Extramedullary Acute Myeloid Leukemia Research Articles

Atypical Presentation of Acute Suppurative Otitis Media with Facial Palsy: Extra Medullary Manifestation of AML in Temporal Bone.

Acute Myeloid Leukemia (AML) is the most common leukemia observed in the adult population, accounting for 80% of all leukemia cases. Extramedullary involvement in AML, where leukemic cells are found in organs or tissues outside the blood or bone marrow, is a rare occurrence [1]. The most frequent sites of extramedullary disease include the skin, central nervous system (CNS), and lymph nodes [2, 3]. In this case report, we present an instance of extramedullary AML in the temporal bone, which initially presented with symptoms such as earache, discharge, and facial asymmetry, mimicking acute suppurative otitis media with facial palsy. The patient underwent mastoid exploration and facial nerve decompression. A post-operative bone marrow biopsy confirmed the diagnosis of AML, leading to the initiation of chemotherapy. The patient is currently under follow-up care.

Acute myeloid leukemia: An unusual manifestation of the trachea.

Hematologic malignancy involving the trachea is rare. It is even less common for tracheal involvement to be the initial manifestation of this disease. We present a case report highlighting an unusual diagnosis of acute myeloid leukemia (AML) that first presented with prominent tracheal manifestations. There have been only three other published case reports of extramedullary AML with involvement of the trachea. We discuss direct laryngoscopy and bronchoscopy findings, including pinkish-white irregular lesions, which were similar to findings described in the available literature for tracheal AML. Laboratory findings from our case are reported, including peripheral smear demonstrating 57% blasts and bone marrow biopsy confirming the diagnosis of AML, and the relevance of these findings is discussed. In patients with unusual airway lesions, laboratory testing and a comprehensive airway evaluation including biopsy are necessary to narrow the differential diagnosis. 5.

Organomegalies as a predictive indicator of leukemia cutis in patients with acute myeloid leukemia.

Leukemia cutis (LC) is an extramedullary acute myeloid leukemia (AML) infiltrate. No previous study has described the clinical characteristics and outcomes of Thai patients diagnosed with AML with LC. We conducted a 7-year retrospective case-control study on Thai AML patients at Siriraj Hospital from November 2013 to July 2020. Patients were divided into LC and non-LC groups. Initial clinical presentations and laboratory findings were examined to identify LC-associated factors. Overall survival (OS) and relapse-free survival (RFS) were assessed. Pathological tissues underwent re-evaluation to validate the LC diagnoses. The study included 159 patients in a 2:1 ratio (106 non-LC and 53 LC). The LC group had a mean ± SD age of 54.3 ± 15.5 years; females were predominant. Three-fifths of the LC patients had intermediate-risk cytogenetics; 20.4% had an adverse risk, and 10.2% had a favorable risk. Most were classified as AML-M4 and AML-M5. Leukemic nodules were the primary finding in 58.5% of the cases, mainly on the legs. In the multivariate analysis of predictive factors associated with LC, organomegalies, specifically hepatomegaly, and lymphadenopathy, remained significant factors associated with LC [OR 4.45 (95%CI 1.20, 16.50); p = 0.026 and OR 5.48 (95%CI 1.65, 18.20); p = 0.005], respectively. The LC group demonstrated a significantly reduced OS (log-rank test p = 0.002) (median OS of 8.6 months vs. 32.4 months). RFS was considerably lower in the LC group (log-rank test p = 0.001) (median duration of 10.3 months vs. 24.4 months in the non-LC). AML patients who developed LC tended to experience notably poorer prognoses. Therefore, it is imperative to consider aggressive treatment options for such individuals. The presence of organomegalies in AML patients serves as a strong predictor of the possible occurrence of LC when accompanied by skin lesions.

Acute myeloid leukemia with monocytic differentiation (myeloid sarcoma) masquerading as bone-soft tissue malignancy

