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Clinical and Translational Science Jan 2024Chronic myelomonocytic leukemia (CMML) treatment remains a pressing clinical challenge. We conducted a retrospective analysis on 52 CMML cases, exploring the...
Chronic myelomonocytic leukemia (CMML) treatment remains a pressing clinical challenge. We conducted a retrospective analysis on 52 CMML cases, exploring the effectiveness of combining venetoclax (Vene) with hypomethylating agents (HMAs). The study's findings show promise: the HMAs plus Vene group (n = 13, 53.8%) demonstrated superior overall response rates compared to the HMA monotherapy (mono) group (n = 19, 31.6%) and HMA plus arsenic trioxide group (n = 9, 22.2%) by the second cycle, and notably higher response rates (53.8% vs. 15.7%, p = 0.04) compared to the HMA mono group after four cycles. Over a median follow-up of 14.7 months, the HMAs plus Vene group exhibited significantly lower cumulative mortality (23.1%) compared to the other two groups (p = 0.003 and p = 0.008, respectively). Furthermore, this group displayed extended overall survival compared to the others. The study also delved into the molecular mechanisms, revealing significant BCL2 mRNA overexpression in patients with CMML. These findings suggest the potential for HMAs combined with Vene therapy in CMML but emphasize the necessity for further prospective studies to determine its precise role in managing CMML.
Topics: Humans; Retrospective Studies; Prospective Studies; Leukemia, Myelomonocytic, Chronic; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 38129985
DOI: 10.1111/cts.13711 -
Cell Reports. Medicine Dec 2023Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active...
Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1β release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1β release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRAS mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
Topics: Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Proto-Oncogene Proteins p21(ras); Leukemia, Myelomonocytic, Chronic; Symptom Burden; Interleukin-1
PubMed: 38118408
DOI: 10.1016/j.xcrm.2023.101329 -
Kidney International Reports Dec 2023Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can...
INTRODUCTION
Chronic myelomonocytic leukemia (CMML) is a hematologic disorder that is an overlap syndrome between myelodysplastic syndromes and myeloproliferative neoplasms, and can be associated with autoimmune and inflammatory diseases. This study aimed to describe kidney involvement in patients with CMML, their treatments, and outcomes.
METHODS
We conducted a French and American multicenter retrospective study in 15 centers, identifying patients with CMML with acute kidney injury (AKI), chronic kidney disease (CKD), and urine abnormalities.
RESULTS
Sixteen patients (males, = 14; median age 76.5 years [71.9-83]) developed a kidney disease 6 months [1.6-25.6] after the diagnosis of CMML. At the time of kidney disease diagnosis, median urinary protein-to-creatinine ratio was 2 g/g [1.25-3.4], and median serum creatinine was 2.26 mg/dl [1.46-2.68]. Fourteen patients (87.5%) underwent a kidney biopsy, and the 2 main pathological findings were lysozyme nephropathy (56%) and renal infiltration by the CMML (37.5%). Ten patients received a new treatment following the CMML-associated kidney injury. Among patients with monitored kidney function, and after a median follow-up of 15 months [9.9-34.9], 4 patients had CKD stage 3, 4 had CKD stage 4, 1 had an end-stage kidney disease. In our patient series, 2 patients evolved to an acute myeloid leukemia (AML), and 5 died. Compared with 116 CMML controls, patients who had a kidney involvement had a higher monocyte count ( < 0.001), had more CMML-1 ( = 0.005), were more susceptible to develop an AML ( = 0.02), and were more eligible to receive a specific hematologic treatment, with hydroxyurea, or hypomethylating agents ( < 0.001), but no survival difference was seen between the 2 groups ( = 0.6978).
CONCLUSION
In this cohort of patients with CMML with a kidney injury, the 2 most frequent renal complications were lysozyme-induced nephropathy and renal infiltration by the CMML. Kidney involvement should be closely monitored in patients with CMML.
