Acute Myelomonocytic Leukemia Research Articles

Analysis of early and treatment related deaths among children and adolescents with acute myeloid leukemia in Poland: 2005-2023.

A personalised approach to the treatment of acute myeloid leukemia (AML) in children and adolescents, as well as the development of supportive therapies, has significantly improved survival. Despite this, some patients still die before starting treatment or in an early phase of therapy before achieving remission. The study analysed the frequency, clinical features and risk factors for early deaths (ED) and treatment related deaths (TRD) of children and adolescents with AML. From January 2005 to November 2023, 646 children with AML treated in the centers of the Polish Pediatric Leukemia and Lymphoma Study Group according to three subsequent therapeutic protocols were evaluated: AML-BFM 2004 Interim (385 children), AML-BFM 2012 Registry (131 children) and AML-BFM 2019 (130 children). Out of 646 children, early death occurred in 30 children, including 15 girls. The median age was 10.7 years (1 day to 18 years). More than half of the patients (53%) were diagnosed with acute myelomonocytic leukemia (M5) and 13% with acute promyelocytic leukemia (M3). The ED rate for the three consecutive AML-BFM protocols was 4.9% vs. 5.3% vs. 3.1%, respectively. In 19 patients, death occurred before the 15th day of treatment, in 11 between the 15th and 42nd day. The most common cause of death before the 15th day (ED15) was leukostasis and bleeding, whereas between the 15th and 42nd day (ED15-42), infections, mainly bacterial sepsis. A significant association was found between ED15 and high leukocyte count (>10 × 109/L), M3 leukemia (p < 0.001), and ED15-42 and age <1 year (p = 0.029). In the univariate analysis only initial high leukocyte count >100 × 109/L, was a significant predictor of early death. The overall TRD for the entire study period was 3.4%. The main cause of death were infections, mainly bacterial sepsis (10 children out of 22, 45.4%). Hyperleukocytosis remains significant factor of early mortality in patients with AML, despite the introduction of various cytoreductive methods. Infections are still the main cause of treatment related deaths. A more individualized approach by using new targeted drugs may be the therapeutic option of choice in the future.

Utility of Targeted Next Generation Sequencing (NGS) to Predict Hematologic Neoplasms with Germline Predisposition

Abstract Introduction/Objective Hematologic neoplasms with germline predisposition are increasingly gaining clinical relevance as associated gene variants are emerging. These variants confer an increased risk for developing hematologic neoplasms as additional somatic aberrations accumulate. Recognition of germline predisposition is crucial to patient management as it would prompt genetic counseling and regular surveillance in affected patients and biological family members, as well as guide therapy, as many patients undergo allogeneic stem cell transplantation for which relatives are typically the preferred donors. Furthermore, these patients may respond differently to conventional therapies. Clinical recognition of germline predisposition is challenging due to phenotypic heterogeneity and a lack of germline testing standards and resources. Next generation sequencing is routinely utilized to detect somatic variants associated with hematopoietic neoplasms. Molecular profiling may also potentially serve as a screening tool to suggest pathogenic germline variants. Methods/Case Report Comprehensive genomic profiling data was reviewed for 301 patients with known hematologic neoplasms. A somatic-germline-zygosity (SGZ) computational method classified variants by origin. Variants of unknown clinical significance were excluded. The final study showed 94 patients predicted to have germline variants. The variables analyzed include germline variants, concurrent mutations, diagnosis, sex, age, and ancestry. Results (if a Case Study enter NA) Acute myeloid leukemia was the most frequent diagnosis, followed by B-cell acute lymphoblastic leukemia, myeloproliferative neoplasms, myelodysplastic syndrome, and chronic myelomonocytic leukemia. The median patient age was 60 years, ranging from 6 months to 91 years. Male gender and European ancestry were proportionally greater. In this study, we identified 70 distinct genes with 145 germline pathogenic variants. The most common pathogenic germline variants were TET2, SRSF2, RUNX1, DNMT3A, and CHEK2. Conclusion In conclusion, SGZ computational methods can be used as a screening tool to predict possible germline mutations in hematologic malignancies, which will help guide treatment and improve patient and family outcomes

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.

Acute Myelomonocytic Leukemia Eosinophilic Variant: Epidemiological, Clinical, and Biological Profile at the Hassan II University Hospital of Fez

