scholarly journals Integration of Molecular Information in Risk Assessment of Patients with Myeloproliferative Neoplasms

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1962
Author(s):  
Giuseppe G. Loscocco ◽  
Giacomo Coltro ◽  
Paola Guglielmelli ◽  
Alessandro M. Vannucchi
Keyword(s):  
Rna Splicing ◽  
Residual Disease ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Chromatin Modification ◽  
Response To Treatment ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Myeloid Neoplasm ◽  
Molecular Landscape

Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are clonal disorders of a hematopoietic stem cell, characterized by an abnormal proliferation of largely mature cells driven by mutations in JAK2, CALR, and MPL. All these mutations lead to a constitutive activation of the JAK-STAT signaling, which represents a target for therapy. Beyond driver ones, most patients, especially with myelofibrosis, harbor mutations in an array of “myeloid neoplasm-associated” genes that encode for proteins involved in chromatin modification and DNA methylation, RNA splicing, transcription regulation, and oncogenes. These additional mutations often arise in the context of clonal hematopoiesis of indeterminate potential (CHIP). The extensive characterization of the pathologic genome associated with MPN highlighted selected driver and non-driver mutations for their clinical informativeness. First, driver mutations are enlisted in the WHO classification as major diagnostic criteria and may be used for monitoring of residual disease after transplantation and response to treatment. Second, mutation profile can be used, eventually in combination with cytogenetic, histopathologic, hematologic, and clinical variables, to risk stratify patients regarding thrombosis, overall survival, and rate of transformation to secondary leukemia. This review outlines the molecular landscape of MPN and critically interprets current information for their potential impact on patient management.

scholarly journals Genetic Landscape of Myeloproliferative Neoplasms with an Emphasis on Molecular Diagnostic Laboratory Testing

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1158
Author(s):  
Arti Easwar ◽  
Alexa J. Siddon
Keyword(s):  
Laboratory Testing ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Chromatin Modification ◽  
Molecular Diagnostic ◽  
Diagnostic Laboratory ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms ◽  
Molecular Alterations ◽  
Molecular Landscape

Chronic myeloproliferative neoplasms (MPNs) are hematopoietic stem cell neoplasms with driver events including the BCR-ABL1 translocation leading to a diagnosis of chronic myeloid leukemia (CML), or somatic mutations in JAK2, CALR, or MPL resulting in Philadelphia-chromosome-negative MPNs with constitutive activation of the JAK-STAT signaling pathway. In the Philadelphia-chromosome-negative MPNs, modern sequencing panels have identified a vast molecular landscape including additional mutations in genes involved in splicing, signal transduction, DNA methylation, and chromatin modification such as ASXL1, SF3B1, SRSF2, and U2AF1. These additional mutations often influence prognosis in MPNs and therefore are increasingly important for risk stratification. This review focuses on the molecular alterations within the WHO classification of MPNs and laboratory testing used for diagnosis.

Current Concepts of Pathogenesis and Treatment of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

2021 ◽  
Vol 41 (03) ◽  
pp. 197-205
Author(s):  
Franziska C. Zeeh ◽  
Sara C. Meyer
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Mutational Analysis ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Standard Of Care ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Therapeutic Decisions ◽  
Jak2 Inhibitors

AbstractPhiladelphia chromosome-negative myeloproliferative neoplasms are hematopoietic stem cell disorders characterized by dysregulated proliferation of mature myeloid blood cells. They can present as polycythemia vera, essential thrombocythemia, or myelofibrosis and are characterized by constitutive activation of JAK2 signaling. They share a propensity for thrombo-hemorrhagic complications and the risk of progression to acute myeloid leukemia. Attention has also been drawn to JAK2 mutant clonal hematopoiesis of indeterminate potential as a possible precursor state of MPN. Insight into the pathogenesis as well as options for the treatment of MPN has increased in the last years thanks to modern sequencing technologies and functional studies. Mutational analysis provides information on the oncogenic driver mutations in JAK2, CALR, or MPL in the majority of MPN patients. In addition, molecular markers enable more detailed prognostication and provide guidance for therapeutic decisions. While JAK2 inhibitors represent a standard of care for MF and resistant/refractory PV, allogeneic hematopoietic stem cell transplantation remains the only therapy with a curative potential in MPN so far but is reserved to a subset of patients. Thus, novel concepts for therapy are an important need, particularly in MF. Novel JAK2 inhibitors, combination therapy approaches with ruxolitinib, as well as therapeutic approaches addressing new molecular targets are in development. Current standards and recent advantages are discussed in this review.

