Table 2 - uploaded by Lisa A Fatheree
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Source publication
Context:
- The classification and prognosis determination in acute leukemia (AL) are complex and it is unclear what testing is being performed in practice.
Objective:
- To survey physicians describing their current practice of test ordering in the diagnosis of AL.
Design:
- In anticipation of a guideline by the College of American Pathologists...
Context in source publication
Context 1
... shown in Table 2, morphologic assessment, flow cytometric analysis, conventional cytogenetics, and fluores- cence in situ hybridization (FISH) studies were performed for both AML and ALL specimens at a similarly high rate. While the survey did not specifically separate peripheral blood smear from bone marrow aspirate smear morphologic assessment, peripheral blood smear morphology was included as a component of the final bone marrow report by a high percentage of survey respondents (Table 3). ...
Citations
... Existing first-generation TKIs include lestaurtinib (CEP-701), sunitinib (SU11248), midostaurin (PKC412), and sorafenib (BAY43-9006) [11]. The antileukemic effects of these multi-kinase inhibitors likely derive from the simultaneous inhibition of FLT3 and parallel pathways, but multiple off-target effects also bring about increased toxicities [12]. Subsequently, second-generation FLT3 inhibitors with higher selectivity and inhibitory activity were identified [13]. ...
Acute myeloid leukemia (AML) is a malignancy of proliferative, clonal, abnormally, or poorly differentiated cells of the hematopoietic system, characterized by clonal evolution and genetic heterogeneity. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation. FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. In this systematic review and meta-analysis, we present a detailed review of current clinical evidence of FLT3 inhibitors and their use in AML, and discrepancies association between FLT3 inhibitors use and prognosis of acute myeloid leukemia and maintenance setting.
... Bone marrow aspirate is one of the most essential diagnostic materials in the diagnostic examination of AML [19,20]. ...
... The ASH/CAP guidelines have summarized the main information [17,20,21]. Molecular genetic analysis and cytogenetic investigation, comprising FISH examination have given novel insights into the diagnostic workup of AML [20,21]. ...
... The ASH/CAP guidelines have summarized the main information [17,20,21]. Molecular genetic analysis and cytogenetic investigation, comprising FISH examination have given novel insights into the diagnostic workup of AML [20,21]. ...
Introduction and importance
Acute myeloid leukemia (AML) is a malignant disease with several risk factors from hematologic disorders, which almost presents as anemia. AML is characterized by the presence of myeloblast in the blood picture. On the other hand, macrocytic anemia characterized by the presence of megaloblastic marrow morphology. We are presenting a rare case of combined Acute myeloid leukemia with macrocytic anemia.
Case presentation
A 45 years old married woman was admitted for hyperthermia, dysuria, and chills. She had suffered from general malaise, weakness, and myalgia for two months. In her laboratories, the peripheral blood sample showed: HGB 26.1% (5.6 g/dL), RBCs 1.4M/μL, WBC 13.3 K/μL. The blood smear showed megaloblastic features, so she was diagnosed with macrocytic anemia, and the treatment was blood transfusion, antibiotics, and muscular Vit B12. After one month, the peripheral blood sample showed an elevation of WBC, the bone marrow aspiration showed myeloblast infiltration represents 60% of the total events, and the flow cytometry for the bone marrow aspiration agrees with Acute Myeloblastic leukemia with Maturation M2 (AML-M2).
Clinical discussion
The incidence of macrocytic anemia and leukemia in one patient is infrequent, case reports give scarce information concerning a potential increased occurrence of leukemia in patients putting up with macrocytic anemia. Several theories discussed the reasons for the association of the two conditions.
Conclusion
we need more research on similar cases to identify the pathological mechanism.
... Finally, many patients do not receive FLT3 testing at all. In a large survey by the American College of Pathologists in 2015, only 51% of new AML referrals received FLT3 testing (18). ...
