard group had an average age of 62.59 years, an average time to chemotherapy initiation of 8.29 days, and an overall survival (OS) rate of 428.12 days. The other therapy group had an average age of 61.86 years, an average time to chemotherapy initiation of six days, and an OS rate of 258.64 days. There was a significant difference in survival rates between the two groups (p=0.009). According to the ELN stratification, the standard group had 11 patients at intermediate risk and six at adverse risk. In contrast, the other therapy group had seven at intermediate risk, four at good risk, and 11 at adverse risk. NGS revealed mutations in 58.97% of patients. Our study suggests that almost half of the patients could have been treated differently if complete molecular and cytogenetic information had been available before therapy initiation, highlighting the potential for more personalized treatments. Additionally, our results showed significant differences in overall survival rates between standard treatment and alternative therapy groups. Our findings emphasize the importance of timely NGS and cytogenetics result generation, guiding institutions to allocate resources for effective patient care.

Adalimumab-associated Philadelphia chromosome positive acute lymphoblastic leukaemia in a patient with Crohn's disease.

The US Food and Drug Administration has approved TNF(Tumor necrosis factor) alpha inhibitors to manage a range of inflammatory conditions, including Crohn's disease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and other inflammatory disorders. However, these inhibitors can potentially increase the risk of secondary blood malignancies due to TNF alpha's role in various cellular processes such as angiogenesis, cell cycle proliferation, apoptosis and differentiation. In this article, we present a unique case study of a patient who developed Philadelphia-positive acute lymphoblastic leukaemia (ALL) while receiving adalimumab, a potent monoclonal antibody that specifically binds to TNF-alpha. We describe the patient's successful treatment using standard-of-care chemotherapy and tyrosine kinase inhibitors, resulting in complete remission with no measurable residual disease. Furthermore, we conducted a literature review on this subject and identified five similar cases of ALL associated with TNF alpha inhibitors.

Acute Graft Versus Host Disease After Kidney-Pancreas Transplant.

Acute graft vs. host disease (aGVHD) results from newly transplanted donor immune cells recognizing recipient tissues as foreign, leading to end-organ damage. Diagnosing aGVHD typically involves a combination of clinical evaluation, histological examination, laboratory tests, and imaging studies. Although typically associated with allogeneic stem cells transplant and less frequently with liver or small bowel transplants, solid organ transplant GVHD (SOT-GVHD) associated with kidney-pancreas transplants is exceedingly rare. Our patient presented with pancytopenia unexplained by typical causes. He developed classical aGVHD findings of fever, diarrhea, rash, and abnormal liver tests. Our case underscores the importance of keeping a broad differential when evaluating solid organ transplant patients.

De novo monocytic-M5b AML with t(8;16) (p11.2; p13.3) KAT6A/CREBBP fusion and FLT3-TKD mutation complicated by chemotherapy-induced Takotsubo cardiomyopathy.

Acute myeloid leukemia (AML) with t(8;16) is a rare cytogenetic abnormality that presents unique characteristics such as hemophagocytosis, disseminated intravascular coagulation, leukemia cutis and varying levels of CD45 expression. It is more common in women and usually associated with prior cytotoxic therapies, accounting for <0.5% of all AML cases. We present a case of de novo t(8;16) AML with FLT3-TKD mutation who relapsed after initial induction and consolidation. Mitelman database analysis reveals only 175 cases with this translocation, majority of which are M5 (54.3%) and M4 (21.1%) AML. Our review reveals very poor prognosis with overall survival ranging from 4.7 to 18.2 months. She also developed Takotsubo cardiomyopathy after receiving 7+3 induction regimen. Our patient died in 6 months from the date of diagnosis. Although a rare occurrence, it has been discussed in literature to identify t(8;16) as a separate subtype of AML due to unique characteristics.

Clinical Significance and Management of MRD in Adults With Acute Lymphoblastic Leukemia.

Measurable residual disease (MRD) quantification is an essential component of caring for patients with acute lymphoblastic leukemia (ALL). Many studies in pediatric and adult populations have validated the prognostic significance of MRD early in and throughout the course of treatment for ALL, and it is generally accepted that achievement of MRD less than 10[-4] (0.01%) is a critical milestone. ALL is uniquely amenable to quantification of MRD by multiple techniques, including multiparameter flow cytometry, various allele-specific and mutation-specific quantitative polymerase chain reaction methods, and more recently amplicon-based next-generation sequencing. Quantification of MRD with these high-sensitivity methods not only facilitates risk stratification, but also is used to determine appropriateness of intensified therapy, such as allogeneic hematopoietic cell transplant, as well as MRD-targeted therapy with blinatumomab. We review the data supporting the use of MRD quantification in ALL to guide clinical decision-making.

The Future of Molecular Analysis in Melanoma: Diagnostics to Direct Molecularly Targeted Therapy.

Melanoma is a malignancy of pigment-producing cells that is driven by a variety of genetic mutations and aberrations. In most cases, this leads to upregulation of the mitogen-activated protein kinase (MAPK) pathway through activating mutations of upstream mediators of the pathway including BRAF and NRAS. With the advent of effective MAPK pathway inhibitors, including the US FDA-approved BRAF inhibitors vemurafenib and dabrafenib and MEK inhibitor trametinib, molecular analysis has become an integral part of the care of patients with metastatic melanoma. In this article, the key molecular targets and strategies to inhibit these targets therapeutically are presented, and the techniques of identifying these targets, in both tissue and blood, are discussed.