scholarly journals A Randomized, Phase 3, Trial of Interferon-α versus Hydroxyurea in Polycythemia Vera and Essential Thrombocythemia

Blood ◽  
2022 ◽  
Author(s):  
John Mascarenhas ◽  
Heidi E. Kosiorek ◽  
Josef T. Prchal ◽  
Alessandro Rambaldi ◽  
Dmitriy Berenzon ◽  
...  
Keyword(s):  
High Risk ◽  
Polycythemia Vera ◽  
Disease Progression ◽  
Essential Thrombocythemia ◽  
Vascular Complications ◽  
Myeloproliferative Disorders ◽  
Complete Response ◽  
Interferon Α ◽  
Phase 3 ◽  
Significant Difference

The goal of therapy for essential thrombocythemia (ET) and polycythemia vera (PV) patients is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for ET and PV patients at high-risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment naïve, high-risk ET/PV patients. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (p=0.80) at 12 months. At 24/36 months, CR was 20%/17% for HU and 29%/33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, while grade 3/4 adverse events were more frequent with PEG (46% vs. 28%). At 12 months of treatment there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment PEG was more effective in normalizing blood counts and reducing driver mutation burden, while HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk ET/PV patients. (Funded by the National Cancer Institute, 5P01CA108671-09; clinicaltrials.gov number (NCT01259856)

scholarly journals What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia?

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 480-488 ◽  
Author(s):  
Alessandro M. Vannucchi ◽  
Paola Guglielmelli
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
State Of The Art ◽  
Myeloproliferative Neoplasms ◽  
Symptom Burden ◽  
Current Treatment ◽  
Interferon Α ◽  
Jak2 Inhibitor ◽  
Chronic Myeloproliferative Neoplasms

Abstract Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the “state of the art” in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies. Several unmet needs remain, above all, the lack of a curative approach that might overcome the still burdensome morbidity and mortality of these hematologic neoplasms, as well as the toxicities associated with therapeutic agents.

scholarly journals Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5109-5117 ◽  
Author(s):  
Shu Xing ◽  
Tina Ho Wanting ◽  
Wanming Zhao ◽  
Junfeng Ma ◽  
Shaofeng Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transgenic Mice ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Gene Promoter ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Transgenic Expression ◽  
Cell Counts

Abstract The JAK2V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2V617F, showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2V617F can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2V617F and to develop treatment for MPDs.

scholarly journals A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study

Blood ◽  
2020 ◽  
Vol 136 (18) ◽  
pp. 2038-2050 ◽  
Author(s):  
Constantine S. Tam ◽  
Stephen Opat ◽  
Shirley D'Sa ◽  
Wojciech Jurczak ◽  
Hui-Peng Lee ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Phase 3 ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Major Response ◽  
Significant Difference ◽  
Duration Of Response ◽  
Btk Inhibitor ◽  
Grade 3

Abstract Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

scholarly journals Complex intracranial vascular complications caused by essential thrombocythemia: a critical case report

BMC Neurology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Jian Xie ◽  
Leiyu Geng ◽  
Baoyu Yuan ◽  
Yijing Guo ◽  
Zhijun Zhang
Keyword(s):  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasm ◽  
Vascular Complications ◽  
Arterial Occlusion ◽  
Vascular Lesions ◽  
Cerebellar Hemisphere ◽  
Interferon Α ◽  
Cell Counts ◽  
Hemorrhagic Complications ◽  
The Right

