Molecular features of 109 patients with chronic myelomonocytic leukemia in a single center / 中华血液学杂志

Objective: To explore the molecular features of chronic myelomonocytic leukemia (CMML) . Methods: According to 2022 World Health Organization (WHO 2022) classification, 113 CMML patients and 840 myelodysplastic syndrome (MDS) patients from March 2016 to October 2021 were reclassified, and the clinical and molecular features of CMML patients were analyzed. Results: Among 113 CMML patients, 23 (20.4%) were re-diagnosed as acute myeloid leukemia (AML), including 18 AML with NPM1 mutation, 3 AML with KMT2A rearrangement, and 2 AML with MECOM rearrangement. The remaining 90 patients met the WHO 2022 CMML criteria. In addition, 19 of 840 (2.3%) MDS patients met the WHO 2022 CMML criteria. At least one gene mutation was detected in 99% of CMML patients, and the median number of mutations was 4. The genes with mutation frequency ≥ 10% were: ASXL1 (48%), NRAS (34%), RUNX1 (33%), TET2 (28%), U2AF1 (23%), SRSF2 (21.1%), SETBP1 (20%), KRAS (17%), CBL (15.6%) and DNMT3A (11%). Paired analysis showed that SRSF2 was frequently co-mutated with ASXL1 (OR=4.129, 95% CI 1.481-11.510, Q=0.007) and TET2 (OR=5.276, 95% CI 1.979-14.065, Q=0.001). SRSF2 and TET2 frequently occurred in elderly (≥60 years) patients with myeloproliferative CMML (MP-CMML). U2AF1 mutations were often mutually exclusive with TET2 (OR=0.174, 95% CI 0.038-0.791, Q=0.024), and were common in younger (<60 years) patients with myelodysplastic CMML (MD-CMML). Compared with patients with absolute monocyte count (AMoC) ≥1×10(9)/L and <1×10(9)/L, the former had a higher median age of onset (60 years old vs 47 years old, P<0.001), white blood cell count (15.9×10(9)/L vs 4.4×10(9)/L, P<0.001), proportion of monocytes (21.5% vs 15%, P=0.001), and hemoglobin level (86 g/L vs 74 g/L, P=0.014). TET2 mutations (P=0.021) and SRSF2 mutations (P=0.011) were more common in patients with AMoC≥1×10(9)/L, whereas U2AF1 mutations (P<0.001) were more common in patients with AMoC<1×10(9)/L. There was no significant difference in the frequency of other gene mutations between the two groups. Conclusion: According to WHO 2022 classification, nearly 20% of CMML patients had AMoC<1×10(9)/L at the time of diagnosis, and MD-CMML and MP-CMML had different molecular features.

Clinical Characteristics and Survival Analysis of Patients with Chronic Myelomonocytic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical characteristics, prognostic factors and efficacy of hypomethylating agent (HMA) in patients with chronic myelomonocytic leukemia (CMML).@*METHODS@#The clinical data of 37 newly diagnosed patients with CMML was analyzed retrospectively, and their clinical characteristics and the efficacy of HMA were summarized. Kaplan-Meier and Log-rank test were used for univariate survival analysis, and Cox proportional hazards regression model was used for multivariate analysis.@*RESULTS@#The median age at diagnosis was 67 years old. Their common manifestations included fatigue, bleeding, abnormal blood routine and fever. Most patients had splenomegaly. According to FAB classification, there were 6 cases of myelodysplastic CMML and 31 cases of myeloproliferative CMML, while according to WHO classification, 8 patients belonged to CMML-0, 9 patients to CMML-1 and 20 patients to CMML-2. At the time of diagnosis, the median white blood cell count was 32.84×109/L, median hemoglobin (Hb) was 101 g/L, median platelet count was 65×109/L, median absolute monocyte count was 9.53×109//L, median absolute neutrophil count (ANC) was 11.29×109//L and median lactate dehydrogenase (LDH) was 374 U/L. Cytogenetic abnormalities were found in 4 cases among the 31 patients who underwent karyotype analysis or fluorescence in situ hybridization detection. There were 12 patients who had analyzable results and gene mutations were identified in 11 cases, including ASXL1, NRAS, TET2, SRSF2 and RUNX1. Among the 6 patients who were treated with HMA and could be evaluated for efficacy, 2 patients achieved complete remission, 1 patient achieved partial remission and 2 patients achieved clinical benefit. Compared with the non-HMA treatment group, overall survival (OS) time was not significantly prolonged in the HMA treatment group. Univariate analysis showed that Hb<100 g/L, ANC≥12×109/L, LDH≥250 U/L and peripheral blood (PB) blasts ≥5% were significantly associated with poor OS, while WHO classification CMML-2, Hb<100 g/L, ANC≥12×109/L, LDH≥250 U/L and PB blasts≥5% were significantly associated with poor leukemia-free survival (LFS) (P<0.05). Multivariate analysis showed that ANC≥12×109/L and PB blasts≥5% were significantly associated with poor OS and LFS (P<0.05).@*CONCLUSION@#CMML has high heterogeneity in clinical characteristics, genetic changes, prognosis and treatment response. HMA can not significantly improve the survival of CMML patients. ANC≥12×109/L and PB blasts≥5% are independent prognostic factors of OS and LFS in patients with CMML.