Introduction: Acute myelomonocytic leukemia with an eosinophilic component (AML4Eo) is a particular and rare hematological entity, representing between 5% and 8% of all acute myeloid leukemias. The aim of our work is to highlight the clinical and cytogenetic epidemiological particularities of this pathology at the Hassan II University Hospital in FES. Patients and Methods: Retrospective descriptive study spread over 14 years (January 2009-January 2023) including all patients diagnosed with LAM4Eo.Myelogram reading as well as immunophenotyping by flow cytometry on Cytomic FC500 were performed at the central hematology laboratory and cytogenetics at the genetics laboratory CHU HASSAN II of FES. Clinical data were collected from patients' medical charts. Results: Thirteen patients were enrolled. The mean age at diagnosis was 20.4 years, with a predominance of males (54%) most patients presented with an altered general condition, signs of cytopenia and a tumor syndrome. All patients presented with profound anemia associated with thrombocytopenia and hyperleukocytosis. Blood smears showed the presence of peripheral blasts in 80% of cases. All medullograms met the morphological criteria established by the FAB (Franco-American-British) classification for the diagnosis of LAM4Eo.Cytochemical staining with myeloperoxidase was performed on all medullograms and was positive in all cases. Immunophenotyping was carried out in 56% of patients, showing the existence of very immature blasts expressing myeloblast and monoblast markers. Four of our patients underwent cytogenetic studies, with no translocation or inversion of chromosome 16. Three patients died immediately after diagnosis. The other patients were put on chemotherapy, two of whom died during treatment. Discussion/Conclusion: LAM4Eo is a rare hematological malignancy with a better prognosis than other myeloid leukemias. Despite the development of cytogenetics and molecular biology techniques, morphological examination ..

Utility of KIT Mutations in Myeloid Neoplasms Without Documented Systemic Mastocytosis to Detect Hidden Mast Cells in Bone Marrow

BackgroundKIT p.D816 mutation is strongly associated with systemic mastocytosis (SM). Next-generation sequencing (NGS) is now routinely performed in almost all bone marrow sample and KIT mutations are detected from patients who are not known or suspected to have SM. Therefore, we wanted to assess if KIT mutations in this patient population are associated with unsuspected SM. MethodsWe searched NGS result in our institution with positive result for KIT mutation from patients with known/suspected myeloid neoplasms. Patients with previously documented history of systemic mastocytosis were excluded. Bone marrow biopsies from patients with KIT mutation were assessed with immunohistochemical stains for CD117 and mast cell tryptase (MST). ResultsBone marrow biopsies were assessed with immunohistochemical stains for CD117 and mast cell tryptase (n = 49). Most patients had acute myeloid leukemia (AML, n = 38) or chronic myelomonocytic leukemia (CMML, n = 6). Immunohistochemical stains for CD117 and tryptase were performed in all 49 patients. A total of 4 patients (8.2%) showed mast cell nodules where spindled shaped mast cells were present, meeting the WHO criteria for SM. All four patients had KIT p.D816V mutation and had high mutant allelic frequency (∼ 50%) except one patient (1%). ConclusionWe discovered approximately 8% of patients who had myeloid neoplasms with unexpected KIT mutations fulfilled the diagnostic criteria for systemic mastocytosis after additional immunohistochemical studies. Our data support that application of additional immunohistochemical studies is recommended to identify underrecognized SM when KIT mutations are found by molecular assays.

A blastic plasmacytoid dendritic cell neoplasm-like immunophenotype is negatively associated with CEBPA bZIP mutation and predicts unfavorable prognosis in acute myeloid leukemia.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.

Breakage and dislocation of the Hickman catheter in pediatric patient

Introduction. The Hickman catheter is a tunneled, open-type catheter often implanted in children for long-term intravenous treatment. Their application can cause numerous complications. Catheter breakage and dislocation of fragments to the intravascular system is a rare but life-threatening condition. When a complication occurs, depending on the patient's clinical condition, the first step is transcutaneous endovascular removal of the catheter's fragment. If this is not possible, surgical thoracotomy is necessary. The objective of this article was to present a case of breakage and dislocation of Hickman catheter in pediatric patient, as well as the diagnostic and therapeutic approach to complications. Case outline. We report a 14-month-old child who had a Hickman catheter because he was undergoing treatment for acute juvenile myelomonocytic leukemia. Due to a malfunction of the catheter, the existing catheter had to be removed. During the surgical procedure, a breakage and dislocation of the catheter fragment occurred. A chest x-ray and an echocardiography confirmed the position of the catheter fragment in the right atrium. A transcutaneous endovascular procedure was successfully performed to remove part of the catheter. Conclusion. Numerous complications can occur during the insertion, management, and removal of long-term catheters. It is necessary to periodically control the catheter's position by chest x-ray and ultrasound of the heart and neck. If a particular complication is detected, an individual approach to treatment with the lowest risk to the patient should be chosen. Dislocated fragments of the Hickman catheter can be safely removed by endovascular transcatheter procedures.

