Analysis of CSF3R mutations in atypical chronic myeloid leukemia and other myeloid malignancies.

We report a series of patients with CSF3R-mutant (CSF3Rmut) atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL) or other hematologic malignancies. We included 25 patients: 5 aCML and 4 CNL CSF3Rmut patients; 1 aCML, 2 CNL, and 2 myelodysplastic/myeloproliferative neoplasm, not otherwise specified patients without CSF3R mutation; and 11 CSF3Rmut patients with other diseases [8 acute myeloid leukemia (AML), 1 chronic myelomonocytic leukemia (CMML), 1 myelodysplastic syndrome (MDS), and 1 acute lymphoblastic leukemia (ALL)]. Patients with aCML or CNL were tested by Sanger sequencing and pyrosequencing to identify CSF3R T618I. Twenty-two patients underwent gene panel analysis. CSF3R mutations, mostly T618I (8/9), were found at high frequencies in both aCML and CNL patients [5/6 aCML and 4/6 CNL]. Two aCML patients in early adulthood with CSF3R T618I and biallelic or homozygous CEBPA mutations without other mutations presented with increased blasts and exhibited remission for >6 years after transplantation. The other 7 CSF3Rmut aCML or CNL patients were elderly adults who all had ASXL1 mutations and frequently presented with SEBP1 and SRSF2 mutations. Five AML patients had CSF3R exon 14 or 15 point mutations, and 6 other patients (3 AML, 1 CMML, 1 MDS, and 1 ALL) had truncating mutations, demonstrating differences in leukocyte counts and mutation status. In conclusion, CSF3R mutations were found at a higher frequency in aCML patients than in previous studies, which might reflect ethnic differences. Additional studies are needed to confirm these findings and the relationship between CSF3R and CEBPA mutations.

A case report of atypical chronic myeloid leukemia with complete hematological and major molecular response to Venetoclax/Azacitidine treatment.

Atypical Chronic Myeloid Leukemia (aCML), a myeloproliferative neoplasm with poor prognosis, was reclassified as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the WHO 2022 classification. Due to the heterogeneity of its clinical features and the lack of unique biomarkers, as well as limited treatment options, aCML currently lacks a standardized treatment protocol. In this case report, we reviewed a young man diagnosed with aCML who achieved complete clinical and hematologic remission subsequent to receiving a therapeutic regimen combining Venetoclax and Azacitidine.

Case report: Safety and efficacy of synergistic treatment using selinexor and azacitidine in patients with atypical chronic myeloid leukemia with resistance to decitabine.

Background: Atypical chronic myeloid leukemia (aCML) is a BCR::ABL1 negative myelodysplastic/myeloproliferative neoplasm with poor overall survival. Some patients can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) from suitable donors. The effectiveness of decitabine or azacitidine (AZA) has recently been reported; however, their combined efficacy with selinexor has not yet been reported. Case description: In this study, we report the case of a patient with aCML who was successfully treated with selinexor combined with AZA. A 67-year-old man with a history of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was admitted to the hospital with fatigue and emaciation. He was diagnosed with aCML and no longer responded to decitabine treatment after undergoing seven cycles. The patient was subsequently administered hydroxyurea (HU), selinexor, and AZA. After four courses of combination therapy, his blood cell counts improved; he no longer required transfusions and was able to discontinue HU. The patient continued receiving selinexor and AZA without severe complications. This case is the first to show that combinatorial selinexor and AZA therapy can effectively treat aCML. Conclusion: Our case sheds light on the importance of selinexor and AZA combined therapy in the exploration of new treatment strategies for aCML. Moreover, this treatment approach offers the possibility of bridging with allo-HSCT.

Differential diagnoses and the mutational landscape of myelodysplastic/myeloproliferative neoplasm with neutrophilia: A case report.