Poor Prognostic Implication of ASXL1 Mutations in Korean Patients With Chronic Myelomonocytic Leukemia

BACKGROUND: Molecular genetic abnormalities are observed in over 90% of chronic myelomonocytic leukemia (CMML) cases. Recently, several studies have demonstrated the negative prognostic impact of ASXL1 mutations in CMML patients. We evaluated the prognostic impact of ASXL1 mutations and compared five CMML prognostic models in Korean patients with CMML. METHODS: We analyzed data from 36 of 57 patients diagnosed as having CMML from January 2000 to March 2016. ASXL1 mutation analysis was performed by direct sequencing, and the clinical and laboratory features of patients were compared according to ASXL1 mutation status. RESULTS: ASXL1 mutations were detected in 18 patients (50%). There were no significant differences between the clinical and laboratory characteristics of ASXL1-mutated (ASXL1+) CMML and ASXL1-nonmutated (ASXL1−) CMML patients (all P>0.05). During the median follow-up of 14 months (range, 0–111 months), the overall survival (OS) of ASXL1+ CMML patients was significantly inferior to that of ASXL1− CMML patients with a median survival of 11 months and 19 months, respectively (log-rank P=0.049). An evaluation of OS according to the prognostic models demonstrated inferior survival in patients with a higher risk category according to the Mayo molecular model (log-rank P=0.001); the other scoring systems did not demonstrate a significant association with survival. CONCLUSIONS: We demonstrated that ASXL1 mutations, occurring in half of the Korean CMML patients examined, were associated with inferior survival. ASXL1 mutation status needs to be determined for risk stratification in CMML.

The 2016 WHO versus 2008 WHO Criteria for the Diagnosis of Chronic Myelomonocytic Leukemia

The 2016 WHO diagnostic criteria for chronic myelomonocytic leukemia (CMML) require both absolute and relative monocytosis (≥1×10⁹/L and ≥10% of white blood cell counts) in peripheral blood. Moreover, myeloproliferative neoplasm (MPN) features in bone marrow and/or MPN-associated mutations tend to support MPN with monocytosis rather than CMML. We assessed the impact of the 2016 WHO criteria on CMML diagnosis, compared with the 2008 WHO criteria, through a retrospective review of the medical records of 38 CMML patients diagnosed according to the 2008 WHO classification. Application of the 2016 WHO criteria resulted in the exclusion of three (8%) patients who did not fulfill the relative monocytosis criterion and eight (21%) patients with an MPN-associated mutation. These 11 patients formed the 2016 WHO others group; the remaining 27 formed the 2016 WHO CMML group. The significant difference in the platelet count and monocyte percentage between the two groups indicated that the 2016 WHO criteria lead to a more homogenous and improved definition of CMML compared with the 2008 WHO criteria, which may have led to over-diagnosis of CMML. More widespread use of molecular tests and more sophisticated clinical and morphological evaluations are necessary to diagnose CMML accurately.

