Autoimmune Myelofibrosis: Clinical Features, Course, and Outcome

Background: Autoimmune myelofibrosis (AIMF) is an underrecognized cause of nonmalignant bone marrow fibrosis which occurs in the presence or absence of a defined systemic autoimmune disease. Patients with AIMF present with cytopenias and autoantibodies, and have a distinctive nonclonal myelofibrosis on bone marrow examination. AIMF is distinguished from primary myelofibrosis by the absence of splenomegaly, eosinophilia, or basophilia, and the absence of abnormal myeloid, erythroid, or megakaryocytic morphology. Objectives: The objective of the study was to describe the clinical presentation and outcomes of patients with AIMF. Methods: We conducted a single-institution, retrospective chart review of patients diagnosed with AIMF to investigate clinical presentations, therapies, and outcomes. Results: Twelve patients with AIMF were identified with a mean follow-up of 5.8 years. All patients had detectable autoantibodies and the majority had concomitant autoimmune disorders. Four patients experienced a complete response of cytopenias and 3 patients experienced a partial response (PR) of cytopenias with immunosuppressive therapy. One patient achieved a PR following splenectomy. No patients were diagnosed with myeloproliferative neoplasms during the follow-up period. Conclusions: AIMF contributes to cytopenias in the subset of patients with various autoimmune disorders. The majority of patients with AIMF experience an improvement in cytopenias with immunosuppressive therapy.

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Prefibrotic Myelofibrosis Presenting with Multiple Cerebral Embolic Infarcts and the Rare MPL W515S Mutation

Case Reports in Hematology ◽

10.1155/2020/8375986 ◽

2020 ◽

Vol 2020 ◽

pp. 1-4

Author(s):

Stephen E. Langabeer ◽

Lisa Lee Tokar ◽

Laura Kearney ◽

Cathal O’Brien ◽

Kowshika Thavarajah ◽

...

Keyword(s):

Bone Marrow ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Driver Mutations ◽

Common Mutation ◽

Limited Information ◽

Phenotypic Data ◽

Activating Mutations ◽

Cerebral Event

Acquired, activating mutations of MPL W515 are recognised driver mutations of the myeloproliferative neoplasms (MPN), namely, essential thrombocythemia and primary myelofibrosis. The most common mutation at this codon is W515L with several other mutations also described at a lower frequency. Of these less common mutations, MPL W515S has only been reported sporadically with limited information on clinicopathological associations. We describe the case of an elderly man with persistent thrombocytosis presenting with an ischemic cerebral event. Bone marrow biopsy showed evidence of prefibrotic myelofibrosis with targeted sequencing demonstrating the presence of the rare MPL W515S mutation. Thrombolytic and cytoreductive therapies resulted in a favorable outcome and follow-up. This case provides additional, necessary, and phenotypic data for the rare MPN-associated MPL W515S mutation.

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Polycythaemia following treatment of lymphoplasmacytic lymphoma

BMJ Case Reports ◽

10.1136/bcr-2020-235687 ◽

2020 ◽

Vol 13 (10) ◽

pp. e235687

Author(s):

Shailendra Prasad Verma ◽

Bhupendra Singh ◽

Rashmi Kushwaha ◽

Punita Pavecha

Keyword(s):

