ABSTRACT
Thrombosis in myeloproliferative neoplasms (MPNs) is an important clinical problem, and risk-stratified management is essential. To identify the clinical characteristics of thrombosis in patients with MPNs, a nationwide multi-institutional retrospective analysis (JSH-MPN-R18) was conducted. The aim of the present study was to perform a sub-analysis of JSH-MPN-R18 findings to clarify the predictive parameters for thrombosis among complete blood count (CBC) results. Among the patients enrolled in JSH-MPN-R18, those with essential thrombocythemia (ET; n = 1152) and polycythemia vera (PV; n = 456) were investigated. We analyzed and compared CBC parameters between patients with and those without any thrombotic events using Welch's T-test. Statistical analyses were performed using the R statistical software. Thrombotic events were observed in 74 patients with ET. In multivariate analysis, only the neutrophil ratio was slightly but significantly higher for ET patients with thrombosis than for those without (p < 0.05). Of note, the absolute neutrophil count (aNeu) was considered a useful predictive tool for thrombosis among patients classified as low-risk according to the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia. Among PV patients, those with thrombosis showed significantly higher hematocrit and aNeu than did those without thrombosis. As a thrombosis-associated factor, the neutrophil ratio was slightly but significantly elevated in patients with ET. This myeloid skew might reflect a higher value of JAK2 V617F allelic frequency in patients with ET with thrombosis; this was not clarified in JSH-MPN-R18. Further accumulation of evidence, including genetic information for JAK2 and other passenger mutations, is warranted.
Subject(s)
Janus Kinase 2 , Neutrophils , Polycythemia Vera , Thrombocythemia, Essential , Thrombosis , Humans , Thrombosis/etiology , Thrombosis/blood , Female , Male , Middle Aged , Janus Kinase 2/genetics , Aged , Retrospective Studies , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/complications , Thrombocythemia, Essential/genetics , Polycythemia Vera/blood , Polycythemia Vera/complications , Polycythemia Vera/genetics , Adult , Myeloproliferative Disorders/blood , Myeloproliferative Disorders/complications , Myeloproliferative Disorders/genetics , Leukocyte Count , Predictive Value of Tests , Aged, 80 and overABSTRACT
Many novel agents have been developed for BCR::ABL1-negaive myeloproliferative neoplasms (MPN), namely, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Some of these agents not only achieve hematologic complete response, reduce spleen size, and alleviate constitutional symptoms, but also induce molecular response, which means that they reduce the allele burden of driver gene mutations. These agents also prevent and alleviate fibrosis in bone marrow, which reduces the incidence of thrombotic events and disease progression and might improve prognosis. This article discusses the latest findings and promising treatments, including ongoing clinical trials, in PV, ET, and PMF.
Subject(s)
Myeloproliferative Disorders , Humans , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/drug therapy , Myeloproliferative Disorders/therapy , Myeloproliferative Disorders/diagnosis , Mutation , Molecular Targeted TherapyABSTRACT
A 47-year-old woman presented with subcutaneous hemorrhage. Blood tests revealed leukoerythroblastosis, anemia, and thrombocytopenia. Bone marrow biopsy led to a diagnosis of primary myelofibrosis (aaDIPSS, DIPSS-plus: intermediate-II risk). JAK2, CALR, and MPL mutations were not detected in peripheral blood, but targeted sequencing of bone marrow specimens revealed a double mutation (Q157R, S34F) in U2AF1. Allo-PBSCT was performed using an HLA-matched related donor, and post-transplantation bone marrow examination showed complete donor chimerism on day 55. Two years after allogeneic transplantation, the patient remains relapse-free. Although U2AF1 gene abnormality is known as a poor prognostic factor in primary myelofibrosis, this patient had a favorable long-term prognosis due to prompt transplantation therapy. This case highlights the importance of detailed gene mutation analysis in patients with triple-negative MF.
