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Sweet syndrome (SS), also referred as acute febrile neutrophilic dermatosis, is an inflammatory process characterised by the abrupt appearance of erythematous papules or nodules with predominant neutrophilic infiltration in the dermis. Fever and neutrophilia are common presenting features. However, extracellular manifestations, including ocular and musculoskeletal, may occur. SS is divided into three subtypes: classical (or idiopathic), malignancy associated and drug induced. Medication-induced subtype accounts for up to 26% of cases. In recent years, emerging evidence has showed that SS may also occur in neutropenic patients who underwent induction for acute myeloid leukemia (AML). The identification of FMS-like tyrosine kinase 3 (FLT3) gene mutation in approximately 30% of patients with AML has promoted the targeted therapy with FLT3-internal tandem duplication (ITD) inhibitors. Midostaurin, a recently Food and Drug Administration-approved medication for FLT3-ITD-positive AML, was reported once as cause for SS. We report a midostaurin-induced SS with neutropenia in a patient following induction chemotherapy of AML

Myeloid malignancies have always been at the forefront of an improved understanding of the molecular pathogenesis of cancer. In accordance, over the last years, basic research focusing on the aberrations underlying malignant transformation of myeloid cells has provided the basis for precision medicine approaches and subsequently has led to the development of powerful therapeutic strategies. In this review article, we will recapitulate what has happened since in the 1980s the use of all-trans retinoic acid (ATRA), as a first targeted cancer therapy, has changed one of the deadliest leukemia subtypes, acute promyelocytic leukemia (APL), into one that can be cured without classical chemotherapy today. Similarly, imatinib, the first molecularly designed cancer therapy, has revolutionized the management of chronic myeloid leukemia (CML). Thus, targeted treatment approaches have become the paradigm for myeloid malignancy, but many questions still remain unanswered, especially how identical mutations can be associated with different phenotypes. This might be linked to the impact of the cell of origin, gene-gene interactions, or the tumor microenvironment including the immune system. Continuous research in the field of myeloid neoplasia has started to unravel the molecular pathways that are not only crucial for initial treatment response, but also resistance of leukemia cells under therapy. Ongoing studies focusing on leukemia cell vulnerabilities do already point to novel (targetable) "Achilles heels" that can further improve myeloid cancer therapy.

Micromegakaryocytes (MMGKs), a common finding in bone marrow, have been rarely described in peripheral blood (PB). MMGKs are known to occur commonly in PB of patients diagnosed with Chronic Myeloid Leukemia (CML).[1][1] A characteristic of chronic phase of CML, they are considered to be dysplastic

Introduction: Tyrosine kinase inhibitors (TKIs) have greatly improved the treatment outcome for most patients with chronic myeloid leukemia (CML). Ponatinib is a new pan-inhibitor of TK active in resistant CML. This study aimed to evaluate the efficacy and safety of ponatinib in patients suffering from CML. Patients and methods: This multicenter, non-randomized, observational, retrospective study evaluated the efficacy and safety of ponatinib administered in adult CML patients in any disease phase, including those with a detected ABL T315I mutation, which were resistant or intolerant to previous-generation TKIs. The study comprised 43 patients benefiting from the ponatinib donation program who were treated in 16 Polish centers. Results: For patients who started treatment with ponatinib in chronic phase (CP) (n=23) and in accelerated phase (AP) (n=3) the median time on ponatinib was 19.5 months (range: 1.0-35.4), and 31.7 months (range: 31.0-34.1), respectively. All these patients were in CP after 1 month of treatment and at the end of observation – none of them progressed to AP or blastic phase (BP) during the study, meaning that progression-free survival was 100% at the end of observation (35.4 months). The estimated 2-year survival in this group of patients was 84%. For all 43 patients, median survival was not reached (lower quartile 6.3 months), and estimated 2-year survival was 60%. Conclusion: Our analysis confirmed ponatinib efficacy in a significant proportion of patients heavily pre-treated with TKIs achieving durable responses in both CP and AP/BP CML groups. Microabstract: Ponatinib is a new pan-inhibitor of tyrosine kinase active in resistant chronic myeloid leukemia (CML). Evaluation of outcomes in 43 patients confirmed ponatinib efficacy in a significant proportion of subjects heavily pre-treated with tyrosine kinase inhibitors achieving durable responses in both chronic phase and accelerated/blastic phase CML groups.

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.

Summary Myelofibrosis (MF) is a BCR-ABL1–negative myeloproliferative neoplasm (MPN) characterized by anemia, extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms and acute myeloid leukemia (AML) progression. Currently, allogeneic haematopoietic stem cell transplantation (AHSCT) therapy is the only curative option for MF patients. However, AHSCT is strictly limited due to the high rates of morbidity and mortality. Janus kinase 2 (JAK2) inhibitor Ruxolitinib is the first-line treatment for intermediate-II or high-risk MF patients with splenomegaly and constitutional symptoms, but most MF patients develop resistance or intolerance to Ruxolitinib. Therefore, MF treatment is a challenge for the medical community. This review summarizes three investigated directions for MF therapy: monotherapies of JAK inhibitors, monotherapies of non-JAK targeted agents, combination therapies of Ruxolitinib and other agents. We emphasize combination of Ruxolitinib and other agents is a promising strategy.

Background The main causes of failure of allogeneic hematopoietic stem cell transplantation (allo-transplant) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are relapse and transplant-related mortality. Different scores have been designed to predict the prognosis of these patients. The objective of this study was to assess which score or combination has better outcome predictive capacity. Methods Retrospective analysis of patients with AML and MDS who received a first peripheral blood allo-transplant in a single center, between December 2001 and October 2019. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), European Group for Blood and Marrow Transplantation (EBMT) and Disease Risk Index (DRI) scores were calculated. For each score and for the HCT-CI/DRI and HCT-CI/EBMT combinations, overall survival (OS), cumulative incidence of relapse (CIR), non-relapse-related mortality (NRM), and graft versus host disease-free relapse-free survival (GRFS) were analyzed. Results 175 patients were evaluated. With a median (range) follow-up of 3.96 (0.32–17.22) years, the 5-year probabilities (95% CI) of OS, CIR, NRM, and GRFS were 36% (28%–44%), 28% (21%–35%), 38% (30%–46%) and 24% (17%–31%), respectively. For OS, only the DRI score selected two groups with statistically significant differences (DRI 0–1: 41% vs. DRI ≥2: 24%; p = 0.011). The combination of DRI 0–1 and HCT-CI 0–2 showed OS probabilities of 45% vs. 26% for those with DRI 0–1 and HCT-CI ≥3; p = 0.041. Conclusions In patients with AML and MDS submitted to allo-transplant, the combination of HCT-CI and DRI scores provided the best stratification for OS.

