Epidemiology of Patients with Classical Philadelphia-Chromosome Negative Myeloproliferative Neoplasms at a Single Academic Medical Center in Singapore

Abstract Introduction: Myeloproliferative Neoplasms (MPNs) represents a disorder that involves abnormal proliferation of cells originating from the myeloid line. The proliferation of these cells can lead to complications that are at times fatal. Despite its potential to cause life threatening complications, there is little data on this disease in Southeast Asia. As Singapore is a multiracial country in Southeast Asia, there may be some disease characteristics exclusive to patients here due to its unique population composition. The data from this Southeast Asian cohort would be useful to determine disease homogeneity in Asian countries. Methods: A retrospective review of the MPN database from National University Hospital, Singapore (NUHS) revealed 320 patients who were clinically diagnosed with MPN from 2008 to 2017. This data included patients with Essential Thrombocythemia (ET), Polycythemia Rubra Vera (PRV), Primary Myelofibrosis (PMF), Myeloproliferative Neoplasm, unclassifiable (MPN-U) and Chronic Eosinophilic Leukemia (CEL) (Figure 1A) as per the 2017 WHO classification. For this analysis, we included only the classical Philadelphia chromosome negative MPN and focused on the epidemiology, transformation and overall survival rate. Results: There was a slight male predominance with a male to female ratio of 1.3:1. The ethnic groups within this cohort consisted of 65.8% ethnic Chinese, 20.7% Malay, 5.5% Indian and the rest were made up of other ethnic groups within the region such as Eurasians, Thai, Filipinos, Burmese, Indonesians, Bangladeshi, Vietnamese and Arabian patients. The mean age at diagnosis for this group was 60.5. The mean age was 59.2 years for ET, 61.2 for PRV and the mean age of PMF was the oldest at 63.8. The mean age of diagnosis for ET and PMF patients in our cohort was slightly older compared to the Korean cohort (55.4 and 59.5 years) (Byun, et al., 2016). The majority of this cohort was made up of ET patients (53.1%) followed by PRV (35.3%) and PMF (11.6%). 77.5% of these patients were JAK2 V617F mutation (JAK2) positive. The percentage of patients who were JAK2 positive for ET, PRV and PMF were 69.2%, 96.9% and 56.3% respectively. The percentage of JAK2 positive patients for the three subtypes were higher in our local population compared to the Chinese and Japanese cohorts. Only 120 patients were tested for Calreticulin Exon 9 (CALR) mutations as this molecular test was only available in our institution from 2015 onwards. ET patients make up 68.4% of CALR positive patients. It was noted that CALR positive patients had comparatively higher mean platelet counts of 925.2 than CALR negative patients with mean platelet counts of 691.7. This phenomenon is seen in both CALR positive ET and CALR positive MF patients. In the 10-year period, 25 patients were lost to follow up and 8 patients transferred their care to another institution. Overall, 27 patients were deceased, with a mean survival of 3.5 years. The death-to-case ratio was 11.5 per 100 cases. The death-to-case ratio for ET, PRV and PMF is 6.1 per 100, 8.2 per 100 and 31.3 per 100 respectively. During this period, only 6 patients had transformation. Three patients progressed to post-ET myelofibrosis and 3 had leukemic transformation. Those who had leukemic transformation were initially diagnosed with PRV (1 patient) and PMF (2 patients). All patients who had leukemic transformation were deceased and had a mean survival of 1.4 years from the transformation event. Conclusion: Whilst there were some observable differences between our data and existing Asian data, there is still insufficient information to determine disease homogeneity. This is partly due to the rapid growth of molecular knowledge in this field and the regular revision of the WHO diagnostic criteria of MPNs over the last decade or so. There needs to be coordinated efforts within the region to ensure that our patients have equal access to these diagnostic platforms and that they receive an accurate diagnosis. Disclosures Chng: Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Aslan: Research Funding; Merck: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses.

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Development of a Murine Model for Leukemic Transformation of Myeloproliferative Neoplasms for Preclinical Therapeutic Studies

Blood ◽

10.1182/blood.v120.21.808.808 ◽

2012 ◽

Vol 120 (21) ◽

pp. 808-808 ◽

Cited By ~ 1

Author(s):

Raajit K. Rampal ◽

Suveg Pandey ◽

Omar Abdel-Wahab ◽

Jennifer J Tsai ◽

Taghi Manshouri ◽

...

Keyword(s):