Abstract Introduction/Objective Myeloid sarcoma is an extramedullary solid neoplasm composed of myeloid precursors with or without maturation. This tumor usually occurs simultaneously or following the onset of acute leukemia. Rarely, it can be the first manifestation of acute myeloid leukemia. We report a case of this rare tumor presenting histologically as a bone sarcoma with features of extraskeletal myxoid chondrosarcoma and myoepithelial carcinoma Methods/Case Report A 76-year-old female was referred to our institution for evaluation of a right foot mass associated with pain and swelling. MRI showed a 2.4 x 1.5x 1.2 cm soft tissue mass along the lateral margin of proximal and mid diaphysis of first metatarsal. The clinical and radiologic differential diagnosis was primary bone-soft tissue malignancy, or infection. Histologically, the biopsies showed sheets and cords of cells in a myxoid background. Cytologically the cells were plasmacytoid, mononuclear, mitotically active with immature chromatin, prominent nucleoli, and moderate to abundant cytoplasm. This morphologic appearance elicited the differential diagnosis of extraskeletal myxoid chondrosarcoma, myoepithelial carcinoma, and plasmacytoma. An initial panel of immunohistochemical stains showed the lesional cells to be negative for S-100, SOX-10, pancytokeratin, desmin, p63, EMA, CAM5.2, and CD138 but positive for CD43. Additional immunohistochemistry showed diffuse reactivity for CD33, and lysozyme; CD163 was focally positive, and the cells were negative for CD20, CD3, CD30, CD99, MUM1, CD138, and CD34. A diagnosis of extramedullary acute myeloid leukemia with monocytic differentiation (myeloid sarcoma) was rendered. Subsequently, patient underwent bone marrow biopsy which showed involvement by acute myeloid leukemia with monocytic differentiation. Results (if a Case Study enter NA) NA Conclusion Myeloid sarcoma is a rare tumor and presentation as an isolated metatarsal mass is highly unusual and exceedingly rare. This can mislead clinicians, radiologists, and pathologists. Pathologists need to keep hematopoietic tumors in their differential diagnosis even when the anatomic sites as well as the morphology are not typical of hematopoietic malignancies.

Outcomes of Extramedullary Acute Myeloid Leukemia with Gemtuzumab Ozogamicin: Real-World Experience

Introduction: Extramedullary AML (EM AML) is characterized by the presence of leukemic cells in organs or tissues outside of the blood or bone marrow and remains a therapeutic challenge with dismal response rates to standard chemotherapy and short overall survival. Gemtuzumab Ozogamicin (GO) is an anti-CD33 antibody drug conjugate currently approved for single-agent therapy or in combination regimens for CD33+ relapsed/refractory (R/R) or newly diagnosed (ND) AML, respectively. Although GO is an active drug in AML, the optimal employment of this agent for treatment of EM AML at initial diagnosis, or at relapse, remains to be defined. Methods: A retrospective chart review on outcomes of GO in adults with EM AML at our institute from 2000 to 2023 was performed. Variables collected included age, sex, type of myeloid malignancy, and European LeukemiaNet (ELN) risk, bone marrow, peripheral blood and radiographic involvement, Response Evaluation Criteria in Solid Tumors (RECIST), prior lines of treatments, including stem cell transplant, next-generation sequencing (NGS), cytogenetics, mutational profile, and overall survival (OS). We screened patients with a diagnosis of EM AML who received GO at any point during their EM AML therapy. Patients with only CNS involvement as the extramedullary site were excluded. The aims of this study were to characterize responses and potential clinical benefit of EM AML to GO based regimens in the upfront and R/R settings. Results: 32 patients(pts) with EM AML received GO: 8 (25%) were ND and received GO-based induction regimen, while 22 (68.75%) received GO for R/R AML, and 2 (6.25%) patients received GO both at initial diagnosis and relapse. The median age of patient with ND EM AML was 66 years (y) (range: 28-84), and 60.5 (43-73) y in R/R EM AML. Twenty-four (75%) were men. One (12.5%) ND EM AML and 5 (10.1%) R/R EM AML had >1 extramedullary sites involved. The most frequent sites of EM-AML were skin (25%), lymph nodes (25%), soft tissues (25%), solid organs (25%), and visceral body cavity fluids (12.5%). Based on ELN 2022 risk group criteria, 17 patients were adverse, 8 with intermediate, and 3 with favorable risk. Next-Generation Sequencing (NGS) available for 21 patients identified mutations in TP53 (14.28%), FLT3 (19.04%), NPM1 (19.04%), KMT2A (19.04%), and ASXL1 (19.04%) as the most common mutations. Normal karyotype was noted in 6 (25%) R/R EM AML, while complex karyotype was present in 1 (12.5%) ND EM AML and 10 (41.67%) of R/R EM AML. While none of the ND pts had prior myeloid malignancy, R/R pts had prior AML (15), MDS (2), MDS-EB (1), CMML (1), therapy-related AML (1), myelofibrosis (1), and myeloid sarcoma (1). Concomitant bone marrow involvement at identification of EM AML was present in most ND cases (7/8, 88%) and R/R settings (16/23, 69.56%) (Table 1). Combination 7+3 plus GO was most frequently administered for ND EM AML (3/8) and R/R EM AML (8/24, 33%). Eleven patients had measurable radiologic findings prior to and following GO. Median OS was 10.91 months (m) (range: 0.2 to 27.1) for ND EM AML and 1.58 m (range: 0.7 to 7.5) for R/R EM-AML (Figure 1). 3 of 8 newly diagnosed EM-AML underwent allogeneic bone marrow transplant (AlloBMT) after GO based induction, followed by relapsed EM AML in 1 patient. Despite 50 percent of R/R EM AML pts undergoing prior AlloBMT, none had a durable disease-free response and received GO after relapse. Based on RECIST criteria, 7 of 11 (63.63%) pts achieved a response including 1 Complete Response (disappearance of all target lesions), 6 Partial Response (at least a 30% decrease in the sum of target lesions), and 2 Stable Disease (neither sufficient shrinkage nor increase). The 30-day mortality for ND and R/R were 12.5% and 8.33%, respectively. The 60-day mortality for ND and R/R were 25% and 50%, respectively. Conclusion: Our real-world single-institute experience in patients with EM AML suggests that GO combined with chemotherapy in the upfront setting results in promising outcomes with high overall response rates (CR 50%, PR 13%) by RECIST criteria, durable remissions, and prolonged overall survival in largely favorable and intermediate risk AML. However, despite high partial response rates (4% CR, 50% PR) following GO-based therapy in R/R EM AML, survival was less than 2 months likely due to the high proportion of patients in this cohort with poor risk disease. Further investigations and larger studies are warranted to establish the optimal use of GO in EM AML.