Acute myeloid leukemia (AML) often presents as an oligoclonal disease whereby multiple genetically distinct subclones can coexist within patients. Differences in signaling and drug sensitivity of such subclones complicate treatment and warrant tools to identify them and track disease progression. We previously identified >50 AML-specific plasma membrane (PM) proteins, and 7 of these (CD82, CD97, FLT3, IL1RAP, TIM3, CD25, and CD123) were implemented in routine diagnostics in patients with AML (n = 256) and myelodysplastic syndrome (n = 33). We developed a pipeline termed CombiFlow in which expression data of multiple PM markers is merged, allowing a principal component–based analysis to identify distinctive marker expression profiles and to generate single-cell t-distributed stochastic neighbor embedding landscapes to longitudinally track clonal evolution. Positivity for one or more of the markers after 2 courses of intensive chemotherapy predicted a shorter relapse-free survival, supporting a role for these markers in measurable residual disease (MRD) detection. CombiFlow also allowed the tracking of clonal evolution in paired diagnosis and relapse samples. Extending the panel to 36 AML-specific markers further refined the CombiFlow pipeline. In conclusion, CombiFlow provides a valuable tool in the diagnosis, MRD detection, clonal tracking, and understanding of clonal heterogeneity in AML.

Right neck swelling and pain occurred in a 49-year-old man. A Blood count showed a slight increase in platelet count without leukemoid reaction. After a biopsy of the cervical mass and bone marrow aspiration, a diagnosis of extramedullary blast crisis (EBC) of chronic myeloid leukemia (CML) was made. Fluorescence in situ hybridization (FISH) analysis showed a BCR-ABL1 fusion signal, but results of real-time polymerase chain reaction (RT-PCR) for major and minor BCR-ABL1 transcripts were negative. We identified a rare e1a 3 BCR-ABL1 fusion transcript. Administration of dasatinib resulted in disappearance of the extramedullary tumor. This is the first reported case of CML-EBC with e1a3 transcript. An aleukemic extramedullary tumor can be the initial presentation of CML.

Background aims The internal tandem duplication of FLT3 (FLT3ITD) and NPM1 mutations (NPM1mut) are well-established prognostic factors in cytogenetically intermediate-risk acute myeloid leukemia (AML) when treated with chemotherapy alone. However, their prognostic value in the setting of allogeneic hematopoietic cell transplantation (HCT) is controversial. Methods FLT3 and NPM1 mutational status was determined at diagnosis using single-gene polymerase chain reaction or next-generation sequencing in 247 adult patients with cytogenetically intermediate-risk AML who underwent myeloablative HCT. Multivariate Fine–Gray and Cox regression was used to analyze the cumulative incidence of relapse (CIR), relapse-free survival (RFS) and overall survival (OS). Results FLT3ITD and NPM1mut were present in 74 of 247 (30%) and 79 of 247 (32%) patients, respectively. There was no significant difference between patients without a FLT3ITD or NPM1mut (FLT3NONITD/NPM1WT) and patients with a FLT3ITD mutation alone (FLT3ITD/NPM1WT) with regard to CIR (P = 0.60), RFS (P = 0.91) or OS (P = 0.66). Similarly, there was no significant difference between FLT3NONITD/NPM1WT and FLT3NONITD/NPM1mut patients with regard to CIR (P = 0.70), RFS (P = 0.75) or OS (P = 0.95). The presence of a concurrent mutation in NPM1 did not appear to modify the impact of having a FLT3ITD mutation. Conclusions In contrast to chemotherapy-only treatment, FLT3 and NPM1 mutational status does not appear to predict outcomes in patients with cytogenetically intermediate-risk AML following HCT. These results suggest that HCT may ameliorate the poor prognostic effect of FLT3ITD mutation and that HCT should be considered over chemotherapy-only treatment in FLT3ITD-mutated AML.

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Under the guidance of cytotoxic activity, crude extracts of 55 fungal strains from the medicinal mangrove Acanthus ilicifolius were evaluated, and one potent cytotoxic natural compound, brefeldin A (BFA), was discovered from Penicillium sp. (HS-N-29). Objective: This study was aimed to determine the cytotoxic activity of BFA and the effect on the activation and expression of BCR-ABL in K562 cells. Method: We evaluated cytotoxic activity by MTT assay and soft agar clone assay; apoptosis and cell cycle distribution by Muse cell analyzer. The protein level of BCR-ABL and signaling molecules was detected by western blotting, and the mRNA level of BCR-ABL was determined by RT-PCR. Results: BFA inhibited cell proliferation, induced G2/M cell cycle arrest, and stimulated cell apoptosis in K562 cells. Importantly, for the first time, we revealed that BFA inhibited the activation of BCR-ABL and consequently inhibited the activation of its downstream signaling molecules in K562 cells. Moreover, we found BFA degraded BCR-ABL without affecting its transcription in K562 cells, and BFA-induced BCR-ABL degradation was related to caspase activation, while not to autophagy or ubiquitinated proteasome degradation pathway. Conclusion: Our present results indicate that BFA acts as a dual functional inhibitor and degrader of BCR-ABL, and BFA is a potential compound for chemotherapeutics to overcome CML.

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.

The treatment landscape for acute myeloid leukemia has expanded significantly in the past 5 years with the approval of several therapeutic small molecules. While agents such as FLT3 inhibitors and IDH inhibitors are restricted for patients with specific mutations, the selective BCL-2 inhibitor venetoclax combined with a hypomethylating agent or low-dose cytarabine was approved after demonstrating frontline efficacy across a molecularly heterogenous group of patients. Currently, venetoclax is being investigated in combination with multiple other therapies as the role of the intrinsic apoptotic pathway in acute myeloid leukemia continues to be explored.