Murine Model ◽

Research Funding ◽

Somatic Mutations ◽

Myeloproliferative Neoplasms ◽

Survival Curve ◽

Philadelphia Chromosome ◽

In Vivo Studies ◽

Leukemic Transformation

Abstract Abstract 808 A subset of patients with Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) (Polycythemia Vera (PV), Essential Thrombocytosis (ET), and Primary Myelofibrosis (PMF)) subsequently transform to acute myeloid leukemia (AML). Leukemic transformation (LT) after MPN occurs in as many as 23% of PMF patients within 10 years of diagnosis, and in 4–8% of PV and ET patients in the first 18 years after diagnosis. The development of AML after an antecedent MPN is associated with a dismal clinical outcome, and is associated with a poor response to conventional anti-leukemic therapies. Although somatic mutations in the JAK-STAT signaling pathway, including in JAK2 and MPL, occur in the majority of MPN patients, the somatic mutations that drive LT from a pre-existing MPN have not been fully delineated. Recent candidate mutational studies have identified recurrent somatic mutations in a subset of known leukemogenic disease alleles at the time of transformation from MPN to AML, including mutations in TP53, IDH1/2, TET2 and SRSF2 as well as deletions in IKZF1. However, the functional contribution of these specific genetic events to LT has not been delineated, and genetically accurate models of transformation of Philadelphia-chromosome negative MPN to AML have not been reported to date. In order to develop a genetically accurate murine model of LT, we have modeled expression of JAK2V617F mutation in combination with TP53 loss in vivo to further our understanding of progression from MPN to AML and to use this preclinical model of LT to test novel therapies. Bone marrow (BM) cells from C57/Bl6 Tp53−/− and littermate control mice were infected with JAK2V617F-IRES-GFP retrovirus, followed by transplantation of transduced cells into lethally irradiated congenic recipients. Of note, transplantation of JAK2V617F/Tp53−/− cells, but not JAK2V617F positive cells was associated with impaired survival; 50% of mice injected with JAK2V617F/Tp53−/− cells died by day 100, whereas all mice injected with JAK2V617F positive cells survived 100 days or longer (p=0.011) (figure 1). Mice injected with JAK2V617F/Tp53−/− cells presented with significant leukocytosis, with a mean WBC of 38.4 in mice engrafted with JAK2V617F/Tp53−/− cells compared with 11.4 in JAK2V617F/Tp53 wildtype mice. At the time of sacrifice, all mice engrafted with JAK2V617F/Tp53−/− cells had increased numbers of blasts in the peripheral blood and bone marrow, as assessed by morphologic evaluation and flow cytometric analysis which noted CD117 expression on leukemic blasts. BM cells from mice engrafted with JAK2V617F/Tp53−/− cells were characterized by increased serial replating (>10 platings), which was not observed in plating studies with JAK2V617F positive cells. In addition, we noted that the disease from JAK2V617F/Tp53−/− cells, but not JAK2V617F positive cells, was transplantable into secondary recipients consistent with increased self-renewal in vivo. We have begun testing the efficacy of novel therapies in this murine model, using both in vitro assays and in vivo studies in secondary transplantation studies. Treatment with the JAK kinase inhibitors INCB18424 and CYT 387 resulted in dose-dependent inhibition of colony formation in vitro. The combination of INCB18424 and Decitabine (which has demonstrated clinical efficacy in post-MPN-AML) is associated with synergistic inhibitory effects in vitro. Based on these results, we are performing in vivo studies with INCB18424, Decitabine, and INCB18424 + Decitabine, and results from these preclinical therapeutic studies will be presented in detail. Taken together, our data demonstrate that expression of JAK2V617F plus Tp53 loss, a genoptype commonly seen in patients who transform to AML after MPN, efficiently models LT in vivo. This model can now be utilized to examine the mechanisms of leukemic transformation, including assessment of the leukemic cell of origin in transformed disease. In addition this model can be utilized to test novel therapeutic strategies in a preclinical setting, which can be used to inform clinical trials in this poor-risk hematologic malignancy. Figure 1: Survival curve of mice transplanted with JAK2V617F in presence and absence of Tp53 Figure 1:. Survival curve of mice transplanted with JAK2V617F in presence and absence of Tp53 Disclosures: Verstovsek: Incyte Corporation: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; SBIO: Research Funding; Lilly Oncology: Research Funding; Bristol-Myers: Research Funding; Geron Corp.: Research Funding; Gilead: Research Funding; YM Biosciences: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Infinity Pharmaceuticals: Research Funding.

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Large Genomic Alterations Occurring in the Transition from Chronic to Blast Phase of Chronic Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2018-99-113048 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3028-3028

Author(s):

Niccolò Bartalucci ◽

Alberto Magi ◽

Elisa Contini ◽

Davide Bolognini ◽

Simone Romagnoli ◽

...

Keyword(s):