Abstract Background Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated and dysfunctional platelets. ET can result in systemic thrombotic and hemorrhagic complications, and it’s a rare cause of stroke. The coexistence of multiple vascular lesions has seldom been reported in patients with essential thrombocythemia. Case presentation A young woman presented with isolated and persistent vertigo and vomiting. The CT scan indicated a hyperdense lesion in the right cerebellar hemisphere. No signs of cerebral artery malformation were observed in the CT angiography (CTA). Besides, the blood tests indicated an increase in platelet and white blood cell counts. The patient then suddenly developed a transient unconsciousness with left horizontal nystagmus when staring to the right. The subsequent cranial magnetic resonance imaging (MRI) scans indicated a diffuse and acute infarction of the pons and hemorrhage in the bilateral cerebellums. Further digital subtraction angiography (DSA) revealed a progressive and critical intracranial vertebral arterial occlusion. The patient’s clinical condition stabilized after cytoreductive therapy with interferon-α (IFN-α), even though endovascular and antiplatelet treatments were restricted because of the simultaneous presence of intracerebral hemorrhage (ICH) and ischemic stroke. A JAK2 V617F mutation was later detected through genetic testing, further confirming the diagnosis of ET. The patient was treated with a continuous regimen of IFN-α, and an antiplatelet treatment (aspirin) was added after ICH. The 1-year follow-up indicated normal platelet levels and no additional stroke event. Conclusions This case demonstrates that ET can be a rare cause of the cerebrovascular disease (CVD), even though the coexistence of ischemic and hemorrhagic complications. Underlying hematological system diseases should be taken into account when abnormal hemogram and CVD are concurrent in a patient. An early multidisciplinary diagnosis and intervention could significantly improve patient’s prognosis.

scholarly journals 1256. Contemporary Evaluation of Racial/Ethnic Disparities in Survival and Disease Progression among People with HIV in the US Midwest

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S451-S452
Author(s):  
Rohan Khazanchi ◽  
Harlan R Sayles ◽  
Sara H Bares ◽  
Susan Swindells ◽  
Jasmine R Marcelin ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Ethnic Disparities ◽  
Hiv Viral Load ◽  
Risk Status ◽  
Cd4 Counts ◽  
Patient Demographics ◽  
Significant Difference ◽  
Race Ethnicity ◽  
Racial Ethnic

Abstract Background Combating HIV-related disparities is a major goal of the 2020 National HIV/AIDS Strategy. However, research on HIV disparities has primarily been conducted in urban settings. A 1997–2007 study of people with HIV (PWH) at our clinic noted significantly increased mortality among high-risk non-Hispanic (NH) Black PWH (73%) compared with NH Whites (88%). This study evaluated demographic disparities in survival and disease progression in a large Midwest clinical cohort. Methods We retrospectively reviewed records of 1,396 PWH receiving treatment at an HIV Clinic in Omaha, Nebraska from 2012 through 2017. We included patients over 19 years old with diagnosed HIV, a minimum of two visits, and no lapse in care >2 years. Patients were stratified into low-risk (CD4 >100 cells/mm3 and HIV viral load <250,000 copies/mL) and high-risk (all others) groups. Cox proportional hazard models and Kaplan–Meier curves with log-rank tests compared patient demographics and mortality. Generalized estimating equations modeled change in CD4 count over time. Results No significant difference in mortality was noted across race/ethnicity categories (P = 0.286). Several clinical and demographic characteristics, including CD4 counts <500 cells/mm3, were significantly associated with increased mortality (Figure 1). Compared with NH Whites, mean CD4 counts (Figure 2) were significantly lower for NH Blacks (P = 0.001), Hispanics (P = 0.006), and Others (P = 0.013). High-risk status was associated with mortality (P < 0.001), but no significant differences in mortality were noted across race/ethnicity categories after stratifying for patient risk status (Figures 3 and 4). Conclusion Significant racial/ethnic disparities in HIV disease progression among PWH at a Midwest HIV Clinic persist. However, in contrast to the 1997–2007 study, disparities in survival were not observed among high-risk PWH. As our patient demographics are essentially the same, the reduction of this disparity suggests needed investigation of whether these changes are the result of better antiretroviral efficacy or if social determinants of health in the region have improved. Systems-level interventions are needed to ensure all PWH benefit from continuing advances in HIV research and care. Disclosures All authors: No reported disclosures.