Acute myeloid leukemia (AML) is the most common acute leukemia of adults, with a five-year survival that remains poor (approximately 25%). Knowledge and understanding of AML genomics have expanded tremendously over the past decade and are now included in AML prognostication and treatment decisions. FMS-like tyrosine kinase 3 (FLT3) is a Class III receptor tyrosine kinase (RTK) expressed primarily in the cell membranes of early hematopoietic progenitor cells, found in 28% of all patients with AML. FLT3 is the second most frequent mutation in adult AML following Nuclear-cytoplasmic shuttling phosphoprotein (NPM1), which is found in 50% of cases.1 FLT3 inhibitors are promising new molecular therapeutics increasingly becoming standard of care for both newly diagnosed and relapsed/refractory FLT3 positive AML. This review will focus on the clinical trials/evidence, similarities, differences, clinical toxicities, and drug interactions relevant to treating clinicians as pertains to 5 FLT3-inhibitors: midostaurin, sorafenib, gilteritinib, crenolanib, and quizartinib.

Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML. Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a “writer–reader” epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.

Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1−/− accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1−/− (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.

Kinase activating mutation in FLT3 is the most frequent genetic lesion associated with poor prognosis in acute myeloid leukemia (AML). Therapeutic response to FLT3 tyrosine kinase inhibitor (TKI) therapy is dismal, and many patients relapse even after allogenic stem cell transplantation. Despite the introduction of more selective FLT3 inhibitors, remissions are short-lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are two principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical responses. Here we show that the JAK2 inhibitor, momelotinib, is an equipotent type-1 FLT3 inhibitor. Momelotinib showed potent inhibitory activity on both mouse and human cells expressing FLT3-ITD, including clinically relevant resistant mutations within the activation loop at residues, D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by FLT3 ligand (FL) and hematopoietic cytokine activated JAK2 signaling. Interestingly, unlike gilteritinib, momelotinib inhibits the expression of MYC in leukemic cells. Consequently, concomitant inhibition of FLT3 and downregulation of MYC by momelotinib treatment showed better efficacy in suppressing the leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type-1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response; thus, warrants its clinical evaluation.Key pointsMomelotinib shows high efficacy against FLT3 mutated AML cells including quizartinib-resistant activation loop variants.Momelotinib effectively suppresses intrinsic resistance conferred by FLT3 ligand and hematopoietic cytokines (GM-CSF and IL3).

Key Points Inhibition of RAB protein function mediates the anti–acute myeloid leukemia activity of statins.Statin sensitivity is associated with enhanced vesicle-mediated traffic., Visual Abstract, Cholesterol homeostasis has been proposed as one mechanism contributing to chemoresistance in AML and hence, inclusion of statins in therapeutic regimens as part of clinical trials in AML has shown encouraging results. Chemical screening of primary human AML specimens by our group led to the identification of lipophilic statins as potent inhibitors of AMLs from a wide range of cytogenetic groups. Genetic screening to identify modulators of the statin response uncovered the role of protein geranylgeranylation and of RAB proteins, coordinating various aspect of vesicular trafficking, in mediating the effects of statins on AML cell viability. We further show that statins can inhibit vesicle-mediated transport in primary human specimens, and that statins sensitive samples show expression signatures reminiscent of enhanced vesicular trafficking. Overall, this study sheds light into the mechanism of action of statins in AML and identifies a novel vulnerability for cytogenetically diverse AML.

Key Points CPX-351 treatment is well tolerated and results in morphologic remission in newly diagnosed pediatric secondary myeloid malignancies.Favorable outcomes are achieved despite the presence of high-risk genetic lesions and previous therapies., Visual Abstract, Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT), but there has been no innovation in cytoreductive regimens. CP X-351, a fixed 5:1 molar ratio of liposomal cytarabine to daunorubicin, has shown favorable safety and efficacy in elderly individuals with secondary AML and children with relapsed de novo AML. We report the outcomes of 7 young patients (6 with newly diagnosed sMDS/AML and 1 with primary MDS/AML) uniformly treated with CP X-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-cell acute lymphoblastic leukemia; 1 had predisposing genomic instability disorder (Cornelia de Lange syndrome) and 1 had MDS-related AML and multiorgan failure. The median age at diagnosis of myeloid malignancy was 17 years (range, 13-23 years). Patients received 1 to 3 cycles of CP X-351 (cytarabine 100 mg/m2 plus daunorubicin 44 mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding an FLT3 inhibitor as individualized therapy in 1 patient. Six patients were alive and leukemia-free at 0.5 to 3.3 years after HCT. One patient died as a result of disease progression before HCT. To summarize, CP X-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML that warrants prospective studies.

BACKGROUND The relationship of early catheter-related bloodstream infections (CRBSIs) with perioperative neutropenia and antibiotic prophylaxis is not well established. We sought to evaluate perioperative factors associated with early CRBSIs in newly diagnosed pediatric cancer patients, particularly hematological indices and antibiotic use. METHODS We retrospectively reviewed national registry records of newly diagnosed pediatric cancer patients with port-a-caths inserted using standardized perioperative protocols where only antibiotic use was not regulated. Thirty-day postoperative CRBSI incidence was correlated with preoperative factors using logistic regression and with postoperative blood counts using linear trend analysis. RESULTS Among 243 patients, 17 CRBSIs (7.0%) occurred at median 14 (range, 8-28) postoperative days. Early CRBSIs were significantly associated with cancer type [acute myeloid leukemia and other leukemias (AML/OLs) vs. solid tumors and lymphomas (STLs): odds ratio (OR), 5.09; P = 0.0036; acute lymphoblastic leukemia vs. STL: OR 0.83; P = 0.0446] but not preoperative antibiotics, absolute neutrophil counts and white blood cell counts. Thirty-day postoperative absolute neutrophil counts and white blood cell trends differed significantly between patients with acute lymphoblastic leukemia and STLs (OR 0.83, P < 0.05) and between AML/OLs and STLs (OR 5.09, P < 0.005), with AML/OL patients having the most protracted neutropenia during this period. CONCLUSIONS Contrary to common belief, low preoperative absolute neutrophil counts and lack of preoperative antibiotics were not associated with higher early CRBSI rates. Instead, AML/OL patients, particularly those with prolonged neutropenia during the first 30 postoperative days, were at increased risk. Our findings do not support the use of empirical preoperative antibiotics and instead identify prolonged postoperative neutropenia as a major contributing factor for early CRBSI.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Background: Despite the beneficial effects of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), they may also cause adverse events (AEs), especially cardiovascular toxicity. The incidence of TKI-induced AEs may vary among ethnic groups, and there is little specific information for Japanese patients. Methods and Results: Sixty-nine consecutive patients who were started on treatment with dasatinib (n=25) or imatinib (n=44) for CML or gastrointestinal stromal tumor (GIST) between December 2008 and December 2019 were retrospectively recruited to the study. We determined the prevalence of AEs through October 2020 and compared the incidence of AEs between the 2 drugs. Baseline characteristics were comparable between the 2 groups. However, compared with the imatinib-treated group, the dasatinib-treated group had a higher incidence of congestive heart failure (CHF; 20.0% vs. 2.3%; P=0.04), pleural effusion (48% vs. 20.5%; P=0.03), pericardial effusion (24% vs. 4.6%; P=0.02), QT prolongation (4 vs. 0 patients; P=0.02), and pulmonary hypertension (3 vs. 0 patients; P=0.04). In the dasatinib-treated group, CHF tended to be associated with tricuspid valve regurgitation pressure gradient, and pleural effusion was observed in all patients. All-cause mortality and other cardiovascular events did not differ significantly between the 2 groups. Conclusions: Cardiotoxic AEs occurred more frequently in Japanese patients with CML and GIST treated with dasatinib than imatinib.