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Gc Content ◽

Chronic Phase ◽

Copy Number Variations ◽

Chromosome 8 ◽

Leukemic Transformation ◽

Blast Phase ◽

Paired Samples ◽

The Mean

Abstract INTRODUCTION Five to 20% of patients with myeloproliferative neoplasms (MPN), including Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary Myelofibrosis (PMF), transform to an aggressive secondary acute myeloid leukemia (sAML). While several studies reported the association of some mutations with the risk of leukemic transformation (Vannucchi AM et al, Leukemia 2013), the mechanisms that contribute to transformation from MPN to sAML remain largely poor characterized. METHODS. We collected annotated samples from 15 chronic-phase (CP) MPN patients (pts), 6 pts with accelerated phase (AP; PB blasts 10-19%) and 12 pts with sAML; for the latter, paired samples (chronic/blast phase-BP) were available. CP and BP samples were separated by a mean of 77 (12 to 216) months interval. We used Illumina whole exome sequencing (WES) to identify copy number variations (CNV) in all samples. In the paired samples set, we also performed long reads genome sequencing by the Oxford Nanopore technology, a uniform process that generates sequences randomly and independently, without classical sources of bias such as GC-content and mappability. Data analysis for CNV detection was performed by a novel devised computational package (Nano-GLADIATOR; Magi A, Bartalucci N et al, Genome Biology, submitted) allowing the analysis of individual samples without the need of paired-analysis. RESULTS. The mean number of CNV detected in CP, AP and BP samples was respectively 130.7±49, 132±42 and 177.4±61 (P=0.03 of BP vs CP). CNV were represented by gain of genomic material in 63.6%, 68.2% and 64.1% of CP, AP and BP. Considering the length of all CNV, expressed as base pairs (bp), we found that 96.8% of CNV in CP were focal alterations spanning <1 Mega bases (Mb) while only 2.9% and 0.3% were larger than 1Mb and 30Mb, respectively. Conversely, alterations involving >1Mb and >30Mb in BP samples were 14.4% (P=0.05) and 2.1% (P=0.04), and corresponding figures in AP were respectively 5.3% (ns vs CP, P=0.05 vs BP) and 0.7% (P=0.04 vs CP). Considering CNV >1Mb only, 53.7% were gains in CP compared with 68.1% in AP and 63.6% in BP, while losses were 46.3%, 31.9% and 36.4% respectively. Furthermore, alterations involving all the short (p) and long (q) -arm or the whole chromosome were found in 77% of BP compared to 36% of AP and 11% only of CP samples (P<0.01), overall indicating that larger alterations are enriched in BP. We used Nanopore platform to analyze paired CP and BP samples. We found that the total number of bp involved in CNV was 380x106 and 2x109 in CP and BP, respectively, with an estimated frequency of 0.01 and 0.07 altered base every 1 base of normal genome. The mean length of CNV was 5.6x106 bp and 23.7x106 bp respectively in CP and BP samples. There was a total of 29 new CNV acquired in BP samples compared to CP, involving 10 different chromosomes. We identified recurrent alterations as double or single deletion of 100,000 bp in chromosome 8 (55.5% of BP), deletion of a 510.000 to 610.000 bp region of chromosome 4q (40% of BP) and an amplification of 32,535,000 bp in chromosome 21q in 34% of BP samples. Alterations involving chromosomes 4 and 8 detected in BP samples were already present at paired CP samples in 75% and 80% of cases, while in the remaining 25% and 20% they were acquired at BP. The same abnormalities were absent from the 15 unpaired CP samples (WES data) whereas they were present in 4/6 and 3/6 of AP patients, respectively. CONCLUSION All together, this data indicate that genomic instability is a hallmark of leukemic transformation of MPN and for the first time identify regions that may be recurrently associated with disease progression from CP to BP, potentially representing novel biomarkers. These finding require confirmation in larger series. Disclosures No relevant conflicts of interest to declare.

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RMC-4550, an Allosteric Inhibitor of SHP2, Displays Therapeutic Efficacy in Pre-Clinical Models of Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-128937 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4198-4198 ◽

Cited By ~ 1

Author(s):

Garima Pandey ◽

Nathan Horvat ◽

Narmin E. Amin ◽

Afua A. Akuffo ◽

Christelle Colin ◽

...

Keyword(s):

Research Funding ◽

Myeloproliferative Neoplasms ◽

Critical Role ◽

Philadelphia Chromosome ◽

Jak2 V617f ◽

Ras Signaling ◽

Jak2 Inhibitor ◽

Stat Signaling ◽

Drug Naïve

Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) are JAK2-driven disorders resulting from mutations in JAK2, MPL, or CALR. Ruxolitinib, the only FDA-approved JAK2 inhibitor for MPNs, alleviates patient symptomology and improves quality of life, but has little effect on reducing mutant allele burden. This persistent survival of MPN cells in the face of ruxolitinib, as well as other JAK2 inhibitors that have been clinically tested, is a major clinical bottleneck to the development of an effective targeted therapy for MPN patients. Identifying new therapeutic targets which play critical roles in MPN cells and/or in JAK2 inhibitor persistence may lead to improved MPN therapies. SHP2 is an oncogenic tyrosine phosphatase that is an effector of growth factor and cytokine receptor signaling. SHP2 plays a critical role in the activation of the RAS-ERK pathway and regulates JAK-STAT signaling via numerous phosphatase-dependent mechanisms. Activating mutations of SHP2(PTPN11) have been identified in leukemia, including 8% of MPN patients whose disease progressed to acute myeloid leukemia (AML). In addition, SHP2 has been shown to mediate adaptive resistance to targeted therapies in several cancers. Given the role of SHP2 in cytokine and JAK-STAT signaling, we envisaged a potential role of SHP2 in MPN cell growth and/or survival and ruxolitinib persistence. Treatment of JAK2-V617F-driven MPN model cell lines (UKE1, SET2, and BaF3-JAK2-V617F) with ruxolitinib blocked constitutive tyrosine phosphorylation of SHP2, including phosphorylation of Y542, a marker for activated SHP2. This phosphorylation, however, was restored in ruxolitinib persistent cells. Combination treatment of the allosteric SHP2 inhibitor RMC-4550 (Revolution Medicines) with ruxolitinib prevented the development of ruxolitinib persistent cells and pre-established persistent cells remained sensitive to SHP2 inhibition. RMC-4550 treatment led to significantly reduced levels of pERK consistent with the role of SHP2 in RAS signaling. Interestingly, pERK levels in persistent cells were more sensitive to SHP2 inhibition compared to drug naïve cells suggesting pERK was more dependent on SHP2 in ruxolitinib persistent cells. SHP2 inhibitor treatment increased pSTAT5(Y694) in drug naïve cells but this increase was not observed in similarly treated persistent cells. Furthermore, while ruxolitinib inhibited pERK levels in UKE1 and SET2 cells, pERK levels recovered within 24 hrs of treatment. SHP2 inhibition prevented the recovery of pERK in the presence of ruxolitinib. Collectively, these data suggest that signaling pathways in MPN cells treated with ruxolitinib can become rewired, gaining greater dependence on SHP2, concomitant with sustained pERK and cell survival/growth. Interestingly, we identified a known activating SHP2 mutation (F71L) in UKE1 cells obtained from two independent sources - consistent with the presence of PTPN11 mutations in post-MPN AML. The persistent survival of UKE1 cells in ruxolitinib was antagonized by CRISPR-mediated reduction of SHP2 expression, providing further evidence that SHP2 contributes to ruxolitinib persistence. To assess the effects of a SHP2 inhibitor on MPN progression in vivo, we employed the MPLW515Lbone marrow transplant mouse model of MPN. Initial assessment of therapeutic treatment of mice with an established MPN phenotype indicated that once daily treatment of RMC-4550 (10 or 30 mg/kg) antagonized the MPN phenotype. Complete blood counts indicated a significant reduction in white blood cells, monocytes, and neutrophils compared to vehicle treated mice, while flow cytometry analysis indicated RMC-4550 diminished CD11b+ cell numbers to near that observed in mice transplanted with MPLWT-transduced bone marrow. RMC-4550 improved the overall health of diseased mice, as indicated by increased weight, and significantly reduced organomegaly of the spleen and liver compared to vehicle treated MPN mice. Finally, erythropoietin independent erythroid colony formation of JAK2V617F-positive MPN patient cells was suppressed following SHP2 inhibition, which synergized or enhanced the inhibition induced by ruxolitinib in this assay. In summary, our results suggest that SHP2 inhibition may represent a potential MPN therapy in both ruxolitinib naïve and resistant patients and is an attractive therapeutic target for future clinical investigation. Disclosures Epling-Burnette: Incyte Corporation: Research Funding; Forma Therapeutics: Research Funding; Celgene Corporation: Patents & Royalties, Research Funding. Reuther:Incyte Corporation: Research Funding.

