scholarly journals Acquisition of JAK2 V617F to CALR ‐mutated clones accelerates disease progression and might enhance growth capacity

2021 ◽  
Author(s):  
Misa Nishimura ◽  
Keiki Nagaharu ◽  
Makoto Ikejiri ◽  
Yuka Sugimoto ◽  
Ryota Sasao ◽  
...  
Keyword(s):  
Disease Progression ◽  
Jak2 V617f ◽  
Growth Capacity

Outcomes of Patients with Myelodysplastic Syndromes/Myeloproliferative Neoplasms with Emphasis On MDS/MPN-Unclassified

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5025-5025
Author(s):  
Charikleia Kelaidi ◽  
Varnavas Constantinou ◽  
George Papaioannou ◽  
Niki Stavroyianni ◽  
Chrysanthi Vadikoliou ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Response Rate ◽  
Conflicts Of Interest ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasms ◽  
Univariate Analysis ◽  
Jak2 V617f ◽  
Female Ratio ◽  
Wbc Count

Abstract Abstract 5025 Background: Data on outcomes of patients (pts) with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), especially MDS/MPN-unclassified (MDS/MPN-U), are scarce. Patients/methods: We retrospectively studied pts followed in our center, with MDS/MPN according to WHO 2008 criteria. Because of overlap characteristics of MPN and MDS, pts with systemic mastocytosis associated with MDS (SM/MDS) were also included. Pts with previous MDS or MPN were excluded. Response and disease progression were defined according to IWG 2006 criteria. Results: Twenty-five pts with MDS/MPN were included. Median age was 70 y (range 19–79). Male/female ratio was 1.77/1. Diagnosis was CMML-1 N=7, CMML-2 N=7, JMML N=1, MDS/MPN-U N=8, systemic mastocytosis (SM)/MDS N=2, with one additional pt with CMML subsequently developing SM. At diagnosis, median WBC count was 18.8 G/L (range 3–120), ANC 15.5 G/L (0.6–70), monocytes 1.9 G/L (0.1–16), left shift 16% (0–28), Hb 11.2 g/dL (6–17), platelets 99 G/L (10–680), peripheral and bone marrow (BM) blasts 5% (0–17) and 7% (2–19), respectively (resp.). 25% of pts had platelets count ≥400 G/L. Splenomegaly, B-symptoms and BM fibrosis were present in 23%, 57% and 27% of pts, resp. Karyotype was fav, int and unfav in 55%, 36% and 9% of pts, with −7, +8, del(12)(p11), del(12)(q14;q21), +10, +21, and previously unreported t(9;12)(q13;q13) in 3, 6, and 1 pt each, resp., while +21 and i(17)(q10) appeared during disease progression other than AML transformation. IPSS was low/int-1 and int-2/high in 50% and 50% of pts, resp. JAK2 V617F and CKIT D816V mutations were detected in 2/6 pts and 2/2 SM/MDS pts, resp. 70% and 29% of pts were transfused at diagnosis with PRBC and platelets, resp. Treatment included erythropoiesis stimulating agents (ESAs), low dose chemotherapy, intensive chemotherapy (IC) and azacitidine (AZA) in 40%, 36%, 16% and 48% of pts resp. Response rate to ESAs, IC and AZA was 60%, 14% and 14% resp. Response rate to AZA in CMML-1 pts was 33%. Dasatinib yielded no response in 1 SM/MDS pt with CKIT D816V. 3-year cumulative incidence of AML and median overall survival (OS) in pts with CMML-1, CMML-2 and MDS/MPN-U were 20%, 40% and 0 (P=0.059) and 39, 8, and 20 mo (P=0.50), resp. The pt with JMML died from AML transformation 3 months after diagnosis. 2/3 pts with SM/MDS died from disease progression w/o AML at a median of 10 mo after diagnosis. Median survival after disease progression other than AML transformation was 35, 15 and 14 mo in pts with CMML-1, CMML-2 and MDS/MPN-U, resp. (P=0.88). Cause of death was disease progression other than AML, AML transformation and unrelated to disease in 50%, 50%, and 0 and 80%, 0 and 20% of cases in CMML and MDS/MPN-U, resp. (P=0.10). Percentage of circulating blasts ≥5% was the only independent factor affecting risk of AML transformation in the overall population (P=0.0004). Diagnosis other than CMML-1, WBC ≥30 G/L, % of circulating blasts ≥5% and IPSS high/int-2 were associated with worse survival in univariate analysis (P=0.06, 0.03, 0.04 and 0.08, resp.). No predictive factor of OS was found in multivariate analysis. Conclusion: MDS/MPN are heterogeneous disorders with respect to disease progression and AML transformation. MDS/MPN-U tended to differ from CMML-1 by shorter survival after disease progression other than AML, and from CMML-2 by lower risk of AML transformation. Mortality of pts with MDS/MPN-U was mainly attributed to disease progression without AML transformation. Alternatively to hypomethylating agents, therapeutic options in pts with MDS/MPN-U could include JAK2 inhibitors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of HMGA2 Collaborates with JAK2V617F to Progress Myeloproliferative Neoplasms