Acute onset of constrictive pericarditis due to acute myelomonocytic leukemia: A case and literature review

Acute onset of constrictive pericarditis due to acute myelomonocytic leukemia: A case and literature review

T-Cells Immune Cluster Analysis Using Cytof Identifies Unique Patient Subgroups with TP53 Mutation and Predicts Complete Remission (CR) in Patients with Acute Myeloid Leukemia (AML) Receiving Venetoclax Plus Hypomethylating Agent Therapy

Introduction The advent of venetoclax (VEN) based chemotherapy has revolutionized the treatment of elderly acute myeloid leukemia (AML), with improvement in remission rates from historical 10%-20% to 60%-70%. However, remission duration is short-lived in patients (pts) with high-risk AML with consequent dismal outcome. As our knowledge of genomic landscape of AML expands and more immunotherapies become available, exploration of the immune tumor microenvironment (TME) of AML may allow identification of subsets of pts that may benefit from immune based therapy. We conducted an investigator initiated prospective study to evaluate TME of pts receiving VEN plus hypomethylating agent (HMA; azacitidine or decitabine) combination. We hypothesize that these pts will cluster into immune-infiltrated vs. immune-depleted sub-types by high-definition immune cell profiling. Methods In 26 newly diagnosed AML pts, who were planned to receive VEN plus HMA therapy, we isolated bone marrow (BM) and peripheral blood (PB) derived mononuclear cells (MC) by density gradient centrifugation and cryopreserved. We performed CyTOF (cytometry time-of-flight) analysis to study their immune signatures. Thawed cells were labeled with metal-conjugated antibodies that bind CD33, CD196, CD19, CD127, CD11b, CD4, IgD, CD11c, CD14, CD56, CD123, TCRgd, CD185/CXCR5, CD45RA, CD27, CD28, CD66b, CD183 (CXCR3), CD161, CD45RO, CD197 (CCR7), CD8a, CD25, CD3, CD20, CD38, HLA-DR, CD194 (CCR4), CD57, CD16 and CD45. We performed a Rphenograph clustering on 25 paired BMMC and PBMC samples (one patient only had PBMC) to create 35 unique clusters for each ( Figure 1). Then we broke down the distribution of cluster by two different groupings: pts with TP53 mutation (m) and those who achieve complete remission. Statistical significance of clusters calculated using t-test. We performed Pearson correlation test on the paired BMMC and PBMC samples to assess correlation between BMMC and PBMC samples. Results Baseline characteristics The median age of the pts was 74 years (range, 53-88), and 17 (65%) pts were male. Ten (37%) pts had secondary AML, and 12 (46%) pts had ELN adverse risk disease (n=6; TP53m). There was no significant difference in median age (p= &amp;gt;0.99), proportion of pts with secondary AML (p= 0.64), acute myelomonocytic leukemia (p= 0.14) white blood cell count (WBC) ≥ 100 (10 9/L) (p= &amp;gt;0.99), and frequency of commonly occurring co-mutations ( ASXL1 [p=0.35]), FLT3 ITD [p=0.54], splicing [p=0.29], IDH1/2 [p=0.28], DNMT3A [p=0.29], NPM1 [p=0.29], TET2 [p=0.35]) in TP53m and TP53 wild-type group. Response 12/20 (60%) evaluable pts achieved complete remission with or without count recovery (CR/CRi). There was no significant difference in median age (p= 0.06), proportion of pts with secondary AML (p= 0.16), therapy related AML (p= 0.60) WBC ≥ 100 (10 9/L) (p= 0.40), and frequency of commonly occurring mutations ( TP53 [p=0.60], ASXL1 [p &amp;gt; 0.99]), FLT3 ITD [p=0.54], splicing [p &amp;gt; 0.99], IDH1/2 [p=0.60], DNMT3A [p=&amp;gt;0.99], NPM1 [p=0.61], TET2 [p &amp;gt;0.99]) in CR/CRi and no-CR/CRi group. CyTOF analysis and Rphenograph clustering on 25 paired BMMC and PBMC samples We found significant clustering with high expression of B-cell activated (cluster 2; p= 0.005), NK cell rich (cluster 1; p= 0.005, cluster 35; p= 0.0009), CD8 T-cells (cluster 31; p= 0.01) and CD4 effector cells (cluster 17; p= 0.005) phenotype among TP53m AML ( Table 1). Among pts who achieved CR/CRi, significant clustering with low expression of B-cell activated (cluster 29; p= 0.01), CD8 cytotoxic (cluster 14; p= 0.01) CD4 activated (cluster 21; p= 0.03) phenotypes observed. Correlation between BMMC and PBMC clustering Among clusters which showed significance for a particular phenotype, we performed Pearson correlation (R 2) and observed strong correlation between BMMC and PBMC samples clustering in cluster 1 (R 2 = 0.99), cluster 2 (R 2 = 0.95), cluster 17 (R 2 = 0.96), cluster 21 (R 2 = 0.99) and cluster 29 (R 2 = 0.93). Conclusion In this single institutional study using CyTOF analysis we have identified novel clustering with immune- infiltrated phenotype among pts with TP53m AML and conversely immune-depleted phenotype among AML pts who responded to VEN plus HMA. Moreover, we found strong correlation in CyTOF analysis conducted from BMMC and PBMC samples. Future studies with larger sample size needed to validate our findings.