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Phase II Trial of SGI-110 (Guadecitabine) in Philadelphia Negative Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-127663 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1666-1666

Author(s):

Pinkal Desai ◽

Niamh Savage ◽

Spencer Krichevsky ◽

Tania Curcio ◽

Sangmin Lee ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Progressive Disease ◽

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Advisory Board ◽

Efficacy And Safety ◽

Advisory Committees

Introduction: Philadelphia negative myeloproliferative neoplasms (Ph- MPN) are hematopoietic stem cell malignancies associated with poor median survival of 12.4 months. They are often excluded from clinical trials because there are no accepted standards for treatment or assessment of disease response. SGI-110 (guadecitabine) is a second-generation DNA hypomethylating agent (HMA) that is currently in clinical trials for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Guadecitabine was designed to resist degradation by protein aminases and prolong the exposure of tumor cells to the active metabolite decitabine. The purpose of this study was to test the efficacy and safety of SGI-110 in Philadelphia chromosome negative MPNs (Ph- MPN) and to also test the clinical applicability of the International IWG MDS/MPN response criteria in a prospective trial1. Methods: This is an interim analysis of an open label single-arm, single-institution study to evaluate the efficacy and safety of SGI-110 in Philadelphia chromosome negative (Ph-) myeloproliferative Neoplasms as classified by WHO, including chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative neoplasm unclassifiable, accelerated phase myelofibrosis and MPN unclassifiable (defined as peripheral and or bone marrow blasts of 10-19%). PV, ET and primary/secondary myelofibrosis were excluded. Patients were required to complete at least 3 cycles of guadecitabine to be considered evaluable for efficacy. Safety analyses were done on all patients who received any treatment with guadecitabine. Guadecitabine was administered subcutaneously at a dose of 60mg/m2 on days 1-5 repeated every 28 days. The IWG MDS/MPN response classification was used to assess treatment response. Results: Baseline characteristics of the study participants are presented in Table 1. Among the 20 treated patients, 2 (10.0%) were treated with previous HMAs, 3 had progressive disease, 1 transferred care, 7 were not yet evaluable for response, and 1 died after receiving only 2 cycles of treatment. Of the 13 evaluable, protocol specific response was seen in 8 (61.5%) patients: 2 (15.4%) achieved complete remission (CR), 3 (23.1%) with optimal marrow response (OMR), 3 (23.1%) with hematological response/clinical benefit (CB). Stable disease was seen in 4 patients (30.8%). Of the 7 patients that were inevaluable: 3 had progressive disease before completing 3 cycles, 2 received <3 cycles of therapy, 1 discontinued treatment due to personal choice, and 1 patient died from infection after receiving 2 cycles of treatment. The median overall survival (OS) for all evaluable patients was 27.4 months with 25.8 months for responders. Median OS for patients who achieved CR was 27.4 months and 25.0 months for OMR. For patients with CB, mean survival was 21.0 months. There was 1 patient with stable disease with prolonged survival (21 cycles), which elevated the mean survival to 26.0 months for the SD category. The median number of cycles to achieve a response was 3. The median times to first and best response were 3.6 and 3.8 months, respectively. The combination of ASXL1 and EZH2 mutations was associated with rapid progression. The most common AEs and SAEs related to guadecitabine are listed in Tables 2 and 3 respectively. Conclusion: SGI-110 was safe and well tolerated in patients with Ph negative MPN, with encouraging efficacy in this difficult-to-treat patient population. Further investigation of this agent in MDS/MPN overlap syndromes is warranted, and the present trial is ongoing. 1. Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. Mar 19 2015;125(12):1857-1865. Disclosures Desai: Cellerant: Consultancy; Astex: Research Funding; Astellas: Honoraria; Sanofi: Consultancy; Celgene: Consultancy. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Ritchie:Celgene, Incyte, Novartis, Pfizer: Consultancy; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Tolero: Other: Advisory board; Genentech: Other: Advisory board. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Prevalence and Prognostic Impact of Allelic Imbalances Associated with Leukemic Transformation of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms.