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 482-482
Author(s):  
Koki Ueda ◽  
Kazuhiko Ikeda ◽  
Kazuei Ogawa ◽  
Akiko Shichishima-Nakamura ◽  
Kotaro Shide ◽  
...  
Keyword(s):  
Disease Progression ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Extramedullary Hematopoiesis ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Epigenetic Modifiers ◽  
One Year

Abstract Myeloproliferative neoplasms (MPN) are characterized by chronic proliferation of myeloid cells, extramedullary hematopoiesis and occasional leukemic transformation. Mutations in JAK2, CALR and MPL have been established as drivers of myeloproliferative phenotype, but their roles in disease progression with clonal expansion remain unclear. In addition, studies have shown mutations in epigenetic modifiers including TET2, DNMT3A, ASXL1 and EZH2, and aberrant expressions of microRNAs in MPN, but downstream of these changes is also largely unknown. Recently, we showed high expression of HMGA2 mRNA partly correlated with reduced microRNA let-7 in granulocytes of patients with MPN, including 100% patients with primary myelofibrosis (MF) and 20% polycythemia vera and essential thrombocythemia (Harada-Shirado et al, Brit J Haematol, 2015). In mice, loss of epigenetic modifiers such as BMI1 and EZH2, along with the Arf/Ink4a knockout (Oguro et al, J Exp Med, 2012) or the JAK2 V617F (Sashida et al, ASH, 2013), leads to overexpression of HMGA2 with accelerating MPN. We have generated transgenic (Tg) mice of Hmga2 cDNA with truncated 3'UTR (ΔHmga2) lacking binding sites of let-7 thatrepresses expression of HMGA2 (Ikeda et al, Blood, 2011). Δ Hmga2 mice overexpress HMGA2 and develop MPN-like disease, and represent a clonal advantage in competitive repopulations with serial bone marrow (BM) transplants (BMT). Here, to clarify if HMGA2 affect JAK2 V617F+ hematopoiesis, we crossed Δ Hmga2+/- mice with JAK2 V617F+/- Tg mice (Shide et al, Leukemia, 2008). Δ Hmga2-/-JAK2 V617F-/- wild type (WT), Δ Hmga2+/-JAK2 V617F-/- (Δ Hmga2 -Tg), Δ Hmga2-/-JAK2 V617F+/- (JAK2 V617F-Tg) and Δ Hmga2+/-JAK2 V617F+/- (double-Tg) mice were born at expected Mendelian ratios and we could analyze 5 - 6 of each. At 3 months old, leukocytosis, thrombocytosis, anemia and splenomegaly were most severe in double-Tg compared with JAK2 V617F-Tg or Δ Hmga2 -Tg mice. Relative to WT, peripheral leukocyte and platelet counts were nearly 16- and 4-fold higher in double-Tg, while 3- and 2-fold higher in JAK2 V617F-Tg mice, respectively. Mean spleen weights were 0.067, 0.10, 0.83 and 2.8 g in WT, Δ Hmga2 -Tg, JAK2 V617F-Tg and double-Tg mice, while BM cell counts were 2.4, 2.8, 0.4 and 1.2 x 107/femur, respectively. However, JAK2 V617F-Tg and double-Tg equally