A Prognostic Score Model for Relapsed/Refractory Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Introduction Patients with acute myeloid leukemia (AML) can achieve complete remission (CR) after receiving initial therapy, while some patients will develop relapsed/refractory AML (R/R-AML), which has a poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been shown to be effective in improving the prognosis of R/R-AML patients. It is necessary to evaluate the factors that can affect the prognosis of patients receiving allo-HSCT for R/R-AML, including leukemia-free survival (LFS) and overall survival (OS). In previous studies, such prognostic evaluation factors included cytogenetics, response to salvage induction therapy before transplantation, time from diagnosis to transplantation, and acute graft-versus-host disease (aGVHD). However, there is still a lack of a prognostic model that can systematically predict prognosis at an early stage after transplantation. In this study, a prognostic model was established to predict the 2-year prognosis of R/R-AML patients receiving allo-HSCT. Method Refractory AML is defined as no CR after 2 courses of intensive induction treatment, while relapsed AML is defined as ≥ 5% bone marrow blasts, reappearance of blasts in the blood or development of extramedullary AML after CR. In this retrospective study, patients receiving allo-HSCT for R/R-AML from January 1, 2015, to June 30, 2021 at Peking University People's Hospital were identified and divided into a derivation cohort and an external validation cohort according to the time of transplantation. Detailed data of all patients were collected from medical records. Categorical variables were analyzed using the 2-tailed Fisher's exact test. Continuous variables were analyzed using the Mann‒Whitney U test. Factors with a P value < 0.10 were included in the multivariate Cox analysis. Factors that were identified as independent prognostic factors in the multivariate Cox analysis were included in the score model. Results A total of 200 patients who received allo-HSCT for relapsed/refractory AML were identified. The median age of diagnosis of AML was 39.5 years (range, 18-68 years), and the median age of transplantation was 40 years (range, 20-68 years). In the overall survival analysis, age at diagnosis, age at transplantation, sex, white blood cell (WBC) count at diagnosis, WBC engraftment time and duration from AML diagnosis to allo-HSCT were identified as potential prognostic factors. In the multivariate Cox analysis, age > 55 years (HR, 3.587; 95% CI, 1.099 to 11.702; P =.034), WBC level at AML diagnosis < 4.0×10^9/L (HR, 4.548; 95% CI, 1.209 to 17.104; P =.009) and duration from AML diagnosis to HSCT > 250 days (HR, 6.541; 95% CI, 0.941 to 5.488; P =.058) were identified as independent prognostic factors. A model for the survival rate of R/R AML patients receiving allo-HSCT was developed according to the regression coefficients of the multivariate analysis. Patients who met the criteria of age > 55 years, WBC level at AML diagnosis < 4.0×10^9/L or duration from AML diagnosis to HSCT > 250 days received 1 point for each variable. Points 0, 1-2, and 3 were defined as low, median and high risk, respectively. This prognostic score model performed well in the external cohort (AuROC =.783; 95% confidence interval,.599 to.966). In the LFS analysis, WBC count at AML diagnosis < 4.0×10^9/L (HR, 3.120; 95% CI, 1.198 to 8.122; P =.020) and female sex (HR, 2.778; 95% CI, 1.013 to 7.617; P =.047) were related to poor LFS . Conclusion In this study, we developed a prognostic score model of 2-year OS for R/R‒AML patients after receiving allo-HSCT. Independent prognostic factors included age at transplantation (> 55 years), WBC count at AML diagnosis (< 4.0×10^9/L) and duration from AML diagnosis to HSCT (> 250 days). This model can effectively evaluate the 2-year mortality of R/R-AML patients after receiving allo-HSCT and help improve the prognosis of patients. There was a higher mortality for patients with R/R‒AML after receiving allo-HSCT when the WBC count at the time of AML diagnosis was lower than the normal range. Considering that the main cause of death of patients in this study was infection, this correlation may be related to the destruction and reconstruction of the immune system.

