Acute Myelogenous Leukemia Research Articles

Compound #41 Targets Acute Myelogenous Leukemia by Inhibiting the Wnt/β-catenin Signaling Pathway.

Aberrant activation of the Wnt/β-catenin signaling pathway contributes to the pathogenesis of acute myelogenous leukemia (AML). Thus, targeting this pathway offers a promising therapeutic strategy against AML. Here, we synthesized a novel dipeptide-type inhibitor of the Wnt/β-catenin signaling pathway, compound #41, and explored its anti-tumor effects on AML cells. We evaluated the inhibitory effect of compound #41 on T cell factor (TCF)/β-catenin transcriptional activity using a luciferase (Luc) reporter assay. The anti-tumor effects were assessed on KG1a and MV4;11 human AML cells using RT-qPCR, western blotting, and WST-8, cell cycle, and apoptosis assays. Differentially expressed genes were analyzed by RNA-sequencing (RNA-seq). Additionally, we investigated the in vivo effects of compound #41 using KG1a-Luc/GFP cells in an orthotopic mouse model. The Luc reporter assay showed that compound #41 decreased the TCF/β-catenin transcriptional activity. Compound #41 blocked the cell cycle progression, inhibited cell proliferation, and induced apoptosis in AML cells. Treatment with compound #41 down-regulated the expression of β-catenin, Survivin, and β-catenin-specific target genes, as demonstrated by RNA-seq. In vivo analysis showed that compound #41 blocked the expansion of KG1a-Luc/GFP cells in the bone marrow and prolonged the overall survival of KG1a-Luc/GFP-transplanted mice. Compound #41 suppressed the Wnt/β-catenin signaling pathway by reducing CTNNB1 levels and induced apoptosis in AML cells. Furthermore, compound #41 inhibited the proliferation of KG1a-Luc/GFP cells in the bone marrow and extended the overall survival of mice. Thus, compound #41 is an attractive Wnt/β-catenin signaling pathway inhibitor of AML.

Representativeness of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trial participants.

Underrepresentation by race and ethnicity in oncology clinical trials, including hematopoietic cell transplantation (HCT), is a known challenge. This analysis studied accrual on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials conducted in 2014-20 by race/ethnicity, age, and sex comparing these characteristics with those of potentially eligible patients identified from SEER and CIBMTR databases for the disease, age, and years of interest of BMT CTN studies. Five BMT CTN trials met inclusion criteria, including one autologous and four allogeneic HCT trials. Two studies focused on multiple myeloma (BMT CTN 1302 and 1401), two studies on graft versus host disease (GVHD) treatment (BMT CTN 1301 and 1501), and one study on post-HCT maintenance therapy in FLT3+ acute myelogenous leukemia (BMT CTN 1506). A decline in the proportion of patients from minority racial and ethnic groups was seen from the SEER population to trial enrollees, with the largest drop seen between the SEER population and all patients transplanted (on or off trial) in US transplant centers. Allogeneic HCT trials which allowed alternate donor graft sources had less decrease from the SEER population. No decrease was seen in clinical trial enrollment with respect to older age and female HCT recipients. This study provides insights into the underrepresentation of racial and ethnic minority patients in BMT CTN clinical trials, largely due to lack of access to HCT in general. Pathways expanding access to donors and improving the outreach of HCT programs to underserved populations are needed to improve access to clinical trials.

FLAER Revealed Normally Expected Non-PNH FLAER-Dim Immature Myeloid Cells (CD117+/CD34-) In Bone Marrow Aspirates and Could Be Utilized as a Marker of Hierarchical Hematopoiesis.

