Hydroxyurea- a cost effective treatment in developing countries for Atypical Chronic Myeloid Leukemia (aCML): Case Report of Two Patients.

INTRODUCTION: Atypical chronic myeloid leukaemia (aCML) is a rare chronic myeloproliferative disorder with a poor prognosis. CASE REPORT: This case report presents two cases of male geriatric patients, both referred from primary care in rural areas and received at an urban clinic in a tertiary care hospital on separate instances. The first patient complained of low-grade fever (on/off), generalized body aches, rapid weight loss and shortness of breath for the last 2 months. The second patient arrived pale looking with symptoms of generalized body aches, dizziness and anorexia. Both patients were diagnosed to have aCML according to the World Health organization criteria. MANAGEMENT & OUTCOME: Both the patients were from a low economic bracket and were treated with Hydroxyurea a relatively economic medicine successfully. The follow-up lasted for 12 months in both cases. No progression to acute myeloid leukaemia (AML) or relapse was observed. DISCUSSION: This case report shows the promising results of Hydroxyurea in treating aCML and can be a cost effective alternate to other expensive treatments (allogeneic hematopoietic stem cell transplantation) and expensive medicines in lower and middle-income countries especially for resource-limited patients. These two cases show promising evidence for further studies to evaluate and conduct pharmaco-economic evaluations as well as clinical trials to compare hydroxyurea with other available alternative treatments for an affordable therapeutic option towards prevention of relapse and disease free survival after aCML.

Defective migration and dysmorphology of neutrophil granulocytes in atypical chronic myeloid leukemia treated with ruxolitinib.

BACKGROUND: The identification of pathologically altered neutrophil granulocyte migration patterns bears strong potential for surveillance and prognostic scoring of diseases. We recently identified a strong correlation between impaired neutrophil motility and the disease stage of myelodysplastic syndrome (MDS). Here, we apply this assay to study quantitively increased neutrophils of a patient suffering from a rare leukemia subtype, atypical chronic myeloid leukemia (aCML). METHODS: A 69-year-old male was analyzed in this study. Besides routine analyses, we purified the patient's neutrophils from peripheral whole blood and studied their migration behavior using time-lapse video microscopy in a standardized assay. These live cell migration analyses also allowed for the quantification of cell morphology. Furthermore, the cells were stained for the markers CD15, CD16, fMLPR, CXCR1 and CXCR2. RESULTS: Despite cytoreductive therapy with hydroxyurea, the patient's WBC and ANC were poorly controlled and severe dysgranulopoiesis with hypogranularity was observed. Neutrophils displayed strongly impaired migration when compared to healthy controls and migrating cells exhibited a more flattened-out morphology than control neutrophils. Because of a detected CSF3R (p.T618I) mutation and constitutional symptoms treatment with ruxolitinib was initiated. Within 1 week of ruxolitinib treatment, the cell shape normalized and remained indistinguishable from healthy control neutrophils. However, neutrophil migration did not improve over the course of ruxolitinib therapy but was strikingly altered shortly before a sinusitis with fever and bleeding from a gastric ulcer. Molecular work-up revealed that under ruxolitinib treatment, the CSF3R clone was depleted, yet the expansion of a NRAS mutated subclone was promoted. CONCLUSION: These results demonstrate the usefulness of neutrophil migration analyses to uncover corresponding alterations of neutrophil migration in rare myeloid neoplasms. Furthermore, in addition to monitoring migration the determination of morphological features of live neutrophils might represent a useful tool to monitor the effectiveness of therapeutic approaches.

CSF3R mutated myeloid neoplasms: Beyond chronic neutrophilic leukemia.

CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.

Synergetic effect of Azacitidine and Sorafenib in treatment of a case of myeloid neoplasm with sole chromosomal abnormality t(8;22)(p11.2;q11.2)/BCR-FGFR1 rearrangement.