Preliminary Results from a Phase 1b/2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine in Patients (Pts) with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202)

Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase Polo-like kinase 4 (PLK4), a unique Polo-like kinase family member, that is a conserved upstream regulator of centriole duplication. Dysregulation of PLK4 expression causes loss of centrosome numeral integrity, promotes genomic instability and also potentially enables cancer cells to tolerate genomic instability (Mason et al, Cancer Cell 2014). Its inhibition likely causes mitotic catastrophe. An investigator-initiated study (IIS) demonstrated clinical activity in relapsed/refractory AML with adverse cytogenetics. Dose limiting toxicity was colitis, sepsis and the RP2D 96 mg, three CR's (9 evaluable pts) across 2 dose levels were observed [Data on File, Murphy et al]. We report updated data on a company sponsored study (TWT-202; NCT04730258). Study Design and Methods: TWT-202 is a study of CFI-400945 with 3+3 design in escalation and Simon 2 stage in expansion. For Part 1 (CFI-400945), pts with relapsed and/or refractory AML, MDS, or CMML after &amp;gt;1 prior therapy will be included. Pts with MDS or CMML must have progressed or no response after 4 cycles of hypomethylating agents. For Part 2, (CFI-400945 with azacitidine), pts should have relapsed and/or refractory AML, untreated MDS or CMML. Untreated pts ineligible for intensive therapy may be included. The maximum tolerated dose (MTD) is defined as the dose where dose-limiting toxicities (DLTs) are &amp;lt;1 out of 6 at or below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed. Results: At 2May2023 cut, 26 pts were enrolled into Part 1. Eighteen (69%) pts had AML, 4 (15%) MDS, 4 (15%) CMML. The median number of prior therapies was 3 (range 1-8), 7 (27%) pts had received a previous stem cell transplant. Twenty (77%) were male, the median age 68 years (range 22, 85). Approximately 80% pts with AML were adverse risk by ELN 2022 criteria. Six pts with AML had TP53 mutations. At 21 days on/7 days off schedule, 5 pts received 32mg, 4 pts 48mg, 3 pts 64mg, 5 pts 80mg, 9 pts 96mg daily. The 28 days on/0 days off schedule was introduced at 96mg, 3 pts enrolled, with 0 DLTs to date. There was 1 DLT at 96mg on the 21/7 schedule (fungemia, gastroparesis, septic shock, enteritis). There have been 23 (89%) SAEs with the following occurring in &amp;gt;3 pts (febrile neutropenia (13 pts), sepsis (5 pts), diarrhea (4 pts), pneumonia (4 pts)). Common treatment emergent adverse events (TEAE) in &amp;gt; 5 pts, all grades, all doses; febrile neutropenia-15 pts (58%), nausea-11 pts (42%), diarrhea, vomiting-both 10pts (39%), hypokalemia- 9 pts (35%), dsypnea, hypophosphatemia-8pts each (31%), anemia-7pts (27%), and abdominal pain, fatigue, hypomagnesemia, pneumonia -6 pts each (23%). 31 % (33 events, 8 pts) ≥grade 3 TEAE's were considered related to CFI-400945 . Three pts (50%) with AML (all with prior venetoclax based therapies) at the 96mg dose level (21/7) from 6 evaluable achieved a response after 1 cycle. One pt (85M) with ELN2022 adverse genetics: complex karyotype, TP53 mutation, achieved CRi, and remains in remission after 3 cycles. One pt (70M) with AML (ELN2022 adverse genetics, complex cytogenetics, TP53 mutation), 2 prior regimens, achieved an MLFS and is pending count recovery. Third pt (51M) had AML normal cytogenetics, ELN 2022 adverse genetics (RUNX1, IDH2, SRSF2), and had relapsed/refractory disease after 5 regimens. The pt achieved an MLFS, however medical complications not related to study drug resulted in dose reduction, therapy hold and subsequent relapse. Pharmacokinetic (PK) evaluations indicated mean terminal-life ranged from 7 - 12 hours. Low accumulation was observed after 21d (AR &amp;lt;2-fold). Exposure in this study is overlapped with that observed in the IIS (Data on File, Murphy et al) study. PD studies evaluating the effect of CFI-400945 on markers of mitosis, ploidy and centriole function are ongoing. Conclusion: CFI-400945 has been generally well tolerated in this difficult to treat patient population, including patients whose disease progressed on or following venetoclax based therapies. Three of 6 evaluable patients with AML achieved a response (MLFS=2, CRi=1) at the 96mg dose. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose expansions are planned and a combination with azacitidine will open shortly. Murphy et al, Data on File, PMCC Mason et al Cancer Cell 26, 163-176

Clinical Features of Myeloid Neoplasms with Germline GATA2 Mutations–a Systematic Review of Clinical Studies Retrieved through Extensive Searching