Comparison of Intravascular Ultrasound Virtual Histology Parameters in Diabetes versus Non-Diabetes with Acute Coronary Syndrome

Cardiology ◽  
2020 ◽  
Vol 145 (9) ◽  
pp. 570-577
Author(s):  
Sreenivas Reddy ◽  
Vikas Kadiyala ◽  
Jeet Ram Kashyap ◽  
Raghavendra Rao ◽  
Hithesh Reddy ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
High Risk ◽  
Intravascular Ultrasound ◽  
Vascular Complications ◽  
Necrotic Core ◽  
High Dose ◽  
Virtual Histology ◽  
Coronary Syndrome ◽  
Minimal Lumen Area ◽  
Significant Difference

Introduction: The progression and pattern of coronary atherosclerosis in diabetes mellitus (DM) is different from non-DM, leading to a higher rate of vascular complications in DM. Objective: This study aims to assess and compare the high-risk plaque characteristics in the culprit artery of DM and non-DM patients with acute coronary syndrome (ACS) using virtual histology intravascular ultrasound (VH-IVUS). Methods: A total of 158 ACS patients were included, 63 of whom were known to have DM. IVUS analysis was done in the de novo target vessel and culprit lesion for which percutaneous coronary intervention was planned. Culprit lesions with a visual-estimate angiographic stenosis of <70% were excluded. Results: The mean age of patients was 52.4 ± 11.6 years. The study group comprised 82% men, 31% with hypertension, and 39.87% with DM. No significant difference was observed between the DM and non-DM groups in relation to quantitative IVUS parameters like lesion length, minimal lumen area, and plaque area. However, there was a significant difference in VH-IVUS parameters like higher necrotic core and dense calcium in the DM patients than in the non-DM patients (p < 0.01). The occurrence of VH-derived thin-cap fibroatheroma (VH-TCFA) in the culprit vessel was significantly higher in the DM group than in the non-DM group (25.3 vs. 5.2%; p < 0.01). Positive vessel-wall remodeling was noted in both groups without any significant difference (p = 0.74). Conclusion: The DM patients had high-risk plaque composition features like a higher necrotic core, which is a marker of plaque vulnerability. Thus, aggressive medical therapy targeting vascular inflammation using high-dose statins would help in the stabilization of unstable plaque morphology and the reduction of major cardiovascular events.

Telomerase and Telomeres in Polycythemia Vera and Essential Thrombocythemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4948-4948
Author(s):  
Andrea Gallamini ◽  
Anna Maria Ferraris ◽  
Daniele Mattei ◽  
Natalija Pujic ◽  
Rosa Mangerini ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Mononuclear Cells ◽  
Chronic Phase ◽  
Extended Period ◽  
Myeloproliferative Disorders ◽  
Telomerase Activity ◽  
Prognostic Indicators ◽  
Immature Myeloid Cells ◽  
Clonal Development