Blood ◽

10.1182/blood.v114.22.1280.1280 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1280-1280

Author(s):

Nils Heinrich Thoennissen ◽

Utz O. Krug ◽

Dhong Hyun Lee ◽

Norohiko Kawamata ◽

Terra L Lasho ◽

...

Keyword(s):

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Snp Array ◽

Chronic Phase ◽

Prognostic Impact ◽

Genomic Alterations ◽

Leukemic Transformation ◽

Blast Phase ◽

Hematopoietic Stem

Abstract Abstract 1280 Poster Board I-302 Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF) are defined as clonal hematopoietic stem cell disorders. These disorders show an inherent tendency for transformation into leukemia (MPN-blast phase) which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, obtained a comprehensive profile of genomic alterations associated with leukemic transformation by using single-nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. A relatively high number of genomic alterations was found in MPN after leukemic transformation with 4.6 ± 0.6 abnormalities per sample compared to only 1.4 ± 0.2 changes per patient in chronic phase (p<0.001). Compared to the cytogenetic data, SNP-chip analysis detected about 47% additional chromosomal changes in the MPN samples, and 31% more in the MPN-blast phase cases, whereas SNP-array allelokaryotyping practically captured all cytogenetic abnormalities in our study population. Several additionally altered regions were detected in patients with MPN-blast phase compared to chronic phase, including both deletion and copy-number neutral-loss of heterozygosity (CNN-LOH) on chromosome 12p (9%) and 21q (9%), involving ETV6 and RUNX1. Notably, deletion and CNN-LOH on 17p involving TP53 were diagnosed in 18% of MPN-blast phase samples, which was highly associated with preceding treatment with alkylating agents (p=0.016). Moreover, trisomy 8, as well as amplification of 8q24.21 involving the MYC gene, were detected in 13% of patients with MPN-blast phase who were almost exclusively negative for the JAK2V617F mutation. Genome-wide inspection of further critical regions with promising new candidate genes involved in the evolution to the MPN-leukemic phase included deletion and CNN-LOH on 7q22.1 (SH2B2) in 18%, duplication/amplification on 19p13.2 (PIN1, ICAM1, CDC37) in 13% and 21q22.2 (ERG) in 9% of MPN patients with blast crisis. In contrast, we detected a decreased frequency of JAK2V617F in MPN-blast phase samples (52%) compared to chronic phase (71%). Also, the percentage of patients with homozygous mutant JAK2 as a result of CNN-LOH was lower in the MPN-blast phase (43%) compared to the chronic phase (53%). Taken together, the data suggest that gain-of-function mutation of JAK2 is not a perquisite for leukemic transformation. Remarkably, CNN-LOH on either 7q or 9p was related to decreased survival after leukemic transformation (p=0.02 and p=0.012, respectively). Given the variety of allelic imbalances, our data suggest that MPN-blast phase appears to be a heterogeneous disease prone to have evolved multiple mechanisms to provide a proliferative advantage to the abnormal leukemic clone. Our analysis of MPN genomes in the chronic compared to the leukemic stage provided new prognostic insights, as well as novel causative genes which might be involved in the transformation to MPN-blast phase. Disclosures No relevant conflicts of interest to declare.

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Thrombosis in MPN with Thrombocythemia Is Associated with Higher Platelet Count At the Time of the Event: Data From the Czech Registry of Patients Treated with Anagrelide,

Blood ◽

10.1182/blood.v118.21.3857.3857 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3857-3857

Author(s):