Fluorescently labeled aerolysin (FLAER) is widely used for the identification of paroxysmal nocturnal hemoglobinuria (PNH) clones in peripheral blood (PB) samples. However, there are only a few reports on the differential fluorescent intensity of FLAER in normal bone marrow (BM) cell subpopulations. The purpose of this study was to evaluate FLAER expression during normal and pathological hematopoiesis, to map the critical existence of non-PNH FLAER-dim cells. A total of 54 BM aspirates were prospectively analyzed with FLAER-based flow cytometric (FC) protocols, during their routine work-up. These were obtained from patients with the following diagnoses: PNH (3), infections/reactive (5), myelodysplastic syndromes (MDS) (7), myelodysplastic/myeloproliferative neoplasms (MDS/MPN) (4), chronic myelogenous leukemia (CML) (3), acute myelogenous leukemia (AML) at diagnosis (20), AML in measurable residual disease (MRD) assessment (7), and B-cell acute lymphoblastic leukemia (B-ALL) in MRD assessment (5). The applied protocols consisted of FLAER, HLA-DR, CD14, CD33, CD34, CD66b, CD38, CD117, CD64, CD45, and FLAER, CD66c, CD14, CD33, CD34, CD66b, CD123, CD16, CD64, and CD45, respectively. FLAER expression was assessed in CD34++/CD38- and CD34+/CD38+ stem cells, CD34-/CD117+/HLA-DR+/CD33+ myeloid precursors, and CD64+/CD14-/HLA-DR+ monocyte precursors but also in mature myeloid cells. All patients revealed an intermediate FLAER intensity in CD34++/CD38- stem cells, with a discrete FLAER-negative subpopulation observed only in maturing CD34+/CD38+ stem cells of patients with PNH. The lowest FLAER intensity was noticed in CD34-/CD117+/HLA-DR+/CD33+ myeloid precursors, not only in patients with PNH but also in PNH-negative BM aspirates. An ascending FLAER intensity was further observed during monocytic and granulocytic maturation, with a discrete FLAER-negative population in CD64+/CD14-/HLA-DR+ monocyte precursors and maturing neutrophils and monocytes of patients with PNH only. The maturation pattern of FLAER expression was further confirmed in a patient with acute promyelocytic leukemia treated with all-trans retinoic acid (ATRA), where FLAER was concurrently upregulated with CD66b in a consecutive series of PB samples tested over a 20-day-period after diagnosis. The application of FLAER in PNH-positive and PNH-negative reactive or malignant BM aspirates identified normally expected non-PNH FLAER-dim CD34-/CD117+/HLA-DR+/CD33+ myeloid precursors in all samples. A specific FLAER-associated maturation pattern was observed, which is proposed for further study within MRD and diagnostic protocols.

Efficacy of haploidentical allogeneic hematopoietic cell transplantation following two courses of venetoclax and azacytidine therapy in patients over 55 years old with acute myelogenous leukemia.

The combination of venetoclax (VEN) and azacytidine (AZA) has demonstrated potential in achieving rapid and effective remissions in elderly patients with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is a promising potential cure for high-risk AML, as VEN-based therapies have a worse prognosis in elderly patients. This study aimed to assess the efficacy of sequential haploidentical HSCT following two courses of VEN and AZA therapy in patients with AML aged 55 years and older. We conducted a retrospective study on AML patients aged 55 to 70 years who received intensive chemotherapy or two courses of VEN/AZA therapy, followed by haplo-HSCT based on disease risk degree, measurable residual disease status and patient's preference. Between January 2019 and December 2023, 141 newly diagnosed AML patients received initial treatment with intensive chemotherapy or VEN/AZA therapy. Among them, 64 patients received haplo-HSCT, while 77 did not. The 1-year over survival (OS) and relapse-free survival (RFS) of patients who received haplo-HSCT were significantly higher than those who did not receive haplo-HSCT (P<0.05). Among patients who received transplantation, there was no significant difference in 1-year OS and RFS between the VEN/AZA and intensive chemotherapy groups: 76.3% vs 69.3% (P = 0.367) for OS, and 74.5% vs 69.7% (P = 0.473) for RFS. High-risk ELN stratification and the presence of ≥4 gene mutations were associated with lower OS and RFS in both univariate and multivariate analysis. AML patients over 55 years of age who received haplo-HSCT after two courses of VEN/AZA therapy had outcomes similar to those who received haplo-HSCT after intensive chemotherapy, suggesting that two courses of VEN/AZA therapy as a bridge to halpo-HSCT are feasible for patients over 55 years old.

Therapeutic strategies targeting aberrant RNA splicing in myeloid malignancies.