The Genomic and Transcriptomic Landscape of Myeloid Sarcoma and Associated Acute Myeloid Leukemia

Background: Myeloid sarcoma (MS) is a distinct form of acute myeloid leukemia (AML) found in ~10% of patients, in which mass-forming myeloid blasts proliferate in extramedullary sites. MS may present as an isolated lesion as the primary manifestation of disease, co-occur with AML, or, more commonly, arise in the setting of AML relapse. It is associated with poor outcomes, and treatment options are sparse. While increased knowledge of AML and its biology have improved the care and survival of AML patients, those with MS continue to have limited successful treatment options, as MS has typically not been included in AML genetic and genomic profiling efforts, and patients are excluded from clinical trials. Leukemia cutis (LC) is a form of extramedullary AML characterized by cutaneous involvement, often with an infiltrative and non-mass forming pattern of growth. Still, historically the literature has not made a clear distinction between MS and LC. Although recent small pilot studies have suggested differences in AML-associated mutations between medullary AML and MS, knowledge of the complete molecular and cellular composition of MS and comprehensive comparison with AML is lacking. While molecular characterization of the extramedullary disease site is encouraged in the updated clinical recommendations, no definitive guidance exists for changes in the management and care of AML patients with MS, given the substantial gap in our current knowledge and understanding of extramedullary AML. Methods: Here, we performed RNA-Seq (n=96), single-cell (sc) RNA-Seq (n=33), and mutation profiling using either whole exome sequencing (WES, n=6) or a 409-gene targeted sequencing panel (n=48) of MS or LC patient samples and bone marrow (BM) aspirates from AML patients with and without extramedullary disease to present the first comprehensive characterization of MS and LC. Results: Our WES data showed thatMS and LC evolve independently in the extramedullary site from concurrent medullary disease with distinct dominant clones, characterized by higher median tumor mutation burden (1.66 vs. 064 mutations per megabase, respectively; p=0.0059) and increased copy number aberrations, which both validated in an MS Tet2 HR mouse model. Notably, we observed location-specific molecular evolution in patients with multiple concurrent MS sites (Figure 1A) and patients with recurring MS in WES and targeted panel data. While targetable mutations (i.e., IDH1/2 mutations and FLT3-ITD/TKD) occur, the inter-site variability of molecular aberrations may explain the short-lived responses of AML patients with MS to IDH/FLT3 inhibitors. Transcriptional profile differences between MS and associated medullary disease included up-regulation of extracellular matrix organization and cell-substrate adhesion and down-regulation of inflammatory response pathways in both bulk and scRNA-seq data (Figure 1B). Further, involved BM malignant cells of MS patients compared to patients without MS up-regulated specific pathways, including interferon-gamma response observed in both bulk and scRNA-seq, as well as chromatin organization and splicing. We further revealed that MS patients without overt BM involvement show remodeling of the BM immune microenvironment, with increased fractions of hematopoietic stem and progenitor cells that down-regulate HLA class II genes. Comparing LC and MS in the skin revealed distinct differences in their expression profiles, including high expression of genes involved in cell migration and immune response in LC, suggesting LC and MS represent distinct disease entities. Lastly, we demonstrated high expression of BCL2 in extramedullary disease (p=0.0074) and presented initial evidence that treatment with BH3-mimetics may be beneficial for the treatment of isolated MS. Conclusions: Myeloid sarcoma shows distinct molecular evolution and microenvironmental composition compared to medullary disease, including location-specific evolution necessitating personalized management consideration. Leukemia cutis is distinct from MS tumorous lesions and should be considered a separate entity. High BCL2 expression in extramedullary disease might represent a promising targetable vulnerability in patients with isolated MS.

Expression profiling of extramedullary acute myeloid leukemia suggests involvement of epithelial-mesenchymal transition pathways.

Extramedullary (EM) colonization is a rare complication of acute myeloid leukemia (AML), occurring in about 10% of patients, but the processes underlying tissue invasion are not entirely characterized. Through the application of RNAseq technology, we examined the transcriptome profile of 13 AMLs, 9 of whom presented an EM localization. Our analysis revealed significant deregulation within the extracellular matrix (ECM)-receptor interaction and focal-adhesion pathways, specifically in the EM sites. The transcription factor TWIST1, which is known to impact on cancer invasion by dysregulating epithelial-mesenchymal-transition (EMT) processes, was significantly upregulated in EM-AML. To test the functional impact of TWIST1 overexpression, we treated OCI-AML3s with TWIST1-siRNA or metformin, a drug known to inhibit tumor progression in cancer models. After 48 h, we showed downregulation of TWIST1, and of the EMT-related genes FN1 and SNAI2. This was associated with significant impairment of migration and invasion processes by Boyden chamber assays. Our study shed light on the molecular mechanisms associated with EM tissue invasion in AML, and on the ability of metformin to interfere with key players of this process. TWIST1 may configure as candidate marker of EM-AML progression, and inhibition of EMT-pathways may represent an innovative therapeutic intervention to prevent or treat this complication.