Myelodysplastic/myeloproliferative neoplasm with neutrophilia (MDS/MPN-N; previously referred to as atypical chronic myeloid leukemia) is a type of myelodysplastic syndrome/myeloproliferative neoplasm. A molecular genetic precondition for diagnosis is BCR::ABL negativity; further diagnostic criteria include clinicopathological assessments, such as peripheral blood leukocyte counts, the number of neutrophils and their precursors, and the presence of dysgranulopoiesis. The present case report highlights the importance of differential diagnoses with a stringent diagnostic workup according to the 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors. A systematic review of the literature from 2013 to 2022 covering the mutational landscape of MDS/MPN-N was also performed to highlight recent improvements in the molecular genetic diagnostics of this disease.

Molecular genetics and management of world health organization defined atypical chronic myeloid leukemia.

Atypical chronic myeloid leukemia (CML) is a rare BCR::ABL1-negative hematopoietic stem cell disease characterized by granulocytic proliferation and granulocytic dysplasia. Due to both the challenging diagnosis and the rarity of atypical CML, comprehensive molecular annotation-based analyses of this disease population have been scarce, and it is currently difficult to identify the optimal treatment for atypical CML. To explore atypical CML genomic landscape and treatment options, we performed a systematic retrospective of the clinical data and outcomes of 31 atypical CML patients. We observed that the molecular landscape of atypical CML was highly heterogeneous, with multiple molecular events driving its pathogenesis. Patients with atypical CML had a low response to current therapies, with an overall response rate (ORR) of 33.3% to hypomethylating agent (HMA)-based therapy. The current treatment strategies, including hematopoietic stem cell transplantation (HSCT), did not improve overall survival (OS) in atypical CML patients, with a median survival of 20 months. Thus, the benefits from HSCT and candidates for HSCT remain to be further evaluated. Acute myeloid leukemia (AML)-like chemotherapy followed by bridging allogeneic HSCT may be an ideal regimen for suitable individuals. The large-scale and prospective clinical studies will help to address the dilemma.

Advances in myelodysplastic/myeloproliferative neoplasms.

The myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) category includes a heterogeneous group of diseases characterized by the co-occurrence of clinical and pathologic features of both myelodysplastic and myeloproliferative neoplasms. The recently published International Consensus Classification of myeloid neoplasms revised the entities included in the MDS/MPN category as well as criteria for their diagnosis. In addition to the presence of one or more increased peripheral blood cell counts as evidence of myeloproliferative features, concomitant cytopenia as evidence of ineffective hematopoiesis is now an explicit requirement to diagnose the diseases included in this category. The increasing availability of modern gene sequencing has allowed better understanding of the biologic characteristics of these myeloid neoplasms. The presence of specific mutations in the appropriate clinicopathologic context is now included in the diagnostic criteria for some of MDS/MPN entities. In this review, we highlight what has changed in the diagnostic criteria of MDS/MPN from the WHO 2016 classification while providing practical guidance in diagnosing these diseases.

Trametinib: Could It Be a Promising Drug to Treat Atypical Chronic Myeloid Leukemia?

Atypical chronic myeloid leukemia (aCML) is a rare disease that is currently classified under the myelodysplastic (MDS)/myeloproliferative neoplasm (MPN) disease spectrum. MDS/MPN diseases are characterized by the absence of the Philadelphia (Ph) chromosome and the overlap between bone marrow fibrosis and dysplastic features. The Ph chromosome, resulting from BCR-ABL1 translocation, helps to distinguish aCML from chronic myeloid leukemia (CML). The currently reported incidence of aCML is imprecise because aCML is diagnosed primarily based on morphological features and other unspecified laboratory findings, and there is an especially high chance of under-diagnosis of aCML and other MDS/MPN diseases. Recent advances in next-generation sequencing (NGS) have allowed a greater understanding of the nature of aCML, providing better opportunities to achieve higher diagnostic accuracy and for the use of more targeted treatment to achieve better outcomes. Herein, we present a case of a 68-year-old woman who came to our hospital complaining of shortness of breath, fatigue, and weakness, who was found to have significantly increased leukocytosis, hepatosplenomegaly, and was negative for the Ph chromosome. Further investigations with NGS revealed mutations in ASXL1, GATA2, NRAS, and SRSF2 but not CSF3R. In addition to this, peripheral smear and bone marrow aspiration findings were suggestive of aCML based on specific morphological findings. Since the patient was ineligible for a stem cell transplant (SCT), symptomatic treatment was started with cell transfusion; however, the patient continued to have symptomatic anemia that required multiple transfusions. A trial with trametinib, a mitogen-activated protein kinase kinase (MEK) inhibitor, was later started as a targeted therapy based on one of her genetic mutations. Interestingly, the patient's blood counts stabilized, she reported feeling better, and she did not need any blood transfusions for four consecutive months during treatment with trametinib. Unfortunately, our patient later died from sepsis resulting from secondary infections. In light of the significant advancements in NGS, clinicians should always consider utilizing it as a helpful tool to not only establish a rare diagnosis of aCML but also to offer the best available targeted therapy when applicable. This might alleviate the burden associated with the poor prognosis of aCML.