In recent years, large-scale sequencing efforts have identified targetable driver mutations in haematopoietic stem cells. These efforts have led to the development and approval of nine novel agents for relapsed or refractory acute myelogenous leukaemia (R/R AML). However, despite an expansion in targeted therapies, achieving a durable remission in AML and high-risk myelodysplastic syndrome (HR-MDS) remains a significant challenge, and there is an urgent need for new effective treatments. Modulation of aberrant RNA splicing has emerged as a novel therapeutic approach in myeloid diseases. Aberrant splicing drives dysregulated gene expression that promotes tumourigenesis through increased proliferation and metastatic potential, immune evasion, decreased apoptosis, and chemotherapy resistance. Mutations in spliceosomal components have been identified in numerous cancer subtypes, with mutations in RNA binding proteins SF3B1, SRSF2, U2AF1, and ZRSR2 occurring frequently in AML and in up to 60% of patients with MDS, as well as in chronic myelomonocytic leukaemia and in 10% of patients with chronic lymphocytic leukaemia. In this review, we explore therapeutic strategies targeting aberrant splicing and the potential of these approaches to drive clinical responses.

A-156 Comparison of blast and variant lymphocyte flagging between the Alinity hq from Abbott and XN-1000 from Sysmex

Abstract Background Blast cells are immature white blood cells (WBC). The presence of blasts in the peripheral blood may be associated with certain diseases such as myelodysplastic syndrome and acute myelogenous leukemia. Variant lymphocytes (i.e., reactive lymphocytes, atypical lymphocytes) are WBCs produced by the immune system in reaction to infections caused by pathogens such as Epstein-Barr virus, cytomegalovirus, etc. It is clinically useful that the automated hematology analyzer is capable of flagging these cells. In this study, the blast (shown as ‘BLAST’ on the Alinity hq and ‘Blast/Abn Lympho?’ or ‘Blast?’ on XN-1000) and variant lymphocyte (shown as ‘VAR LYM’ on the Alinity hq, and ‘Atypical Lympho?’ on XN-1000) flagging was compared between the Alinity hq from Abbott and XN-1000 from Sysmex. Alinity hq has different sensitivity settings available for BLAST and VAR LYM flagging. In this study, the default setting for Alinity hq was used. For XN-1000, the Q-Flag default setting is 100. In this study, the setting was 120 for ‘Blast/Abn Lympho’ and 100 for “Atypical lympho?’. Methods Blood specimens were tested on the Alinity hq and XN-1000 analyzers. Two smears per specimen were made manually or by the Alinity hs slide maker stainer and read by two independent readers. The specimens showing any of the following flagging were included in the analysis: ‘BLAST’ on Alinity hq, ‘VAR LYM’ on Alinity hq, ‘Blast/Abn Lympho?’ or ‘Blast?’ on XN-1000, ‘Atypical lympho?’ on XN-1000. The flagging reports of these samples from both analyzers were compared to the smear review to determine if each analyzer's blast and variant lymphocyte flagging were true positive, false positive, true negative, or false negative. Results A total of 520 specimens were tested, yielding 41 specimens for blast flagging analysis and 80 specimens for variant lymphocyte flagging analysis. Due to the scarce availability of true positive samples from the manual review, true positive and false negative rate were not compared. For blast flagging using smear results of >=1% or >=5% as the positive criterion, Alinity hq yielded a 9.8% (=4/41) false positive rate and 87.8% (=36/41) true negative rate. XN-1000 yielded a 75.6% (=31/41) false positive rate and 22.0% (=9/41) true negative rate. For variant lymphocyte flagging using smear results of >=5% as the positive criterion, Alinity hq yielded a 6.3% (=5/80) false positive rate and 92.5% (=74/80) true negative rate. XN-1000 yielded a 91.3% (=73/80) false positive rate and 7.5% (=6/80) true negative rate. Conclusions This study demonstrated that Alinity hq achieved a much lower false positive rate and much higher true negative rate for both blast and variant lymphocyte flagging when compared to the XN-1000. Manual blast and variant lymphocyte morphology classification is laboratory- and technician-dependent. Both analyzers allow different sensitivity/specificity levels to flag blasts and variant lymphocytes. Each individual laboratory should evaluate and choose the setting that is most suitable for their specific patient populations to obtain the desired flagging rate.