Bone Marrow ◽

Bone Marrow Examination ◽

Severe Anaemia ◽

Polycythaemia Vera ◽

Lymphoplasmacytic Lymphoma ◽

Transfusion Therapy ◽

Remission Maintenance ◽

Symptomatic Anaemia ◽

Complete Haematological Response

A 61-year-old man presented to the department of clinical haematology in February 2016 with symptomatic anaemia, generalised lymphadenopathy and hepatomegaly. Routine investigations showed severe anaemia with the presence of lymphoplasmacytoid cells in the peripheral smear, and bone marrow examination with IHC and serum protein electrophoresis confirmed diagnosis of lymphoplasmacytic lymphoma. The patient received supportive transfusion therapy and combination chemotherapy. After VI cycles, the patient had a complete haematological response with marrow in remission. Maintenance rituximab was planned every 3 months for 2 years. At the time of first dose of maintenance rituximab, his haemoglobin (Hb) was 189 g/L with low normal erythropoietin level. During the last 3 years follow-up, his Hb ranged between 16.5 and 20.1 g/dL. All causes of secondary polycythaemia were ruled out. Workup for polycythAemia vera (PV), including JAK-2 and bone marrow, was not suggestive of PV. We labelled it as a case of polycythaemia due to undetermined aetiology.

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Clonality in Granulocytes Detected by an Improved HUMARA Assay: A Good Prognostic Marker in Bone Marrow Failure Patients Exhibiting Chromosomal Abnormalities of Indefinite Significance.

Blood ◽

10.1182/blood.v104.11.3702.3702 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3702-3702

Author(s):

Ken Ishiyama ◽

Chiharu Sugimori ◽

Hirohito Yamazaki ◽

Akiyoshi Takami ◽

Shinji Nakao

Keyword(s):

Bone Marrow ◽

Chromosomal Abnormalities ◽

Bone Marrow Failure ◽

Bone Marrow Examination ◽

Refractory Anemia ◽

Clonal Population ◽

Dividing Cells ◽

Humara Assay

Abstract Some patients with aplastic anemia (AA) and approximately 40% of patients with refractory anemia (RA) of myelodysplastic syndrome exhibit karyotypic abnormalities in bone marrow dividing cells. Although some of the patients undergo evolution to acute myeloid leukemia (AML), others follow a clinical course similar to AA patients without chromosomal abnormalities. Except for several abnormalities such as −7 and 5q-, the clinical significance of such chromosomal abnormalities in bone marrow failure patients remains unclear. We recently developed a reliable HUMARA assay capable of detecting a clonal population in granulocytes which constitutes 30% or more of total granulocytes (Blood. 2003;102:1211–1216). Studying correlation between chromosomal abnormalities and the presence of clonality may help in understanding the pathogenetic role of chromosomal abnormalities in AA and RA. We thus analyzed 50 acquired AA and 28 RA female patients who were heterozygous for the HUMARA gene. Chromosomal abnormalities such as add(5)(q13), 9q–9q+ and del(7)(q14q22) were found in 8% of AA and 21% of RA patients. Clonality was detected in 38% of AA patients and 39% of RA patients. Incidence of chromosomal abnormalities in patients with clonality (27%) was higher than that in patients without clonality (4%, p<0.01). In two AA patients who respectively exhibited add(5)(q13) in 10% and +8 in 38% dividing cells, clonality was not detected and these abnormal clones became undetectable at the time of subsequent bone marrow examination. Clonality was detected in the other 2 AA patients respectively exhibiting 9q–9q+ in 40% and del(7)(q14q22) in 25% dividing cells, and in all 5 RA patients respectively exhibiting +8 in 10%, del(5)(q13q31), dup(1)(q32q12) in 90%, del(5)(q13), add(11)(q23), inv(9) in 65% and X,-X in 100% of dividing cells. None of the 50 AA patients including 2 patients with clonality and chromosomal abnormalities underwent evolution to AML during 2-year follow up while one of 28 RA patients who exhibited del(5)(q13q31) progressed to AML. The proportion of clonal granulocytes in total granulocytes estimated by the HUMARA assay remained unchanged in most patients with clonality except for the transformed one. These data indicate that the chromosomal abnormality in bone marrow dividing cells is not necessarily associated with presence of clonal granulocyte population in peripheral blood and that detection of clonality in granulcytes in bone marrow failure patients with chromosomal abnormalities of indefinite significance is useful in predicting prognosis of these patients.

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Prognostic Significance of Serial Determinations of LDH Levels in Primary (De Novo) Myelodysplastic Syndromes.