Irradiated Extramedullary Acute Myeloid Leukemia Increases Survival in a Leukemic Mouse Model

The systemic nature of AML likely limits their immunogenicity because antigen presentation is primarily mediated by splenic dendritic cells, which induces immune tolerance. Since antigen presentation in tissue draining lymph nodes can induce anti-tumor immune responses, we hypothesized that local irradiation of cutaneous, extramedullary leukemias will increase immunogenic cell death, dendritic cell maturation and improved survival. A murine AML cell line C1498 was assessed for immunogenic markers calreticulin (CALR), HMGB1 and cGAS-STING pathway using fluorescence cytometry and qRT-PCR. Syngeneic mice were injected with C1498 subcutaneously to model extramedullary lesions and intravenously to model systemic leukemias. Cells and subcutaneous tumor were focally irradiated with 2 Gy or 8 Gy. Two-way ANOVA and Student's t-test were used for paired-wise comparisons. Survival was estimated by Kaplan-Meier plot and groups were compared using log-rank test. C1498 cells or tumors irradiated with 2 Gy or 8 Gy showed increased CALR and HMGB1 as well as (cGAS/Md21b1; 5-fold; p<0.001) and interferon alpha (Ifna; 3-fold; p<0.001) after 48h (18- and 4-fold, respectively; p<0.05) compared to not treated controls (NTC). Irradiated C1498 subcutaneous tumors displayed increased CD11b-positive cells (9-fold; p<0.001), CD11c (6-fold; p<0.001), and MHCII-positive CD11c cells (4-fold; p<0.01) in irradiated tumors compared to NTC. Irradiation of subcutaneous C1498 tumors increased median survival in mice also injected with C1498 cells intravenously compared to non-irradiated mice bearing systemic leukemias (46 vs. 25 days; p<0.01). Irradiation of C1498 tumors combined with anti-PDL1 treatment further increased median survival in our leukemia model compared to untreated controls (>50 vs. <30 days; p<0.001). Irradiated extramedullary AML increased immunogenic markers and activation of immune effector cells that correlated with increased survival in mice also bearing systemic leukemia. These results suggest focal irradiation of extramedullary AML may facilitate eradiation of systemic leukemias.

The Role of CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 Ligands in Molecular Cancer Processes and Clinical Aspects of Acute Myeloid Leukemia (AML).

Acute myeloid leukemia (AML) is a type of leukemia known for its unfavorable prognoses, prompting research efforts to discover new therapeutic targets. One area of investigation involves examining extracellular factors, particularly CXC chemokines. While CXCL12 (SDF-1) and its receptor CXCR4 have been extensively studied, research on other CXC chemokine axes in AML is less developed. This study aims to bridge that gap by providing an overview of the significance of CXC chemokines other than CXCL12 (CXCR1, CXCR2, CXCR3, CXCR5, and CXCR6 ligands and CXCL14 and CXCL17) in AML's oncogenic processes. We explore the roles of all CXC chemokines other than CXCL12, in particular CXCL1 (Gro-α), CXCL8 (IL-8), CXCL10 (IP-10), and CXCL11 (I-TAC) in AML tumor processes, including their impact on AML cell proliferation, bone marrow angiogenesis, interaction with non-leukemic cells like MSCs and osteoblasts, and their clinical relevance. We delve into how they influence prognosis, association with extramedullary AML, induction of chemoresistance, effects on bone marrow microvessel density, and their connection to French-American-British (FAB) classification and FLT3 gene mutations.

Early occurrence of acute myelomonocytic leukemia (M4/M5) after liver transplantation: a case report

IntroductionAcute myeloid leukemia is a rare event in post-liver-transplantation recipients. In the present report, we described a case of extramedullary acute myeloid leukemia, M4/M5 subtype, following orthotopic liver transplant.Case presentationThe patient was a 50-year-old Iranian woman who underwent orthotopic liver transplant due to hepatitis B-related cirrhosis (Child C, MELD (model for end-stage liver disease score) = 22). Orthotopic liver transplant was performed using the piggy back technique in January 2022. Induction immunosuppressive therapy was 1 gm methylprednisolone for 3 days followed by a triple maintenance immunosuppressive regimen including mycophenolate mofetil, prednisolone, and tacrolimus. About 5 months after orthotopic liver transplant in June 2022, the patient presented with leukocytosis, with white blood cell count of 99.4 × 103/µl, and physical examination revealed only cervical lymphadenopathy. Biopsy of cervical lymph nodes showed a myeloid tumor. She was immediately hospitalized. Eight hours after hospitalization, the patient gradually developed lethargy and decreased O2 saturation to approximately 89%. Flow cytometry demonstrated the markers of a myelomonocytic acute myeloid leukemia (M4/M5). Cytoreduction was immediately started by intensive leukopheresis followed by induction therapy. Because of a septic complication during the induction therapy, further chemotherapy was discontinued and broad-spectrum antibiotics and antifungal treatments started. Unfortunately, our patient died of severe septic shock 42 days after hospitalization.ConclusionAcute myeloid leukemia is a rare phenomenon after liver transplantation, and it can follow a rapidly fatal clinical course.