Abstract Polycythemia Vera (PV) and Essential Thrombocythemia (ET) are chronic myeloproliferative disorders (CMPD) with a relatively favorable prognosis and a long natural history. They originate from a multipotent progenitor cell with dominance of the transformed clone over normal hematopoiesis. However, the heterogeneity of these diseases with respect to clonal development from a common progenitor has been established, and no specific molecular or cytogenetic markers are so far considered useful prognostic indicators. In the current study we correlate telomerase activity (TA) and telomeres [terminal restriction fragment (TRF)] lengths in granulocytes (PMN) and mononuclear cells (MNC), with the results of the clonality status, as determined by investigation of X chromosome inactivation patterns (XCIPs), from 22 informative female patients with ET and PV. All patients were in chronic phase without immature myeloid cells in the peripheral blood. After testing for heterozygosity at the HUMARA locus PMN expressed a monoclonal XCIP in 9 out of 13 subjects with ET (69%), and in 6 out of 9 with PV (67%). MNC were always polyclonal. The amount of TA for each reaction was expressed in Total Product Generated (TPG) units. ΔTRF length was calculated by subtracting the telomer length of PMNs from that of MNCs and expressed as kilobases. TA and ΔTRF results were blindly compared with those from XCIP analysis. Monoclonal PMN displayed a TA ranging between 47.6 and 212.5 TPG units (mean 118.2 ± 45.5 SD), whereas polyclonal PMN had a TA between 1.0 and 33.3 TPG units (mean 14.4 ± 11.9 SD) (p<0.001). MNC had a TA similar to that of polyclonal PMN. Mean ΔTRF of clonal PMNs was 4.6 kilobases, while that of polyclonal PMNs was 0.44 kilobases (p<0.001). PMNs from normal control subjects had a mean ΔTRF of 0.1 kilobases, similar to that of polyclonal PMNs (p= n.s.). The results of our study clearly show the existence of two distinct subgroups of CMPD, with polyclonal or monoclonal granulopoiesis, each of them correlating with a peculiar pattern of TA and telomere lengths. Although none of the patients analyzed showed any difference in clinical characteristics with respect to the parameters considered, we believe that TA and ΔTRF analysis and their relationship with clonality status may represent an useful tool for further investigation, to predict survival in larger cohorts of patients with PV and ET, over an extended period of follow up.

Methylation of Progesterone Receptor Promoter-Associated CpG Island in Polycythemia Vera and Related Myeloproliferative Disorders.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3507-3507
Author(s):  
Jaroslav Jelinek ◽  
Srdan Verstovsek ◽  
Carlos E. Bueso-Ramos ◽  
Josef T. Prchal ◽  
Jean-Pierre J. Issa
Keyword(s):  
Progesterone Receptor ◽  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Cpg Island ◽  
Cpg Islands ◽  
Myeloproliferative Disorders ◽  
Receptor Expression ◽  
Quantitative Detection ◽  
Jak2 Mutation ◽  
A Genome

Abstract Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF) are clonal myeloproliferative disorders (MPD). A recently discovered activating mutation of JAK2 tyrosine kinase has been found in most patients with polycythemia vera (PV), in about half of those with essential thrombocythemia (ET) and myelofibrosis (MF), and in 10–20% patients with chronic myelomonocytic leukemia, Philadelphia-negative CML, atypical or unclassified MPD and megakaryocytic leukemia. It is not known what other factors determine the disease phenotype of PV, MF, and other MPD, and what factors other than JAK2 lead to disease progression. Very little is known about epigenetic changes in PV. DNA methylation of promoter-associated CpG islands is a well-recognized mechanism of epigenetic silencing used by tumors for evasion from regulatory mechanisms, and it is an alternative to genetic lesions in cancer causation. Using a genome-wide screen for differentially methylated CpG islands, we found methylation of progesterone receptor promoter region (PGR) in PV granulocytes. We then developed pyrosequencing assays for quantitative detection of PGR methylation in bisulfite-treated PCR-amplified DNA. The PGR methylation above normal control levels was observed in ET (2/12 patients, 17%), PV (10/22 patients, 45%), MF (8/12 patients, 67%), and patients with acute myeloid leukemia and antecedent PV (6/7 patients, 86%). We compared the levels of PGR methylation in MPD with the mutation status of JAK2. The 1849G&gt;T JAK2 mutation was present in 16/27 (59%) MPD patients with unmethylated PGR and 21/26 (80%) patients with methylated PGR; the difference not statistically significant; p=0.135. The role of progesterone receptor signaling in hematopoiesis is not known. Using real time quantitative RT-PCR assay for progesterone receptor expression we found detectable levels in granulocytes from 4/5 normal individuals while the expression in granulocytes from 5/5 PV patients was not detectable. To assess the functional significance of progesterone receptor silencing, we explored the effect of mifepristone, a progesterone receptor antagonist, on the response of BFU-E progenitors to erythropoietin. Mifepristone increased the sensitivity of BFU-E progenitors from normal blood to low concentrations of erythropoietin (60–250 mU/ml) suggesting that disabling of progesterone receptor may increase the response of hematopoietic cells to proliferative stimuli. In conclusion, our data show that PGR methylation is present in half of PV patients and it is even more frequent in MF and PV transformed to AML. Silencing of progesterone receptor by methylation may be an epigenetic change contributing to MPD phenotype and transformation to leukemia.