Jiri Schwarz ◽

Miroslav Penka ◽

Petra Ovesna ◽

Olga Cerna ◽

Yvona Brychtova ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

Jak2 V617f ◽

Protein C Deficiency ◽

Thrombotic Risk ◽

Female Ratio ◽

Platelet Counts ◽

Cell Counts ◽

Registry Entry

Abstract Abstract 3857 Background: Recent studies of prognostic parameters in Ph- myeloproliferative neoplasms with thrombocythemia (MPN-t) indicate that WBC counts at diagnosis, rather than platelet (Plt) counts, determine the risk of thrombosis. We have studied these and other risk parameters in our patient cohort. Patients: 843 prospectively assigned patients from the Czech segment of the International registry of patients treated with anagrelide (ANG; Thromboreductin®) were studied. The male: female ratio was 2:3, the median age was 51 (0–96) years. The majority of patients (68.1%) was pretreated by other cytoreducing drugs. According to PVSG criteria, the diagnoses were the following: essential thrombocythemia – 569, primary myelofibrosis – 155, polycythemia vera – 92, or other – 27 patients. Data from the time of diagnosis, from the time of registry entry (at the start of ANG therapy) and from the time of the thrombotic event were evaluated. The median follow-up since registry entry was 33 (0–117) months and the follow-up comprised 2505 patient-years. All patients were treated with ANG and in 80% of follow-up reports, acetylsalicylic acid (ASA) was mentioned to be given in parallel. In 18% of entries (from registration and follow-up), administration of another cytoreducing drug (mainly hydroxyurea or interferon) in combination with ANG was noted. Results: Of 449 thrombotic events reported, 335 occurred in history (i.e. before registry entry) and 114 during follow-up. The numbers of arterial, venous, and microcirculatory events in history were 147, 124 and 64, respectively. Of the 114 thrombotic events in 88 patients during follow-up (3.79 events/100 patient-years), 45 were classified as major. There were 61 arterial, 16 venous and 37 microcirculatory events. ANG ± ASA therapy dramatically decreased the number of venous events (7.8-fold), while arterial and microcirculatory events were reduced 2.4-fold and 1.7-fold, respectively. At diagnosis, the strongest predictors of all thrombotic events jointly were JAK2 V617F mutation (P=0.001), hereditary or acquired thrombophilia (P<0.001), hypertension (P=0.006), smoking (P=0.02) and diabetes mellitus (P=0.04). Also previous thrombosis predicted a subsequent thrombotic event (P=0.002). Age >65 yrs was a less powerful predictor (P=0.08). WBC and hematocrit levels positively correlated with the thrombotic risk (P=0.002 and P=0.006, respectively), whereas Plt counts correlated inversely with all thrombotic events (P=0.012) but correlated positively with microcirculatory events (P=0.01). Some of the factors (age, hypertension, diabetes, and smoking) powerfully predicted rather arterial events, whereas others (f.V “Leiden” mutation, protein C deficiency, elevated f.VIII levels, presence of antiphospholipid antibodies) were connected preferentially with venous events. However, when full blood cell counts from the time of the thrombotic events were studied and compared to mean levels of all entries during follow-up, we could detect higher platelet counts at the time of the thrombotic event (454 vs 420 G/L, P=0.007), while we could not demonstrate any significance of the WBC counts at the time of the event. The correlation of the Plt count was marked in all types of events and was most conspicuous in microcirculatory events. Thrombotic events during follow-up were also associated with lack of ASA therapy: only 6/16 (37.5%) patients at the time of the venous event, 35/61 (57.4%) patients at the time of the arterial event and 11/37 (29.7%) patients at the time of the microcirculatory event received ASA therapy (whereas ASA administration was reported in 80.0% of follow-up entries). Conclusions: The current study indicates that during ANG ± ASA therapy, the incidence of thrombosis is very low in MPN-t and especially the rate of venous events is extraordinarily low. The predictors of the thrombotic events are similar as previously published by others. Above that, we have proven the usefulness of detection of the so-called thrombophilic states. However, in contrast with the prevailing current opinion, we have shown that higher platelet counts (and not WBC counts) are important at the time of thrombosis, albeit at diagnosis the Plt counts may inversely and WBC counts positively correlate with the thrombotic risk. This discrepancy may result from treatment: patients with higher Plt counts at diagnosis may receive more cytoreducing and/or antiaggregation therapy. Disclosures: Schwarz: AOP Pharmaceuticals: Consultancy.

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Pharmacokinetics (PK) of Lenalidomide When Administered Alone or in Combination with Dexamethasone in Chinese Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): The MM-021 Trial

Blood ◽

10.1182/blood.v120.21.5046.5046 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5046-5046

Author(s):

Nianhang Chen ◽

Dao-bin Zhou ◽

Li Yu ◽

Jay Mei ◽

Liangang Liu ◽

...

Keyword(s):