showed MF whereas no MF was detected in WT and DHmga2-Tg, suggesting that HMGA2 partly recovers cellularity in fibrotic BM. In the absence and presence of JAK2 V617F, HMGA2 augments lineage- Sca1+ Kit+ cells (WT: Δ Hmga2-Tg: JAK2 V617F-Tg: double-Tg= 0.17%: 0.19%: 0.17%: 0.27% in BM cells), endogenous erythroid colonies (1: 11: 13: 21 CFU-E/104 BM cells) and CD71+ Ter119+ erythroblasts (23%: 29%: 5.7%: 10% in BM and 2.0%: 4.4%: 7.9%: 16% in spleen cells), indicating HMGA2 contributes to expansion of hematopoietic stem/progenitor cells (HSPC) and erythroid commitment in JAK2 V617F+ hematopoiesis. Most Δ Hmga2-Tg and JAK2 V617F-Tg survived for over one year, but all double-Tg mice died within 4 months after birth due to severe splenomegaly and MF with no acute leukemia. To study the effect of HMGA2 on JAK2 V617F+ HSPC activity, we performed BMT with 0.25 x 106 Ly5.2+Δ Hmga2-Tg, JAK2 V617F-Tg or double-Tg cells with 0.75 x 106 Ly5.1+ competitor WT cells to lethally irradiated Ly5.1+ WT mice. Proportions of Ly5.2+ cells were higher in recipients of Δ Hmga2 -Tg than double-Tg cells, while JAK2 V617F-Tg cells were almost rejected at 8 weeks after BMT. To confirm role of HMGA2 without let-7 repression in JAK2 V617F+ hematopoiesis, we performed another BMT with 1 x 104 KIT+ cells of JAK2 V617F-Tg mice transduced with retroviral vector of Hmga2 with each let-7 -site-mutated full-length 3'UTR (Hmga2-m7) to sublethally irradiated WT mice. Recipients of JAK2 V617F-Tg cells with Hmga2-m7 developed MPN-like disease, whereas donor cells were rejected in recipients of JAK2 V617F cells with empty vector. In conclusion, HMGA2 may play a crucial role in hematopoiesis harboring JAK2 V617F by expanding HSPC, leading to disease progression. Disclosures No relevant conflicts of interest to declare.

scholarly journals JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders

Cancer ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 2206-2211 ◽  
Author(s):  
Elisa Rumi ◽  
Francesco Passamonti ◽  
Daniela Pietra ◽  
Matteo G. Della Porta ◽  
Luca Arcaini ◽  
...  
Keyword(s):  
Disease Progression ◽  
Somatic Mutation ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Genetic Event

scholarly journals Hippo Kinase Inactivation Contributes to Del(20q) Malignancies and Cooperates with JAK2-V617F to Promote Myelofibrosis in Mice

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 99-99
Author(s):  
Samuel A Stoner ◽  
Ming Yan ◽  
Katherine Liu ◽  
Takahiro Shima ◽  
Huan-You Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Hematologic Malignancy ◽  
Bone Marrow Failure ◽  
Myeloproliferative Neoplasm ◽  
Jak2 V617f ◽  
Similar Degree ◽  
Healthy Controls ◽  
Acute Leukemias ◽  
Hematopoietic Stem