The Mathematical Models To Analyze The Impact Of An Adoptive T - Cells Therapy On The Coexistence Of Chronic Lymphocytic And Acute Myelogenous Leukemia

Leukemia is a cancerous and progressive disease that affects the myeloid and lymphoid cells of the bone marrow. It causes a lot of problems for families, patients as well as the healthcare systems around the world. This study investigated how adoptive T - cell therapy affects the growth of coexistence of Acute Myelogenous Leukemia (AML) and Chronic Lymphocytic Leukemia (CLL) in a single patient. The methodology involves the development of both classical and fractional differential systems to analyze the coexistence of CLL and AML in a single patient. The numerical simulations were also performed to confirm the results of the analysis. The studies showed that the concentration levels of both types of leukemia cells were very high before the introduction of immunotherapy of the adoptive T cells. The disease free and endemic equilibrium points were proved to be globally asymptotically stable

S4532 Idiopathic Refractory Ascites: A Rare and Fatal Complication of Haemopoietic Stem Cell Transplant in a Patient With Acute Myelogenous Leukemia

S4532 Idiopathic Refractory Ascites: A Rare and Fatal Complication of Haemopoietic Stem Cell Transplant in a Patient With Acute Myelogenous Leukemia

Which allogeneic hematopoietic cell transplant recipients have an increased risk for delayed-onset clinically significant cytomegalovirus infection after letermovir prophylaxis?

Cytomegalovirus (CMV) reactivation is one of the most common complications after allogeneic hematopoietic stem cell transplantation (HSCT). Letermovir is approved for CMV prophylaxis among high-risk recipients. However, delayed-onset post-prophylaxis clinically significant CMV infection (csCMVi) has been observed, suggesting the potential for extending letermovir prophylaxis beyond the first one hundred days post-HSCT. Retrospective multicenter cohort study of allogeneic HSCT patients from August 2018 to March 2023. The primary aim of this study was to identify the risk factors at day 100 associated with delayed onset csCMVi, in patients who received letermovir prophylaxis up to day 100. Competing risk analysis was used to evaluate incidence with specific risk factors, using Gray's Test comparing groups for each event. Among 166 eligible allogeneic HSCT recipients, the most common primary hematological diagnosis was acute myelogenous leukemia (AML) (42.2%). Twenty-six (15.7%) developed a breakthrough csCMVi. Delayed-onset csCMVi occurred in 23.5%, at a median time of 133 days after SCT. On multivariate analysis, having a matched unrelated donor (odds ratio [OR] 2.46) and a CMV donor negative/recipient positive status (OR 3.47) were associated with delayed onset csCMVi. In contrast, AML had a lower odd of having delayed-onset csCMVi (OR 0.23). Having a matched unrelated donor, a CMV donor negative/recipient positive status, and a non-AML underlying disease were associated with delayed onset csCMVi. Prospective studies are needed to evaluate whether extended letermovir prophylaxis is beneficial for these patients.

Loss of mismatched HLA during relapse in haplo stem cell transplant recipients with acute myelogenous leukemia

Loss of mismatched HLA during relapse in haplo stem cell transplant recipients with acute myelogenous leukemia

Certainty in uncertainty: Determining the rate and reasons for reclassification of variants of uncertain significance in haematological malignancies

AbstractIntroductionVariants of uncertain significance (VUS) are commonly reported in cancer with the widespread adoption of diagnostic massive parallel sequencing. The rate of reclassification of VUS in patients with haematological malignancy is not known and we evaluated this retrospectively. We also investigated whether re‐evaluating VUS in 12–24 months or greater than 24 months post‐initial classification was significant.MethodA retrospective audit of patients with haematological malignancies referred to the Molecular Medicine Department at the John Hunter Hospital in Newcastle, Australia between September 2018 and December 2021. Data was analysed for VUS, which was then re‐analysed in standard software using current somatic variant guidelines. Proportions of VUS at baseline were compared to post‐re‐analysis.ResultsThe most common diagnoses in the patient cohort (n = 944) were acute myelogenous leukaemia (41%), myelodysplastic syndrome (31%), and chronic myelomonocytic leukaemia (7%). A total of 210 VUS were re‐analysed. The most common VUS were in the TET2 (20%), RUNX1 (10%) and DNMT3A (9%) genes. A total of 103 were re‐analysed at 24–39 months post‐initial classification and 107 variants were re‐analysed between 12 and 24 months post‐initial classification. Of these, 33 (16%) of VUS were re‐classified at 24–39 months and 12 (11%) were re‐classified at 12–24 months post‐initial classification. The most common variants that were re‐classified in both groups were CSF3R (32%), TET2 (29%), ASXL1 (11%) and ZRSR2 (11%).ConclusionThis study on reclassification of VUS in blood cancers demonstrated that one in seven VUS were re‐classified 12 months post initial classification. This can inform practice guidelines and potentially impact the prognosis, diagnosis and treatment of haematological malignancies.

