scholarly journals Secondary Acute Myeloid Leukemia in a One-Year-Old Girl Diagnosed with JAK2-V617F Mutation Positive Myeloproliferative Neoplasm

2014 ◽  
Vol 2014 ◽  
pp. 1-4
Author(s):  
Gary M. Woods ◽  
Rajinder P. S. Bajwa ◽  
Samir B. Kahwash ◽  
Terri Guinipero
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Myeloproliferative Neoplasms ◽  
Pediatric Population ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Secondary Acute Myeloid Leukemia ◽  
One Year ◽  
Acute Myeloid

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by hyperproliferation of hematologic cell lines and have been associated with tyrosine kinase JAK2-V617F mutations. Secondary acute myeloid leukemia (sAML) is a known complication of JAK2-V617F+ MPNs and bears a poor prognosis. Although the evolution of a JAK2-V617F+ MPN to a mixed-lineage leukemia has been reported in the pediatric population, no evolutions into sAML have been described. We present a case of a one-year-old girl diagnosed with JAK2-V617F+ MPN with evolution into sAML. Despite initial morphologic remission, she eventually relapsed and succumbed to her disease.

scholarly journals Protracted Clonal Trajectory of a JAK2 V617F-Positive Myeloproliferative Neoplasm Developing during Long-Term Remission from Acute Myeloid Leukemia

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Stephen E. Langabeer ◽  
Karl Haslam ◽  
Maria Anne Smyth ◽  
John Quinn ◽  
Philip T. Murphy
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Time Frame ◽  
Divergent Evolution ◽  
Common Precursor ◽  
Previously Treated ◽  
Acute Myeloid

Although transformation of the myeloproliferative neoplasms (MPNs) to acute myeloid leukemia (AML) is well documented, development of an MPN in patients previously treated for, and in remission from, AML is exceedingly rare. A case is described in which a patient was successfully treated for AML and in whom a JAK2 V617F-positive MPN was diagnosed after seven years in remission. Retrospective evaluation of the JAK2 V617F detected a low allele burden at AML diagnosis and following one course of induction chemotherapy. This putative chemoresistant clone subsequently expanded over the intervening seven years, resulting in a hematologically overt MPN. As AML relapse has not occurred, the MPN may have arose in a separate initiating cell from that of the AML. Alternatively, both malignancies possibly evolved from a common precursor defined by a predisposition mutation with divergent evolution into MPN through acquisition of the JAK2 V617F and AML through acquisition of different mutations. This case emphasizes the protracted time frame from acquisition of a disease-driving mutation to overt MPN and further underscores the clonal complexity in MPN evolution.

scholarly journals Number of Mutations and Type of Prior Myeloproliferative Neoplasm Are Prognostic Factors in Acute Myeloid Leukemia Post Myeloproliferative Neoplasms

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2806-2806 ◽  
Author(s):  
Edmond Chiche ◽  
Sarah Bonnet ◽  
Sarah Bertoli ◽  
Andrew T Kuykendall ◽  
Lauris Gastaud ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Induction Treatment ◽  
Calr Mutations ◽  
Acute Myeloid