Usefulness of Middle Meningeal Embolization to Prevent Recurrent Spontaneous Chronic Subdural Hemorrhage

Spontaneous chronic subdural hematoma (SDH) is a rare condition that could develop in association with hematologic disease. A 66-year-old male developed a chronic SDH as an initial manifestation of chronic myelomonocytic leukemia (CMML). He experienced recurrent chronic subdural hemorrhage and newly developed intracerebral hemorrhage. Considering the scheduled long-term chemotherapy, bilateral middle meningeal artery (MMA) embolization was performed to prevent recurrence of subdural hemorrhage. Although pancytopenia occurred during the 7 months' follow-up period, residual chronic subdural hemorrhage was absorbed without recurrence. To our best knowledge, this is the first report of CMML with spontaneous chronic SDH. MMA embolization is potentially a useful and safe treatment option in the challenging clinical situations with underlying pathologies.

A Case of Myeloid Neoplasm with a PDGFRB Rearrangement and Eosinophilia / 대한내과학회지

Myeloid neoplasia with eosinophilia and platelet-derived growth factor receptor beta (PDGFRB) rearrangements is an uncommon Philadelphia-negative myeloproliferative neoplasm. Their most common morphological diagnosis is chronic myelomonocytic leukemia with eosinophilia, which is associated with t(5;12)(q33;p13) and results in the formation of the ETV6-PDGFRB fusion gene. Here, we report a 49-year-old man with a myeloid neoplasm with a PDGFRB rearrangement, who was incidentally diagnosed with hyperleukocytosis and eosinophilia during a health screening. A chromosome analysis of a bone marrow sample revealed 46, XY, t(5;12)(q33;p13), and fluorescence in situ hybridization analysis revealed the PDGFRB gene rearrangement. The patient was treated with imatinib and subsequently achieved complete hematological and molecular remission.

Therapy-related myeloid neoplasms in children and adolescents

BACKGROUND: This retrospective study aimed to characterize and analyze the outcome of therapy-related myeloid neoplasms (t-MNs) in children and adolescents. METHODS: The medical records of 16 patients under 21 years of age at the time of t-MN diagnosis were reviewed. RESULTS: The median patient age was 11.5 years (range, 1.6–20.4 yr). Twelve patients had therapy-related acute myeloid leukemia, 3 patients had myelodysplastic syndrome, and 1 patient had chronic myelomonocytic leukemia. The median latency period was 29 months (range, 11–68 mo). Fourteen patients had cytogenetic aberrations, 8 of whom had an 11q23 abnormality. Of the 13 patients treated with curative intent, 12 patients received myeloid-type induction therapy that led to complete remission (CR) in 8 patients. Nine patients underwent allogeneic transplantation; 4 patients did not undergo transplantation due to chemotherapy-related toxic death (N=3) or parental refusal (N=1). The 5-year overall survival and event-free survival of the 13 patients treated with a curative intent were 46.2% and 30.8%, respectively. For the 9 patients who underwent allogeneic transplantation, the 5-year event-free survival was 66.7%. CONCLUSION: A significant proportion of young patients with t-MNs can experience long-term survival, and allogeneic transplantation plays a key role for attaining cure in these patients.

Déficit adquirido de factor X en leucemia mielomonocítica crónica: reporte de un caso / Isolated factor X deficiency in chronic myelomonocytic leukemia: Report of one case

Bleeding disorders are commonly associated with hemato-oncologic diseases. We report a 68 years old male with a chronic myelomonocytic leukemia derived from a long lasting mielodysplastic syndrome that did not respond to treatment with Azacitidine. The patient was hospitalized due to tonic clonic seizures. A CAT scan showed a hematoma in the frontal lobe. A new assessment of hemostasis revealed an isolated deficiency of Factor X. We speculate that this deficit could be secondary to consumption due to the chronic Myelomonocytic Leukemia.

Clinical Analysis on Treatment of Chronic Myelomonocytic Leukemia with Allogeneic Hematopoietic Stem Cell Transplantation / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To analyze retrospectively the therapeutic efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelomonocytic leukemia (CMML).</p><p><b>METHODS</b>The engraftment, graft versus host disease (GVHD), infection, relapse, and survival of 13 CMML patients received allo-HSCT were observed. The clinical outcome of allo-HSCT for CMML was analyzed.</p><p><b>RESULTS</b>Thirteen (10 males and 3 females) CMML patients with a median age of 38 years old received allo-HSCT including 4 from HLA-matched unrelated donors, 6 from HLA-matched sibling donors and 3 from haploidentical related donors. All 13 patients achieved engraftment, and the median time of neutrophil engraftment and platelet engraftment were 12 (11-18) days and 15 (10-55) days respectively, acute GVHD occurred in 8 patients. After the median follow-up of 13 (6-29) months, the overall survival, disease free survival and relapse were 53.8%, 53.8%, 7.7%, respectively.</p><p><b>CONCLUSION</b>Allo-HSCT can improve the survival of patients with CMML, and is a effective method for treatment of CMML.</p>

T618I-Mutated Colony Stimulating Factor 3 Receptor in Chronic Neutrophilic Leukemia and Chronic Myelomonocytic Leukemia Patients who Underwent Allogeneic Stem Cell Transplantation

No abstract available.