Subject(s)
Primary Myelofibrosis , Female , Humans , Middle Aged , Primary Myelofibrosis/genetics , Primary Myelofibrosis/therapy , Primary Myelofibrosis/diagnosis , Splicing Factor U2AF/genetics , Mutation , Bone Marrow/pathology , Transplantation, Homologous , Janus Kinase 2/genetics , Calreticulin/geneticsABSTRACT
BACKGROUND: Improper prescriptions can cause adverse reactions in patients with chronic kidney disease (CKD). MATERIALS AND METHODS: Hospital pharmacists investigated improper prescriptions, prerenal acute kidney injury (AKI) prescriptions, and adverse effects in AKI in 199 CKD patients at Kouseikai Hospital from July 2020 to June 2021, as well as combinations of "triple whammy" drugs (renin-angiotensin-system inhibitors, diuretics, and non-steroidal anti-inflammatory drugs) plus active vitamin D preparations. All participants (average age, 73.6 ± 16.2 years) were residents of Nagasaki City or its suburbs. RESULTS: Adverse reactions occurred in 38 of the 199 patients (19.1%). 13 patients had AKI, and 9 of these cases developed during the summer. A comparison of the 38 patients in the adverse reaction group and the 161 patients in the non-occurrence group showed that the former group was significantly older and had a lower body weight. In terms of renal function, estimated glomerular filtration rate (mL/min/1.73m2) was significantly lower, blood urea nitrogen/serum creatinine (BUN/S-Cr) was higher, dehydration was involved, and active vitamin D preparations were significantly more common in the adverse reaction group. CONCLUSION: Our findings suggest that concomitant prescription of active vitamin D in combination with the drugs that constitute the triple whammy should be avoided. The absence of hypercalcemia should be confirmed and adequate fluid intake should be encouraged to prevent prerenal nephropathy.
Subject(s)
Acute Kidney Injury , Renal Insufficiency, Chronic , Humans , Middle Aged , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Vitamin D/adverse effects , Angiotensin Receptor Antagonists/adverse effects , Drug Combinations , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/chemically induced , Acute Kidney Injury/chemically induced , Acute Kidney Injury/complicationsABSTRACT
BACKGROUND: Proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits (PGNMID) is a disease entity with nonorganized granular glomerular deposition with monoclonal proteins of both heavy and light chains. Dysproteinemia was observed in only 30% of the patients with PGNMID. We herein report a case of PGNMID with discrepancy between serum and glomerular deposits. CASE PRESENTATION: The patient was a 50-year-old man who had been followed at a local clinic due to hypertension, type 2 diabetes, hyperlipidemia, hyperuricemia, fatty liver, and obesity. Proteinuria had been noted five years previously, and he had been referred to a hematology department due to hyperproteinemia, high gamma globulin, and κ Bence-Jones protein (BJP) positivity one year previously. Bone marrow aspiration showed 5% plasma cells, and he was referred to the nephrology department to evaluate persistent proteinuria. He was hypertensive, and his estimated glomerular filtration rate was 54.2 ml/min/1.73 m2. His urinary protein level was 0.84 g/gâ Cr. Urine and serum immunofixation showed BJP-κ type and IgG-κ type, respectively. Kidney biopsy showed an increase in mesangial cells and matrix without nodular lesions under a light microscope. Immunofluorescence microscopy showed granular deposits of IgG and C3 on the capillary wall and weak positivity for C1q. IgG3 was predominant among the IgG subclasses, and intraglomerular κ and λ staining was negative for κ and positive for λ. Direct fast scarlet staining was negative. Electron microscopy showed lumpy deposits without a fibrillar structure in the subepithelial area. Based on the above findings, a diagnosis of membranous nephropathy-type PGNMID was made. Since proteinuria increased gradually after three years of treatment with valsartan (40 mg, daily), oral prednisolone (30 mg, daily) was initiated, which led to decreased proteinuria. The dose of oral prednisolone was gradually tapered to 10 mg per day. At that time, proteinuria was 0.88 g/gâ Cr. We found 204 cases in 81 articles in the PubMed database, among which 8 showed discrepancy in the heavy and/or light chains between serum and kidney. CONCLUSIONS: We experienced a case of membranous nephropathy-type PGNMID with discrepancy in light chains between serum and kidney that was successfully treated with oral prednisolone.