Patients with myeloproliferative neoplasms (MPN) who later develop ph+ chronic myelogenous leukemia (CML): A case series.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18563-e18563
Author(s):  
Shahina Patel ◽  
Seo-Hyun Kim ◽  
Jamile M. Shammo ◽  
Jerald P. Radich ◽  
Howard R. Terebelo
Keyword(s):  
Lead Time ◽  
Chart Review ◽  
Myeloproliferative Neoplasms ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Case Series ◽  
Myelogenous Leukemia ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
True Incidence

e18563 Background: Myeloproliferative Neoplasms are divided by the presence or absence of the Philadelphia Chromosome. Ph- MPN, typically possess driver mutations of JAK-2, MPL and CALR. CALR is involved with apoptosis and cell proliferation . MPL leads to TPO receptor stimulation and mutations are reported as a known cause of AA. JAK-2 mutations render hematopoietic stem cells more sensitive to growth. Though the true incidence is unknown, there are infrequent reports of pts with ET who later develop CML. CALR, MPL and JAK-2 mutations may have some further role in determining whether these are two separate events or clonally derived. We report three pts with MPN who later developed CML. Methods: Chart Review Results: Pt 1 had ET, diagnosed 21 yrs earlier treated with hydroxyurea. He then developed a rising WBC and platelets which necessitated a marrow which detected Ph+ CML. He was CALR positive. NGS was negative for nondriver mutations. Platelets initially declined from 3 million to 975K with TKI and he achieved a MMR. However, the inability to control his thrombocytosis required the addition of ruxolitinib. Pt 2 was diagnosed with ET and was treated with P32. Nine yrs later CML was diagnosed and TKI administration achieved a MMR. Subsequently, a profound anemia evaluation diagnosed PNH requiring eculizumab without benefit and repeat marrow with NGS revealed a MPLmutation and post-ET myelofibrosis. Pt 3 presented with a JAK-2 positive mutation and Polycythemia Vera. After four yrs of hydroxyurea extreme leukocytosis led to a marrow revealing a diagnosis of Ph+ CML. Dasatinib achieved a prompt MMR. NGS revealed KIT D618 V , coinciding with a diagnosis of systemic mastoytosis (SM). Conclusions: The rare observation of patients with both ET and CML have been reported by others with some recent implications of CALR as a common clone with double-mutant properties of CML. Our patients had a lead time of 21, 9, and 4 yrs, all having different mutations. Pts with MPN who develop unexplained leuko or thrombocytosis should be evaluated for CML.We plan to retrieve archival tissue to perform serial genetic analyses. Further work is required to determine whether these events are stochastic or represents clonal evolution.

scholarly journals Genomics of MPN progression

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 440-449
Author(s):  
Anand A. Patel ◽  
Olatoyosi Odenike
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Clonal Evolution ◽  
Philadelphia Chromosome ◽  
Prognostic Information ◽  
Leukemic Transformation ◽  
Hematopoietic Stem ◽  
Heterogenous Group ◽  
Calr Mutations ◽  
Molecular Landscape ◽  
Therapeutic Decision Making