PubMed: 38106568
DOI: 10.1016/j.ekir.2023.09.005 -
Frontiers in Immunology 2023Classically, particle-induced periprosthetic osteolysis at the implant-bone interface has explained the aseptic loosening of joint replacement. This response is preceded... (Review)
Review
Classically, particle-induced periprosthetic osteolysis at the implant-bone interface has explained the aseptic loosening of joint replacement. This response is preceded by triggering both the innate and acquired immune response with subsequent activation of osteoclasts, the bone-resorbing cells. Although particle-induced periprosthetic osteolysis has been considered a foreign body chronic inflammation mediated by myelomonocytic-derived cells, current reports describe wide heterogeneous inflammatory cells infiltrating the periprosthetic tissues. This review aims to discuss the role of those non-myelomonocytic cells in periprosthetic tissues exposed to wear particles by showing original data. Specifically, we discuss the role of T cells (CD3, CD4, and CD8) and B cells (CD20) coexisting with CD68/TRAP multinucleated giant cells associated with both polyethylene and metallic particles infiltrating retrieved periprosthetic membranes. This review contributes valuable insight to support the complex cell and molecular mechanisms behind the aseptic loosening theories of orthopedic implants.
Topics: Humans; Osteolysis; Joint Prosthesis; Osteoclasts; Inflammation; Polyethylene
PubMed: 38106424
DOI: 10.3389/fimmu.2023.1310262 -
International Journal of... Oct 2023Solid organ transplantation from the same donor is an established procedure for end-stage organ failure that developed after a previous hematopoietic stem cell...
Solid organ transplantation from the same donor is an established procedure for end-stage organ failure that developed after a previous hematopoietic stem cell transplantation (HSCT); however, it is rarely done in patients transplanted with unmanipulated haplo-HSCT. There are no pediatric reports regarding the long-term performance of organ transplantation after haplo-HSCT with post-transplant cyclophosphamide (PTCY). A juvenile myelomonocytic leukemia patient, who underwent unmanipulated haplo-HSCT with PTCY from her mother at the age of 3 years, developed chronic liver graft versus host disease (GvHD) which was refractory to specific GvHD treatment. Liver transplantation (LT) from her mother (the donor of her haplo-HSCT) was decided as the next line of treatment. LT was performed on day 540 post-HSCT, and the donor's left lateral segment was appropriately removed and attached to the recipient. The symptoms of GvHD completely regressed in a month. The patient died on day 121 after LT, because of a possible hepato-pulmonary syndrome. Organ failure can develop after allo-HSCT secondary to GvHD and therefore performing HSCT from a haplo-donor may be superior to a matched unrelated donor in terms of subsequent organ transplantation for organ failure.
PubMed: 38076781
DOI: 10.18502/ijhoscr.v17i4.13921 -
Blood Mar 2024The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the...
The World Health Organization (WHO) classification of hematolymphoid tumors and the International Consensus Classification (ICC) of 2022 introduced major changes to the definition of chronic myelomonocytic leukemia (CMML). To assess its qualitative and quantitative implications for patient care, we started with 3311 established CMML cases (according to WHO 2017 criteria) and included 2130 oligomonocytosis cases fulfilling the new CMML diagnostic criteria. Applying both 2022 classification systems, 356 and 241 of oligomonocytosis cases were newly classified as myelodysplastic (MD)-CMML (WHO and ICC 2022, respectively), most of which were diagnosed as myelodysplastic syndrome (MDS) according to the WHO 2017 classification. Importantly, 1.5 times more oligomonocytosis cases were classified as CMML according to WHO 2022 than based on ICC, because of different diagnostic criteria. Genetic analyses of the newly classified CMML cases showed a distinct mutational profile with strong enrichment of MDS-typical alterations, resulting in a transcriptional subgroup separated from established MD and myeloproliferative CMML. Despite a different cytogenetic, molecular, immunophenotypic, and transcriptional landscape, no differences in overall survival were found between newly classified and established MD-CMML cases. To the best of our knowledge, this study represents the most comprehensive analysis of routine CMML cases to date, both in terms of clinical characterization and transcriptomic analysis, placing newly classified CMML cases on a disease continuum between MDS and previously established CMML.
Topics: Humans; Consensus; Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukocytosis; World Health Organization; Prognosis; Organic Chemicals
PubMed: 38064663
DOI: 10.1182/blood.2023021199 -
Journal of Inflammation Research 2023The fusion gene is commonly reported in chronic myelomonocytic leukemia with eosinophilia, yet patients with presenting myeloid and lymphoid neoplasms successively...
Myeloid/Lymphoid Neoplasms with Fusion Gene: A Rare Case of Poor Response to Imatinib and Possible Transformation Mechanisms from Myeloid Neoplasms of Bone Marrow to T-Cell Lymphoblastic Lymphoma Invasion in Lymph Nodes.