Abstract BACKGROUND Post myeloproliferative neoplasms (MPN) acute myeloid leukemia (AML) occurs respectively in 1.5%, 7.0% and 11% of patients with essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). This subgroup of AML has very poor prognosis and are often excluded from clinical trials. Therefore, only few cohorts including molecular data are available. MATERIAL AND METHODS We retrospectively collected data from 111 patients treated in four centers in France for post MPN-AML. Clinical, molecular and treatment information was available for all patients at AML and MPN stages. DNA was extracted from samples at diagnosis of MPN chronic phase, at diagnosis of AML phase and after induction treatment. JAK2-V617F mutations were identified by qPCR (Ipsogen® MutaQuant kit, Qiagen, Germany), MPL-W515L/K mutations were identified by PCR (Ipsogen® MutaScreen kit, Qiagen, Germany) and CALR mutations were identified by conventional sequencing (Applied Biosystems, 3500Genetic Analyzer). NGS on 36 genes using Ampliseq librairy and Ion Proton sequencing (Thermofisher, Waltham, MA, USA) were performed in 96/111 patients. Overall response rate (ORR) was defined by complete remission (CR), CR with incomplete hematologic recovery (CRi), partial remission (PR) and stable disease (SD). Overall survival (OS) was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analyses were performed using SPSS v.22 software (IBM SPSS Statistics). RESULTS 111 patients treated for post MPN-AML were retrospectively included in this study. Sex ratio M/F was 54%/46%. Median age at AML diagnosis was 66 years (28-89, range). Cytogenetic categories were favorable, intermediate and adverse in 2 (2%), 51 (46%) and 47 (42%) patients, respectively. 25/111 (23%) patients had a monosomal karyotype (MK). Median number of additional mutations excluding from JAK2/MPL/CALR mutations was 2 (0-6, range). The most frequent additional mutations were TP53 (23%), ASXL1 (17%), TET2 (13%), SRSF2 (10%), DNMT3A (8%), SF3B1 (8%) and RUNX1 (8%). Only 2 patients were mutated for NPM1 and 2 and 4 patients were FLT3-ITD and FLT3-TKD, respectively. Prior MPN were PV, ET and PMF in 20%, 34% and 46% of patients, respectively. First line treatment was intensive chemotherapy (IC) for 61 (55%) patients, hypomethylating agents (HMA) for 10 (9%) or other treatments including best supportive care, cytoreduction for the other ones. 24/111 (22%) underwent to ASCT. ORR was 54% (with 30/71 (42%) in CR/CRi) in patients treated by IC or HMA. We did not identify factors predicting a higher rate of CR/CRi. OS was 12 months [6-18] and was not influenced by transplant, cytogenetic categories or by the type and allele frequencies of JAK2/CALR/MPL mutations. OS was significantly longer in the group treated with HMA as compared to IC (10 versus 46 months, respectively, p=0.006); in patients with prior PV as compared to ET or MF (26 months [0-57] versus 10 months [7-13] versus 10 months [4-16] respectively, p=0.07) and in patients with presence of additional mutations other than JAK2/CALR/MPL (5 months [0-12] versus 46 months [32-60] in 38 patients without mutation versus 58 patients with presence of at least one mutation, respectively, p=0.04). By multivariate analysis, only presence of additional mutations was predictive for OS with a hazard ratio (HR) = 0.42 [0.18-0.97] (p=0.04). Finally, we followed the VAFs of JAK2 in seven patients before and after IC. We observed in 2 patients an increase of JAK2 clone correlated with CR whereas no variation of VAFs was associated with absence of CR. CONCLUSIONS In conclusion, we confirmed the poor prognosis of post MPN AML. Classical AML prognostic factors were not validated in our cohort. We identified the presence of mutations other than JAK2/MPL/CALR as the main prognostic factor whereas post-PV AML appeared to do better than post-ET and post-PMF AML. The very poor result of IC with or without ASCT highlights the need to develop specific clinical trials in this subgroup of AML. Disclosures Kuykendall: Celgene: Honoraria; Janssen: Consultancy. Sallman:Celgene: Research Funding, Speakers Bureau. Cluzeau:CELGENE: Consultancy; MENARINI: Consultancy; JAZZ PHARMA: Consultancy.

Successful use of high-dose cytarabine in a patient with acute myeloid leukemia and severe hepatic dysfunction

2016 ◽  
Vol 22 (6) ◽  
pp. 811-815 ◽  
Author(s):  
Jacob A Barker ◽  
Bernard L Marini ◽  
Dale Bixby ◽  
Anthony J Perissinotti
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Hepatic Dysfunction ◽  
Hematologic Malignancy ◽  
Survival Rates ◽  
Myeloproliferative Neoplasm ◽  
High Dose ◽  
Secondary Acute Myeloid Leukemia ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Acute myeloid leukemia is a hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and other tissues. Prognosis is poor with 5-year survival rates ranging from 5–65% depending on demographic and clinical features. Outcomes are worse for patients that have an antecedent myeloproliferative neoplasm that evolves to acute myeloid leukemia, with a survival rate of <10%. Treatment for acute myeloid leukemia has remained cytarabine and an anthracycline given in the standard 3 + 7 regimen. However, for patients with liver dysfunction this regimen, among many others, cannot be given safely. There is currently a lack of data regarding the use of cytarabine in patients with severe hepatic dysfunction. In this case report, we present a patient with secondary acute myeloid leukemia who successfully received a modified regimen of high-dose cytarabine while in severe hepatic dysfunction (bilirubin >15 mg/dL).

Secondary Acute Myeloid Leukemia Following Myeloproliferative Neoplasms–A Unicentric Study

2019 ◽  
Vol 19 ◽  
pp. S227
Author(s):  
Andreea Trifu ◽  
Cristina Constantin ◽  
Mihaela Dragomir ◽  
Silvia Aposteanu ◽  
Camelia Dobrea ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid

scholarly journals Development of a myelodysplastic/myeloproliferative neoplasm-unclassifiable in a patient with acute myeloid leukemia: a case report and literature review

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110184
Author(s):  
Meifang Zhao ◽  
Jingnan Sun ◽  
Shanshan Liu ◽  
Hongqiong Fan ◽  
Yu Fu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Hematologic Malignancies ◽  
Prior History ◽  
History Of ◽  
Factor Therapy ◽  
Growth Factor Therapy ◽  
Acute Myeloid

Myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a heterogeneous group of hematologic malignancies characterized by dysplastic and myeloproliferative overlapping features in the bone marrow and blood. The occurrence of the disease is related to age, prior history of MPN or MDS, and recent cytotoxic or growth factor therapy, but it rarely develops after acute myeloid leukemia (AML). We report a rare case of a patient diagnosed with AML with t(8; 21)(q22; q22) who received systematic chemotherapy. After 4 years of follow-up, MDS/MPN-unclassifiable occurred without signs of primary AML recurrence.