The sole t(8;22)(p11.2;q11.2)/BCR- FGFR1 chromosomal abnormality formerly known as aCML is an extremely rare disease entity with a history of rapid progression. Though patients resemble phenotypically chronic myeloid leukemia, the treatment of patients with sole BCR-FGFR1 rearrangement are still challenging for clinicians due to rapid progressive nature and unavailability of uniform treatment guidelines. In present case study, we describe a case of myeloid neoplasm with sole chromosomal abnormality of t(8;22)(p11.2;q11.2)/BCR-FGFR1 rearrangement which is successfully managed by Sorafenib with Azacitidine. Hence our case report suggests that combination of Sorafenib and Azacitidine treatment is effective in sole BCR-FGFR1 rearrangement, however this combination therapy should be studied in large clinical trials.

Definitions, Biology, and Current Therapeutic Landscape of Myelodysplastic/Myeloproliferative Neoplasms.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving various transcription factors (e.g., RUNX1), signaling molecules (e.g., NRAS, JAK2), splicing factors (e.g., SF3B, SRSF2), and epigenetic regulators (e.g., TET2, ASXL1, DNMT3A), as well as specific cytogenetic abnormalities (e.g., 8 trisomies, 7 deletions/monosomies). Clinical studies exploring therapeutic options for higher-risk MDS/MPN overlap syndromes mostly involve hypomethylating agents, but other treatments such as lenalidomide and targeted agents such as JAK inhibitors and inhibitors targeting PARP, histone deacetylases, and the Ras pathway are under investigation. While these treatment modalities can provide partial disease control, allogeneic bone marrow transplantation (allo-BMT) is the only potentially curative option for patients. Important prognostic factors correlating with outcomes after allo-BMT include comorbidities, splenomegaly, karyotype alterations, and the bone marrow blasts percentage at the time of transplantation. Future research is imperative to optimizing therapeutic strategies and enhancing patient outcomes in MDS/MPN neoplasms. In this review, we summarize MDS/MPN diagnostic criteria, biology, and current and future treatment options, including bone marrow transplantation.

Myelodysplastic Syndromes/Myeloproliferative Overlap Neoplasms and Differential Diagnosis in the WHO and ICC 2022 Era: A Focused Review.

The myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) category comprises a varied group of myeloid neoplastic diseases characterized by clinical and pathologic overlapping features of both myelodysplastic and myeloproliferative neoplasms. For these reasons, these tumors are challenging in terms of diagnosis. The recent World Health Organization (WHO) 2022 classification and the International Consensus Classification (ICC) made changes in the classification of MDS/MPN compared to the previous 2016 WHO classification and improved the diagnostic criteria of these entities. The aim of this review is to describe the main entities reported in the more recent classifications, focusing on chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia (or atypical CML [aCML]), and MDS/MPN with SF3B1 mutation and thrombocytosis/MDS/MPN with ring sideroblasts and thrombocytosis. A particular emphasis is given to the differential diagnosis and analysis of subtle divergences and semantic differences between the WHO classification and the ICC for these entities.

Allogeneic Hematopoietic Stem Cell Transplantation for Mixed or Overlap Myelodysplastic/Myeloproliferative Disorders.

Chronic myelomonocytic leukemia (CMML) and the remaining, less frequent hybrid, mixed, or overlap myelodysplastic syndromes/myeloproliferative neoplasms (MDSs/MPNs) are difficult to treat neoplastic hematological disorders, exhibiting substantial clinical and prognostic heterogeneity, for which clear therapeutic guidelines or effective treatment options are still missing. CMML has an overall survival ranging from a few months to several years. Although patients with proliferative or dysplastic features may benefit from hydroxyurea and hypomethylating agent treatment, respectively, none of these treatments can establish long-term remission and prevent the inevitable transformation to acute leukemia. Novel targeted treatment approaches are emerging but are still under investigation. Therefore, currently, allogeneic stem cell transplantation (allo-SCT) remains the only treatment modality with a curative potential, but its widespread application is limited, due to significant morbidity and mortality associated with the procedure, especially in the elderly and in patients with comorbidities. Recognition of patient eligibility for allo-SCT is crucial, and the procedure should be addressed to patients with a good performance status without severe comorbidities and mainly to those in intermediate- to high-risk category, with a suitable stem cell donor available. The issues of best timing for performing transplantation, patient and donor eligibility, the type of conditioning regimen, and the outcomes after various allo-SCT procedures are the topics of this review.