Trametinib Sensitivity is Defined by a Myeloid Differentiation Profile in Acute Myeloid Leukemia.

Acute myelogenous leukemia (AML) is a common blood cancer marked by heterogeneity in disease and diverse genetic abnormalities. Additional therapies are needed as the 5-year survival remains below 30%. Trametinib is a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor that is widely used in solid tumors and also in tumors with activating RAS mutations. A subset of patients with AML carry activating RAS mutations; however, a small-scale clinical trial with trametinib showed little efficacy. Here, we sought to identify transcriptomic determinants of trametinib sensitivity in AML. We tested the activity of trametinib against a panel of tumor cells from patients with AML ex vivo and compared this with RNA sequencing (RNA-Seq) data from untreated blasts from the same patient samples. We then used a correlation analysis between gene expression and trametinib sensitivity to identify potential biomarkers predictive of drug response. We found that a subset of AML tumor cells were sensitive to trametinib ex vivo, only a fraction of which (3/10) carried RAS mutations. On the basis of our RNA-Seq analysis we found that markers of trametinib sensitivity are associated with a myeloid differentiation profile that includes high expression of CD14 and CLEC7A (Dectin-1), similar to the gene expression profile of monocytes. Further characterization confirmed that trametinib-sensitive samples display features of monocytic differentiation with high CD14 surface expression and were enriched for the M4 subtypes of the FAB classification. Our study identifies additional molecular markers that can be used with molecular features including RAS status to identify patients with AML that may benefit from trametinib treatment.

Emerging applications of hypomethylating agents in the treatment of glioblastoma (Review).

DNA hypomethylating agents (HMAs) such as decitabine and 5-azacytidine have established roles in the treatment paradigms for myelodysplastic syndrome and acute myelogenous leukemia, where they are considered to exert their anticancer effects by restoring the expression of tumor suppressor genes. Due to their relatively favorable adverse effect profile and known ability to pass through the blood-brain barrier, applications in the treatment of glioblastoma (GBM) and other central nervous system malignancies are under active investigation. The present review examines the types of HMAs currently available, their known and less-understood antineoplastic mechanisms, and the evidence to date of their preclinical and clinical efficacy in glioblastoma and other solid malignancies. The present review discusses the potential synergies HMAs may have with established and emerging GBM treatments, including temozolomide, immune checkpoint inhibitors and cancer vaccines. Recent successes and setbacks in clinical trials for newly diagnosed and recurrent GBM are summarized in order to highlight opportunities for HMAs to improve therapeutic responses. Challenges for future clinical trials are also assessed.

CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization.

Acute myeloid leukemia (AML) is a malignancy of immature myeloid blast cells with stem-like and chemoresistant cells being retained in the bone marrow through CXCL12-CXCR4 signaling. Current CXCR4 inhibitors mobilize AML cells into the bloodstream where they become more chemosensitive have failed to improve patient survival, likely reflecting persistent receptor localization on target cells. Here we characterize the signaling properties of CXCL12-locked dimer (CXCL12-LD), a bioengineered variant of the dimeric CXCL12 structure. CXCL12-LD binding resulted in lower levels of G protein, β-arrestin, and intracellular calcium mobilization, consistent with the locked dimer being a partial agonist of CXCR4. Further, CXCL12-LD failed to induce chemotaxis in AML cells. Despite these partial agonist properties, CXCL12-LD increased CXCR4 internalization compared to wildtype and locked-monomer forms of CXCL12. Analysis of a previously published AML transcriptomic data showed CXCR4 positive AML cells co-express genes involved in chemoresistance and maintenance of a blast-like state. The CXCL12-LD partial agonist effectively mobilized stem cells into the bloodstream in mice suggesting a potential role for their use in targeting CXCR4. Together, our results suggest that enhanced internalization by CXCL12-LD partial agonist signaling can avoid pharmacodynamic tolerance and may identify new avenues to better target GPCRs.