Introduction In acute myeloid leukemia (AML), FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is a common driver mutation associated with high tumor burden and poor prognosis. This mutation is common in normal karyotype AML and such patients have high leukocyte count. The presence of this mutation can be predicted by certain hematological and immunophenotypic characteristics in day-to-day practice. Objective This study was undertaken to assess the strength of association between FLT3 gene mutation and hematological and immunophenotypic characteristics. Materials and Methods Morphological, hematological, immunophenotypic, and cytogenetic characteristics of FLT3 mutations recorded in 424 patients of AML in adults and children between 2016 and 2019 in a tertiary care cancer center in Western India. Blasts were classified according to French-American-British method. Tumor burden was assessed by serum lactate dehydrogenase (LDH) levels, leucocyte count, and peripheral smear blast percentage. Results Out of 424 cases, FLT3-ITD and FLT3-tyrosine kinase domain mutation were found in 72 and 25 AML patients, respectively. Patients with FLT3 mutation had high tumor burden, characterized by high leukocyte count (p < 0.001), peripheral blood (p = 0.01) and bone marrow (p = 0.03) blast percentage, and high serum LDH (mean 777.8 vs. 586; p = 0.10) compared with FLT3-negative patients. They also featured high platelet count (p < 0.001). Morphological, immunophenotypic, and cytogenetic characteristics also have been presented in the study. Conclusion Observations of the study suggest the presence of definitive hematological and immunophenotypic characteristics along with raised serum LDH levels serve as surrogate markers and indicators of FLT3 mutation in AML patients.

Key Points Isolated and comutated DDX41 myeloid neoplasms have different characteristics.DDX41-mutated AML has a relatively favorable outcome comparable to core binding factor AML., Visual Abstract, DDX41 mutations (germline and somatic) are associated with late onset myelodysplastic syndromes/acute myeloid leukemia (MDS/AML). Myeloid neoplasms (MN) with germline predisposition was identified as a distinct category in the 2016 WHO classification revision, including MN with germline DDX41 mutation. We retrospectively analyzed the molecular findings and clinical characteristics of thirty-three DDX41-mutated (mDDX41) patients at our institution. We identified 14 distinct pathogenic DDX41 variants in 32 patients and 8 DDX41 variants of unknown significance (VUS) in 9 patients. Five (16%) patients had a second DDX41 somatic mutation p.R525H and 13 (40%) had at least one additional oncogenic co-mutation in other genes. The median age at the time of diagnosis was 66 years, with male predominance (72%) and the majority of patients had normal cytogenetics (91%). Two-year overall survival (OS) was 86% and 6 (21%) MDS/AML patients with relatively preserved hematopoietic function were observed without further intervention. In comparison to AML patients with prognostically more favorable subtypes [t(8;21), n=27 and inv(16), n=40], mDDX41 patients in our cohort showed similarly favorable OS. Our study highlights that mDDX41-MN patients often have an indolent course and mDDX41-AML has comparable OS to favorable-risk AML.

Key Points The semaphorin receptor PLXNC1 is an IDO1-interacting gene and a strong predictor of survival in AML.An IDO1-related immune gene signature, including PLXNC1, predicts survival in AML., Visual Abstract, The contribution of the bone marrow (BM) immune microenvironment to acute myeloid leukemia (AML) development is well-known, but its prognostic significance is still elusive. Indoleamine 2,3-dioxygenase 1 (IDO1), which is negatively regulated by the BIN1 proto-oncogene, is an interferon-γ-inducible mediator of immune tolerance. With the aim to develop a prognostic IDO1-based immune gene signature, biological and clinical data of 982 patients with newly diagnosed, nonpromyelocytic AML were retrieved from public datasets and analyzed using established computational pipelines. Targeted transcriptomic profiles of 24 diagnostic BM samples were analyzed using the NanoString’s nCounter platform. BIN1 and IDO1 were inversely correlated and individually predicted overall survival. PLXNC1, a semaphorin receptor involved in inflammation and immune response, was the IDO1-interacting gene retaining the strongest prognostic value. The incorporation of PLXNC1 into the 2-gene IDO1-BIN1 score gave rise to a powerful immune gene signature predicting survival, especially in patients receiving chemotherapy. The top differentially expressed genes between IDO1low and IDO-1high and between PLXNC1low and PLXNC1high cases further improved the prognostic value of IDO1 providing a 7- and 10-gene immune signature, highly predictive of survival and correlating with AML mutational status at diagnosis. Taken together, our data indicate that IDO1 is pivotal for the construction of an immune gene signature predictive of survival in AML patients. Given the emerging role of immunotherapies for AML, our findings support the incorporation of immune biomarkers into current AML classification and prognostication algorithms.