The FLT3 receptor is overexpressed on the majority of acute myeloid leukemia (AML) blasts. Mutations in FLT3 are the most common genetic alteration in AML, identified in approximately one third of newly diagnosed patients. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple small molecule inhibitors of FLT3 signaling have been identified, two of which (midostaurin and gilteritinib) are currently approved in the United States, and many more of which are in clinical trials. Despite significant advances, resistance to FLT3 inhibitors through secondary FLT3 mutations, upregulation of parallel pathways, and extracellular signaling remains an ongoing challenge. Novel therapeutic strategies to overcome resistance, including combining FLT3 inhibitors with other antileukemic agents, development of new FLT3 inhibitors, and FLT3-directed immunotherapy are in active clinical development. Multiple questions regarding FLT3-mutated AML remain. In this review, we highlight several of the current most intriguing controversies in the field including the role of FLT3 inhibitors in maintenance therapy, the role of hematopoietic cell transplantation in FLT3-mutated AML, use of FLT3 inhibitors in FLT3 wild-type disease, significance of non-canonical FLT3 mutations, and finally, emerging concerns regarding clonal evolution.
... A low rate of manual differentials may indicate poor aspirates rather than a lack of awareness of the WHO guidelines. For poor quality aspirates immunohistochemistry may be useful; however, use of flow cytometry to determine blast percentage by counting CD34 + cells is discouraged because not all leukemic blasts express CD34, and hemodilution and processing artifacts can cause inaccurate estimation of blast percentage [28,35]. In a physician survey, respondents reported routinely using flow cytometry, immunohistochemistry, and karyotyping with poor quality aspirates [36]. ...
Diagnostic and molecular genetic testing are key in advancing the treatment of acute myeloid leukemia (AML), yet little is known about testing patterns outside of clinical trials, especially in older patients. We analyzed diagnostic and molecular testing patterns over time in 565 patients aged ≥ 55 years with newly diagnosed AML enrolled in the Connect® MDS/AML Disease Registry (NCT01688011) in the United States. Diagnostic data were recorded at enrolment and compared with published guidelines. The percentage of bone marrow blasts was reported for 82.1% of patients, and cellularity was the most commonly reported bone marrow morphological feature. Flow cytometry, karyotyping, molecular testing, and fluorescence in situ hybridization were performed in 98.8%, 95.4%, 75.9%, and 75.7% of patients, respectively. Molecular testing was done more frequently at academic than community/government sites (84.3% vs 70.2%; P < .001). Enrolment to the Registry after 2016 was significantly associated with molecular testing at academic sites (odds ratio [OR] 2.59; P = .023) and at community/government sites (OR 4.85; P < .001) in logistic regression analyses. Better understanding of practice patterns may identify unmet needs and inform institutional protocols regarding the diagnosis of patients with AML.
... Despite this, a 2017 survey carried out among AML experts in Europe and the United States reported that only 51.4% of specialists evaluate FLT3-ITD in all patients [28]; while at the national level, a recent survey among AML experts in Spanish clinics revealed that 7.5% "never" or "sometimes" carried out the analysis of FLT3 mutations [29]. These data demonstrate that there is still a lack of understanding of the prognostic and therapeutic indications of the presence of FLT3 mutations. ...
p>Advances in Next-Generation Sequencing technologies (NGS) are revealing germline and somatic mutations that, together with karyotype, determine the diagnosis and subtype of Acute Myeloid Leukemia (AML). Molecular testing is also essential for the genetic risk stratification of patients with AML, in particular for those with normal karyotype AML (CN-AML), a large and highly heterogeneous group of patients. Patients determined to be at high risk could benefit from a more aggressive first-line therapy, or a more directed therapy, such as midostaurin (for FLT3-mutated AML) or ivosidenib (for IDH1-mutated AML). Here, we will summarize the molecular testing currently recommended in AML and introduce new mutations that may have prognostic value and clinical application in the near future.</p
... Molecular genetic analysis and cytogenetic studies, including FISH testing is considered essential in the AML diagnostic workup. 7,8 Real-time reverse transcriptase (RT) polymerase chain reaction (PCR) is increasingly being used to identify transcripts of fusion proteins, which is performed when there is a suspicion of a subtype where translocations result in fusion proteins. ...
... Materials used for AML workup include BM aspirate and/or touch imprints, BM biopsy and/or clot, PB, and other tissues. 7,8 With regard to materials, two aspects need to be considered: the type of material used and the preparation method. ...