POSTER: AML-440 Extramedullary Acute Myeloid Leukemia: Could New Targets and Allogeneic Stem Cell Transplantation Improve Outcomes?

POSTER: AML-440 Extramedullary Acute Myeloid Leukemia: Could New Targets and Allogeneic Stem Cell Transplantation Improve Outcomes?

AML-440 Extramedullary Acute Myeloid Leukemia: Could New Targets and Allogeneic Stem Cell Transplantation Improve Outcomes?

AML-440 Extramedullary Acute Myeloid Leukemia: Could New Targets and Allogeneic Stem Cell Transplantation Improve Outcomes?

Extramedullary involvement in pediatric myeloid leukemia: challenges of diagnosis and treatment. Clinical cases and a literature review

The problem of extramedullary (EM) involvement in acute myeloid leukemia (AML) in children is of considerable relevance since its pathogenesis remains understudied and the impact on prognosis is still unclear. The variability of tissue and organ involvement depends on immunophenotypic, cytogenetic, and molecular features of myeloid cells and can cause difficulties in diagnosis, thus making it necessary to combine imaging and laboratory tools for timely and accurate diagnosis of EM disease. The prognostic significance of EM involvement has not been established unequivocally, thus the need for intensification of chemotherapy, as well as for allogeneic hematopoietic stem cell transplantation in first remission, remain debatable. The results of target therapy in EM AML are encouraging and may reduce the risk of AML relapse. This article describes the clinical features of EM AML in children and reviews the diagnostic approaches as well as the advantages and limitations of existing laboratory and imaging methods. The molecular features of EM AML, current treatment options and prognosis have also been analyzed. The patients' parents gave their consent to the use of their children's data, including photographs, for research purposes and in publications.

PLEURAL EFFUSION AS AN INITIAL PRESENTATION OF EXTRAMEDULLARY ACUTE MYELOID LEUKEMIA: A RARE PHENOMENON

PLEURAL EFFUSION AS AN INITIAL PRESENTATION OF EXTRAMEDULLARY ACUTE MYELOID LEUKEMIA: A RARE PHENOMENON

AML-396 Venetoclax-Containing Regimens Improve Outcomes of Intensive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation in Patients With Extramedullary Acute Myeloid Leukemia

The optimal treatment strategy for patients with extramedullary acute myeloid leukemia (eAML) is questionable, especially as applied to extramedullary tumor persistence while bone marrow response is achieved. To determine whether venetoclax-containing regimens, intensive treatment, and allogeneic hematopoietic stem cell transplantation (alloHSCT) can improve outcomes in patients with eAML. Overall, 27 patients with verified eAML were included: 14 were male and 13 were female with a median age of 40 years (13-84). Standard ("7+3"), high-intensity ("HiDAC", "FLAG±Ida"), and low-intensity chemotherapy regimens were administered to all patients. Ten patients (37%) received venetoclax with 5-azacytidine (VEN-AZA) because of comorbidities or refractory disease. AlloHSCT was performed in 17 patients (63%). According to the 2017 ELN risk stratification system, 18.5% (5/27) were favorable risk, 25.9% (7/27) were intermediate risk, and 55.6% (15/27) were adverse risk. Patients with favorable genetic alterations achieved bone marrow remission more frequently (100% vs. 44%, P=0.044) but did not have advantages in the rate of complete extramedullary response (75% vs. 68%, P>0.05). Using HiDAC enabled eradication of extramedullary lesions in case of failure of standard and low-intensity regimens (85% vs. 0%, P=0.044) and decreased the rate of early (during the first 12 months) relapse (38% vs. 100%, P=0.019). The overall response rate to VEN-AZA was 70% (7/10). Five patients (50%) achieved complete eradication of extramedullary tumor after venetoclax; among them, 3 still had persistent extramedullary disease after HiDAC. Performing alloHSCT in first complete remission decreased the risk of early relapse (12% vs. 80%, P=0.015) and demonstrated better median overall survival (38.85 vs. 7.57 months, P=0.013) and relapse-free survival (38.85 vs. 3.78 months, P=0.0021) compared to alloHSCT performed in second and subsequent complete remissions. Favorable genetic aberrations do not increase the frequency of extramedullary response. Intensive treatment helps to achieve complete eradication of extramedullary tumor and reduces early relapse rate. Using VEN-AZA is effective among patients with eAML, including patients who were refractory to intensive treatment, and allows complete response achievement before alloHSCT. The best time to perform the alloHSCT among patients with eAML is the first complete remission.

Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations.