Abstract Recurring chromosome abnormalities are frequent events in cancer and are especially prevalent in hematologic neoplasms. Somatic heterozygous deletions on chromosome 20q are detected in a variety of hematopoietic malignancies including myelodysplastic syndrome (MDS), classical myeloproliferative neoplasm (MPN), MDS/MPN overlap disorders such as chronic myelomonocytic leukemia (CMML), and acute leukemias. Del(20q) is especially prevalent in MPN patients (~10-15%), where it is the most commonly detected cytogenetic abnormality associated with primary myelofibrosis (PMF) and post-polycythemia vera myelofibrosis (MF). This suggests that heterozygous loss of genes in the del(20q) common deleted region (CDR) may contribute to adverse MPN progression. Despite these observations, relatively few genes located within the CDR have been unambiguously implicated, highlighting a significant need for further investigation. To identify genes that may play an important role in the biology of del(20q)-associated malignancies we utilized a published gene expression dataset of bone-marrow derived CD34+ cells from MDS patients and healthy controls (Gerstung et al, 2015). Comparison of the patients harboring del(20q) to healthy controls revealed STK4 (encoding Hippo kinase MST1) to be the most significantly downregulated gene (mean: 3.5-fold) among those located within the chromosome 20q CDR. We therefore set out to assess the role of Hippo kinase inactivation in hematologic malignancy using conditional gene inactivation in mice. We found that complete inactivation of both Hippo kinases (Stk4 and Stk3) within the hematopoietic system using Vav1-Cre (Stk4-/-Stk3-/-) resulted in a lethal bone marrow failure (median survival: 7 weeks) associated with myelodysplastic features and frequent extramedullary hematopoiesis in the spleen. A single copy of Stk4 rescued the lethality due to bone marrow failure, however sub-haploinsufficient mice displayed thrombocytopenia with a trend towards mild anemia; phenotypes that closely resemble those observed in MDS patients with isolated del(20q). Both a reduced number of mature megakaryocytes and the presence of dysplastic megakaryocytes were apparent in bone marrow sections. Inducible Hippo kinase inactivation in adult mice using the Mx1-Cre system similarly recapitulated several phenotypic features of both MDS and MPN. In competitive bone marrow transplant assays we found that Stk4-/-Stk3-/- hematopoietic stem cells (HSC) completely lacked engraftment potential and failed to reconstitute normal hematopoiesis, revealing a potential role for Hippo kinase function in HSC homing and retention in the bone marrow. Heterozygous HSCs maintained relatively normal steady-state hematopoiesis in peripheral blood and bone marrow for up to 48 weeks in primary and secondary transplantations, although upon aging these mice were prone to development of thrombocytopenia with increased mean platelet volume. Given the high frequency of del(20q) in MPN, especially PMF, we asked whether heterozygous Hippo kinase inactivation may cooperate with the common driver mutation JAK2-V617F to accelerate disease progression. Using an HSC-enriched retroviral transduction/transplantation model in C57BL/6 recipient mice, we monitored MPN progression for 36 weeks in heterozygous Stk4+/-Stk3+/-, or control (Vav1-Cre-), cells with or without expression of JAK2-V617F. While both JAK2-V617F groups initially displayed a similar degree of polycythemia relative to controls, we found heterozygous Hippo kinase inactivation to promote accelerated disease progression towards lethal bone marrow fibrosis during the course of observation. Recipients in this group showed significantly reduced overall survival, which was associated with higher grade fibrosis in bone marrow, elevated peripheral granulocyte counts, enhanced splenomegaly, and increased frequencies of hematopoietic stem and progenitor populations in the spleen. Together, these findings implicate aberrant Hippo kinase loss-of-function in the pathogenesis of del(20q)-associated hematologic malignancies, and shed new light on the molecular events that contribute to adverse MPN progression. Disclosures Bejar: Genoptix: Consultancy; Modus Outcomes: Consultancy; Celgene: Consultancy, Honoraria; Takeda: Research Funding; Astex/Otsuka: Consultancy, Honoraria; AbbVie/Genentech: Consultancy, Honoraria; Foundation Medicine: Consultancy. Guan:Vivace: Equity Ownership.