Blood ◽

10.1182/blood.v108.11.4828.4828 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4828-4828

Author(s):

Friedrich Wimazal ◽

Wolfgang R. Sperr ◽

Anja Vales ◽

Michael Kundi ◽

Alexandra Boehm ◽

...

Keyword(s):

Bone Marrow ◽

Lactate Dehydrogenase ◽

Disease Progression ◽

Myelodysplastic Syndromes ◽

Prognostic Value ◽

De Novo ◽

Prognostic Significance ◽

Bone Marrow Examination ◽

Probability Of Survival

Abstract An increased lactate dehydrogenase (LDH) level at diagnosis is associated with a reduced probability of survival and an enhanced risk of AML development in primary (de novo) myelodysplastic syndromes (MDS). However, so far, little is known about the prognostic value of an increase in LDH levels during the follow up in these patients. We have serially determined LDH levels in 221 patients (102 males, 119 females) with de novo MDS (median age 70 years; FAB-types: RA, n=62; RARS, n=46; RAEB, n=48; RAEBT, n=36; CMML, n=29), and examined the prognostic value of LDH as a follow-up parameter. Confirming previous data, an elevated LDH level at diagnosis was found to be associated with a significantly increased probability of AML evolution and a significantly decreased probability of survival (p<0.05). In the follow up, an increase in LDH (from normal to elevated) was found to be associated with progression of MDS and AML evolution in most cases. Moreover, in those patients who progressed to AML, LDH levels were found to be significantly higher in the two three-months-periods preceding progression compared to the two initial three-months-periods examined (p<0.005). In most patients, the increase in LDH was accompanied or followed by other signs of disease progression, such as the occurrence of thrombocytopenia or an increase in blasts. Together, our data show that LDH can be employed as a prognostic follow-up variable in patients with MDS. In those patients in whom an increase in LDH is noted, a thorough re-evaluation of the progression-status of the disease including a bone marrow examination should be considered.

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A Heterogeneous Response Pattern to Interferon-alpha2 with Induction of a Significant Decrease in the Calreticulin Mutant Allele Burden in a Subset of Patients with Essential Thrombocythemia and Primary Myelofibrosis

Blood ◽

10.1182/blood.v126.23.4057.4057 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4057-4057

Author(s):

Sabrina Cordua ◽

Lasse Kjaer ◽

Morten Orebo Holmström ◽

Niels Pallisgaard ◽

Vibe Skov ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Mutant Allele ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Allele Burden ◽