Genomic landscape of extramedullary acute myeloid leukemia (EM-AML), including myeloid sarcoma (MS) and leukemia cutis (LC), is not well characterized. The potential utility of next-generation sequencing (NGS) using EM tissue is not established. In this multicenter retrospective study, clinical and NGS data were collected on patients with EM-AML. All statistical analyses were performed in SPSS Statistics (v 26). Our study included 58 patients with EM-AML. The median age at diagnosis was 62 years; 59% of patients had MS and 33% had LC. EM-AML was isolated (i.e., without blood or marrow involvement) in 31% and was first noted at relapse in 60% of patients. Median overall survival in our cohort was 18.2 months overall, with 19.1 months and 11.6 months in the newly diagnosed and the relapsed/refractory patients, respectively. At least one targetable or potentially targetable alteration was present in 52% of patients with EM-site NGS, with 26% IDH1, 21% NPM1, 11% IDH2, 6% FLT3, and 13% KMT2A-PTD. Mutations in IDH1 were significantly more prevalent on NGS from EM tissue than non-EM (blood or marrow) samples (26% vs. 3%; p= .030). Three of four patients treated with IDH inhibitors based on EM-site NGS experienced a complete response. Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML.

Clinicopathologic characteristics and treatment outcomes of de novo myeloid sarcoma.

e19002 Background: Extramedullary disease in acute myeloid leukemia (AML), also known as myeloid sarcoma (MS), is an uncommon presentation of de novo AML. Clinicopathologic characteristics and optimal treatment strategies of de novo MS remain unclear in both isolated MS without bone marrow (BM) involvement and synchronous MS with BM involvement. Methods: In a single-site retrospective study, medical records of patients with de novo extramedullary AML who received oncological care at any Mayo Clinic site between 1996 and 2021 were analyzed. Using BlueSky Statistics software, survival outcomes were analyzed using Kaplan-Meier and Cox-proportional hazard models for univariate and multivariate analysis, respectively. Results: 83 patients with de novo MS were identified; 49 (59%) presented with synchronous MS and 34 (41%) exhibited isolated MS. Median age at diagnosis was 56 years (range, 17-89); 63% were male. Next-generation sequencing of the blood +/- BM revealed abnormalities in 24/27 (88%) analyzed patients; aberrations included mutations in RTK-RAS pathways (12/27), NPM1 (10/27), TET2 (6/27), and IDH2 (4/27). Median length of follow-up was 1.73 years (95% CI; 0.03-3.0); 53 patients (64%) had expired. Median event free survival was 0.64 years and 0.61 years in isolated and synchronous MS, respectively (p = 0.5). Median overall survival (mOS) in isolated and synchronous MS was 2.1 years and 1.5 years, respectively (p = 0.5). Induction treatment with intensive chemotherapy (IC) was administered in 70 patients (84%). IC regimens included 7+3, MEC, CLAG-M, and hyper-CVAD. Variables associated with improved survival in both groups included treatment with IC +/- allogenic stem cell transplant (alloSCT) (p &lt; 0.001), normal or favorable risk karyotype (p = 0.001), and age less than 60 (p = 0.001). Localized therapy (LT) did not provide an added survival benefit. Patients with synchronous MS were more likely to relapse in the BM and blood than isolated MS (p = 0.02). Conclusions: Enriched with RTK-RAS mutations, de novo MS remains an aggressive form of AML, particularly in patients with intermediate or high-risk genomics or those with skin, soft tissue, or lymphatic involvement. IC should be employed with consideration of alloSCT in eligible patients, particularly in synchronous MS due to a heightened risk for medullary and leukemic relapse.[Table: see text]

Extramedullary Acute Myeloid Leukemia: Testicular Myeloid Leukemia, Leukemia Cutis with Leptomeningeal Involvement