The study aimed to investigate the positive rate of TEL-AML 1 fusion gene in acute lymphoblastic leukemia (ALL) children and the clinical characteristics of ALL patients with TEL-AML 1 fusion gene positively expressed, as well as the expression level of MRP-1. 40 ALL children were selected, with their medical records collected. The TEL-AML 1 fusion gene was screened by nested RTPCR. Bone marrow specimens were taken for G-banded karyotype analysis and flow cytometry immunophenotyping of the marrow chromosome. A semi-quantitative RT-PCR method was used to study the mRNA expression level of MRP 1. The results showed that the positive rate of TEL-AML 1 fusion gene in ALL patients was 22.5% (9/40). The positive group exhibited lower gene expression level, the hepatosplenomegaly degree, the total number of peripheral white blood cells, the absolute count of naive cells, and the Hb level at the first visit, indicating that the tumor burden of children in the positive group was lower. The complete remission rate of the positive group was higher (P < 0.05). The mRNA expression level of MRP 1 gene positive group was lower. In conclusion, patients with positive TEL-AML 1 fusion gene were more sensitive to chemotherapeutic drugs, and their treatment responses and prognosis were better.

Imatinib is a crucial therapeutic strategy against chronic myeloid leukemia. Though superficial edema is a common adverse effect of imatinib, massive fluid retention is rarely reported. Here, we report the case of an adolescent who had tolerated imatinib for a long time, and then presented with massive pleural/pericardial effusion during an episode of Campylobacter jejuni bacteremia. A stepwise and comprehensive survey excluded all other plausible causes of disease. The Naranjo scale was used to assess the probability of an adverse effect of medication, and the score turned out to be 9, indicating severe fluid retention to be a definite reaction to imatinib. Drug discontinuation, antibiotic administration, and invasive procedures improved this condition. After this episode, the patient could tolerate imatinib again, illustrating the transient and reversible nature of this reaction. Since prolonged imatinib usage is crucial for chronic myeloid leukemia control, alertness to drug-related adverse effects is recommended, even if the subject has previously shown a good tolerance to the drug due to various physical conditions, especially physiological stressors, like infection or inflammation.

Introduction. Extramedullary sites of leukemic proliferation, harboring an adverse outcome, are rare and usually found in the blastic phase of chronic myeloid leukemia. We report a case of a newly diagnosed patient with chronic myeloid leukemia in the chronic phase, with leukemic infiltration of the right ovary on disease presentation. Case report. The patient presented with abdominal pain, leukocytosis, and anemia. A peripheral blood smear indicated chronic myeloid leukemia, and cytoreductive treatment was started. Due to the worsening of the abdominal pain, computed tomography was done. It revealed a cystic tumor of the right ovary. The tumor was surgically removed. Bone marrow examination confirmed the diagnosis of chronic myeloid leukemia in the chronic phase. Immunohistochemical analysis of the ovarian tumor showed leukemic infiltration with 5% of blasts. The patient was treated with imatinib for one year. Due to treatment failure, imatinib was switched to nilotinib. Allogeneic stem cell transplantation was considered. Conclusion. This case highlights the critical role of the multidisciplinary team approach and close treatment monitoring to achieve the best possible outcome in these patients.

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders. The 2020 Surveillance, Epidemiology, and End Results data demonstrates the incidence rate of MDS increases with age especially in those greater than 70 years of age. Risk stratification that impact prognosis, survival, and rate of acute myeloid leukemia (AML) transformation in MDS is largely dependent on revised International Prognostic Scoring System along with molecular genetic testing as a supplement. Low risk MDS typically have a more indolent disease course in which treatment is only initiated to ameliorate symptoms of cytopenias. In many, anemia is the most common cytopenia requiring treatment and erythroid stimulating agents, are considered first line. In contrast, high risk MDS tend to behave more aggressively for which treatment should be initiated rapidly with Hypomethylating Agents (HMA) being in the frontline. In those with high risk MDS and eligible, evaluation for allogeneic stem cell transplant should be considered as this is the only potential curative option for MDS. With the use of molecular genetic testing, a personalized approach to therapy in MDS has ensued. As the treatment landscape in MDS continues to flourish with novel targeted agents, we ambitiously seek to improve survival rates especially among the relapsed/refractory and transplant ineligible.

Acute myeloid leukemia (AML) remains a clinical challenge. Venetoclax is an effective Bcl-2 selective inhibitor approved by the U.S. Food and Drug Administration (FDA) for treatment of AML in patients who are 75 years and older or who have comorbidities. However, resistance to venetoclax limits its clinical efficacy. Mcl-1 has been identified as one determinant of resistance to venetoclax treatment. In this study, we investigate the Mcl-1 inhibitor S63845 in combination with venetoclax in AML cells. We found that S63845 synergizes with venetoclax in AML cell lines and primary patient samples. Bak/Bax double knockdown and treatment with the pan-caspase inhibitor Z-VAD-FMK revealed that the combination induces intrinsic apoptosis in AML cells. Inhibition of Mcl-1 using another Mcl-1 selective inhibitor, AZD5991, also synergistically enhanced apoptosis induced by venetoclax in a caspase-dependent manner. Importantly, S63845 in combination with venetoclax can effectively combat AML cells with acquired resistance to the standard chemotherapy drug cytarabine. In light of these facts, the combined inhibition of Mcl-1 and Bcl-2 shows promise against AML cells, including relapse/refractory AML.

YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in acute myeloid leukemia (AML) and that it is required for the proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We found that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem and progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides compelling evidence that shows an oncogenic role and a distinct mechanism of YTHDC1 in AML.

AML can be associated with autoimmune or inflammatory phenomena (AIP) occurring prior, concomitantly, or after its diagnosis. Trisomy 8 is one of the most common cytogenetic abnormalities associated with AML. We describe three patients with AML, trisomy 8, and associated AIP and review the known literature on this association. All of our patients had major symptomatic relief when treated with leukemia-directed therapy and corticosteroids. AIP in AML may be an underdiagnosed phenomenon, particularly in patients with trisomy 8.

The BCR-ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic (PK) model-based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration-time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed-effects modelling. Ponatinib PK was described by a 2-compartment model with first-order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19-85 years), race, body weight (40.7-152.0 kg), total bilirubin (0.1-3.16 mg/dL), alanine aminotransferase (6-188 U/L), albumin (23.0-52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15-45 mg result in steady-state average concentrations that are in the pharmacological range for BCR-ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier NCT00660920; NCT01667133; NCT01650805 This article is protected by copyright. All rights reserved.