scholarly journals JAK2 V617F as a Marker for Long-Term Disease Progression and Mortality in Polycythemia Vera and its Role in Economic Modeling

2020 ◽  
Vol 7 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Jonas Hjelmgren ◽  
Kristoffer Nilsson ◽  
Gunnar Birgegård
Keyword(s):  
Polycythemia Vera ◽  
Disease Progression ◽  
Observational Studies ◽  
Jak2 V617f ◽  
Economic Modeling ◽  
Janus Kinase ◽  
Economic Evaluations ◽  
Base Case ◽  
Real World Data

Background: In order to facilitate sound economic evaluations of novel treatments, health-economic models of polycythemia vera (PV) must combine effects on surrogate endpoints in trials with disease progression (DP) and mortality in long-term cohort data. Objective: We validate an economic model for PV that uses Janus Kinase 2 (JAK2) burden as a surrogate endpoint to predict DP (thrombosis, myelofibrosis, and acute leukemia) and overall survival (OS) based on progression-specific mortality. Methods: Long-term observational studies that include information about baseline JAK2 burden were identified via PubMed searches and used to validate the model. Kaplan-Meier (KM) OS curves were extracted using a digitizing software. External validity of the model was analyzed by visually comparing OS curves of the model with the KM curves of the included studies, as well as calculating differences in mean OS estimated as area under the curve (AUC). Results: The model’s predictions of cumulative DP were somewhat lower than the published studies. Over 20 years’ time, our base case model predicted a mean OS for a PV patient (15.0–16.5 years), which was in line with the published studies (15.8–17.5 years). Modeled mean OS was almost two years longer (1.6–1.9 years) for patients with JAK2 <50% than patients with JAK2 ≥50%. Only three long-term observational studies that satisfied the predefined criteria were found and could be used in the validation, but these studies did not capture JAK2 evolution over time. Improved model predictions of DP and mortality based on the longitudinal evolution of JAK2 could be derived from real-world data sources. Such data are currently scarce and future observational studies should be designed to capture the long-term impact of JAK2 on DP and mortality in PV.

JAK2 V617F Mutational Status in Myelofibrosis at and before Disease Progression Including Leukemic Transformation: A Longitudinal Study in 68 Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2575-2575
Author(s):  
Ruben A. Mesa ◽  
Heather Powell ◽  
Terra Lasho ◽  
Ayalew Tefferi
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Peripheral Blood ◽  
Jak2 V617f ◽  
Wild Type ◽  
Leukemic Transformation ◽  
Myeloid Metaplasia ◽  
Patient Cohort ◽  
Mutational Status ◽  
Over Time

Abstract Background: An acquired point mutations of JAK2 (V617F) was recently described in a substantial proportion of patients with myeloproliferative disorders (MPD), including myelofibrosis with myeloid metaplasia (MMM). The current study examines i) JAK2 V617F mutational status at time of leukemic transformation (LT) of MMM and its clinical correlates, ii) the possibility of changes over time in mutational status in MMM patients that have either undergone leukemic transformation (LT) or experienced disease progression. Methods: Mutation analysis for JAK2 V617F was performed in DNA derived from either peripheral blood mononuclear cells (PBMC) (i.e. fresh specimens) using genomic DNA amplified by PCR, or extracted from cytogenetic pellets in archived specimens. Fluorescent dye chemistry sequencing was performed using the same primers used for amplification. Results: The study population consisted of 68 patients including 33 patients with disease transformation into AML. i. MMM patient cohort with LT (n=33). The JAK2 V617F mutant allele was detected in 21 of the 33 patients (64%; homozygous in 6%) at the time of LT. As expected, PPMM was over-represented in the group with the mutation but the presence of the mutation affected neither the clinical presentation at time of LT or overall outcome. Furthermore, in 9 patients (7 heterozygotes and 2 with wild-type allele), archived bone marrow that was collected at a median of 23 months (range, 3–105) before LT was available and disclosed no change in mutational status. ii. MMM patient cohort with disease progression without LT (n=35; 19 AMM, 9 PPMM, 7 PTMM): Each patient in this group had at least two bone marrow or peripheral blood samples that were collected at two different time points separated by a median of 18.2 months (range (3–82). Of the total 35 patients in this group, 32 (91%) showed no change in JAK2 V617F mutational status over time including 3 patients in whom the first sample was collected before they transformed into MMM from antecedent PV or ET. In the remaining 3 patients, a switch from wild-type to heterozygous state (1 patient), and heterozygous to homozygous (2 patients), was documented after 78, 43, and 83 months, respectively. Conclusions: In most instances, JAK2 V617F mutational status in MMM remains unchanged over time including during leukemic transformation. Furthermore, the presence of the mutation in MMM-related LT does not appear to affect clinical outcome. These observations undermine the role of JAK2 V617F in either disease progression or LT in MMM.