Travel Grant ◽

Ifn Treatment

Abstract Introduction The discovery of mutations in the calreticulin (CALR) gene in the majority of JAK2 -V617F negative patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) (Klampfl et al., 2013; Nangalia et al., 2013) has improved the diagnostic accuracy considerably, and most recently distinct clinical and hematological characteristics according to mutational status have been described (Park et al., 2015). The perspective is to personalize and optimize treatment according to the molecular and clinical landscape. This may be achieved by obtaining more information on responses in myeloproliferative neoplasms (MPN) to existing treatment strategies as assessed by the allele burden. Mutations in the CALR gene have proven to play a major role in oncogenic and immunologic processes (Lu, Weng, & Lee, 2015). In this context, it is highly relevant to explore the effectiveness of interferon-alpha2 (IFN) in reducing the CALR -mutated clone. Until now, only one paper has reported a decrease in allele burden in two patients during IFN treatment (Cassinat, Verger, & Kiladijan, 2014). The objective of this report is to expand current knowledge on this important topic by describing the mutant CALR allele burden over time in a larger group of IFN-treated patients. Method Clinical data were collected retrospectively from a single institution on all IFN-treated CALR positive MPN patients with sequential determinations of the mutant allele burden. Type 1 and type 2 mutations were initially identified by a previously published fragment analysis (Klampfl et al 2013). We have developed a Taqman qPCR assay for precise determination of the mutant allele burden of type 1 and type 2 mutations. Stored DNA was subsequently analysed to increase follow-up time. Results Twenty-one patients were included. Fifteen patients had a diagnosis of PMF; 7 of these were diagnosed with prefibrotic myelofibrosis. Six patients had ET. The type 1 and 2 mutations were found in 15 and 6 patients, respectively. Median age was 60 years (range 42-79) and the sex ratio (M/F) was 8/13. Fifteen patients (71%) were in ongoing treatment with IFN, whereas treatment was discontinued in 6 (29%) because of side effects. Median time of IFN treatment was 756 days (range 42-3927). The IFN prescribed was either subcutaneous injection of Pegasys® (median: 45 microgram (ug) per week), PegIntron® 25-50 ug per week, or Multiferon® 3 x 3 million IU per week. Median follow up time since the first CALR measurement was 756 days (range 294-2108). Fourteen patients (67%) maintained an unchanged allele burden during follow up; 1 patient (5%) presented a temporary decrease (from 39% to 27% in allele burden) but increased to the initial level within months while still on IFN treatment (presumably due to low compliance); 1 patient (5%) displayed an increase in allele burden during transformation to acute myelogenous leukemia (Figure 1); and 5 patients (24%) exhibited a marked decrease in allele burden (median decrease: 32%, range 18-45) during treatment with IFN (Figure 2). All 5 patients with decreasing allele burden (Table 1) normalized their platelet counts within a median time of 5 weeks (range 4-20) after initiating treatment with IFN. Conclusion Using a novel sensitive assay for the CALR mutant allele burden, we have demonstrated and substantiated the effectiveness of IFN to reduce the allele burden in a larger series of CALR positive patients with PMF and ET. Importantly, we report for the first time on highly heterogeneous response patterns. Our observation of one fourth of the CALR positive patients responding to treatment with IFN strongly suggests that IFN significantly influences the CALR mutational load. Further clinical and molecular studies are urgently needed to explore the mechanisms behind the heterogeneous response patterns and the clinical implications in regard to clonal evolution and disease progression in non-responding patients. We are currently analysing these issues to assess the definite role of IFN in future treatment strategies in CALR positive MPN patients. Table 1. Patients responding to interferon-alpha2 Characteristics Number/median (range) Patients 5 Age, years 53 (42-62) Sex (M/F) 1/4 Diagnosis- Essential thrombocythemia- Primary myelofibrosis- Prefibrotic myelofibrosis 221 Calreticulin mutation type- type 1- type 2 50 Duration of interferon-alpha2 treatment, days 960 (177-2790) Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Cordua: Janssen-Cilag: Other: travel grant. Off Label Use: interferon alpha2 for myeloproliferative neoplasms. Holmström:La Roche Ltd: Other: travel grant. Pallisgaard:Qiagen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Speakers Bureau; Bristol Meyer Squibb: Speakers Bureau; Novartis: Other: travel grant, Research Funding, Speakers Bureau; Roche: Other: travel grant. Hasselbalch:Novartis: Research Funding.

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Next-Generation Sequencing Mutational Landscape and Clinical Features of Chinese Adults with Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-145837 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4641-4641

Author(s):

Lan Zhang ◽

Xingnong Ye ◽

Shengjie Wang ◽

Keyi Jin ◽

Shuna Luo ◽

...