WT1 overexpression is frequently identified in acute myeloid leukemia (AML) and has been reported to be a potential marker for monitoring measurable residual disease (MRD). We evaluated the use of postinduction WT1 MRD level as a prognostic factor, as well as the interaction between postinduction WT1 MRD response and the effect of allogeneic stem cell transplantation (allo-SCT) in the first complete remission (CR). In the ALFA-0702 trial, patients with AML, aged 18 to 59, had a prospective quantification of WT1 MRD. The occurrence of a WT1 MRD ratio >2.5% in bone marrow or >0.5% in peripheral blood was defined as MRDhigh, and ratios below these thresholds were defined as MRDlow. The prognostic value of MRD after induction chemotherapy was assessed in 314 patients in first CR by comparing the risk of relapse, the relapse-free survival (RFS), and the overall survival (OS). Interaction between MRD response and the allo-SCT effect was evaluated in patients by comparing the influence of allo-SCT on the outcomes of patients with MRDhigh with those with MRDlow. The results showed that patients with MRDhigh after induction had a higher risk of relapse and a shorter RFS and OS. The MRD response remained of strong prognostic value in the subset of 225 patients with intermediate-/unfavorable-risk AML who were eligible for allo-SCT, because patients with MRDhigh had a significantly higher risk of relapse resulting in worse RFS and OS. The effect of allo-SCT was higher in patients with MRDlow than in those with MRDhigh, but not significantly different. The early WT1 MRD response highlights a population of high-risk patients in need of additional therapy.

A potent graft-versus-leukemia (GVL) response is crucial in preventing relapse, the major impediment to successful allogeneic hematopoietic cell transplantation (HCT). In preclinical studies, type 1 interferon (IFN-α) enhanced cross-presentation of leukemia-specific antigens by CD8α dendritic cells (DCs) and amplified GVL. This observation was translated into a proof-of-concept phase 1/2 clinical trial with long-acting IFN-α (pegylated IFN-α [pegIFNα]) in patients undergoing HCT for high-risk acute myeloid leukemia (AML). Patients with treatment-resistant AML not in remission or those with poor-risk leukemia were administered 4 dosages of pegIFNα every 14 days beginning at day −1 before HCT. Dose selection was established by adaptive design that continuously assessed the probability of dose-limiting toxicities throughout the trial. Efficacy was evaluated by determining the 6-month incidence of relapse at the maximum tolerated dose (MTD). Thirty-six patients (median age, 60 years) received pegIFNα treatment. Grade 3 or greater severe adverse events occurred in 25% of patients, establishing 180 μg as the MTD. In phase 2, the incidence of relapse was 39% at 6 months, which was sustained through 1-year post-HCT. The incidence of transplant-related mortality was 13%, and severe grade III-IV acute graft-versus-host disease (GVHD) occurred in 11%. Paired blood samples from donors and recipients after HCT revealed elevated levels of type 1 IFN with cellular response, the persistence of cross-presenting DCs, and circulating leukemia antigen-specific T cells. These data suggest that prophylactic administration of pegIFNα is feasible in the peri-HCT period. In high-risk AML, increased toxicity was not observed with preliminary evidence for reduction in leukemia relapse after HCT. This trial was registered at www.clinicaltrials.gov as #NCT02328755.

Drug resistance and relapse are common challenges in acute myeloid leukemia (AML), particularly in an aggressive subset bearing internal tandem duplications (ITDs) of the FLT3 receptor (FLT3-ITD+). The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet resistance to gilteritinib remains a clinical concern, and the underlying mechanisms remain incompletely understood. Using transcriptomic analyses and functional validation studies, we identified the calcium-binding proteins S100A8 and S100A9 (S100A8/A9) as contributors to gilteritinib resistance in FLT3-ITD+ AML. Exposure of FLT3-ITD+ AML cells to gilteritinib increased S100A8/A9 expression in vivo and in vitro and decreased free calcium levels, and genetic manipulation of S100A9 was associated with altered sensitivity to gilteritinib. Using a transcription factor screen, we identified the transcriptional corepressor BCL6, as a regulator of S100A9 expression and found that gilteritinib decreased BCL6 binding to the S100A9 promoter, thereby increasing S100A9 expression. Furthermore, pharmacological inhibition of BCL6 accelerated the growth rate of gilteritinib-resistant FLT3-ITD+ AML cells, suggesting that S100A9 is a functional target of BCL6. These findings shed light on mechanisms of resistance to gilteritinib through regulation of a target that can be therapeutically exploited to enhance the antileukemic effects of gilteritinib.

Aberrant expression of Ecotropic Viral Integration Site 1 (EVI1) is a hallmark of acute myeloid leukemia (AML) with inv(3) or t(3;3), which is a disease subtype with especially poor outcome. In studying transcriptomes from AML patients with chromosome 3q rearrangements, we identified a significant upregulation of the Nuclear Receptor Interacting Protein 1 (NRIP1) as well as its adjacent non-coding RNA LOC101927745. Utilizing transcriptomic and epigenomic data from over 900 primary samples from patients as well as genetic and transcriptional engineering approaches, we have identified several mechanisms that can lead to upregulation of NRIP1 in AML. We hypothesize that the LOC101927745 transcription start site harbors a context-dependent enhancer that is bound by EVI1, causing upregulation of NRIP1 in AML with chromosome 3 abnormalities. Furthermore, we showed that NRIP1 knockdown negatively affects the proliferation and survival of 3qrearranged AML cells and increases their sensitivity to all-trans retinoic acid, suggesting that NRIP1 is relevant for the pathogenesis of inv(3)/t(3;3) AML and could serve as a novel therapeutic target in myeloid malignancies with 3q abnormalities.

Internal tandem duplication within FLT3 (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and correlates with a poor prognosis. Whereas the FLT3 receptor tyrosine kinase is activated at the plasma membrane to transduce PI3K/AKT and RAS/MAPK signaling, FLT3-ITD resides in the endoplasmic reticulum and triggers constitutive STAT5 phosphorylation. Mechanisms underlying this aberrant FLT3-ITD subcellular localization or its impact on leukemogenesis remain poorly established. In this study, we discovered that FLT3-ITD is S-palmitoylated by the palmitoyl acyltransferase ZDHHC6. Disruption of palmitoylation redirected FLT3-ITD to the plasma membrane and rewired its downstream signaling by activating AKT and extracellular signal-regulated kinase pathways in addition to STAT5. Consequently, abrogation of palmitoylation increased FLT3-ITD–mediated progression of leukemia in xenotransplant-recipient mouse models. We further demonstrate that FLT3 proteins were palmitoylated in primary human AML cells. ZDHHC6-mediated palmitoylation restrained FLT3-ITD surface expression, signaling, and colonogenic growth of primary FLT3-ITD+ AML. More important, pharmacological inhibition of FLT3-ITD depalmitoylation synergized with the US Food and Drug Administration–approved FLT3 kinase inhibitor gilteritinib in abrogating the growth of primary FLT3-ITD+ AML cells. These findings provide novel insights into lipid-dependent compartmentalization of FLT3-ITD signaling in AML and suggest targeting depalmitoylation as a new therapeutic strategy to treat FLT3-ITD+ leukemias.