Regaining the response to erythropoietin following azacitidine in chronic myelomonocytic leukemia previously evolved from refractory anemia

No abstract available.

Leucemia mielomonocítica crónica / Chronic myelomonocytic leukemia

La leucemia mielomonocítica crónica es un desorden clonal de las células progenitoras hematopoyéticas clasificado como neoplasia mielodisplásica mieloproliferativa. Se caracteriza por la presencia de monocitosis absoluta y persistente en la sangre periférica (> 1.0 x 10 9/L) con la presencia de displasia celular y mieloproliferación en la médula ósea. Los pacientes presentan síntomas relacionados a las citopenias y al estado de hipercatabolismo y al examen físico se encuentra esplenomegalia. El diagnóstico se establece con la combinación del examen de la lámina de sangre periférica, el aspirado medular y la biopsia de médula ósea, el inmunofenotipaje y el estudio molecular de las anomalías que se presentan. El pronóstico de la enfermedad es malo. El tratamiento de elección es el trasplante alogénico de progenitores hematopoyéticos con régimen de acondicionamiento de toxicidad reducida. En alrededor del 30 por ciento de los pacientes la enfermedad se transforma en una leucemia mieloide aguda...

Chronic myelomonocytic leukemia is a clonal hematopoietic stem cell disorder classified as a myelodysplastic/myeloproliferative neoplasm. It is characterized by absolute monocytosis (>1.0 x 10(9)/ L) in the peripheral blood that persists for at least 3 months, with dysplastic and myeloproliferation in the bone marrow. Patients may show symptoms related to cytopenias and hypercatabolic state with splenomegaly. The diagnosis is established by combination of complete blood count, peripheral blood smear, bone marrow aspirate, bone marrow biopsy, immunophenotypic profile and study of molecular abnormalities. The prognosis is bad. The treatment of election is the hematopoietic allogeneic stem cell transplantation with regimen of reduced toxicity. In around 30 percent of these patients the disease transforms to acute myeloid leukemia...

Clinical manifestation of the SRSF2 gene mutation in Chinese patients with chronic myelomonocytic leukemia / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Spliceosome mutations have been recently identified and associated with hematological malignancies. SRSF2, one of components of the splicing machinery, has a high mutation frequency during chronic myelomonocytic leukemia, according to previous reports. However, the relevance of this finding in Chinese populations remains unknown.</p><p><b>METHODS</b>We recruited 50 Chinese patients with chronic myelomonocytic leukemia to analyze the state of SRSF2 and to assess the corresponding clinical features by polymerase chain reaction followed by direct sequencing.</p><p><b>RESULTS</b>Ten of 50 patients (20%) harbored SRSF2 mutations, including five P95R, two 95H, and three P95L point mutations. The patient group was older than the wild type group (P < 0.01). No significant statistical differences were observed with regard to the other clinical characteristics (sex, peripheral blood count, serum lactate dehydrogenase, karyotype, World Health Organization classification, etc.) between these two groups. Two of the patients showed an early evolution to acute myeloid leukemia.</p><p><b>CONCLUSIONS</b>SRSF2 mutations are frequent in chronic myelomonocytic leukemia patients, but show a relatively lower incidence in Chinese patients. Moreover, the mutation can be related to old age and an unfavorable prognosis. Our results provide valuable insights for the development of a diagnostic marker, or for the identification of a therapeutic target for chronic myelomonocytic leukemia.</p>

Allogeneic hematopoietic stem cell transplantation for chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia / 中国实验血液学杂志