... 5 If BM evaluation needs to be entirely avoided due to a compelling clinical reason, PB may be used for studies if sufficient blasts are present in the PB. 5 In AML cases with an extramedullary presentation and without apparent BM or PB involvement, biopsy of the extramedullary tissue should be used for evaluation. 5,7,8 Bone marrow biopsy can be used to assess blast count and to perform IHC to enumerate blast count in conditions with low or poor aspirate yield. BM biopsy also provides valuable information regarding architectural abnormalities which could help in identifying the subtype, for example extensive BM necrosis is often associated with acute erythroid leukemia while extensive BM fibrosis is associated with acute megakaryocytic differentiation and acute panmyelosis with myelofibrosis. ...
Acute myeloid leukemia (AML) is a neoplasm of immature myeloid cells and is associated with a wide variety of clinical presentations, morphological features, immunophenotypes, and genetic findings. Recent advances in identification of cytogenetic abnormalities and mutations have provided novel insights into the pathogenesis of AML. Based on the above‐mentioned parameters, the World Health Organization (WHO) classified AML into 25 subtypes, including 2 provisional entities, which differ in prognosis and treatment. In addition, certain mutations are associated with germline predisposition and increase the risk of inherited AML, which warrants family screening. Therefore, precise diagnosis and classification of AML are the most important steps in patient management. Both these steps require incorporation of history, clinical presentation, and laboratory results with studies performed by a pathologist. Pathologist‐initiated studies include morphologic evaluation on the bone marrow aspirate and/or core biopsy, immunophenotyping by flow cytometry and/or immunohistochemistry, cytogenetic analysis by karyotyping and/or fluorescence in situ hybridization, and molecular testing using gene panels and/or next‐generation sequencing. A similar approach is employed during follow‐up of patients after beginning treatment. Here, we describe in detail the various aspects of the workup, including purpose, limitations, and practice guidelines for the different studies. The process of choosing appropriate materials for the different studies is also addressed. We also provide an algorithm for the workup and risk stratification of AML based on guidelines recommended by the WHO, College of American Pathologists, National Comprehensive Cancer Network, American Society of Clinical Oncology, European Society of Medical Oncology, and the European LeukemiaNet.
... A total of 294 completed surveys were received, and 36 were excluded owing to survey abandonment. Survey results from 258 respondents were tabulated as the baseline data for AL testing practices and published by George et al. 8 A follow-up survey is planned for 18 to 24 months after the AL LPG publication to compare to the baseline results and to evaluate the adoption of the 2017 AL LPG. ...
Context.—:
To date, the College of American Pathologists (CAP) has developed 17 laboratory practice guidelines (LPGs) including updates. In 2013, the CAP was awarded a 5-year cooperative agreement grant from the United States Centers for Disease Control and Prevention to increase the effectiveness of LPGs.
Objective.—:
To assess the awareness and adoption of 2 CAP LPGs: immunohistochemical (IHC) assay validation and initial workup of acute leukemia.
Design.—:
Baseline surveys for each LPG were conducted in 2010 and 2015, respectively. To measure the adoption of guideline recommendations and inform future updates, a follow-up study consisting of surveys, telephone interviews, and focus group sessions was conducted in laboratories that indicated they perform IHC testing. A follow-up study for the acute leukemia LPG is planned.
Results.—:
For the IHC Validation LPG, a total of 1624 survey responses, 40 telephone interviews, and discussions with 5 focus group participants were analyzed. The response rate for the aforementioned 3 modalities was 46%, 13%, and 3%, respectively. All modalities indicated most respondents were aware of the LPG and had adopted most or all of its recommendations. Respondents expressed needs for continued communication, increased specificity, and more prescriptive recommendations when the guideline is updated.
Conclusions.—:
While data-driven development of evidence-based LPGs requires significant resources, active data collection to identify gaps and assess adoption contributes to improved laboratory testing practices in support of patient care. The CAP identified sustainable modalities to track metrics and developed multiple tools that should improve guideline development, adoption, and implementation. Of these modalities, written or electronic surveys were the most logistically feasible and had the highest response rate.
... Only 51% of respondents indicated that they tested for FLT3-ITD in new AML referrals. Flow cytometry and karyotyping, on the other hand, were found to be routinely performed for the diagnosis of acute leukemia [13]. With increasing recognition of the importance of routine testing for FLT3 mutations in AML and the availability of FLT3 inhibitors, the frequency of FLT3 testing will likely increase in the future. ...