Body Weight ◽

Plasma Concentration ◽

Board Of Directors ◽

Ethnic Groups ◽

Research Funding ◽

Geometric Mean ◽

Chinese Patients ◽

Advisory Committees ◽

Multiple Doses ◽

The Mean

Abstract Abstract 5046 Introduction: Lenalidomide (LEN), in combination with dexamethasone (DEX), has been approved in many countries for treatment of MM in pts who have received ≥1 prior therapy. The PK of LEN has been previously evaluated in Caucasian and Japanese pts with MM. However, its ethnic sensitivity has not been investigated elsewhere. MM021 is the first study in China to evaluate the PK of LEN, when administered alone or in combination with DEX, in Chinese pts with RRMM. The PK results obtained from this study were compared with those historically observed in Japanese/Caucasian MM pts. Patients and Methods: MM021 is a phase 2, multicenter, open-label study to assess the efficacy and safety of LEN + DEX. A subset of Chinese MM pts aged ≤75 years who were eligible to receive DEX at the starting dose of 40 mg were included in the PK assessments of this study. In treatment cycle 1, these pts received oral LEN 25 mg/d on Days 1–21, and 40 mg oral DEX on Days 8, 15, and 22. Serial plasma sampling for PK analysis was performed 24 hours (hrs) after the LEN dose on Days 1, 7, and 8. LEN PK in the absence of DEX was evaluated after a single dose (Day 1) and after multiple doses (Day 7). The effect of DEX was evaluated by comparing the multiple doses of LEN in the absence (Day 7) and presence (Day 8) of DEX. To compare systemic LEN exposures among ethnic groups, the maximum concentration (Cmax) and area under the concentration-time curve from time zero extrapolated to infinity (AUC∞) observed in Japanese and Caucasian MM pts were normalized to the levels at 25 mg. Plasma concentration of LEN was determined by validated liquid chromatography mass spectrometry (LC-MS/MS) assay. Results: A total of 11 Chinese MM pts were enrolled for PK analysis. These pts were mostly male (72%), with a median age of 56 yrs (range 44–68) and median body weight of 66 kg (range 54–84). The median creatinine clearance (CrCL) estimated by Cockcroft-Gault formula at baseline was 86 mL/min (range 42–154). When administered alone to Chinese MM pts, LEN was absorbed rapidly, with a median time of approximately 1 hr to reach Cmax. Consistent with a mean terminal half-life (t1/2) of approximately 3 hrs and a dosing interval of 24 hrs, LEN did not accumulate in plasma with multiple doses (Figure 1). There was no time-dependence in t1/2 and apparent total clearance (CL/F), supporting the linear PK. In 1 pt who had moderate renal impairment (CrCL = 42 mL/min), LEN AUC∞was increased by approximately two-fold, compared with the mean value for all pts. The mean LEN plasma concentration vs. time profile in the presence of DEX was almost identical to that in the absence of it (Figure 1). The 90% confidence interval for the ratio of geometric means between LEN alone and LEN + low-dose DEX was contained within the equivalence limits of 80% and 125% for both Cmax and AUC. Since the elimination of LEN is primarily renal, comparison of LEN PK parameters among ethnic groups was done only in pts with CrCL ≥60 mL/min (Table 1). Mean plasma AUC∞ in Chinese MM pts administered 25 mg LEN (2202 h·ng/mL) was comparable to that historically observed in Japanese and Caucasian MM pts (2305 and 2124 h·ng/mL, respectively), with a similar inter-patient variability of approximately 25–30%, even though Chinese pts had a lower median body weight compared with Caucasian pts. There was also no difference observed in other PK parameters between Chinese, Japanese, and Caucasian MM pts (Table 1). Conclusion: Co-administration with DEX has no effect on the PK of LEN. There are no apparent ethnic differences in the PK of LEN among Chinese, Japanese, and Caucasian MM pts. Only pts with CLcr >= 60 mL/min are included; median (range) are presented for age, body weight, CrCL and Tmax; geometric mean (CV%) data are presented for other parameters. Disclosures: Chen: Celgene Corporation: Employment. Mei:Celgene Corporation: Employment. Liu:Celgene Corporation: Employment. Wang:Celgene Corporation: Employment. Wortman-Vayn:Celgene Corporation: Employment. Hou:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Xian: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jensen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Financial Burden of Myeloproliferative Neoplasms on Patients: Results from the MPN Landmark Survey in the United States

Blood ◽

10.1182/blood.v126.23.5561.5561 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5561-5561 ◽

Cited By ~ 1

Author(s):

Shreekant V. Parasuraman ◽

Ahmad B. Naim ◽

Dilan C. Paranagama ◽

Maureen Thyne ◽

Sara Goldberger ◽

...

Keyword(s):

Health Insurance ◽

Household Income ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Financial Burden ◽

Work Hours ◽

Annual Household Income ◽

Employment Equity ◽

Equity Ownership ◽

The Mean

Abstract Background: Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPNs). Patients across all 3 MPNs experience marked disease burden in terms of symptoms and negative effects on quality of life (QoL), productivity, and activities of daily living (ADL). To improve the lives and health of patients with MPNs, it is also important to have a current understanding of these burdens from a financial standpoint. This analysis of MPN Landmark survey data examined the financial burden of patients who reported that their MPN affected their employment (ie, reduced work hours, discontinued employment, or went on medical disability) or experienced no such effects on their employment. Methods: Patients diagnosed with MF, PV, or ET were recruited to participate in a real-world retrospective study (MPN Landmark survey) in the US (fielded May - July 2014). Only respondents who were diagnosed before 2013 and were 16 to 65 years of age at the time of diagnosis were eligible for this analysis. Participants were asked if their MPN had an impact in terms of reduced work hours, discontinued employment, medical disability, or no impact; the first 3 categories were not mutually exclusive. Participants provided information on their annual household income in 2013 before taxes by selecting from the following categories: ≤$15,000, $15,001-$25,000, $25,001-$35,000, $35,001-$50,000, $50,001-$75,000, $75,001-$100,000, and >$100,000. The mid value of each range was used to calculate mean income levels within each subgroup evaluated. Results: A total of 813 patients completed the web-based Landmark survey and 369 eligible patients were included in this analysis (MF, 85; PV, 172; ET, 112). Median age among patients with ET was slightly lower than among patients with MF and PV at time of MPN diagnosis (ET, 48 years; MF, 56 years; PV, 53 years). The majority of respondents were women (MF, 62%; PV, 52%; ET, 75%). Almost all patients (99%) had health insurance, primarily group commercial insurance through an employer (MF, 46%; PV, 53%; ET, 57%) and Medicare (MF, 40%; PV, 34%; ET, 24%). Most patients had at least some college education (ie, some college, 4-year degree, or postgraduate degree): MF, 86%; PV, 90%; ET, 88%. The mean 2013 household income of patients with MF, PV, and ET were similar to each other ($79,800, $80,200, and $80,400, respectively) and slightly higher than the total 2013 US mean household income of $75,839. A notable proportion of patients in each MPN group reported that their disease led to reduced work hours, discontinued employment, and medical disability: MF, 38%, 35%, and 33%, respectively; PV, 33%, 28%, and 15%; ET, 28%, 21%, and 4%. Patient demographics, such as age and health insurance status, were similar among patients who reported MPN-associated effects on employment and patients who did not within each MPN. In each MPN group, the mean percentage household income loss in patients with reduced work hours, discontinued employment, and medical disability were: MF, 16%, 18%, and 28%, respectively; PV, 15%, 24%, and 17%; and ET, 0%, 24%, and 37%, compared with patients who did not experience any effects of their MPN on employment (Figure 1). Discontinued employment and medical disability tended to have a greater impact compared with reduced work hours across MPNs. Conclusion: Patients withMPNs may experience a considerable negative impact on their employment status, which in turn may be associated with reduced annual household income. Therefore, across all MPNs, forestalling or reversing discrete aspects of the diseases that negatively impact individual productivity is an important factor in the management of these chronic neoplasms. Disclosures Parasuraman: Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Paranagama:Incyte Corporation: Employment, Equity Ownership. Thyne:Incyte Corporation: Speakers Bureau. Mascarenhas:Incyte Corporation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; Promedior: Research Funding; Roche: Research Funding; CTI Biopharma: Research Funding; Kalobios: Research Funding. Mangan:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Fazal:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Miller:Incyte Corporation: Honoraria, Research Funding. Mesa:Promedior: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; NS Pharma: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Pfizer: Research Funding.