AML-029 A Descriptive Study on the Efficacy of FLAG+IDA in Acute Myelogenous Leukemia Patients in The Medical City

AML-029 A Descriptive Study on the Efficacy of FLAG+IDA in Acute Myelogenous Leukemia Patients in The Medical City

Comparative Analysis of AML Classification Systems: Evaluating the WHO, ICC, and ELN Frameworks and Their Distinctions.

Comprehensive analyses of the molecular heterogeneity of acute myelogenous leukemia, AML, particularly when malignant cells retain normal karyotype, has significantly evolved. In 2022, significant revisions were introduced in the World Health Organization (WHO) classification and the European LeukemiaNet (ELN) 2022 guidelines of acute myeloid leukemia (AML). These revisions coincided with the inception of the first version of the International Consensus Classification (ICC) for AML. These modifications aim to improve diagnosis and treatment outcomes via a comprehensive incorporation of sophisticated genetic and clinical parameters as well as facilitate accruals to innovative clinical trials. Key updates include modifications to the blast count criteria for AML diagnosis, with WHO 2022 eliminating the ≥20% blast requirement in the presence of AML-defining abnormalities and ICC 2022 setting a 10% cutoff for recurrent genetic abnormalities. Additionally, new categories, such as AML with mutated TP53 and MDS/AML, were introduced. ELN 2022 guidelines retained risk stratification approach and emphasized the critical role of measurable residual disease (MRD) that increased the use of next-generation sequencing (NGS) and flow cytometry testing. These revisions underscore the importance of precise classification for targeted treatment strategies and improved patient outcomes. How much difference versus concordance these classifications present and the impact of those on clinical practice is a continuing discussion.

Enhancing Selectivity and Inhibitory Effects of Chemotherapy Drugs Against Myelogenous Leukemia Cells with Lippia alba Essential Oil Enriched in Citral.

Acute myelogenous leukemia (AML) is one of the most lethal cancers, lacking a definitive curative therapy due to essential constraints related to the toxicity and efficacy of conventional treatments. This study explores the co-adjuvant potential of Lippia alba essential oils (EO) for enhancing the effectiveness and selectivity of two chemotherapy agents (cytarabine and clofarabine) against AML cells. EO derived from L. alba citral chemotype were produced using optimized and standardized environmental and extraction protocols. Rational fractionation techniques were employed to yield bioactive terpene-enriched fractions, guided by relative chemical composition and cytotoxic analysis. Pharmacological interactions were established between these fractions and cytarabine and clofarabine. The study comprehensively evaluated the cytotoxic, genotoxic, oxidative stress, and cell death phenotypes induced by therapies across AML (DA-3ER/GM/EVI1+) cells. The fraction rich in citral (F2) exhibited synergistic pharmacological interactions with the studied chemotherapies, intensifying their selective cytotoxic, genotoxic, and pro-oxidant effects. This shift favored transitioning from necrosis to a programmed cell death phenotype (apoptotic). The F2-clofarabine combination demonstrated remarkable synergistic anti-leukemic performance while preserving cell integrity in healthy cells. The observed selective antiproliferative effects may be attributed to the potential dual prooxidant/antioxidant behavior of citral in L. alba EO.

Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia.

Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors. We retrospectively reviewed 40 patients between 2017-2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML. Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (p = 0.21), respectively. Rates of dose reductions (6% vs. 0%, p = 0.26) and held doses (17% vs. 14%, p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups. Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size.