Extramedullary Acute Myeloid Leukemia: Testicular myeloid leukemia, leukemia cutis with leptomeningeal involvementZ Saeed, H Aslam, A Weil, M MuzaffarMyeloid sarcoma also called granulocytic sarcoma, myeloblastoma, or chloroma is an extramedullary tumor of immature granulocytic cells. Extramedullary soft tissue manifestations are relatively rare in hematological malignancies. One of the rarest manifestations is myeloid sarcoma (MS). MS develops as part of acute myeloid leukemia, myeloproliferative neoplasm, or myelodysplastic syndrome or at relapse, especially following allogeneic hematopoietic stem cell transplant. Demographically, it has a slight male predominance with a male to female ratio of 1.2: 1. It may occur at any age and any site in the body leading to varied clinical presentations. The most reported sites are lymph nodes, skin and soft tissues, bone, testes, gastrointestinal tract, and peritoneum.44 year old male with past medical history of diabetes mellitus type 2 and morbid obesity presented with right testicular pain and swelling and underwent radical orchiectomy. Pathology reported seminoma and received adjuvant Carboplatin for pT3 disease. He developed left testicular pain and swelling 2 months later and underwent left radical orchiectomy. Pathology reported CD4+, CD56+ high grade hematopoietic neoplasm. It was sent for second opinion to NIH and was consistent with myeloid sarcoma with monoblastic features. Repeat evaluation of right testicular specimen was CD45+. Bone marrow biopsy showed normocellular marrow with multilineage hematopoiesis. PET scan showed hyper metabolic activity in the right hemi scrotum, widespread osseous areas of increased uptake and 3 soft tissue nodules within the subcutaneous tissues of the left abdominal wall. FNA of the subcutaneous nodule showed CD56 positive monocytoid cells. Induction chemotherapy with 7+3 (cytarabine 200 mg/m2, daunorubicin 60mg/m2) with gemtuzumab 3mg/m2 on day 1, 4, 7 was completed. Cerebrospinal fluid studies (CSF) showed monoblastic/monocytic proliferation and received intrathecal (IT) chemotherapy alternating between methotrexate and cytarabine every week. CSF studies were cleared after 2 IT chemotherapy. Patient remained in the hospital for 87 days due to poor count recovery and development of pulmonary embolism. Myeloid mutation screening identified a mutation in NRASG13D. Repeat PET scan showed 7 areas of hypermetabolic foci involving nodular densities of bilateral lower anterior abdominal wall. One of the lesion was biopsied that was negative. He completed 2 cycles of high dose cytarabine for consolidation but had repeated hospital admissions and therapy was switched to azacytidine and venetoclax. Patient was evaluated by bone marrow transplant team. He had disease progression at tenth month when he presented with severe back pain and lower extremity weakness. MRI brain and spine showed new patchy T2 hyperintense signal in the right frontal white matter, increased number and size of marrow replacing lesions throughout the visualized skeleton. Patient underwent bone biopsy that showed >90% marrow involvement (sheets of infiltrative cells with identical phenotype. Positive for CD56 (>90% of marrow cellularity), CD4 and lysozyme. Hospital course was complicated with renal failure, electrolytes imbalance and hemodynamically instability requiring vasopressor support. Discussions were held for re-induction with CLAG (cladribine 5mg/m2, and cytarabine 2gm/m2) vs best supportive care. Patient decided to pursue comfort care and passed away peacefully.The uniqueness of this case is the myeloid sarcoma of testes as initial presentation with normal bone marrow. Misdiagnosis is not uncommon and can delay the appropriate treatment. Extra medullary involvement from leukemia is very aggressive and needs high suspicious and prompt treatment. Systemic chemotherapy using AML-like regimens should be commenced early, even in non leukemic disease. Allogeneic hematopoietic stem cell transplantation has demonstrated promising results, particularly in patients who achieved complete remission with AML-induction protocols, and recent advances in genetic profiling may enable the development of novel targeted therapies. Prospective multicenter controlled trials are required to further refine management decisions and investigate the role of novel targeted therapies. DisclosuresNo relevant conflicts of interest to declare.

Extramedullary acute myeloid leukemia (eAML): Retrospective single center cohort study on clinico-pathological, molecular analysis and survival outcomes

Introductionextramedullary acute myeloid leukemia (eAML) is characterized by extramedullary tumor formation infiltrated by myeloid blasts, with or without maturation and effaced architecture. The clinical, genetic and molecular aspects and overall outcomes are well defined worldwide, but not well characterized in our region. Purpose and methodsThis is a retrospective single center cohort study on 32 patients, who were identified over 10 years to study the clinical, pathologic and genetic-molecular aspects, and survival outcomes. ResultseAML is rare (1%), occurs at a younger age with male predominance. Central nervous system (CNS) with facial bone invasion is most commonly identified (34.4%). 45.5% were positive for conventional myeloid markers (MPO), CD33, CD117, and 36% positive for CD34 and CD68. 54% with normal karyotype had deleterious mutations on further testing. NGS revealed pathogenic mutations in 76%(N-9/17) and none tested positive for P53, IDH1 or IDH2. At a median follow up time of 43mo (range, 8.6–80mo); 37.5%(N-12) were in complete remission, 62.5%(N-20) relapsed. 28% of relapses were after allotransplant. 31%(N-10) alive and continued in complete remission(CR), and 69%(N-22) of patients have died.Median overall survival (OS) is 18.4 and relapse free survival (RFS) 18.7 months. OS and RFS were significantly better in patients, who attained CR after induction (IC 11.9 mo vs zero; P = 0.0001; IC 12mo vs zero; P = 0.0001) compared to patients with relapsed disease; and in patients who received allo-transplant consolidation with median OS and RFS 42 vs 8.5mo (P = 0.002) and 42months vs 10 mo (P = 0.006). Thus allotransplant may be considered for all eligible patients in first CR. Conclusionachievement of complete remission after induction therapy is associated with improved outcomes in eAML. Allotransplant in first complete remission may be the most effective modality for achieving long-term remissions.