Keyword(s):

Next Generation Sequencing ◽

Comprehensive Evaluation ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Clinical Parameters ◽

Next Generation ◽

School Of Medicine ◽

Medical Discipline ◽

Generation Sequencing

Abstract Myeloproliferative neoplasms (MPNs) include three classical subtypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Since prefibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity in the 2016 revised classification of MPN, it has been a subject of debate among experts due to its indefinite diagnosis. However, pre-PMF usually has a distinct outcome compared with either ET or overt PMF. We conducted a retrospective study of MPN patients from October 2014 to June 2020 in the Fourth Affiliated Hospital of Zhejiang University. Patients who were diagnosed with ET, pre-PMF or overt-MF according to the 2016 WHO Classification were included. We reviewed the clinical parameters, haematologic information, and genetic mutations of patients using next-generation sequencing (NGS). Mutation screening was performed in 44 patients by next-generation sequencing techniques, 84 genes and 258 mutations were detected. JAK2 was the most frequently mutated gene (25/44, 56.82%), followed by TET2 (14/44, 31.82%), KMT2C (13/44, 29.55%), and ASXL1 (10/44, 23.73%) in MPN (Figure 1-A). The VAFs of all studied genes with mutation frequencies >10% are shown in Figure 1-B. Of the 20 patients with ET, 9 (45%) were positive for the JAK2 mutation, 5 (25%) carried FAT1, 5 (25%) carried KMT2C, and 4 (20%) carried CALR. Of the 5 patients with pre-PMF, 4 (80%) carried JAK2, 3 (60%) carried EP300, and 2 (40%) carried TET2. Of the 19 patients with overt PMF, 12 (63%) carried JAK2, 10 (53%) carried TET2, 7 (37%) carried ASXL1, and 6 (32%) carried KMT2C, as reported in Figure 2. The median follow-up was 36 months for ET, 42 months for pre-PMF, and 53 months for overt PMF. Overall survival between pre-PMF, overt PMF, and ET was significantly different (P<0.001), as shown in Figure 3. During the follow-up time, only one death of ET was registered, so we analysed the impact of clinical parameters and mutational status at diagnosis on outcome in PMF, including pre-PMF and overt PMF. We performed Kaplan-Meier curves to examine the relationships between the clinical parameters and patient survival. We found that male sex (P=0.0107), MPN10 symptoms (P=0.0354), anaemia (haemoglobin<120g/L, P=0.0239), and thrombocytopenia (platelet count <100 ×10 9/L, P=0.0002) were significantly related to inferior OS (Figure 4). Pre-PMF patients exhibited higher leukocyte counts, higher LDH values, a higher frequency of splenomegaly, and a higher incidence of hypertension than ET patients. On the other hand, pre-PMF patients had higher platelet counts and haemoglobin levels than overt PMF patients. Molecular analysis revealed that the frequency of EP300 mutations was significantly increased in pre-PMF patients compared with ET and overt PMF patients. In terms of outcome, male sex, along with symptoms including MPN10, anaemia, thrombocytopenia, and KMT2A and CUX1 mutations, indicated a poor prognosis for PMF patients. In conclusion, we identified differences in the clinical, haematologic, and molecular presentations of ET, pre-PMF, and overt PMF patients, indicating that comprehensive evaluation of not only BM features but also clinical, haematologic, and molecular profiles is needed for accurate diagnosis and treatment of these three disease entities. The molecular analysis revealed that pre-PMF might be relevant to EP300 mutation, demonstrating the value of molecular examination. The results of this study indicated that comprehensive evaluation of BM features, clinical phenotypes, haematologic parameters, and molecular profiles is needed for the accurate diagnosis and treatment of ET, pre-PMF, and overt PMF patients. Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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MPL W515 L/K mutations in myeloproliferative neoplasms

Egyptian Journal of Medical Human Genetics ◽

10.1186/s43042-019-0039-9 ◽

2019 ◽

Vol 20 (1) ◽

Author(s):

Sohaila Eldeweny ◽

Hosny Ibrahim ◽

Ghada Elsayed ◽

Mohamed Samra

Keyword(s):

Bone Marrow ◽

Polycythemia Vera ◽

Ethnic Groups ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Myelogenous Leukemia ◽