Aims: Recent findings increasingly find individuals are being recognized as having germline predisposition to myeloid malignancies. GATA2 mutation is one of the most extensively studied germline mutations. However, until recently most of studies have focused on the mechanism of how GATA2 as one of the driver mutations causes malignancies. As regards the clinical features, such as the treatment and prognosis of myeloid neoplasms associated with germline GATA2 mutations, only small studies published, based on which they were insufficiently studied. Therefore, we did the systematic review to summarize the diagnosis, therapeutic methods and prognosis of myeloid malignant diseases associated with germline GATA2 mutations. Methods: Two reviewers independently comprehensively searched Pubmed and hand searched the professional journals and the reference lists of related and included articles from Jan 1 st, 1990 until May 1 st, 2023. They also independently screened and evaluated the retrieved records and then extracted data of included studies. Studies reported clinical materials on the diagnosis, treatment and prognosis of myeloid malignant patients with germline GATA2 mutations will be included and the clinical data will be summarized. Searching strategies were as follows: #1 germline or predispo* or somat* or famil* or germ line or congenit* or altera* or non-tumor; #2 gene* or genom* or sequenc* or muta* or SNP or abnormal* or translocat* or chromosom* or frameshift* or exom* or GATA; #3 “acute myeloid leukemia” “Leukemia, Myeloid, Acute” “Myelodysplastic Syndromes” “refractory anemia” “myeloid or myeloblast*” or AML or MDS; #4 #1 and #2 and #3 Results: 2457 records were retrieved and 23 studies with 396 patients were included. Screening process was shown in Figure 1. Studies included were all small sample sized. The diagnosis age was from three to 78 years old, most of the median ages of included studies were less than 30 years indicated carriers would have symptoms in young age, on the other hand, there were also patients who began having symptoms in old age (the oldest 78 years) or remained asymptomatic carriers without getting sick in the whole life. There was no sex difference. Emberger syndrome which caused lymphedema and MonoMAC and/or DCML (dendritic cell, monocyte, B-lymphocyte and NK-lymphocyte) deficiency syndromes that caused cytopenia and infections were generally appeared earlier before myeloid malignancies. Myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) are common malignant diseases for patients with germline GATA2 mutations predisposition. The morbidity was not able to be calculated based on the data available. MDS was the most common myeloid neoplasm compared with AML and CMML which were always transformed from MDS. Other hematologic malignancies were rare. The disease transformation was shown from refractory cytopenia to malignant clonal hematopoiesis that caused MDS, and then transformed into leukemia. In total, 311/396 (78.5%) patients developed malignant myeloid diseases. Nine studies had done the family pedigree analysis and there were 162 family members who had the germline GATA2 mutations predisposition, in which there were 32 asymptomatic carriers (19.7%). 128 patients were reported to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT), 81 (63.3%) were alive and 44 (34.4%) died of relapse or transplantation related complications. Three patients' outcome was unknown. In study Michael A. Spinner et al, survival rate was 54% by 4 years after allo-HSCT (21 patients included). Nearly all patients (15/18) with myeloid malignancies who did not receive transplantation had died. The most common cytogenetic abnormalities were monosomy 7 and trisomy 8, and other abnormalities were also common. Conclusions: Most of germline GATA2 mutation carriers will have symptoms in young age and many of them will progress into malignant myeloid diseases. Allo-HSCT was effective to treat symptomatic patients, especially for patients with malignant hematologic diseases, and furthermore that is the only curative treatment. Asymptomatic carriers are not rare and for them regular tests are essential. More clinical studies on germline GATA2 mutations for myeloid neoplasms are needed to clarify the clinical features in this setting and improve its treatment and prognosis.

A Phase II Study of Vibecotamab, a CD3-CD123 Bispecific T-Cell Engaging Antibody, for MDS or CMML after Hypomethylating Failure and in MRD-Positive AML