Subject(s)
Diabetes Mellitus, Type 2 , Glomerulonephritis, Membranous , Glomerulonephritis , Hypertension , Kidney Diseases , Male , Humans , Middle Aged , Immunoglobulin G , Glomerulonephritis/diagnosis , Glomerulonephritis/drug therapy , Proteinuria , Antibodies, MonoclonalABSTRACT
Philadelphia chromosome-negative myeloproliferative neoplasms (Ph- MPN) in children, adolescents, and young adults (AYA) attract attention from hematologists because they are identified more than before due to the recognition and advancement of diagnostic capacity for Ph- MPN. The clinical features of Ph- MPN diagnosed in children and AYA are found to be different from those of Ph- MPN that occur in patients in their 60s, peak age of onset. Ph- MPN diagnosed in children and AYA has more triple-negative cases with no identifiable driver genes and a larger proportion of venous thrombosis in thrombotic events. In terms of treatment, there are still problems to be resolved that are unique to younger patients, such as choosing cytoreductive agents for long-term use and the development of optimal prevention of thrombotic or bleeding events during pregnancy and childbirth. In this paper, we will discuss the clinical research supporting these claims and offer some practical advice for treating young children with Ph- MPN daily.
Subject(s)
Myeloproliferative Disorders , Neoplasms , Thrombosis , Venous Thrombosis , Pregnancy , Female , Humans , Young Adult , Adolescent , Child , Child, Preschool , Philadelphia Chromosome , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/genetics , Myeloproliferative Disorders/therapy , Thrombosis/etiology , Neoplasms/complicationsABSTRACT
Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN), wherein JAK2 V617F mutation exists as a common driver mutation, and the JAK-STAT pathway is constitutively activated. The treatment goal for ET and PV is the prevention of thrombosis and bleeding. The treatment strategy for ET is careful observation or antiplatelet therapy with or without cytoreductive therapy based on the thrombotic risk. The treatment strategy for all PV patients is phlebotomy with a target hematocrit of <45% in addition to antiplatelet therapy. Moreover, for patients at a high risk of thrombosis, additional cytoreductive therapy is considered beneficial. In this session, we discuss important points for ET diagnosis, thrombotic risk stratification, and the details of treatment strategy and current practice with evidence from clinical trials in ET. Furthermore, current topics in the treatment of ET and PV will be introduced with a focus on clinical data about interferon-α, which is reported to induce not only hematologic response but also molecular and histopathologic response in MPN.
Subject(s)
Myeloproliferative Disorders , Polycythemia Vera , Thrombocythemia, Essential , Thrombosis , Hemorrhage , Humans , Janus Kinase 2/genetics , Polycythemia Vera/diagnosis , Polycythemia Vera/therapy , Thrombocythemia, Essential/diagnosis , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/therapy , Thrombosis/etiology , Thrombosis/prevention & controlABSTRACT
A 53-year-old male presented with pancytopenia for 13 months. He had a past history of follicular lymphoma and hypopharyngeal cancer, which was treated via chemotherapy and radiotherapy. Bone marrow aspiration biopsy of the patient revealed a hypocellular marrow with 32% of hypergranular blasts without Auer bodies. There were also erythroid and megakaryocytic dysplasia in the bone marrow. Although the PML/RARA transcript was detected by fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR), the G-banding karyotype analysis showed a complex karyotype without t (15;17). The PML/RARA fusion signal was identified on chromosome 15 by metaphase FISH. The patient was diagnosed of therapy-related acute promyelocytic leukemia (t-APL) with cryptic PML/RARA. He successfully attained molecular complete remission with all-trans retinoic acid (ATRA) and two courses of arsenic trioxide (ATO). He was subsequently administered nivolumab without ATRA maintenance therapy because of a progressing metastasis of a hypopharyngeal cancer to the lung. The patient had a relapse of t-APL following nine courses of nivolumab, 8 months after ending consolidation therapy with ATO. Reinduction therapy with ATRA was not effective for the relapsed t-APL that was accompanied by del (5q) and monosomy 7. Little has been previously reported on t-APL with cryptic PML/RARA. Therefore, the clinical course of this patient may provide useful insights about the characteristics of t-APL with cryptic PML/RARA.