Egyptian Population ◽

Ph Chromosome ◽

Pathological Variant

Abstract Background Myeloproliferative neoplasms (MPNs) describe a group of diseases involving the bone marrow (BM). Classical MPNs are classified into chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). This classification is based on the presence of Philadelphia (Ph) chromosome (BCR/ABL1). CML is BCR/ABL1-positive while PV, ET, and PMF are negative. JAK2 p. Val617Phe pathological variant is the most associated mutation in BCR/ABL1-negative MPNs. The frequency of JAK2 p. Val617Phe is 90–95% in PV patients, 50–60% in ET, and 40–50% in patients with PMF. Studies on MPL gene led to the revelation of a gain of function pathological variants in JAK2 p. Val617Phe-negative myeloproliferative neoplasms (MPNs). MPL p. W515 L/K pathological variants are the most common across all mutations in MPL gene. The prevalence of these pathological variants over the Egyptian population is not clear enough. In the present study, we aimed to investigate the prevalence of MPL p. W515 L/K pathological variants in the Philadelphia (Ph)-negative MPNs over the Egyptian population. Results We have tested 60 patients with Ph-negative MPNs for MPL p. W515 L/K pathological variants. Median age was 51 (22–73) years. No MPL p. W515 L/K pathological variants were detected among our patients. JAK2 p. Val617Phe in PV and PMF patients showed significantly lower frequency than other studies. Splenomegaly was significantly higher in ET patients compared to other studies. Conclusion MPL p. W515 L/K pathological variants are rare across the Egyptian Ph-negative MPNs, and further studies on a large number are recommended. MPN patients in Egypt are younger compared to different ethnic groups.

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Autoimmune myelofibrosis associated with autoimmune hemolytic anemia successfully treated with ruxolitinib

10.21203/rs.3.rs-363573/v1 ◽

2021 ◽

Author(s):

Shuku Sato ◽

Wataru Kamata ◽

Yotaro Tamai

Keyword(s):

Bone Marrow ◽

Hemolytic Anemia ◽

Autoimmune Hemolytic Anemia ◽

Transforming Growth Factor ◽

Myeloproliferative Neoplasms ◽

Bone Marrow Examination ◽

Coombs Test ◽

Bone Marrow Fibrosis ◽

Cytokine Levels ◽

Antiglobulin Test

Abstract A 55-year-old man suffered from dyspnea, general malaise, and jaundice. His laboratory date showed pancytopenia and hemolytic anemia, and computed tomography showed splenomegaly. Bone marrow examination revealed myelofibrosis (MF)-1. The hemolytic anemia was diagnosed as IgM autoimmune hemolytic anemia (AIHA) with negative direct and indirect Coombs test but positive IgM-direct antiglobulin test. We started ruxolitinib 20 mg, which improved not only bone marrow fibrosis, symptoms related to myeloproliferative neoplasms and splenomegaly, but also AIHA. AIHA may be associated with Autoimmune MF (AIMF), and cytokines such as transforming growth factor (TGF)-β are thought to be involved in such cases. This case suggests that ruxolitinib may improve the cytokine levels and may lead to the treatment of AIHA as well as AIMF.

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Advanced forms of MPNs are accompanied by chromosomal abnormalities that lead to dysregulation of TP53

Blood Advances ◽

10.1182/bloodadvances.2018024018 ◽

2018 ◽

Vol 2 (24) ◽

pp. 3581-3589 ◽

Cited By ~ 11

Author(s):

Bridget K. Marcellino ◽

Ronald Hoffman ◽

Joseph Tripodi ◽

Min Lu ◽

Heidi Kosiorek ◽

...