Mass Cytometry Analysis Of Myelofibrosis and Secondary Acute Myeloid Leukemia Reveals Constitutive and Cytokine Induced Signaling Abnormalities With Differential Sensitivities To Ruxolitinib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1610-1610
Author(s):  
Daniel A.C. Fisher ◽  
Gregory K. Behbehani ◽  
Garry P. Nolan ◽  
Sean C. Bendall ◽  
Stephen T. Oh
Keyword(s):  
Acute Myeloid Leukemia ◽  
Single Cell ◽  
Myeloid Leukemia ◽  
Ex Vivo ◽  
Jak2 V617f ◽  
Signaling Molecules ◽  
Mass Cytometry ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid

Abstract The classic myeloproliferative neoplasms (MPNs), including primary and secondary myelofibrosis (MF), are frequently associated with the JAK2 V617F mutation or other genetic alterations in members of the JAK-STAT axis. These mutations induce hyperactivated JAK-STAT signaling in cell lines and mouse models. Other mutations have been found recurrently in human MPNs, however, including mutations associated with transformation of chronic MPNs to secondary acute myeloid leukemia (sAML). The aggregate effects of these mutations on in vivo myeloproliferative signaling and disease phenotypes are not yet well understood. While targeted inhibitors of JAK2 have shown activity in MPNs, evidence of a selective effect on the underlying malignant clone has been lacking. These findings suggest that dysregulation of other signaling molecules may be important in MPN pathogenesis, and that therapeutic targeting of these molecules could be beneficial. Therefore, a more complete assessment of JAK-STAT and related signaling pathways in MPNs is needed. Mass cytometry is a novel technology that merges flow cytometry with mass spectrometry and enables the simultaneous measurement of 30+ parameters at the single cell level. We utilized this approach to examine bone marrow or peripheral blood samples from four MF patients and five sAML patients, as well as three normal controls. Cells were exposed to five different perturbation conditions ex vivo, including the cytokines thrombopoietin (TPO) and G-CSF, and/or the JAK1/2 inhibitor ruxolitinib. Cells were stained with a panel of 18 surface markers and 16 intracellular signaling effectors and analyzed on a CyTOF mass cytometer. Single cell data was analyzed using traditional gating strategies, as well as with SPADE (spanning-tree analysis of density-normalized events), which distills multidimensional data down to interconnected cell subsets based on shared surface marker expression. These methods grouped cells into distinct cell populations including hematopoietic stem/progenitors (HSPCs) and myeloid and lymphoid lineage subsets. Heat maps were constructed to depict basal and induced activation of each intracellular marker. MF and sAML patient samples exhibited abnormal cytokine-induced signaling that varied in a patient-specific manner. HSPC responses to TPO ranged from hyposensitive to hypersensitive compared with normal. Markedly abnormal basal (unstimulated) signaling in the HSPC compartment was observed in all MF and sAML patients. Each sample exhibited increased total IkBα and/or pCREB, typically accompanied by elevated phosphorylation of one or more additional signaling molecules. Both basal elevation and cytokine hypersensitivity were frequently observed within a MAP kinase signaling axis represented by pERK and downstream targets pCREB and pS6. Conversely, repressed basal STAT1 phosphorylation was observed in all patients. These abnormalities were not exclusive to sAML versus MF, nor specific to patients with or without the JAK2 V617F mutation. Widespread dysregulation of total IkBα, pERK-pCREB-pS6, and pSTAT1 suggest that these signaling effectors may be characteristic of a general myeloproliferative signaling phenotype. Ex vivo ruxolitinib effectively inhibited the majority of observed hypersensitive cytokine-stimulated signaling effects. In contrast, most basal signaling elevations were insensitive to ruxolitinib. The signaling molecules most frequently insensitive to ruxolitinib were those most frequently basally elevated in MF and sAML HSPC, namely pCREB and total IkBα. In contrast, phosphorylation of the JAK2 substrates STAT3 and STAT5 was almost always sensitive to ruxolitinib. These results suggest that targeting of myeloproliferative signaling pathways either downstream or independent of JAK2 activity may be valuable for improved treatment of MF and sAML patients. Ongoing experiments are focused on determining whether constitutive ruxolitinib-insensitive signaling abnormalities can be identified in patients treated with ruxolitinib in vivo, which may underlie the incomplete responses observed clinically. Taken together, these approaches will provide a deeper understanding of altered signaling networks in the context of targeted therapies in MPNs. Disclosures: Oh: Incyte: Consultancy, Research Funding, Speakers Bureau.

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