Hybrid or Mixed Myelodysplastic/Myeloproliferative Disorders - Epidemiological Features and Overview.

The WHO-category Myelodysplastic/Myeloproliferative neoplasms (MDS/MPNs) recognizes a unique group of clonal myeloid malignancies exhibiting overlapping features of myelodysplastic as well as myeloproliferative neoplasms. The group consists of chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR-ABL1-negative (aCML), juvenile myelomonocytic leukemia (JMML), myelodysplastic/myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U). The most frequent entity in this category is CMML, while all other diseases are extremely rare. Thus, only very limited data on the epidemiology of these subgroups exists. An appropriate diagnosis and classification can be challenging since the diagnosis is still largely based on morphologic criteria and myelodysplastic as well as myeloproliferative features can be found in various occurrences. The diseases in this category share several features that are common in this specific WHO-category, but also exhibit specific traits for each disease. This review summarizes published data on epidemiological features and offers a brief overview of the main diagnostic criteria and clinical characteristics of the five MDS/MPN subgroups.

Molecular Pathogenesis of BCR-ABL-Negative Atypical Chronic Myeloid Leukemia.

Atypical chronic myeloid leukemia is a rare disease whose pathogenesis has long been debated. It currently belongs to the group of myelodysplastic/myeloproliferative disorders. In this review, an overview on the current knowledge about diagnosis, prognosis, and genetics is presented, with a major focus on the recent molecular findings. We describe here the molecular pathogenesis of the disease, focusing on the mechanisms of action of the main mutations as well as on gene expression profiling. We also present the treatment options focusing on emerging targeted therapies.

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.

Comprehensive mutation profiling and mRNA expression analysis in atypical chronic myeloid leukemia in comparison with chronic myelomonocytic leukemia.

Atypical chronic myeloid leukemia (aCML) and chronic myelomonocytic leukemia (CMML) represent two histologically and clinically overlapping myelodysplastic/myeloproliferative neoplasms. Also the mutational landscapes of both entities show congruencies. We analyzed and compared an aCML cohort (n = 26) and a CMML cohort (n = 59) by next-generation sequencing of 25 genes and by an nCounter approach for differential expression in 107 genes. Significant differences were found with regard to the mutation frequency of TET2, SETBP1, and CSF3R. Blast content of the bone marrow revealed an inverse correlation with the mutation status of SETBP1 in aCML and TET2 in CMML, respectively. By linear discriminant analysis, a mutation-based machine learning algorithm was generated which placed 19/26 aCML cases (73%) and 54/59 (92%) CMML cases into the correct category. After multiple correction, differential mRNA expression could be detected between both cohorts in a subset of genes (FLT3, CSF3R, and SETBP1 showed the strongest correlation). However, due to high variances in the mRNA expression, the potential utility for the clinic is limited. We conclude that a medium-sized NGS panel provides a valuable assistance for the correct classification of aCML and CMML.

A typical atypical chronic myeloid leukemia.

In the context of leukocytosis due to increased number of neutrophils and their precursors, with significant dysgranulopoiesis and no or minimal basophilia and no or minimal monocytosis, the typical feature of "clumped" chromatin, in irregularly coarse compacted nuclei, should lead to suspect the diagnosis of atypical chronic myeloid leukemia.

The Challenge of Treating Myelodysplastic Syndromes/Myeloproliferative Neoplasms.

Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) comprise a spectrum of myeloid disorders with both dysplastic and proliferative features, arising from hematopoietic stem cells. MDS/MPN are neither MDS nor MPN but a distinct World Health Organization-defined subclassification of diseases that, by definition, do not arise from a pre-existing MDS or MPN, inherently creating diagnostic and therapeutic challenges. Appropriately recognizing and classifying MDS/MPN is paramount for appropriately formulating treatment strategies and accurate prognostication. Highlighting the unique molecular, morphologic, and clinical characteristics among the subclassifications of MDS/MPN can assist in the appropriate diagnosis and aid in choice of therapeutic strategies. We describe the challenges of the appropriate diagnosis and treatment of MDS/MPN.

Clinical management of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes.

The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a unique group of hematologic malignancies characterized by concomitant myelodysplastic and myeloproliferative features. According to the 2008 WHO classification, the category includes atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), MDS/MPN-unclassifiable (MDS/MPN-U), and the provisional entity refractory anemia with ring sideroblasts and thrombocytosis (RARS-T). Although diagnosis currently remains based on clinicopathologic features, the incorporation of next-generation platforms has allowed for the recent molecular characterization of these diseases which has revealed unique and complex mutational profiles that support their distinct biology and is anticipated to soon play an integral role in diagnosis, prognostication, and treatment. Future goals of research should include the development of disease-modifying therapies, and further genetic understanding of the category will likely form the foundation of these efforts.

Identification of novel point mutations in splicing sites integrating whole-exome and RNA-seq data in myeloproliferative diseases.

Point mutations in intronic regions near mRNA splice junctions can affect the splicing process. To identify novel splicing variants from exome sequencing data, we developed a bioinformatics splice-site prediction procedure to analyze next-generation sequencing (NGS) data (SpliceFinder). SpliceFinder integrates two functional annotation tools for NGS, ANNOVAR and MutationTaster and two canonical splice site prediction programs for single mutation analysis, SSPNN and NetGene2. By SpliceFinder, we identified somatic mutations affecting RNA splicing in a colon cancer sample, in eight atypical chronic myeloid leukemia (aCML), and eight CML patients. A novel homozygous splicing mutation was found in APC (NM_000038.4:c.1312+5G>A) and six heterozygous in GNAQ (NM_002072.2:c.735+1C>T), ABCC 3 (NM_003786.3:c.1783-1G>A), KLHDC 1 (NM_172193.1:c.568-2A>G), HOOK 1 (NM_015888.4:c.1662-1G>A), SMAD 9 (NM_001127217.2:c.1004-1C>T), and DNAH 9 (NM_001372.3:c.10242+5G>A). Integrating whole-exome and RNA sequencing in aCML and CML, we assessed the phenotypic effect of mutations on mRNA splicing for GNAQ, ABCC 3, HOOK 1. In ABCC 3 and HOOK 1, RNA-Seq showed the presence of aberrant transcripts with activation of a cryptic splice site or intron retention, validated by the reverse transcription-polymerase chain reaction (RT-PCR) in the case of HOOK 1. In GNAQ, RNA-Seq showed 22% of wild-type transcript and 78% of mRNA skipping exon 5, resulting in a 4-6 frameshift fusion confirmed by RT-PCR. The pipeline can be useful to identify intronic variants affecting RNA sequence by complementing conventional exome analysis.

Myelodysplastic syndrome transformed to atypical chronic myeloid leukemia——Three cases report and review of literature / 中国癌症杂志

Purpose:To report three cases of myelodysplastic syndrome(MDS) transformed to atypical chronic myeloid leukemia(aCML).Methods:Compared the clinical findings,hemograms and bone marrow features in two different courses of the disease,discussed with review of related literatures.Results:The three patients were all old age.They onset with chronic anemia,the results of BM smear were MDS-RAS and MDS-RAEB;Then leukocytosis occurred in 6-65 months.The aCML were diagnosed according to the BM smear and normal chromosome.Conclusions:The MDS/MPD is a new category of the WHO classification that have both dysplastic and proliferative features.Atypical CML lacks the Ph chromosome and BCR/ABL fusion gene that are the hallmarks of classic CML.This kind of case is seldom seen.