This study was purposed to explore the therapeutic efficacy and influencing factors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with chronic myelomonocytic leukemia (CMML) and in patients with juvenile myelomonocytic leukemia (JMML). The clinical data of 3 cases of CMML and 2 cases of JMML underwent allo-HSCT were analysed in term of multiparameter. The results showed that the hematopoietic stem cells in 5 patients grafted successfully. One case of JMML died of pulmonary disease, other 4 cases survive without disease. The analysis found that the disease burden before transplant, chromosome karyotype, acute GVHD II-IV and poor risk cytogenetics all associated with the relapse rate and disease-free survival rate of CMML. The low intensity conditioning regimen was better than myeloablative conditioning regimen. Type of donor and source of stem cells did not statistically and significantly affect OS and RFS. The splenectomy before allo-HSCT as well as spleen size at time of the alloHSCT did not influence on posttransplantation outcome of JMML. However, cord blood HSCT for JMML patients delayed hematologic recovery as compared to that of bone marrow or peripheral blood HSCT. The age, GVHD, HbF level played an important role in leukemia replace. It is concluded that the allogeneic hematopoietic stem cell transplantation is a curative regimen for CMML and JMML, but there also is a serial problems to be resolved.

Role of ASXL1 mutation in myeloid malignancies / 中国实验血液学杂志

Additional sex comb-like 1 ( ASXL1) is an enhancer of Trithorax and Polycomb family, which are necessary for the maintenance of stable repression of homeotic and other loci. Recently, alterations of ASXL1 gene were identified in the hematopoietic cells from patients with a variety of myeloid malignancies, including chronic myelomonocytic leukemia (CMML, 43% of cases), myelodysplastic syndrome (MDS, 20%), myeloproliferative neoplasms (MPN, 10%) and acute myeloid leukemia (AML, 20%). The majority of ASXL1 mutations are frameshift and nonsense mutations. These clinical data suggest an important role of ASXL1 in the pathogenesis and/or transformation of myeloid malignancies. However, the role of ASXL1 in the pathogenesis of myeloid malignancies and in normal hematopoiesis in vivo, as well as the underlying mechanisms remains unknown. This article reviews the structure and function of ASXL1, the clinical characteristic and prognostic significance of ASXL1 mutation, the association of ASXL1 with other gene mutation, as well as ASXL1 knock-down or silence in vitro and in vivo models.

Acute myeloid leukemia arising from chronic myelomonocytic leukemia during hypomethylating therapy

No abstract available.

Investigation on the prevalence of leukaemia at a tertiary care hospital, Lahore

Cancer in all forms is causing about 12% deaths throughout the world. After recent advances and improvement in treatment and prevention in cardiovascular diseases, tumour is an important cause of morbidity and mortality[1]. The incidence of leukaemia across the world is i per 100,000 annually. It contributes to 25% of childhood cancers[2]. The study was designed to investigate the Prevalence ofLeukemia subtypes at Lahore General Hospital/The Graduate Medical Institute, Lahore and was carried out in the Bone Marrow Clinic. The study was cross - sectional prospective. The period of the study was two year from 01 June, 2010 to 30 June, 2012. Complete blood counts, bone marrow aspiration and trephine biopsies were performed according to standard methods. In a total of 45 cases of leukaemia, acute leukemia was more prevalent than chronic leukaemia. The ratio of acute and chronic leukaemias was 4:1. Male to female ratio was 1.3: 1. Most of the patients [42%] were below the age of 15 years. ALL [49%] was more common than AML [31%]. Among chronic leukaemias, CML [16%] was more common than CLL [2%] and CMML [2%]. The study of acute leukaemia subtypes revealed that ALL - L[2] was more common [77%] than L[1] [24%]. In AML subtypes, M[3] [57%] was most prevalent while M[2] [14%] and M[4] [14%] and M[1] [7%] and M[6] [7%] were less prevalent of leukaemia subtypes. Acute leukaemias were more prevalent than chronic leukaemias. Leukaemias of all types were slightly more prevalent in male patients. ALL was more common than AML and was found to be a childhood malignancy. In leukaemia subtypes, ALL - L[2] and AML-M[3] were most common and in chronic leukaemias CML was most common

Fighting back against chronic myelomonocytic leukemia

No abstract available.

Allogeneic hematopoietic cell transplantation in adult patients with myelodysplastic/myeloproliferative neoplasms

BACKGROUND: In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT. METHODS: This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen. RESULTS: Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease. CONCLUSION: Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.