Total Body Irradiation and Fludarabine with Post-Transplantation Cyclophosphamide for Mismatched Related or Unrelated Donor Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation (HCT) remains the sole curative treatment for most patients with hematologic malignancies. A well-matched donor (related or unrelated) remains the preferred donor for patients undergoing allogeneic HCT; however, a large number of patients rely on alternative donor choices of mismatched related (haploidentical) or unrelated donors to access HCT. In this retrospective study, we investigated outcomes of patients who underwent mismatched donor (related or unrelated) HCT with a radiation-based myeloablative conditioning MAC regimen in combination with fludarabine, and post-transplantation cyclophosphamide (PTCy) as higher-intensity graft-versus-host disease (GVHD) prophylaxis. We retrospectively assessed HCT outcomes in 155 patients who underwent mismatched donor HCT (related/haploidentical versus unrelated [MMUD]) with fractionated-total body irradiation (fTBI) plus fludarabine and PTCy as GVHD prophylaxis at City of Hope from 2015 to 2021. Diagnoses included acute lymphoblastic leukemia (46.5%), acute myelogenous leukemia (36.1%), and myelodysplastic syndrome (6.5%). The median age at HCT was 38 years, and 126 patients (81.3%) were an ethnic minority. The Hematopoietic Stem Cell Transplantation Comorbidity Index was ≥3 in 36.1% of the patients, and 29% had a Disease Risk Index (DRI) of high/very high. The donor type was haploidentical in 67.1% of cases and MMUD in 32.9%. At 2 years post-HCT, disease-free survival (DFS) was 75.4% and overall survival (OS) was 80.6% for all subjects. Donor type did not impact OS (hazard ratio [HR], .72; 95% confidence interval [CI], .35 to 1.49; P = .37) and DFS (HR, .78; 95% CI, .41 to 1.48; P = .44), but younger donors was associated with less grade III-IV acute GVHD (HR, 6.60; 95% CI, 1.80 to 24.19; P = .004) and less moderate or severe chronic GVHD (HR, 3.53; 95% CI, 1.70 to 7.34; P < .001), with a trend toward better survival (P = .099). The use of an MMUD was associated with significantly faster neutrophil recovery (median, 15 days versus 16 days; P = .014) and platelet recovery (median, 18 days versus 24 days; P = .029); however, there was no difference in GVHD outcomes between the haploidentical donor and MMUD groups. Nonrelapse mortality (HR, .86; 95% CI, .34 to 2.20; P = .76) and relapse risk (HR, .78; 95% CI, .33 to 1.85; P = .57) were comparable in the 2 groups. Patient age <40 years and low-intermediate DRI showed a DFS benefit (P = .004 and .029, respectively). High or very high DRI was the only predictor of increased relapse (HR, 2.89; 95% CI, 1.32 to 6.34; P = .008). In conclusion, fludarabine/fTBI with PTCy was well-tolerated in mismatched donor HCT, regardless of donor relationship to the patient, provided promising results, and increased access to HCT for patients without a matched donor, especially patients from ethnic minorities and patients of mixed race.

Venous Thromboembolism Post-allogeneic Hematopoietic Cell Transplant: Risk Factors, Incidence, and Outcomes.

Venous thromboembolism (VTE) is a well-documented complication of both solid and hematologic malignancies, but there are fewer data on allogeneic hematopoietic cell transplant (HCT) recipients. Therefore, we studied the incidence, risk factors, and impact of VTE on post-HCT outcomes in a contemporary cohort. We retrospectively reviewed patients who underwent allogeneic HCT between January 2014 and August 2019 to identify patients with post-HCT VTE. Patient, disease, and transplant-related risk factors for VTE were investigated using competing risk analysis. A total of 431 patients were included in this study. Median (interquartile range [IQR]) age in years was 59 (46-65) at transplant. The most common indication for transplant was acute myelogenous leukemia (49.4%). Within our cohort, 64 patients (14.8%) developed post-HCT VTE with a median (IQR) follow-up time of 24.6 (8.4-47.1) months. The cumulative incidence of VTE was 4.2% at 6 months, 9.0% at 12 months, 12.6% at 24 months, and 13.8% at 36 months. In multivariable analysis, older age (hazard ratio [HR] per 10-year increase: 1.36, 95% confidence interval [CI]: 1.09-1.70), history of VTE (HR: 1.95, 95% CI: 1.09-3.49), and grade 2-4 acute graft versus host disease (GVHD; HR: 1.75, 95% CI: 1.05-2.94) were independently associated with VTE. VTE was significantly associated with an increased risk of nonrelapse mortality (NRM; HR: 4.09, 95% CI: 2.47-6.74) and decreased overall survival (OS; HR: 2.19, 95% CI: 1.48-3.24). VTE is an important complication after allogeneic HCT and is significantly associated with increased NRM and decreased OS. Older patients, those with prior VTE, and patients with acute GVHD are at increased risk for development of VTE after HCT.