BACKGROUND The cytogenetics of acute myeloid leukemia (AML) increases exponentially with age. Adolescent and young adult (AYA) patients have specific psychosocial and other challenges, influencing their ability to access appropriate treatment. Therefore, in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for AML, inferior outcomes would be observed in AYA patients compared to children. METHODS We defined the age range of AYA patients as 15 to 29 years. Sixty-three patients who underwent allo-HSCT from 1998 to 2020 at Chang Gung Children Hospital were enrolled in this study. Overall survival was the time duration from HSCT to death from any cause. Disease-free survival was the time duration from HSCT to the last follow-up or first event (failure to achieve complete remission, relapse, secondary malignancy, or death from any cause). RESULTS Thirty-seven (59%) patients were

Background: Although monosomal karyotype (MK) has been recognized as an adverse risk factor in adult acute myeloid leukemia (AML), its impact on pediatric AML outcomes remains unclear. Methods: Clinical characteristics, cytogenetic and molecular profiling, and prognostic impact of MK were analyzed in a cohort of 284 children with AML in a Chinese population. Results: MK was present in 14 (4.5%) cases of the study cohort. MK-AML showed low prevalence of TP53 mutant and 17p13 aberrations. Children with MK-AML had shorter overall survival (OS) and event-free survival (EFS) compared to those with intermediate-risk features (OS: 26 ± 9.7% vs. 2 ± 1.5%, p

Acute myeloid leukemia (AML) is a severe hematologic malignancy that threatens human health. Long non-coding RNA (lncRNA) is emerged as a key player in human cancer. Herein, we explored the role of LINC00998 in human AML. LINC00998 was significantly decreased in human AML, which was linked to relapse and poor prognosis. Stable overexpression of LINC00998 inhibited AML cell viability, colony ability, DNA synthesis rate and increased apoptosis. LINC00998 was mainly located in the cytoplasm, in which interacted with ZFP36 ring finger protein (ZFP36), a mRNA destabilizing factor, resulting in increased decay of mammalian target of rapamycin complex 2 (mTORC2), a well-known proto-oncogene in AML. Overexpression of mTORC2 partly blocked the tumor suppressive effects of LINC00998. Importantly, LINC00998 shortened in vivo AML cell survival in xenograft tumor model. Taken together, we found that LINC00998 is a novel tumor-inhibiting lncRNA in human AML. The dysregulation of LINC00998/ZFP36/mTORC2 axis is linked to leukemogenesis and progression.

Background Mutations in TP53 in myeloid neoplasms patients have been associated with poor prognosis. Effective treatments to these patients remain unclear. Patients and Methods In this study, we retrospectively analyzed diagnostic and outcomes of 31 Acute Myeloid leukemia (AML) and 9 Myelodysplastic syndromes (MDS) patients with TP53 mutation at our hospital from September 2015 to October 2020. Results A total of 42 variants (28 unique variants) in the coding region of TP53 gene were identified, and most were missense mutation (34 of 42, 81%). The median overall survival (OS) was 8 months for the AML patients (1-32 months) and 7 months for the MDS patients (3-27 months). There were 35 and 13 patients underwent frontline chemical therapy and Allo-HSCT, respectively. The overall response rate was 45.3% (16/35) for the frontline treatment. There was no significant difference between intensive and low-intensity regimens on either response to the frontline treatment (P = .255) or overall survival (P = .078). Patients, who achieved complete or partial remission at the frontline treatment, presented a higher survival than patients in non–remission, no matter transplant or not. Conclusion This study corroborates that improving the response to the first-line treatment could prolong the survival of myeloid neoplasms patients with TP53 mutation. Allo-HSCT could be a curative option for patients with TP53 mutation, when in complete remission during the first-line treatment.

Epigenetic alterations of chromatin structure affect chromatin accessibility and collaborate with genetic alterations in the development of cancer. Lysine demethylase 4B (KDM4B) has been identified as a JmjC domain‐containing epigenetic modifier that possesses histone demethylase activity. Although recent studies have demonstrated that KDM4B positively regulates the pathogenesis of multiple types of solid tumors, the tissue specificity and context dependency have not been fully elucidated. In this study, we investigated gene expression profiles established from clinical samples and found that KDM4B is elevated specifically in acute myeloid leukemia (AML) associated with chromosomal translocation 8;21 [t(8;21)], which results in a fusion of the AML1 and the eight‐twenty‐one (ETO) genes to generate a leukemia oncogene, AML1‐ETO fusion transcription factor. Short hairpin RNA‐mediated KDM4B silencing significantly reduced cell proliferation in t(8;21)‐positive AML cell lines. Meanwhile, KDM4B silencing suppressed the expression of AML1‐ETO‐inducible genes, and consistently perturbed chromatin accessibility of AML1‐ETO‐binding sites involving altered active enhancer marks and functional cis‐regulatory elements. Notably, transduction of murine KDM4B orthologue mutants followed by KDM4B silencing demonstrated a requirement of methylated‐histone binding modules for a proliferative surge. To address the role of KDM4B in leukemia development, we further generated and analyzed Kdm4b conditional knockout mice. As a result, Kdm4b deficiency attenuated clonogenic potential mediated by AML1‐ETO and delayed leukemia progression in vivo. Thus, our results highlight a tumor‐promoting role of KDM4B in AML associated with t(8;21).