Subject(s)
Leukemia, Promyelocytic, Acute , Chromosomes, Human, Pair 15/genetics , Humans , In Situ Hybridization, Fluorescence , Karyotype , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/genetics , Male , Metaphase , Middle Aged , Oncogene Proteins, Fusion/genetics , TretinoinABSTRACT
We investigated the involvement of CXCL12-CXCR4 interactions in human lymphohematopoiesis by coculture with telomerized human stromal cells. CXCR4 expression was low in CD34+CD38-CD45RA-CD10-CD7-CD19- immature hematopoietic stem/precursor cells (HSPCs) but higher in CD34+CD38-CD45RA+CD10+CD7+/-CD19- early lymphoid precursors and even higher in CD34+CD38+CD45RA+CD10+CD7-CD19+ pro-B cells. Inhibition of the effect of stromal cell-produced CXCL12 by an anti-CXCR4-blocking Ab suppressed the generation of CD45RA+CD10-CD7+CD19- early T lymphoid precursors (ETPs) and CD45RA+CD10+CD7-CD19+/- B lymphoid precursors on stromal cells, but it did not affect the generation of ETPs in conditioned medium of stromal cell cultures. Replating assays showed that contact with stromal cells was critical for HSPC-derived CD45RA+CD10+CD7-CD19- B lineage-biased precursors to differentiate into CD19+ pro-B cells, which was suppressed by the anti-CXCR4 Ab. Conversely, HSPC-derived ETPs possessed T and B lymphoid and monocytic differentiation potential; stromal cell contact was not required for their growth but rather promoted B lymphoid differentiation. The anti-CXCR4 Ab did not affect the growth of ETPs in conditioned medium, but it suppressed their B lymphoid differentiation on stromal cells. CD14-CD11c-HLA-DR+CD123highCD303+ plasmacytoid dendritic cells developed from HSPCs and ETPs exclusively in contact with stromal cells, which was suppressed by the anti-CXCR4 Ab. These data indicate that CXCL12 plays an essential role in stromal cell contact-mediated B lymphoid and plasmacytoid dendritic cell differentiation from immature hematopoietic and early T lymphoid precursors with a multilineage differentiation potential, but it does not participate in contact-independent generation of early T lymphoid precursors.
Subject(s)
B-Lymphocytes/physiology , Cell Differentiation , Chemokine CXCL12/metabolism , Dendritic Cells/physiology , Lymphocytes/physiology , Receptors, CXCR4/metabolism , T-Lymphocytes/physiology , Antigens, CD19/genetics , Antigens, CD34/genetics , Bone Marrow Cells/cytology , Cell Differentiation/immunology , Cell Lineage , Chemokine CXCL12/antagonists & inhibitors , Chemokine CXCL12/biosynthesis , Chemokine CXCL12/immunology , Coculture Techniques , Culture Media, Conditioned/pharmacology , Hematopoiesis , Humans , Immunophenotyping , Receptors, CXCR4/genetics , Receptors, CXCR4/immunology , Signal Transduction/immunology , Stromal Cells/drug effects , Stromal Cells/physiologyABSTRACT
The JAK2V617F mutation is the commonest major genetic mutation of myeloproliferative neoplasms (MPNs) and has been defined in the WHO diagnostic criteria for MPNs. However, there is still no approved in vitro diagnostic test kit available in Japan. We evaluated a JAK2V617F allele quantification kit (test method) in a prospective, multicenter clinical performance study involving patients with MPNs who were diagnosed with polycythemia vera, essential thrombocythemia, and primary myelofibrosis; healthy volunteers were also included in the analysis. Good correlation was observed between the allele burden determined using the test method vs. that determined using next-generation sequencing (NGS) in the patient group (r=0.998, y=1.071x-0.069; n=156). Furthermore, all allele burdens in the healthy group (n=54) were below the lower limit of the measurement range of the test method (0.042%). Our results confirmed that the test method could quantitatively measure the JAK2V617F allele burden in patients with MPN. Thus, the novel JAK2V617F allele quantification kit can be considered useful for the diagnosis of MPNs.