CSF3R T618I mutated chronic myelomonocytic leukemia: A proliferative subtype with a distinct mutational profile.

Chronic myelomonocytic leukemia (CMML) is a clonal myeloid neoplasm characterized by sustained monocytosis and mutations in TET2, ASXL1, SRSF2, SETBP1, NRAS, and KRAS. We describe a rare case of CSF3R T618I mutated CMML that has a proliferative phenotype, myelodysplasia, and additional mutations in ASXL1, SETBP1, KRAS, and PTPN11. Comparing the clinicopathologic features of this case to previously reported cases of CSF3R T618I mutated CMML and CSF3R non-T618I mutated CMML, CSF3R T618I seems to define a unique proliferative subtype of CMML with a distinct mutational profile. The diagnostic challenges and molecular pathogenesis associated with this case are also briefly discussed.

Atypical Chronic Myeloid Leukemia: New Developments from Molecular Diagnosis to Treatment.

Atypical Chronic Myeloid Leukemia, BCR-ABL1 negative (aCML) is a rare hematological entity, included in the group of myelodysplastic (MDS)/myeloproliferative (MPN) overlap syndromes. It is characterized by an aggressive course, a high rate of acute myeloid leukemia (AML) transformation, and a dismal outcome. The clinical presentation includes splenomegaly and leukocytosis with neutrophilia and left-shifted granulocytosis accompanied by granulocytic dysplasia and sometimes multilineage dysplasia. In past years, the disease incidence was likely underestimated, as diagnosis was only based on morphological features. Recently, the improving knowledge in the molecular biology of MDS/MPN neoplasms has made it possible to distinguish aCML from other overlapping syndromes, basing on next generation sequencing. Among the most commonly mutated genes, several involve the Jak-STAT, MAPK, and ROCK signaling pathways, which could be actionable with targeted therapies that are already used in clinical practice, opening the way to tailored treatment in aCML. However, currently, there are few data available for small samples, and allogeneic transplant remains the only curative option for eligible patients.

Molecular genetics of MDS/MPN overlap syndromes.

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a heterogenous group of myeloid malignancies hallmarked by clinicopathologic features that overlap with myelodysplastic syndromes and myeloproliferative neoplasms. Formally recognized by the World Health Organization, this group includes the entities chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, MDS/MPN with ring sideroblasts and thrombocytosis and MDS/MPN, unclassifiable. Advancements in next generation sequencing have begun to unravel the molecular underpinnings of these diseases, identifying an array of recurrently mutated genes involved in epigenetic regulation, RNA splicing, transcription, and cell signaling. Despite molecular overlap with other myeloid malignancies, each entity displays a unique spectrum of somatic mutations supporting their unique pathobiology and clinical features. Importantly, molecular profiling is becoming an integral tool utilized in routine clinical practice. This review summarizes our current understanding of the molecular pathogenesis of overlap syndromes and details the impact of somatic mutations in diagnostic, prognostic, and therapeutic decision-making.

A rare atypical chronic myeloid leukemia BCR-ABL1 negative with concomitant JAK2 V617F and SETBP1 mutations: a case report and literature review.