Frequency of the JAK2 Mutation and Its Usefulness as a Marker for Treatment Response and Disease Progression in Korean Patients with Chronic Myeloproliferative Disorders.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4876-4876 ◽  
Author(s):  
Myung-Geun Shin ◽  
Hyeoung Joon Kim ◽  
Hye-Ran Kim ◽  
Sun-Young Lee ◽  
Il-Kwon Lee ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Response ◽  
Real Time ◽  
Real Time Pcr ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Quantitative Real Time Pcr ◽  
Jak2 Mutation ◽  
Korean Patients ◽  
V617f Mutation

Abstract Background: The recent discovery of a single point mutation in the JAK2 gene (V617F) is a major advance in our understanding of the pathogenesis of BCR/ABL-negative chronic myeloproliferative disorders (CMPD). The frequency of the JAK2 V617F mutation in CMPD differs according to methods and research groups. We investigated the frequency of JAK2 mutations in Korean CMPD patients and demonstrated their usefulness as a new molecular marker for treatment response and disease progression in BCR/ABL-negative CMPD using quantitative real time PCR and pyrosequencing. Methods: Seventy-eight patients with BCR/ABL-negative CMPD comprising 42 cases of essential thrombocythemia (ET), 26 of polycythemia vera (PV), 7 with idiopathic myelofibrosis (MF), and 3 unclassifiable (UC) CMPD were enrolled in this study. A 364-bp PCR product containing the JAK2 V617F mutation was sequenced in both directions from total bone marrow cells. Restriction enzyme-based assessment with BsaXI was also used to search for JAK2 mutations. A quantitative real-time PCR-based allelic discrimination assay and pyrosequencing (Pyrosequencer PSQ96) were used to quantify the JAK2 V617F mutation status. Results: A single JAK2 V617F point mutation was identified in 20 (77%) of 26 patients with PV, 12 (26%) of 42 with ET, 7 (100%) of 7 with MF, and 2 (67%) of 3 with UC. The V617F mutation was present in over half of Korean patients with BCR/ABL-negative CMPD, giving an overall frequency of 53%. The proportion of mutant alleles ranged from 36 to 100% in the real-time PCR and pyrosequencing analysis. Patients with MF had a higher percentage of JAK2 mutant alleles than patients with ET (MF&gt;PV&gt;ET). PV patients (n=8) with a good response (phlebotomy only) had a relatively low proportion (58.9±20.1%) of the JAK2 mutant, while patients (n=9) showing a poor response (additional chemotherapy) initially had a higher proportion (76.6±19.0%; p=0.04185). Conclusion: The frequency of the JAK2 V617F mutation in Korean patients with PV was lower than that in reports from Western countries, although the overall frequency in Korean patients with BCR/ABL-negative CMPD was similar to previous reports. The results also suggest that the JAK2 mutation (quantification of JAK2 mutant alleles) can be used as a new marker for treatment response and disease progression in BCR/ABL-negative CMPD using quantitative real-time PCR or pyrosequencing.