Subject(s)
Genetic Testing/instrumentation , Janus Kinase 2/genetics , Myeloproliferative Disorders/genetics , Polycythemia Vera/genetics , Case-Control Studies , Humans , Japan , Mutation , Prospective StudiesABSTRACT
A 23-year-old man from Mie Prefecture, Japan, with past and family history of hematuria was diagnosed with influenza A and admitted to our hospital on the following day because of hemoglobinuria. He was diagnosed with thrombotic microangiopathy and was suspected of having atypical hemolytic uremic syndrome (aHUS). C3 p.I1157T missense mutation, which we had previously reported in eight aHUS patients from six families in Mie Prefecture, was identified. The laboratory findings and symptoms of our patient promptly improved after administering eculizumab. Little information is available on abnormalities of the complement system in aHUS or on mutation-specific outcomes of eculizumab therapy. Eculizumab was effective for treating our aHUS patient with C3 p.I1157T missense mutation.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Atypical Hemolytic Uremic Syndrome/drug therapy , Atypical Hemolytic Uremic Syndrome/genetics , Complement C3/genetics , Mutation, Missense , Atypical Hemolytic Uremic Syndrome/epidemiology , Humans , Japan/epidemiology , Male , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Transfusion-mediated human parvovirus B19 (PVB19) infection is rare but often causes severe hematologic disorders. In Japan, routine blood donor screening for PVB19 antigen (detection sensitivity, 106.4 IU/mL) using a chemiluminescent enzyme immunoassay (CLEIA) was introduced in 2008. However, there is no consensus on the minimal infectious dose of PVB19 permissible for red blood cells (RBCs). CASE REPORT: A 64-year-old man, who had received hemodialysis for diabetic nephropathy for 5 years, underwent an RBC transfusion for anemia caused by hemorrhagic enterocolitis. He developed persistent high fever and progressive thrombocytopenia. He was diagnosed with PVB19 infection when a marrow examination showed giant erythroblasts, and his serum was positive for PVB19 DNA. His serum was negative for PVB19 immunoglobulin (Ig)M and IgG before transfusion, but positive for both after transfusion. This PVB19 infection was deemed to be transmitted by the RBC transfusion because low levels of PVB19 DNA (1.10 × 104 IU/mL) were detected in one of the blood donors. A DNA homology test of PVB19 showed complete genomic identity between the virus in the donor and our patient. CONCLUSION: We report a patient who developed persistent PVB19 infection from an RBC transfusion containing low levels of PVB19. This is the second case of transfusion-mediated PVB19 infection since the introduction of CLEIA in 2008. Transmission may occur in immunocompromised patients lacking PVB19-neutralizing antibodies. The report of further such cases will allow the establishment of minimal threshold values and more effective screening tests for PBV19 transmission through RBC products.
Subject(s)
Erythrocyte Transfusion , Parvoviridae Infections/pathology , Parvoviridae Infections/therapy , Parvovirus B19, Human/pathogenicity , Thrombocytopenia/pathology , Thrombocytopenia/therapy , DNA, Viral/genetics , Humans , Immunoenzyme Techniques , Male , Middle Aged , Parvovirus B19, Human/geneticsABSTRACT
Chronic myeloid leukemia (CML) typically causes leukocytosis rather than thrombocytosis. We encountered two women in their thirties with remarkable thrombocytosis, whose platelet counts were over 3,000×103/µl, and without significant leukocytosis. Although their clinical findings resembled that of essential thrombocythemia (ET), they were diagnosed with CML because of the presence of Philadelphia chromosome. JAK2, CALR, and MPL were unmutated. On fluorescence in situ hybridization analysis, only 19.8% of granulocytes in case 2 were found to be BCR/ABL positive in peripheral blood (PB). We reviewed 11 CML cases whose platelet counts were over 2,000×103/µl, but their WBC counts were not significantly elevated (<12,000/µl). Most of them were young females with a normal or a high neutrophil alkaline phosphatase score and without immature myeloid cells in PB. These findings suggested that there is a subgroup of CML patients with marked thrombocytosis and without significant leukocytosis, which may be misdiagnosed as ET.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Thrombocytosis/etiology , Adult , Chromosomes, Human, Pair 22 , Chromosomes, Human, Pair 9 , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Leukocytosis , Pregnancy , Pregnancy Complications, Hematologic , Pregnancy Complications, NeoplasticABSTRACT
Loss of heterozygosity affecting chromosome 7q is common in acute myeloid leukemia and myelodysplastic syndromes, pointing toward the essential role of this region in disease phenotype and clonal evolution. The higher resolution offered by recently developed genomic platforms may be used to establish more precise clinical correlations and identify specific target genes. We analyzed a series of patients with myeloid disorders using recent genomic technologies (1458 by single-nucleotide polymorphism arrays [SNP-A], 226 by next-generation sequencing, and 183 by expression microarrays). Using SNP-A, we identified chromosome 7q loss of heterozygosity segments in 161 of 1458 patients (11%); 26% of chronic myelomonocytic leukemia patients harbored 7q uniparental disomy, of which 41% had a homozygous EZH2 mutation. In addition, we describe an SNP-A-isolated deletion 7 hypocellular myelodysplastic syndrome subset, with a high rate of progression. Using direct and parallel sequencing, we found no recurrent mutations in typically large deletion 7q and monosomy 7 patients. In contrast, we detected a markedly decreased expression of genes included in our SNP-A defined minimally deleted regions. Although a 2-hit model is present in most patients with 7q uniparental disomy and a myeloproliferative phenotype, haplodeficient expression of defined regions of 7q may underlie pathogenesis in patients with deletions and predominant dysplastic features.