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Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome–negative myeloproliferative neoplasms

Blood ◽

10.1182/blood-2009-07-235119 ◽

2010 ◽

Vol 115 (14) ◽

pp. 2882-2890 ◽

Cited By ~ 81

Author(s):

Nils H. Thoennissen ◽

Utz O. Krug ◽

Dhong Hyun Tony Lee ◽

Norihiko Kawamata ◽

Gabriela B. Iwanski ◽

...

Keyword(s):

Target Genes ◽

Chromosomal Abnormalities ◽

Myeloproliferative Neoplasms ◽

Neutral Loss ◽

Philadelphia Chromosome ◽

Snp Array ◽

Chronic Phase ◽

Prognostic Impact ◽

Leukemic Transformation ◽

Blast Phase

Abstract Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and primary myelofibrosis show an inherent tendency for transformation into leukemia (MPN-blast phase), which is hypothesized to be accompanied by acquisition of additional genomic lesions. We, therefore, examined chromosomal abnormalities by high-resolution single nucleotide polymorphism (SNP) array in 88 MPN patients, as well as 71 cases with MPN-blast phase, and correlated these findings with their clinical parameters. Frequent genomic alterations were found in MPN after leukemic transformation with up to 3-fold more genomic changes per sample compared with samples in chronic phase (P < .001). We identified commonly altered regions involved in disease progression including not only established targets (ETV6, TP53, and RUNX1) but also new candidate genes on 7q, 16q, 19p, and 21q. Moreover, trisomy 8 or amplification of 8q24 (MYC) was almost exclusively detected in JAK2V617F− cases with MPN-blast phase. Remarkably, copy number–neutral loss of heterozygosity (CNN-LOH) on either 7q or 9p including homozygous JAK2V617F was related to decreased survival after leukemic transformation (P = .01 and P = .016, respectively). Our high-density SNP-array analysis of MPN genomes in the chronic compared with leukemic stage identified novel target genes and provided prognostic insights associated with the evolution to leukemia.

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The effects of plasma viscosity in thromboembolic events among patients with essential thrombocytosis: A case-control study

Clinical Hemorheology and Microcirculation ◽

10.3233/ch-211137 ◽

2021 ◽

pp. 1-8

Author(s):

Tekin Güney ◽

Ferda Can ◽

Afra Alkan ◽

Sema Akıncı ◽

İmdat Dilek

Keyword(s):

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Plasma Viscosity ◽

World Health ◽

Control Group ◽

Study Group ◽

Thromboembolic Events ◽

History Of ◽

Patient Groups ◽

The Mean

INTRODUCTION: Essential thrombocythemia (ET) is an entity of classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized by thrombocytosis with megakaryocytic hyperplasia where in the thrombocytes are increased with abnormal function. Thrombotic events are seen frequently and represent the main cause of morbidity and mortalityin patients with MPNs, mainly polycythemia vera and ET. This study has aimed to research the effects of clonally increased thrombocytes on plasma viscosity (PV) levels among patients with ET and the relationship between PV and thromboembolism history, according to the hypotheses about the effects of PV in thromboembolic events among patients with ET. METHODS: A total of 55 patients were enrolled in the study group, 18 of who had been newly diagnosed with ET according to 2016 World Health Organization criteria and had not previously been treated. 37 of them had already been diagnosed with ET and had been treated. There were 47 healthy volunteers in the control group. 5 cc blood samples were taken from the patients into tubes including an anticoagulant to measure their PV levels. RESULTS: PV of the control group was found to be lower than in the study group and both each patient groups (p < 0.05). No relationship was found between the patient groups in terms of PV (p = 0.404). The mean PV levels of the 16 patients with a history of thromboembolism and the 39 patients with no such history were 2.42±0.17 cP and 2.33±0.20 cP, respectively. The mean PV levels were found to be similar according to their history of thromboembolism in all patient groups and in treated patients (p = 0.572 vs p = 0.991). CONCLUSION: We have found that PV levels were increased in clonally increased thrombocytes in patients with ET when compared with the control group. This is the first study in this field according to our knowledge.

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