Genomic investigations of acute myeloid leukemia (AML) have demonstrated that several genes are recurrently mutated, leading to new genomic classifications, predictive biomarkers, and new therapeutic targets. Mutations of the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all AML cases, with the internal tandem duplication (ITD) representing the most common type of FLT3 mutation (FLT3-ITD; approximately 25% of all AML cases). FLT3-ITD is a common driver mutation that presents with a high leukemic burden and confers a poor prognosis in patients with AML. The prognostic value of a FLT3 mutation in the tyrosine kinase domain (FLT3-TKD), which has a lower incidence in AML (approximately 7–10% of all cases), is uncertain. Accumulating evidence demonstrates that FLT3 mutational status evolves throughout the disease continuum. This so-called clonal evolution, together with the identification of FLT3-ITD as a negative prognostic marker, serves to highlight the importance of FLT3-ITD testing at diagnosis and again at relapse. Earlier identification of FLT3 mutations will help provide a better understanding of the patient’s disease and enable targeted treatment that may help patients achieve longer and more durable remissions. First-generation FLT3 inhibitors developed for clinical use are broad-spectrum, multikinase inhibitors; however, next-generation FLT3 inhibitors are more specific, more potent, and have fewer toxicities associated with off-target effects. Primary and secondary acquired resistance to FLT3 inhibitors remains a challenge and provides a rationale for combining FLT3 inhibitors with other therapies, both conventional and investigational. This review focuses on the pathological and prognostic role of FLT3 mutations in AML, clinical classification of the disease, recent progress with next-generation FLT3 inhibitors, and mechanisms of resistance to FLT3 inhibitors.
... More recently (2015), 294 members of professional societies in the United States and Europe were surveyed about their testing practices. Among responders, 51 and 46% indicated that they tested for FLT3-ITD in all patients and selected patients, respectively [41]. This survey was intended to provide a baseline for testing prior to the release of the diagnostic workup guidelines jointly issued by the College of American Pathologists and the American Society of Hematology in 2017 [36]. ...
Activating mutations in FMS-like tyrosine kinase 3 (FLT3), including internal tandem duplications (ITDs) and tyrosine kinase domain (TKD) mutations, are common in patients with acute myeloid leukemia (AML). FLT3-ITD is a negative prognostic factor that remains prognostically relevant even after intensive chemotherapy and/or stem cell transplant. FLT3 testing was historically viewed as being purely prognostic; however, with the advent of FLT3 inhibitors, it will likely be seen as both prognostic and predictive. The multikinase inhibitor midostaurin, in combination with chemotherapy, is the first targeted agent to significantly prolong survival in patients with newly diagnosed FLT3-mutated AML and was recently approved by health authorities. Recently, the European LeukemiaNet recommended FLT3 testing (both TKD and ITD) for all patients with AML, with results required within 3 days. The need for optimized, multigene platform testing incorporating FLT3 mutations will increase as knowledge of interactions between FLT3 and other myeloid-relevant mutations grows.
Context.—:
The College of American Pathologists published guideline recommending bone marrow synoptic reporting for hematologic neoplasms.
Objective.—:
To evaluate the impact of pathology-driven algorithmic testing (PDAT) with integrated reporting for bone marrow examination on test utilization, ability to render a specific World Health Organization diagnosis, and clinician satisfaction 1 year after implementation.
Design.—:
We reviewed the hematopathology reports, integrated synoptic reports, and ancillary test results generated during a 12-month period. The initial diagnosis from the hematopathology report was compared with the final diagnosis on the integrated synoptic reports. Test utilization data were compared with a previous year in which ancillary testing was ordered at clinician discretion. Clinicians were anonymously surveyed to assess their satisfaction with PDAT and integrated reporting.
Results.—:
Integrated reporting resulted in a World Health Organization diagnosis for 80 of 85 cases (94%) compared with 54 (64%) for the hematopathology report alone. Unnecessary testing decreased from 45% pre-PDAT (124 of 274 cases) to 0.7% PDAT (2 of 268 cases), and PDAT resulted in fewer omissions of necessary tests. Clinicians preferred PDAT and valued integrated reporting for a variety of reasons, including the ease of finding relevant prognostic information.
Conclusions.—:
Pathology-driven algorithmic testing with integrated reporting improves the pathologist's ability to render a specific World Health Organization diagnosis and improves test utilization. Clinicians prefer PDAT to clinician-ordered testing. This is the first study to examine how synoptic reporting can modify hematologic diagnoses.