Keyword(s):

Disease Progression ◽

Chromosomal Abnormalities ◽

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Primary Myelofibrosis ◽

Chromosome 17 ◽

Transcript Levels ◽

History Of ◽

Tumor Protein P53

Abstract The Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and the prefibrotic form of primary myelofibrosis (PMF), frequently progress to more overt forms of MF and a type of acute leukemia termed MPN-accelerated phase/blast phase (MPN-AP/BP). Recent evidence indicates that dysregulation of the tumor suppressor tumor protein p53 (TP53) commonly occurs in the MPNs. The proteins MDM2 and MDM4 alter the cellular levels of TP53. We investigated in 1,294 patients whether abnormalities involving chromosomes 1 and 12, which harbor the genes for MDM4 and MDM2, respectively, and chromosome 17, where the gene for TP53 is located, are associated with MPN disease progression. Gain of 1q occurred not only in individuals with MPN-BP but also in patients with PV and ET, who, with further follow-up, eventually evolve to either MF and/or MPN-BP. These gains of 1q were most prevalent in patients with a history of PV and those who possessed the JAK2V617F driver mutation. The gains of 1q were accompanied by increased transcript levels of MDM4. In contrast, 12q chromosomal abnormalities were exclusively detected in patients who presented with MF or MPN-BP, but were not accompanied by further increases in MDM2/MDM4 transcript levels. Furthermore, all patients with a loss of 17p13, which leads to a deletion of TP53, had either MF or MPN-AP/BP. These findings suggest that gain of 1q, as well as deletions of 17p, are associated with perturbations of the TP53 pathway, which contribute to MPN disease progression.

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Prognostic and therapeutic impact of cytogenetic abnormalities in patients with myelodysplastic/myeloproliferative neoplasms, unclassifiable.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.7058 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 7058-7058

Author(s):

Abhishek Avinash Mangaonkar ◽

Hassan Alkhateeb ◽

Aref Al-Kali ◽

Naseema Gangat ◽

Kebede Begna ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Treatment Guidelines ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Prognostic Impact ◽

Trisomy 8 ◽

Abnormal Karyotype ◽

Immature Myeloid Cells

7058 Background: The 2016 WHO classification includes myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U), as an MDS/MPN overlap syndrome not meeting criteria for well-defined entities such as CMML. No standard prognostication or treatment guidelines exist for such patients. Methods: We retrospectively identified MDS/MPN-U cases from 1990-2016 through our myeloid malignancies database. All bone marrow reports were reviewed to ensure compliance with 2016 WHO criteria. Clinical & cytogenetic parameters at diagnosis were assessed & compared with treatment outcomes. Results: Eighty nine patients met study criteria, with a median age of 69 years (range: 37-93); 58 (65%) males. Median follow-up was 22.2 months (range: 0-172), with 41 (46%) deaths & 13 (15%) leukemic transformations. Median OS was 24.8 months (range: 0-172). 43 (53%) patients had an abnormal karyotype, with common abnormalities being trisomy 8 (12%), complex karyotype (9%) & del (20q) (6%). Given the fewer types of abnormalities identified, the IPSS cytogenetic stratification was more effective than IPSS-R, with risk categorization including; 45 good (55%), 20 intermediate (25%) & 16 high risk (20%) respectively (8 unavailable). On univariate analysis, increased age (p = 0.05), decreased hemoglobin (p = 0.02), higher ANC (p = 0.03), circulating immature myeloid cells (p = 0.02), higher LDH (p = 0.009), absence of bone marrow ring sideroblasts (p = 0.001) & higher risk (intermediate & high) IPSS cytogenetic categories (p = 0.01) adversely impacted OS. In a multivariate model that included the aforementioned variables, higher risk IPSS cytogenetics retained a negative prognostic impact (p = 0.04). 28 patients received a median of 6 cycles (range: 1-21) of hypomethylating agent therapy (HMA), with an overall response rate of 18% (CR-3, PR-2). All responders had an abnormal karyotype (p = 0.01). However, HMA did not affect either OS or LFS. Conclusions: Intermediate & high risk IPSS cytogenetic categories independently & adversely impact survival in WHO defined MDS/MPN-U patients. HMA use did not impact OS; however, patients with abnormal karyotypes were more likely to respond.

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