Background Leukemic stem cells have high expression of CD123 compared to normal hematopoietic stem cells and is therefore a therapeutic target in multiple leukemias including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has shown clinical activity in relapsed/refractory AML, particularly in low-blast disease. We therefore sought to evaluate vibecotamab in other low-blast states, including MDS or CMML after hypomethylating agent failure and MRD-positive AML. Methods In this two-arm, open-label, phase II study, adults with either MDS (IPSS-R intermediate or higher risk) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents or AML in first or second morphologic remission with detectable MRD at a level of ≥0.1% by flow cytometry were eligible. CD123 expression ≥20% on aberrant myeloid blasts was required for enrollment. Vibecotamab was given IV in a ramp-up dose schedule on days 1 (0.43µg/kg), 3 (0.75µg/kg), 5 (1.1µg/kg), and 8 (1.7µg/kg) in cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7µg/kg. Patients (pts) received up to 4 cycles of vibecotamab in 28-day cycles. The primary endpoint of the MDS/CMML cohort was response rate (CR + mCR + PR + HI + clinical benefit) within 4 cycles. The primary endpoint of the AML MRD cohort was the MRD negativity rate within 4 cycles. Results Between May 2022 and July 2023, 23 pts were treated (11 MDS/CMML, 12 AML MRD). Baseline characteristics are shown in Table 1. In the MDS/CMML cohort, 7 pts (63%) had received two or more prior lines of therapy, 8 pts (73%) had prior venetoclax exposure, and 2 pts (18%) had prior hematopoietic stem cell transplant (HSCT). Six MDS pts (66%) were IPSS-R high or very high risk. In the AML cohort, 6 pts (50%) had received two or more lines of prior therapy, 11 pts (92%) had prior venetoclax exposure, and 5 pts (42%) had prior HSCT. Ten pts (83%) were ELN 2022 adverse risk. The baseline CD123 expression was 72% (range, 43%-99%) in the MDS/CMML cohort and 89% (range, 55%-99%) in the AML MRD cohort. The baseline MRD by flow cytometry in the AML MRD cohort was 1.1% (range, 0.1%-3.9%). Responses are shown in Table 2. In the MDS/CMML cohort, 7 pts responded (64%), with 6 pts (56%) achieving marrow complete remission (mCR) and 1 pt (9%) achieving hematologic improvement (HI) per International Working Group (IWG) 2006 criteria. Among the 9 MDS pts, 4 (44%) achieved mCR + HI (2 HI-N, 1 HI-P, and 1 HI-P + HI-N), and 1 (11%) achieved HI (HI-N + HI-P). Per revised IWG 2023 MDS response criteria, 5 of the 9 MDS pts (56%) achieved complete remission with limited count recovery (CR L). Two of 4 MDS pts (50%) with TP53 mutations achieved CR L. Both CMML pts achieved mCR, with one pt also achieving HI-N. Among 9 pts with baseline bone marrow blasts =&amp;gt;5% at trial enrollment, 6 (67%) achieved a mCR, with or without HI. Best response occurred after the first cycle in all pts. CD123 expression was not associated with likelihood of response. Of the 7 responders, 5 are in ongoing response (range 0.3-6.9 months), one died in CR L from non-hematologic complications (heart failure), and one relapsed 5 months after achieving CR L. Of the 12 pts in the AML MRD cohort, 3 (25%) achieved MRD negativity, all of which occurred after 1 cycle of vibecotamab. Among the 3 responders, all were ELN adverse risk and had prior venetoclax exposure, 2 had prior HSCT, and 1 had inv(3). The median MRD and CD123 expression in responders was 0.2% (range 0.1%-0.2%) and 98% (range 95%-99%) vs 1.8% (range 0.5%-3.9%) and 87% (range 66%-96%) in non-responders, respectively. At last follow-up, all 3 responders are still in MRD-negative remission (range 3.2-12.8 months). Vibecotamab was well-tolerated with no pts requiring dose reductions or being taken off study due to adverse events. Ten pts (44%) experienced grade 2 infusion reactions and 1 pt (4%) experienced a grade 3 infusion reaction. Myelosuppression was minimal, consistent with previous studies of vibecotamab. Conclusion Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 64% in MDS/CMML after HMA failure and 25% in MRD-positive AML. The clinical activity of vibecotamab, including in pts with prior venetoclax exposure and/or HSCT, and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML.

NECROTIZING ULCERATIVE GINGIVITIS AS A COMPLICATION OF FEBRILE NEUTROPENIA IN ACUTE MYELOID LEUKEMIA PATIENT

Background: Necrotizing ulcerative gingivitis (NUG) is a periodontal disease characterized by gingival pain, interdental gingival necrosis, and bleeding. NUG is closely related to immunosuppression, smoking, poor oral hygiene, malnutrition, and stress. Acute myeloid leukemia (AML) is a bone marrow malignant neoplasm. Chemotherapy as the treatment for AML often causes febrile neutropenia which results in immunosuppression conditions and is a risk factor for NUG. This case report aimed to discuss NUG as a complication of febrile neutropenia. Case: A 22-year-old woman was referred from hemato-oncology with acute myelomonocytic leukemia (AML-M4) and febrile neutropenia due to her oral complaints. She had undergone one cycle of chemotherapy and developed febrile neutropenia. Intra-oral showed ulcers covered with white-grayish plaques on the gingival region 35 to 45 and 15 to 25. There were white plaques that could be removed leaving an erythematous area on the dorsal tongue. Blood laboratory tests showed pancytopenia and severe neutropenia. The diagnoses were necrotizing ulcerative gingivitis and pseudomembranous candidiasis. Case management: Debridement using 1.5% hydrogen peroxide solution, rinsing with 0.2% chlorhexidine gluconate, as well as cleaning teeth and tongue 2 times daily. The internal medicine department gave meropenem. The lesions and gingiva were healed after three weeks of therapy. Conclusion: Febrile neutropenia due to chemotherapy reduces the body's ability to fight infection, oral homeostasis is disturbed therefore bacterial growth increases, neutrophils carry out phagocytosis forming reactive oxygen species which causing necrotic cells and then NUG occurred. Appropriate, adequate, and immediate therapy is needed to avoid further complications. Keywords: Acute myeloid leukemia, Febrile neutropenia, Necrotizing ulcerative gingivitis

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

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

Cutaneous involvement in Ph-negative myeloproliferative neoplasms: from extramedullary hematopoiesis to myeloid metastasis with histiocytic differentiation. A systematic review of the literature.