Subject(s)
Bone Marrow Diseases/genetics , Chromosome Aberrations , Chromosomes, Human, Pair 7 , Loss of Heterozygosity , Adult , Aged , Bone Marrow Diseases/epidemiology , Bone Marrow Diseases/pathology , Chromosome Deletion , Chromosomes, Human, Pair 7/genetics , Cohort Studies , Female , Genetic Association Studies , Genome, Human , Humans , Loss of Heterozygosity/genetics , Male , Middle Aged , Myelodysplastic Syndromes/epidemiology , Myelodysplastic Syndromes/genetics , Myeloid Cells/metabolism , Myeloid Cells/pathology , Polymorphism, Single NucleotideABSTRACT
Bing-Neel syndrome is known as Waldenström's macroglobulinemia with central nervous system infiltration by neoplastic lymphoplasmacytoid and plasma cells. A 74-year-old man was admitted because of progressive cognitive impairment. Serum immunoelectrophoresis showed a monoclonal IgM-kappa component. Bone marrow aspiration revealed 59% small lymphocytes showing plasmacytoid differentiation. Bone marrow flow cytometry disclosed a population of kappa light-chain positive lymphoid cells expressing CD19, CD20, CD38, and CD138. Magnetic resonance imaging of the brain demonstrated gadolinium-enhancement in the right temporo-parieto-occipital meninges with sulcal enhancement. Cerebrospinal fluid cytology showed a population of lymphoplasmacytoid cells, positive for CD19, CD20, CD25, and kappa light-chain. Based on these findings, Bing-Neel syndrome was diagnosed. Although combination chemotherapy consisting of intrathecal methotrexate and oral cyclophosphamide was started, his symptoms continued to worsen. Then, we initiated treatment with a regimen consisting of fludarabine/rituximab (FR). After 6 courses of this FR regimen, a complete remission was achieved. Our case suggests the FR regimen to potentially be an effective treatment option for Bing-Neel syndrome of the scattered type.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Vidarabine/analogs & derivatives , Waldenstrom Macroglobulinemia/drug therapy , Aged , Bone Marrow/pathology , Drug Combinations , Humans , Magnetic Resonance Imaging , Male , Rituximab , Vidarabine/therapeutic use , Waldenstrom Macroglobulinemia/pathologyABSTRACT
Background: Chronic myelomonocytic leukemia is a clonal hematological disorder with an inherent risk of transformation to acute myeloid leukemia. Recently, there has been exponential discovery of molecular abnormalities in patients with chronic myelomonocytic leukemia. Some of these mutations independently contribute to a higher risk of transformation and result in inferior overall survival. Treatment strategies for patients undergoing blastic transformation in chronic myelomonocytic leukemia, especially after progressing on hypomethylating agents, are currently limited.Case presentation: We present a case of a 70-year-old male patient with chronic myelomonocytic leukemia blastic transformation with RUNX1 mutation following azacitidine monotherapy. Notably, he achieved hematological complete remission after the first course of venetoclax plus azacitidine, leading to the disappearance of RUNX1 mutation. We performed serial assessments of molecular analysis by next generation sequencing throughout his clinical course.Conclusion: The presence of RUNX1 mutation is associated with higher response rates to venetoclax-based combination therapies in chronic myelomonocytic leukemia with blastic transformation. Our findings suggest that even after azacitidine monotherapy, venetoclax plus azacitidine is effective in targeting leukemic clones harboring RUNX1 mutations. Furthermore, we emphasize the significance of molecular analysis, including next-generation sequencing, in providing insights into the detailed dynamics of clonal evolution and guiding treatment decisions.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Core Binding Factor Alpha 2 Subunit , Leukemia, Myelomonocytic, Chronic , Mutation , Sulfonamides , Humans , Leukemia, Myelomonocytic, Chronic/drug therapy , Leukemia, Myelomonocytic, Chronic/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Male , Aged , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Sulfonamides/therapeutic use , Sulfonamides/administration & dosage , Azacitidine/therapeutic use , Azacitidine/administration & dosage , Antineoplastic Agents/therapeutic useABSTRACT
Chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, is characterized by monocytic proliferation, dysplasia, and progression to acute myeloid leukemia. CMML has been associated with somatic mutations in diverse recently identified genes. We analyzed 72 well-characterized patients with CMML (N = 52) and CMML-derived acute myeloid leukemia (N = 20) for recurrent chromosomal abnormalities with the use of routine cytogenetics and single nucleotide polymorphism arrays along with comprehensive mutational screening. Cytogenetic aberrations were present in 46% of cases, whereas single nucleotide polymorphism array increased the diagnostic yield to 60%. At least 1 mutation was found in 86% of all cases; novel UTX, DNMT3A, and EZH2 mutations were found in 8%, 10%, and 5.5% of patients, respectively. TET2 mutations were present in 49%, ASXL1 in 43%, CBL in 14%, IDH1/2 in 4%, KRAS in 7%, NRAS in 4%, and JAK2 V617F in 1% of patients. Various mutant genotype combinations were observed, indicating molecular heterogeneity in CMML. Our results suggest that molecular defects affecting distinct pathways can lead to similar clinical phenotypes.
Subject(s)
DNA (Cytosine-5-)-Methyltransferases/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Leukemic , Histone Demethylases/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Mutation , Nuclear Proteins/genetics , Transcription Factors/genetics , Adult , Aged , Aged, 80 and over , Chromosome Aberrations , DNA Methyltransferase 3A , DNA Mutational Analysis , Enhancer of Zeste Homolog 2 Protein , Female , Humans , Leukemia, Myelomonocytic, Chronic/epidemiology , Male , Middle Aged , Polycomb Repressive Complex 2 , Survival AnalysisABSTRACT
Chronic myelomonocytic leukemia is a heterogeneous disease with multifactorial molecular pathogenesis. Various recurrent somatic mutations have been detected alone or in combination in chronic myelomonocytic leukemia. Recently, recurrent mutations in spliceosomal genes have been discovered. We investigated the contribution of U2AF1, SRSF2 and SF3B1 mutations in the pathogenesis of chronic myelomonocytic leukemia and closely related diseases. We genotyped a cohort of patients with chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia for somatic mutations in U2AF1, SRSF2, SF3B1 and in the other 12 most frequently affected genes in these conditions. Chromosomal abnormalities were assessed by nucleotide polymorphism array-based karyotyping. The presence of molecular lesions was correlated with clinical endpoints. Mutations in SRSF2, U2AF1 and SF3B1 were found in 32%, 13% and 6% of cases of chronic myelomonocytic leukemia, secondary acute myeloid leukemia derived from chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, respectively. Spliceosomal genes were affected in various combinations with other mutations, including TET2, ASXL1, CBL, EZH2, RAS, IDH1/2, DNMT3A, TP53, UTX and RUNX1. Worse overall survival was associated with mutations in U2AF1 (P=0.047) and DNMT3A (P=0.015). RAS mutations had an impact on overall survival in secondary acute myeloid leukemia (P=0.0456). By comparison, our screening of juvenile myelomonocytic leukemia cases showed mutations in ASXL1 (4%), CBL (10%), and RAS (6%) but not in IDH1/2, TET2, EZH2, DNMT3A or the three spliceosomal genes. SRSF2 and U2AF1 along with TET2 (48%) and ASXL1 (38%) are frequently affected by somatic mutations in chronic myelomonocytic leukemia, quite distinctly from the profile seen in juvenile myelomonocytic leukemia. Our data also suggest that spliceosomal mutations are of ancestral origin.