The fusion gene is commonly reported in chronic myelomonocytic leukemia with eosinophilia, yet patients with presenting myeloid and lymphoid neoplasms successively have not been reported. Here, we report the first case of a 35-year-old man with myeloid and lymphoid neoplasms harboring an fusion gene who demonstrated poor response to imatinib. The patient was diagnosed with an fusion gene myeloid neoplasm on initial diagnosis at our hospital. After 5 months of treatment with imatinib, he was diagnosed with T-cell lymphoblastic lymphoma. turned negative after increasing the dose of imatinib, but enlarged superficial lymph nodes reappeared the following year. Notably, the patient exhibited a worse response to imatinib treatment. This study describes this rare case and speculates on a possible mechanism.
PubMed: 38026242
DOI: 10.2147/JIR.S427995 -
Journal of Medical Virology Nov 2023Human cytomegalovirus (HCMV) can undergo either a latent or a lytic infection in cells of the myeloid lineage. Whilst the molecular mechanisms which determine the...
Human cytomegalovirus (HCMV) can undergo either a latent or a lytic infection in cells of the myeloid lineage. Whilst the molecular mechanisms which determine the outcome of infection are far from clear, it is well established that a key factor is the differential regulation of the major immediate early promoter (MIEP) responsible for driving lytic immediate early gene expression. Using a myelomonocytic cell line stably transduced with a GFP reporter under the control of the MIEP, which recapitulates MIEP regulation in the context of virus infection, we have used an unbiased CRISPR-Cas9 sub-genomic, epigenetic library screen to identify novel cellular factors involved in MIEP repression during establishment and maintenance of latency in myeloid cells. One such cellular factor identified was MORC3. Consistent with MORC3 being a robust repressor of the MIEP, we show that THP1 cells devoid of MORC3 fail to establish latency. We also show that MORC3 is induced during latent infection, recruited to the MIEP and forms MORC3 nuclear bodies (MORC3-NBs) which, interestingly, co-localize with viral genomes. Finally, we show that the latency-associated functions of MORC3 are regulated by the deSUMOylase activity of the viral latency-associated LUNA protein likely to prevent untimely HCMV reactivation.
Topics: Humans; Adenosine Triphosphatases; Cytomegalovirus; Cytomegalovirus Infections; DNA-Binding Proteins; Gene Expression Regulation, Viral; Myeloid Cells; Promyelocytic Leukemia Nuclear Bodies; Virus Latency
PubMed: 38009611
DOI: 10.1002/jmv.29227 -
International Journal of Molecular... Nov 2023Chronic myelomonocytic leukemia (CMML) is a hematological neoplasm characterized by monocytosis, splenomegaly, thrombocytopenia, and anemia. Moreover, it is associated...
Chronic myelomonocytic leukemia (CMML) is a hematological neoplasm characterized by monocytosis, splenomegaly, thrombocytopenia, and anemia. Moreover, it is associated with mutations and, rarely, with variants. We present the case of an 84-year-old patient with persistent anemia and monocytosis. Due to the presence of dysmorphic granulocytes, monocyte atypia, and myeloid precursors in the peripheral blood cells, the patient was subjected to a bone marrow examination. The diagnosis was consistent with CMML type 2. The Hemocoagulative test showed an increase in fibrinolysis markers. Next-generation targeted sequencing showed and mutations, along with an unexpected germline missense variant, rarely encountered in CMML. The patient started Azacitidine treatment and achieved normal hemostatic process values. In conclusion, we identified a heterozygous germline mutation that, together with and variants, was responsible for the hemorrhagic manifestation.
Topics: Humans; Aged, 80 and over; Leukemia, Myelomonocytic, Chronic; Germ-Line Mutation; Genetic Predisposition to Disease; Mutation; Anemia; Germ Cells; Receptors, Colony-Stimulating Factor
PubMed: 38003211
DOI: 10.3390/ijms242216021 -
Cancers Nov 2023Leukemia cutis (LC) is defined as the leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously... (Review)
Review
Leukemia cutis (LC) is defined as the leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding a number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as the genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, the complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis, and treatment of leukemic skin involvement in different types of leukemia.
PubMed: 38001655
DOI: 10.3390/cancers15225393