A Phase 3 Pilot Study of Continuous Imatinib Versus Pulsed Imatinib with or without G-CSF in Patients with Chronic Phase CML Who Have Achieved a Complete Cytogenetic Response to Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1033-1033 ◽  
Author(s):  
Nicholas Heaney ◽  
Mark Drummond ◽  
Jaspal Kaeda ◽  
Franck Nicolini ◽  
Richard Clark ◽  
...  
Keyword(s):  
Pilot Study ◽  
Disease Progression ◽  
Residual Disease ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Phase 3 ◽  
Significant Difference ◽  
Ifn Therapy

Abstract Imatinib mesylate (IM) induces complete cytogenetic responses (CCR) in the majority of patients with CML in chronic phase (CP). Despite this reduction in disease burden many patients continue to have detectable Bcr-Abl transcripts in peripheral blood. We believe that IM-resistant Ph+ haemopoietic stem cells (HSC) contribute to this residual disease. IM has been shown to selectively target proliferating CML HSC, while simultaneously exerting an antiproliferative effect on the quiescent population-causing accumulation. We have previously characterised these quiescent cells and shown that intermittent in-vitro exposure of Ph+HSC to exogenous G-CSF leads to a reduction in number of quiescent and total HSC in culture (Clin Can Res 2006, 12: 626). This randomised, multi-centre, pilot phase 3 study was established to determine the safety and efficacy of combining G-CSF with IM in patients with CP CML who had achieved CCR on IM. 45 patients were equally randomised between 3 arms: continuous IM (cIM); pulsed IM (pIM 3 weeks IM and 1 week no drug); and pIM-G-CSF (pIM-G 3 weeks IM and 1 week G-CSF). The dose of IM administered was the dose on which the patient had achieved CCR. Patients had a median age of 59y (25–76y) and had been diagnosed with CML for a median of 36m (8–171m). 21 patients had prior IFN therapy with 4 autografted. Hasford scores were 36% low, 46% Intermediate, and 18% high. At baseline 25 patients had a major molecular response (MMR cIM 7, pIM 8, pIM-G 10). Patients were assessed monthly for 1 year with clinical examination, routine blood tests and Bcr-Abl Q-RT-PCR. Significant cardiovascular events were seen in 2 patients - 1 patient died of myocardial infarction (pIM-G) and 1 survived a stroke (cIM). There was a trend to less IM-associated side effects (diarrhoea, muscle cramps) in the experimental arms, though bony pain was reported in pIM-G (5 patients). Statistical analysis (ANCOVA) was performed on Bcr-Abl readings taken during the trial and no significant difference was detectable between the 3 arms. Further endpoint analyses showed that 4 achieved MMR (4 cIM) 21 maintained MMR (6 cIM, 6 pIM, 9 pIM-G) and 7 showed disease progression with loss of MMR (1 cIM, 2 pIM, 1 pIM-G) and/or loss of CCR (2 pIM, 1 pIM-G). 4 patients were withdrawn as a result of disease progression (3 pIM, 1 pIM-G). In conclusion both experimental arms appeared safe and well tolerated. In this pilot study there was no clear difference in efficacy when either pIM or pIM-G was compared to cIM, despite the 25% effective dose reduction of IM in the experimental arms. The absence of a clear benefit means that this approach cannot be recommended as an alternative to standard IM dosing, however may be applicable to a selected group of patients who cannot tolerate standard daily dosing.

Sign in / Sign up

Export Citation Format

Share Document