BCR-ABL Positive Chronic Myeloid Leukaemia (CML) with Del 11q22 and JAK 2 V617F Positive Chronic Myelomonocytic Leukaemia (CMML) in One Patient – a Rare Coincidence

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4891-4891
Author(s):  
Sonja Burgstaller ◽  
Gerald Webersinke ◽  
Beate Mayrbaeurl ◽  
Thomas Kuhr ◽  
Josef Thaler
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Peripheral Blood ◽  
Research Funding ◽  
Blood Count ◽  
Molecular Level ◽  
Jak2 V617f ◽  
Case Vignette ◽  
Hypercellular Marrow ◽  
Dual Colour

Abstract Abstract 4891 Introduction: Coincidence of BCR-ABL positive CML and JAK2 V617F positive CMML in one patient is a rare phenomenon. Case report: We report on a 61 year old patient with a diagnosis of CML in August 2008. Peripheral blood count showed a WBC of 3.1 G/l and a mild thrombocytopenia with 139 G/l thrombocytes. Differential blood count revealed virtually all cells of the neutrophilic line with myelocytes, metamyelocytes and blasts, basophils were elevated with 3%. While bone marrow (BM) aspirate was not representative, histologic examination of the BM biopsy showed a hypercellular marrow with a pattern of cell maturation similar to peripheral blood. An increase in reticulin fibrosis and vascularity was demonstrated correlating with a diagnosis of CML. Cytogenetics confirmed diagnosis of CML with a t(9;22)(q34;q11) in 4 out of 21 metaphases, 11 metaphases showed a deletion 11q and 2 metaphases showed both, a del 11 q and a Philadelphia translocation. Four metaphases showed a normal karyotype. BCR-ABL and JAK2 V617F have been demonstrated on the molecular level. Imatinib was started with a standard dose of 400 mg daily. The patient achieved a complete cytogenetic response (CCR) and a complete molecular response (CMR – BCR-ABL transcripts not detectable with quantitative and nested PCR) after 3 and 7 months of therapy, respectively. Despite having achieved an excellent response on cytogenetic and molecular level a complete haematological response was not obtained. At that time bone marrow examination revealed a marked hypercellular marrow with 10% blasts and 15% monocytic forms consistent with the diagnosis of CMML. Philadelphia chromosome was absent. The deletion 11q and JAK2 V617F were still detectable. Beause of comorbidities allogeneic stem cell transplantation was no treatment option for this patient. In July 2009 therapy with azacitidine, a hypomethylating agent licensed for the use in CMML was initiated. Imatinib was administered intermittently on azacitidine free days dependent on the current haematological situation. BCR-ABL transcript levels varied between one log up/down reflecting the intermittent imatinib administration. CMR and MMR were lost after 4 and 9 months, respectively. Subsequently, an additional deletion 7q was detected in 20% of metaphases with a deletion 11q (no Ph+ or normal metaphases were present). Azacitidine was stopped because of disease progression and hydroxyurea was commenced with no significant response. Cutaneous infiltrations resistant to systemic therapy reflected further disease progression. WBC increased to 334 G/l and the patient died 25 months after diagnosis due to progression of CMML to acute leukaemia. Methods: Conventional karyotyping was done using Giemsa-Trysin banding. For FISH, BCR-ABL dual colour fusion probes and MLL dual colour break apart probes (both Abott Molecular) were used. JAK2V617F mutation was detected by melting curve analysis. BCR-ABL RNA monitoring was performed according to the Europe Against Cancer protocol (Gabert et al.). Conclusions: Coincidence of two distinct myeloproliferative disorders in one patient is relatively rare. Both, conventional cytogenetics and molecular biology provided important information for diagnosis, course and treatment. This case vignette illustrates the importance of repeated cytogenetic and molecular analyses demonstrating an unexpected turn of an apparently predetermined course. Disclosures: Burgstaller: AOP Orphan Pharmaceuticals AG: Research Funding. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.

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