Abstract The Philadelphia chromosome–negative (Ph−) myeloproliferative neoplasms (MPNs) are a heterogenous group of hematopoietic stem cell diseases characterized by activated JAK/STAT signaling and a variable propensity toward myelofibrotic and leukemic transformation. Acquisition of somatic mutations in addition to the canonical JAK2, MPL, and CALR mutations found in MPNs is an important catalyst in the clonal evolution and progression of these disorders. In recent years, our increasing understanding of the molecular landscape of Ph− MPNs has generated important prognostic information that informs our approach to risk stratification and therapeutic decision-making. This review will focus on the critical impact of genomics on our approach to management of advanced Ph− MPNs.

scholarly journals Cancer Immune Therapy for Philadelphia Chromosome-Negative Chronic Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1763 ◽  
Author(s):  
Morten Orebo Holmström ◽  
Hans Carl Hasselbalch ◽  
Mads Hald Andersen
Keyword(s):  
Cancer Immunotherapy ◽  
Myeloproliferative Neoplasms ◽  
Immune Therapy ◽  
Philadelphia Chromosome ◽  
Driver Mutations ◽  
Interferon Α ◽  
Therapeutic Vaccination ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms ◽  
Anti Cancer

Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN.

scholarly journals Synergic Crosstalk between Inflammation, Oxidative Stress, and Genomic Alterations in BCR–ABL-Negative Myeloproliferative Neoplasm

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1037
Author(s):  
Alessandro Allegra ◽  
Giovanni Pioggia ◽  
Alessandro Tonacci ◽  
Marco Casciaro ◽  
Caterina Musolino ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cell ◽  
Chronic Inflammation ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Tumor Stage ◽  
Driver Mutations ◽  
Hematopoietic Stem ◽  
Chronic Myeloproliferative Neoplasms ◽  
Inflammatory State

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) have recently been revealed to be related to chronic inflammation, oxidative stress, and the accumulation of reactive oxygen species. It has been proposed that MPNs represent a human inflammation model for tumor advancement, in which long-lasting inflammation serves as the driving element from early tumor stage (over polycythemia vera) to the later myelofibrotic cancer stage. It has been theorized that the starting event for acquired stem cell alteration may occur after a chronic inflammation stimulus with consequent myelopoietic drive, producing a genetic stem cell insult. When this occurs, the clone itself constantly produces inflammatory components in the bone marrow; these elements further cause clonal expansion. In BCR–ABL1-negative MPNs, the driver mutations include JAK 2, MPL, and CALR. Transcriptomic studies of hematopoietic stem cells from subjects with driver mutations have demonstrated the upregulation of inflammation-related genes capable of provoking the development of an inflammatory state. The possibility of acting on the inflammatory state as a therapeutic approach in MPNs appears promising, in which an intervention operating on the pathways that control the synthesis of cytokines and oxidative stress could be effective in reducing the possibility of leukemic progression and onset of complications.

scholarly journals Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2100
Author(s):  
Lasse Kjær
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Clinical Intervention ◽  
Driver Mutation ◽  
Response Monitoring ◽  
Driver Mutations ◽  
Clonal Hematopoiesis ◽  
Disease Biology ◽  
Background Population ◽  
The Impact

Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.

scholarly journals Genetics of MDS

Blood ◽  
2019 ◽  
Vol 133 (10) ◽  
pp. 1049-1059 ◽  
Author(s):  
Seishi Ogawa
Keyword(s):  
Rna Splicing ◽  
Myeloid Leukemia ◽  
Chromatin Modification ◽  
Driver Mutations ◽  
Subsequent Transformation ◽  
The Past ◽  
Sequencing Technologies ◽  
Age Related ◽  
Clonal Origin ◽  
Dna Methylations