Myeloid neoplasms may metastasize to the skin, presenting a wide range of clinical-pathological features that often lead to a reduction in patients' survival. The presentation varies depending on the category of myeloid neoplasm and its prognostic significance. The literature has specifically focused on the features of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML). In this article, we aimed to uncover the peculiarities of clonal skin proliferations in the course of Ph-negative myeloproliferative neoplasms (MPNs). We conducted a systematic review and statistical analysis of the literature data. MPN patients mainly exhibited cutaneous extramedullary hematopoiesis, while a minority displayed cutaneous histiocytic lesions. Furthermore, these patients showed lower survival rates compared to the median survival of MPN patients, especially when calculating survival from the appearance of cutaneous lesions. Our work highlights, for the first time, the prognostic relevance and histological heterogeneity of cutaneous lesions in MPN. Moreover, it emphasizes the importance of dermatological and histological examinations when cutaneous lesions are present.

Impact of CSF3R Mutation on Treatment Response and Survival of Patients with Acute Myeloid Leukemia

To investigate the expression of CSF3R mutation in acute myeloid leukemia (AML) and analyze its clinical characteristics and prognosis. A retrospective study was conducted in 212 patients with AML who were newly diagnosed in the Second Hospital of Shanxi Medical University from January 1th 2018 to June 30th 2021, including 22 patients with CSF3R mutations as mutation group and 190 patients with CSF3R wild type ［66 cases of them were screened by propensity score matching (PSM), as control group］. The early efficacy and survival between the two groups were compared. The median age of patients in the mutation group was 50(17-73) years old, and the ratio of male to female was 1.2:1 The main types were AML with maturation (11 cases) and acute myelomonocytic leukemia (9 cases). Prognostic stratification was carried out according to the risk stratification system of the European leukemia network in 2017, with 16 cases (72.73%) in the middle and high-risk group. At the initial diagnosis, the median count of white blood cell (WBC) was 44.75(1.30-368.71)×109/L, among which 15 cases (68.18%) were >10×109/L, and the median count of platelet (PLT) was 24(4-55)×109/L. CSF3R T618I (68.18%) was a common mutation site, which had concomitant gene mutations, in which CEBPA mutation was the most common (10 cases, 45.45%), but only existed in CSF3R T618I mutation. The CR/CRi rate was 68.18% and 71.21% in the mutant group and the control group (P >0.05), the median over all survival time was 15 months and 9 months (P >0.05), and the median disease-free survival time was 8 months and 4 months (P >0.05), respectively. Most AML patients with CSF3R mutation are middle-aged patients, the main types are AML with maturation and acute myelomonocytic leukemia, and most of them have middle and high-risk prognosis. CSF3R mutation may not be an independent prognostic marker for newly diagnosed AML patients.

A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure.

TPS7076 Background: CD123 is a marker of leukemic stem cells that is differentially overexpressed in most patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). In contrast, CD123 is expressed at negligibly low levels on normal hematopoietic progenitors, making it a potentially promising therapeutic target. Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has established clinical activity in relapsed/refractory AML. In a phase I study, the overall response rate was 14.8% in patients who received vibecotamab at a dose of ≥ 0.75 µg/kg (Ravandi F et al. ASH 2020 abstract #460). Response rates were notably higher in those with lower disease burden (bone marrow blasts ≤ 25%) where the overall response rate was 25.9%. In light of the activity of vibecotamab in relapsed/refractory low-blast AML, we designed this phase II study to evaluate vibecotamab in other low-blast states, including CD123-positive, MRD-positive AML and in MDS or CMML after failure of hypomethylating agents. Methods: This is a two-arm, open-label, phase II study of vibecotamab in patients with AML in first or second morphological remission with detectable MRD at a level of ≥0.1% by flow cytometry and in patients with MDS (intermediate or higher-risk by IPSS-R) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents. CD123 expression ≥20% on aberrant myeloid blasts is required for study eligibility. Vibecotamab is given IV in a ramp-up dose schedule on days 1, 3, 5 and 8 of cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7 µg/kg. Patients may receive up to 4 cycles of vibecotamab in 28-day cycles. The primary objective of the AML MRD cohort is to determine the MRD negativity rate after 4 cycles; the primary objective of the MDS/CMML cohort is to determine the response rate (CR + mCR + PR + HI + clinical benefit) after 4 cycles. The target MRD response in the AML MRD cohort is 50%, and the target response rate in the MDS/CMML cohort is 30%. Secondary endpoints include remission duration, duration of MRD response (AML MRD arm), CR rate (MDS/CMML arm), relapse-free survival, overall survival, and safety. Exploratory endpoints include correlation of clinical outcomes with CD123 expression and the dynamics of CD123 expression at treatment initiation and at the time of relapse. Additional immunological correlatives will be performed, including 1.) determination of molecular immune states that predict response or resistance, 2.) functional interrogation of TCR-antigen interactions, and 3.) nomination of leukemic neo-antigens. The planned enrollment is 40 patients (20 in each of the two cohorts). To date, 13 patients have been enrolled (7 in the AML MRD cohort and 6 in the MDS/CMML cohort). The trial is actively accruing at MD Anderson Cancer Center. Clinical trial information: NCT05285813 .