Atypical chronic myeloid leukemia (aCML) BCR-ABL1 negative is a rare myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) for which no standard treatment currently exists. The advent of next-generation sequencing has allowed our understanding of the molecular pathogenesis of aCML to be expanded and has made it possible for clinicians to more accurately differentiate aCML from similar MDS/MPN overlap syndrome and MPN counterparts, as MPN-associated driver mutations in JAK2, CALR, or MPL are typically absent in aCML. A 55-year old male with main complaints of weight loss and fatigue for more than half a year and night sweats for more than 2 months was admitted to our hospital. Further examination revealed increased white blood cells, splenomegaly, and grade 1 bone marrow fibrosis with JAK2 V617F, which supported a preliminary diagnosis of pre-primary marrow fibrosis. However, in addition to JAK2 V617F (51.00%), next-generation sequencing also detected SETBP1 D868N (46.00%), ASXL1 G645fs (36.09%), and SRSF2 P95_R102del (33.56%) mutations. According to the 2016 World Health Organization diagnostic criteria, the patient was ultimately diagnosed with rare aCML with concomitant JAK2 V617F and SETBP1 mutations. The patient received targeted therapy of ruxolitinib for 5 months and subsequently an additional four courses of combined hypomethylating therapy. The patient exhibited an optimal response, with decreased spleen volume by approximately 35% after therapy and improved symptom scores after therapy. In diagnosing primary bone marrow fibrosis, attention should be paid to the identification of MDS/MPN. In addition to basic cell morphology, mutational analysis using next-generation sequencing plays an increasingly important role in the differential diagnosis. aCML with concomitant JAK2 V617F and SETBP1 mutations has been rarely reported, and targeted therapy for mutated JAK2 may benefit patients, especially those not suitable recipients of hematopoietic stem cell transplants.

Atypical CML- the role of morphology and precision genomics.

Atypical chronic myeloid leukemia is an esoteric myeloid malignancy with features of both myeloproliferative and myelodysplastic syndromes. This disease is characterized primarily by morphologic-based criteria, and has clinical and molecular features overlapping with other myeloid malignancies. No one molecular abnormality is specific, and multiple mutations are often present in various combinations, due to the malignant multi-step clonal evolution of myeloid malignancies. In this review, we will address what we know about atypical chronic myeloid leukemia; evaluate how the molecular landscape in myeloid malignancies overlaps, and discuss what we can learn by incorporating individualized precision genomic strategies.

[Mediastinal abscess due to Aspergillus in a patient with atypical chronic myeloid leukemia, BCR-ABL1-negative].

A 64-year-old male presented with a rapidly growing anterior mediastinal mass during the clinical course of atypical chronic myeloid leukemia. A needle biopsy performed for suspected myeloid sarcoma revealed the presence of Aspergillus abscess. Early diagnosis of mediastinal abscesses, which are associated with a high mortality rate, can prevent the progression of severity. Infectious abscesses should be considered for prompt qualitative diagnosis in patients with mediastinal masses. Thymoma, germ cell tumor, and malignant lymphoma are the most common anterior mediastinal tumors, whereas infectious abscesses should also be considered when myeloid sarcoma is suspected in patients with an underlying myeloid tumor.

Accelerated Phase of Atypical Chronic Myeloid Leukemia with Severe Disseminated Intravascular Coagulation at Initial Presentation.

Patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) are often asymptomatic and thus can remain undiagnosed until they become symptomatic due to progression to the accelerated phase (AP) or transformation to acute leukemia (leukemic transformation; LT). We herein report the case of a previously healthy 38-year-old man who had hyperleukocytosis with dysplastic myeloid precursor cells and severe disseminated intravascular coagulation. Hematopoietic recovery with features of atypical chronic myeloid leukemia (aCML) after induction chemotherapy was a diagnostic clue. Although rare, this case highlights the limitation of the diagnostic approach for aCML with AP or LT at the initial presentation.

Decitabine combined with CAG for the treatment of atypical chronic myeloid leukemia: a case report and literature review.

Atypical chronic myeloid leukemia BCR/ABL1 negative (aCML) is a rare hematopoietic stem/progenitor cell disorder characterized by neutrophilia, high rate of transformation to acute myeloid leukemia and poor survival. Currently, there is no consensus on the treatment for aCML. In this study, we report the case of a 52-year-old female aCML patient treated with decitabine in combination with CAG chemotherapy who achieved complete remission after the first course. The patient was subsequently treated with three cycles of the same regimen as consolidation treatment. Approximately two months after the completion of the fourth cycle, the patient was in good general health with less than 0.01% minimal residual leukemic cells. The findings of this case report indicate that decitabine in combination with CAG chemotherapy may be an effective treatment for aCML.