Key Points Patients with AML who received IC were compared with those who received ven to investigate predictors of outcomes.Presence of RUNX1 mutations is associated with better outcomes for ven/aza compared with IC., Visual Abstract, Venetoclax (ven) plus azacitidine (aza) is the standard of care for patients with newly diagnosed acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed patients with newly diagnosed AML who received ven/aza (n = 143) or IC (n = 149) to compare outcomes, seek variables that could predict response to 1 therapy or the other, and ascertain whether treatment recommendations could be refined. The response rates were 76.9% for ven/aza and 70.5% for IC. The median overall survival (OS) was 884 days for IC compared with 483 days for ven/aza (P = .0020). A propensity-matched cohort was used to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC compared with not reached for ven/aza (P = .0667). Variables that favored response to ven/aza over IC included older age, secondary AML, and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk, and RUNX1 mutations favored ven/aza over IC, whereas intermediate risk favored IC over ven/aza. In conclusion, patients receiving IC have improved OS compared with those receiving ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward favorable OS for ven/aza. Specific variables, such as RUNX1 mutations, reported here for the first time, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.

Fms-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) mutations drive malignancy in acute myeloid leukemia (AML), which accounts for approximately 40% of AML cases. Treatment with FLT3 or IDH1/2 inhibitors is used for such patients; however, it is not considered for most patients with AML who lack mutations on the respective genes. In this study, p90 ribosomal S6 kinase (RSK) was found to serve as a new therapeutic target in various AMLs with or without FLT3 mutations. BI-D1870, a potent inhibitor of RSK, significantly suppressed the proliferation of AML cell lines, among which three encoded wild-type FLT3 and three contained FLT3 driver mutations, compared with chronic myeloid leukemia K562 cells or other adherent cancer cells. BI-D1870 inhibited protein synthesis by dephosphorylating the p70 S6 kinase and eukaryotic initiation factor 4E-binding protein 1 in all AML cells except KG-1a cells. Meanwhile, the expression of microtubule-associated protein light chain 3B-I and -II increased in KG-1a cells treated with BI-D1870. BI-D1870 induced caspase-dependent apoptosis in all AML cells, including KG-1a cells. We next investigated the synergistic effect of BI-D1870 with cytarabine, a traditional anticancer drug used in AML. Synergistic effects of BI-D1870 and cytarabine were not observed in any of the cell lines. The findings suggested that BI-D1870 alone exerts an adequate antiproliferative effect on AML with or without FLT3 mutations and serves as a novel AML therapeutic agent.

Resistance to the BCR-ABL inhibitor imatinib mesylate poses a major problem for the treatment of chronic myeloid leukemia. Imatinib resistance often results from a secondary mutation in BCR-ABL that interferes with drug binding. However, sometimes there is no mutation in BCR-ABL, and the basis of such BCR-ABL-independent imatinib mesylate resistance remains to be elucidated. SOS1, a guanine nucleotide exchange factor for Ras protein, affects drug sensitivity and resistance to imatinib. The depletion of SOS1 markedly inhibits cell growth either in vitro or in vivo and significantly increases the sensitivity of chronic myeloid leukemia cells to imatinib. Furthermore, LC-MS/MS and RNA-seq assays reveal that SOS1 negatively regulates the expression of SLC22A4, a member of the carnitine/organic cation transporter family, which mediates the active uptake of imatinib into chronic myeloid leukemia cells. HPLC assay confirms that intracellular accumulation of imatinib is accompanied by upregulation of SLC22A4 through SOS1 inhibition in both sensitive and resistant chronic myeloid leukemia cells. BAY-293, an inhibitor of SOS1/Ras, was found to depress proliferation and colony formation in chronic myeloid leukemia cells with resistance and BCR-ABL independence. Altogether these findings indicate that targeting SOS1 inhibition promotes imatinib sensitivity and overcomes resistance with BCR-ABL independence by SLC22A4-mediated uptake transport., Graphical Abstract, Liu et al. provide evidence that targeting inhibitor SOS1 promotes imatinib sensitivity and overcomes resistance with BCR-ABL independence by SLC22A4-mediated uptake transport.

Introduction: Asthma and hypereosinophilia have been treated with different therapeutics in the past. Some of them appear to be more effective in symptoms resolution and decreasing eosinophilic count. Case Presentation: We report here an unusual case of asthma with hypereosinophilia secondary to Chronic Myeloid Leukemia (CML) with high prevalence of eosinophilic infiltrate, treated simultaneously with an anti-IL-5 antibody (Mepolizumab) and Tyrosine-kinase Inhibitors (TKI: Imatinib and Bosutinib) for three years. The patient showed a promising reduction of pulmonary exacerbations and good control of CML without developing side effects. Conclusion: We hope that this finding could inspire further studies on the efficacy and safety of the concomitant use of anti-IL-5 and TKI.

Background/purpose Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but advanced age with multiple comorbidities limits the eligibility for allo-HSCT. We conducted a retrospective study to investigate the comorbidities assessments and prognostic factors that predict outcomes for these patients. Methods Clinical data of patients older than 50 years who had received diagnoses of AML or MDS and underwent allo-HSCT were obtained. Information on patient characteristics, including age, gender, allogeneic transplant type, conditioning regimens, Charlson comorbidity index (CCI), and presence of acute graft-versus-host disease (GVHD) or chronic GVHD, were collected and analyzed. Results Two hundred fifty-five elderly patients with a median age at allo-HSCT of 57 years were included. The significant prognostic factors associated with worse overall survival (OS) were CCI ≥3 (hazard ratio: 1.88) and grade III–IV acute GVHD (3.18). Similar findings were noted in the non-relapse mortality analysis. To investigate the effects of chronic GVHD on patient outcomes, OS analysis was performed for those with survival >100 days after transplantation. The results revealed CCI ≥3 (1.88) and grade III–IV acute GVHD (2.73) remained poor prognostic factors for OS, whereas mild chronic GVHD (0.43) was associated with better OS. Conclusion This cohort study suggests that CCI ≥3 predicts poor outcomes, primarily due to a higher NRM risk. Careful management of GVHD after transplantation could improve outcomes in elderly patients with AML or MDS after allo-HSCT.

Acute erythroid leukemia (AEL) is a subtype of acute myeloid leukemia (AML) with features such as accumulation of maturation-arrested erythroblasts. Compared with AML, the progression of AEL is faster and the prognosis to available therapy is worse. However, its categorization is still being updated and the pathophysiology of AEL is still under research, making diagnosis and chemotherapy challenging for physicians. To achieve better outcomes, therapies should be optimized and new drugs should be developed. In this review, we summarize current strategies of diagnosis and therapies of AEL, and discuss prospective targets for chemotherapeutic agents based on the biological characteristics of AEL neoplastic cells as well as transcriptional factors and pathways related to erythroid differentiation.