Abstract Our knowledge about the genetics of myelodysplastic syndromes (MDS) and related myeloid disorders has been dramatically improved during the past decade, in which revolutionized sequencing technologies have played a major role. Through intensive efforts of sequencing of a large number of MDS genomes, a comprehensive registry of driver mutations recurrently found in a recognizable fraction of MDS patients has been revealed, and ongoing efforts are being made to clarify their impacts on clinical phenotype and prognosis, as well as their role in the pathogenesis of MDS. Among major mutational targets in MDS are the molecules involved in DNA methylations, chromatin modification, RNA splicing, transcription, signal transduction, cohesin regulation, and DNA repair. Showing substantial overlaps with driver mutations seen in acute myeloid leukemia (AML), as well as age-related clonal hematopoiesis in healthy individuals, these mutations are presumed to have a common clonal origin. Mutations are thought to be acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis, ultimately giving rise to MDS and subsequent transformation to AML in many patients. Significant correlations between mutations suggest the presence of functional interactions between mutations, which dictate disease progression. Mutations are frequently associated with specific disease phenotype, drug response, and clinical outcomes, and thus, it is essential to be familiar with MDS genetics for better management of patients. This review aims to provide a brief overview of the recent progresses in MDS genetics.

scholarly journals Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study

2017 ◽  
Vol 35 (16) ◽  
pp. 1795-1802 ◽  
Author(s):  
Giovanni Martinelli ◽  
Nicolas Boissel ◽  
Patrice Chevallier ◽  
Oliver Ottmann ◽  
Nicola Gökbuget ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Relapse Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Response ◽  
Minimal Residual

Purpose Few therapeutic options are available for patients with Philadelphia chromosome–positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) −based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ ALL. Patients and Methods This open-label phase II study enrolled adults with Ph+ ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). Results Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. Conclusion Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph– ALL.

Prevention Of Minimal Residual Disease In Ph+ ALL

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1265-1265
Author(s):  
Iris Appelmann ◽  
Elisa DeStanchina ◽  
Gregory Carbonetti ◽  
Chong Chen ◽  
Scott W. Lowe ◽  
...  
Keyword(s):  
B Cells ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Janus Kinase ◽  
Response To Treatment ◽  
Cytokine Signaling ◽  
Minimal Residual

Abstract Aggressive Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease can be induced by the introduction of cultured p185 (BCR-ABL)-expressing Arf-null pre/pro-B cells into healthy, unconditioned syngeneic mice. Only 20 polyclonal donor cells are sufficient to induce lethal ALL within 30 days of their IV administration, indicating that BCR-ABL expression and Arf inactivation are sufficient to guarantee leukemogenesis in healthy recipient animals. Leukemic mice enter transient remission in response to treatment with potent second generation tyrosine kinase inhibitors (TKI) such as dasatinib (SprycelTM). However, like human patients with Ph+ ALL, the continuously treated animals ultimately relapse with the emergence of leukemic clones containing clinically relevant BCR-ABL mutations, the nature of which depends upon the intensity of TKI treatment. Premature withdrawal of dasatinib when animals are in remission results in re-emergence of leukemia; surprisingly, leukemic B cells recovered from these animals lack BCR-ABL mutations and remain sensitive to dasatinib ex vivo. Hence, minimal residual disease depends upon salutary signaling within the hematopoietic microenvironment. In agreement, the response to TKI therapy can be significantly improved by abrogating cytokine signaling through a knockdown of the common gamma chain of the cytokine receptor. Administration of the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi™) mimics this response. Although ruxolitinib demonstrated no anti-leukemic activity of its own, the overall survival of leukemic mice inoculated with 200,000 p185+ Arf-/- pre/pro-B cells was significantly extended after administration of a targeted combination therapy of ruxolitinib and dasatinib in comparison with mice treated with dasatinib alone. Addition of dexamethasone further reduced the leukemic burden, prevented CNS relapse, and led to prolonged survival. This implicates prevention of minimal residual disease and relapse by a non-toxic combination of targeted treatments. These studies have provided a rationale for a Phase I/II clinical trial employing these agents, particularly in older patients who are ineligible for bone marrow transplantation or do not tolerate cytotoxic chemotherapy. Disclosures: Lowe: Blueprint Medicines: Consultancy; Constellation Pharmaceuticals: Consultancy; Mirimus Inc.: Consultancy.

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