Next-generation sequencing reveals unique combination of mutations in cis of CSF3R in atypical chronic myeloid leukemia.

BACKGROUND: Atypical chronic myeloid leukemia (aCML) is a hematologic disorder characterized by leukocytosis with increased dysplastic neutrophils and their precursors. In CSF3R gene, the activation mutation including T618I is frequently reported in aCML but is rarely accompanied by truncation mutations. Herein, we report a unique aCML patient with two CSF3R mutations (T618I and Y779*) in the same DNA strand. METHODS: High-coverage next-generation sequencing for 40 genes related with myeloid leukemia was performed. Sanger sequencing was performed to confirm CSF3R mutations. To confirm whether two CSF3R mutations are in cis or not, TA cloning was used. Clinical information and bone marrow pathology were reviewed by two hematopathologists. RESULTS: In the patient diagnosed with aCML in bone marrow study, two CSF3R mutations, (T618I and Y779*) a SETBP1 mutation (G870S) and an U2AF1 mutation (Q157P), were identified by high-coverage next-generation sequencing. The two CSF3R mutations were confirmed to be located in the same DNA strand by TA cloning, indicating that the two mutations are harbored in one malignant clone. The SETBP1 mutation is known to be related with poor prognosis in aCML. Likewise, the patient was refractory to hydroxyurea and showed disease progression. Additionally, we discussed the potential therapeutic targets by reviewing the molecular profile of the patient. CONCLUSION: We believe that the accurate diagnosis and maximum therapeutic chance could be achieved by profiling the mutations and their characteristics.

[MYC gene amplification attributed to double minutes in a patient with atypical chronic myeloid leukemia].

A 61-year-old man was admitted to our hospital with fever and massive leukocytosis. A bone marrow smear revealed an increased density of myeloid cells in various stages of maturation as well as dysplasia in the neutrophils. There was no proliferation of blasts, eosinophils, or basophils. Genomic analysis of the bone marrow cells revealed no detectable abnormalities associated with myeloproliferative neoplasms, including BCR-ABL1. Therefore, the patient was diagnosed with atypical chronic myeloid leukemia (aCML). Chromosomal analysis revealed the presence of 1-17 double minute chromosomes (dmin) in 20 of 20 tumor cells examined. Multiple MYC signals were detected via interphase fluorescence in situ hybridization, indicating MYC gene amplification in the dmins. Three months after the oral administration of hydroxyurea, leukocytosis reoccurred. Therefore, induction therapy followed with umbilical cord blood transplantation was performed. However, MYC signals remained detectable in the bone marrow sample obtained immediately after neutrophil engraftment, indicating the presence of residual tumor cells. To the best of our knowledge, this is the first case report of aCML with dmin gene amplification, suggesting that the dmin MYC amplification exacerbated the patient's disease.

Myeloid/Lymphoid Neoplasm with PDGFRB Rearrangement with t (5;10) (q33;q22) Harboring a Novel Breakpoint of the CCDC6-PDGFRB Fusion Gene.

Myeloid/lymphoid neoplasms with PDGFRB rearrangement are a distinct type of myeloid neoplasms that occur in association with rearrangement of PDGFRB at 5q32. The hematological features most often show prominent eosinophilia. We herein report a patient with myeloid/lymphoid neoplasms with PDGFRB rearrangement with t (5;10) (q33;q22) who showed atypical chronic myeloid leukemia-like clinical features without eosinophilia and achieved an optimal response to imatinib. A sequence analysis showed a CCDC6-PDGFRB fusion gene with a new break point in the PDGFRB gene. This is the sixth case of myeloid/lymphoid neoplasm with PDGFRB rearrangement harboring a CCDC6-PDGFRB fusion gene, and it has a new breakpoint in the PDGFRB fusion gene.