Sabatolimab (MBG453) model-informed drug development for dose selection in patients with myelodysplastic syndrome/acute myeloid leukemia and solid tumors.

Sabatolimab is a novel immunotherapy with immuno-myeloid activity that targets T-cell immunoglobulin domain and mucin domain-3 (TIM-3) on immune cells and leukemic blasts. It is being evaluated for the treatment of myeloid malignancies in the STIMULUS clinical trial program. The objective of this analysis was to support the sabatolimab dose-regimen selection in hematologic malignancies. A population pharmacokinetic (PopPK) model was fit to patients with solid tumors and hematologic malignancies, which included acute myeloid leukemia, myelodysplastic syndrome (including intermediate-, high-, and very high-risk per Revised International Prognostic Scoring System), and chronic myelomonocytic leukemia. The PopPK model, together with a predictive model of sabatolimab distribution to the bone marrow and binding to TIM-3 was used to predict membrane-bound TIM-3 bone marrow occupancy. In addition, the total soluble TIM-3 (sTIM-3) kinetics and the pharmacokinetic (PK) exposure-response relationship in patients with hematologic malignancies were examined. At intravenous doses above 240 mg Q2w and 800 mg Q4w, we observed linear PK, a plateau in the accumulation of total sTIM-3, and a flat exposure-response relationship for both safety and efficacy. In addition, the model predicted membrane-bound TIM-3 occupancy in the bone marrow was above 95% in over 95% of patients. Therefore, these results support the selection of the 400 mg Q2w and 800 mg Q4w dosing regimens for the STIMULUS clinical trial program.

Estimating the prevalence of pediatric hematological malignancies in Al-Madinah Al-Munawwarah, Saudi Arabia.

To provide an updated estimate to the prevalence of pediatric hematological malignancies (HMs) in the Al-Madinah Al-Munawwara, Saudi Arabia. This is a retrospective study that was carried out between 2016 and 2022. The study population was comprised of 171 children under 16 who had been diagnosed with HMs. The data was compiled from King Salman Medical City's Maternity and Children's Hospital, Al-Madinah Al-Munawwarah, Saudi Arabia. Among the 171 HM patients (64% males and 36% females), 13 subtypes were identified, with B-cell acute lymphoblastic leukemia having the highest incidence (70.3%). Acute myelomonocytic leukemia (8.7%), T-cell acute lymphoblastic leukemia (4.7%), and acute promyelocytic leukemia (3.5%) were the next most common types of HMs. Other rare cases were also found. Prevalence rate can be utilized to monitor the progression of disease incidence. Here, HMs demonstrated a pattern of increasing incidence in males over a 7-year period, with a higher rate in early childhood. There were 13 types of HMs diagnosed, with B-acute lymphocytic leukemia having the highest incidence. Although juvenile cancer is rare, it is nonetheless a significant cause of mortality in children. A successful prognosis requires prompt and accurate diagnosis and treatment.

Clinical Features and Prognosis of Multiple Myeloma Patients with Secondary Primary Malignancies

To explore the clinical characteristics and prognosis of multiple myeloma(MM) patients with secondary primary malignancies. The clinical data of newly diagnosed MM patients admitted to the First Affiliated Hospital of Zhengzhou University from January 2011 to December 2019 were retrospectively analyzed. The patients with secondary primary malignancies were retrieved, and their clinical features and prognosis were evaluated. A total of 1 935 patients with newly diagnosed MM were admitted in this period, with a median age of 62 (18-94) years old, of which 1 049 cases were hospitalized twice or more. There were eleven cases with secondary primary malignancies (the incidence rate was 1.05%), including three cases of hematological malignancies (2 cases of acute myelomonocytic leukemia and 1 case of acute promyelocytic leukemia) and eight cases of solid tumors (2 cases of lung adenocarcinoma, and 1 case each of endometrial cancer, esophageal squamous cell carcinoma, primary liver cancer, bladder cancer, cervical squamous cell carcinoma, and meningioma). The median age of onset was 57 years old. The median time between diagnosis of secondary primary malignancies and diagnosis of MM was 39.4 months. There were seven cases with primary or secondary plasma cell leukemia, the incidence rate was 0.67%, and the median age of onset was 52 years old. Compared with the randomized control group, the β2-microglobulin level in the secondary primary malignancies group was lower (P=0.028), and more patients were in stage I/II of ISS (P=0.029). Among the 11 patients with secondary primary malignancies, one survived, ten died, and the median survival time was 40 months. The median survival time of MM patients after the secondary primary malignancies was only seven months. All seven patients with primary or secondary plasma cell leukemia died, with a median survival time of 14 months. The median overall survival time of MM patients with secondary primary malignancies was longer than that of the patients with plasma cell leukemia (P=0.027). The incidence rate of MM with secondary primary malignancies is 1.05%. MM patients with secondary primary malignancies have poor prognosis and short median survival time, but the median survival time is longer than that of patients with plasma cell leukemia.