scholarly journals Oral idasanutlin in patients with polycythemia vera

Blood ◽  
2019 ◽  
Vol 134 (6) ◽  
pp. 525-533 ◽  
Author(s):  
John Mascarenhas ◽  
Min Lu ◽  
Heidi Kosiorek ◽  
Elizabeth Virtgaym ◽  
Lijuan Xia ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Polycythemia Vera ◽  
Phase 1 ◽  
Jak2 V617f ◽  
Receive Combination Therapy ◽  
Low Grade ◽  
Hematopoietic Stem ◽  
Prior Therapy ◽  
Mdm2 Antagonist ◽  
Interferon Α2a

Abstract A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.

Dysregulated Expression of miRNAs in Polycythemia Vera Erythroid Progenitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3613-3613
Author(s):  
Hana Bruchova ◽  
Amos S. Gaikwad ◽  
Joshua Mendell ◽  
Josef T. Prchal
Keyword(s):  
Gene Expression ◽  
Polycythemia Vera ◽  
Jak2 V617f ◽  
Prediction Algorithm ◽  
Erythroid Cell ◽  
Molecular Defect ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Homogeneous Population

Abstract Polycythemia vera (PV), the most common myeloproliferative disorder, arises due to somatic mutation(s) of a single hematopoietic stem cell leading to clonal hematopoiesis. A somatic JAK2 V617F point mutation is found in over 80% of PV patients; however, it is not clear if the JAK2 V617F is the disease initiating mutation, sincethere are PV JAK2 V617F negative patients who have monoclonal hematopoiesis and erythropoietin independent erythropoiesis;in individual PV families, there are PV subjects with and without the JAK2 V617F mutation; andanalysis of clonal PV populations reveals the presence of <50 and >50% mutated JAK2 cells (Nussenzweig’ abstract this mtg), suggesting a mixed population of cells with regard to JAK2 status.In order to search for possible PV contributing molecular defect(s), we studied microRNAs (miRNAs) in a homogeneous population of in vitro expanded erythroid progenitors. MiRNAs are non-coding, small RNAs that regulate gene expression at the posttranscriptional level by direct mRNA cleavage, by translational repression, or by mRNA decay mediated by deadenylation. MiRNAs play an important regulatory role in various biological processes including human hematopoiesis. In vitro expanded erythroid progenitors were obtained from peripheral blood mononuclear cells of 5 PV patients (JAK2 V617F heterozygotes) and from 2 healthy donor controls. The cells were cultured in an erythroid-expansion medium for 21 days resulting in 70–80% homogenous erythroid cell population of identical differentiation stage. Gene expression profiling of miRNAs (Thomson, Nature Methods, 1:1, 2004) was performed using a custom microarray (Combimatrix) with 326 miRNA probes. Data were normalized by the global median method. The miRNAs with expression ratios greater than 1.5 or less than 0.5 were considered to be abnormal. Comparative analyses of controls versus PV samples revealed up-regulated expression of miR-let7c/f, miR-16, miR-451, miR-21, miR-27a, miR-26b and miR-320 and down-regulation of miR-150, miR-339 and miR-346 in PV. In addition, miR-27a, miR-26b and miR-320 were expressed only in PV. The putative targets of these miRNAs were predicted by TargetScan prediction algorithm. Up-regulated miR-let-7, miR-16 and miR-26b may modulate cyclin D2, which has an important role in G1/S transition and can be a target in the JAK2/STAT5 pathway (Walz, JBC, 281:18177, 2006). One of the putative targets of up-regulated miR-27a is EDRF1 (erythroid terminal differentiation related factor1), a positive regulator of erythroid differentiation. The BCL-6 gene is predicted to be the target of miR-339 and miR-346, and its activation blocks cellular differentiation. MiR-16 is known to be down-regulated in CLL, where it targets anti-apoptotic BCL-2; in contrast, we show that miR-16 is up-regulated in PV erythroid cells. We identified differentially expressed miRNAs in PV which target genes involved in the JAK/STAT pathway or genes that are modulated by JAK2 downstream molecules. This study indicates that miRNA dysregulation may play an important role in erythropoietic differentiation and proliferation in PV. Expression analyses of these miRNAs in a larger set of PV samples, using quantitative Real-Time-PCR, are in progress. Further, earlier erythroid and pluripotent hematopoietic progenitors are also being analyzed.

An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive Polycythemia Vera and Essential Thrombocytosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 99-99 ◽  
Author(s):  
Alison R Moliterno ◽  
Gail J. Roboz ◽  
Martin Carroll ◽  
Selina Luger ◽  
Elizabeth Hexner ◽  
...  
Keyword(s):  
Adverse Events ◽  
Polycythemia Vera ◽  
Performance Status ◽  
Jak2 V617f ◽  
Spleen Size ◽  
Inclusion Criteria ◽  
Essential Thrombocytosis ◽  
Serious Adverse Events ◽  
Hematopoietic Stem ◽  
Secondary Endpoints

Abstract Polycythemia vera (PV) and essential thrombocytosis (ET) are clonal hematopoietic stem cell disorders characterized by the over production of phenotypically normal circulating blood cells. Most PV and approximately half of ET patients harbor the activating mutation JAK2 V617F. CEP-701 is an orally available, potent low nanomolar inhibitor of both the wild-type and mutated JAK2 tyrosine kinase, with its inhibitory effect demonstrated both in enzymatic and cellular assays and in vivo, where CEP-701 significantly inhibited the growth of JAK2 V617F-positive HEL.92 xenografts in mice. These findings suggest that CEP-701 is an attractive candidate for clinical evaluation in JAK2 V617F-positive myeloproliferative disorders. The purpose of this study is to test the safety and efficacy of CEP-701 administration in JAK2 V617F positive ET and PV patients. The primary endpoint is reduction in JAK2 V617F neutrophil allele burden; secondary endpoints are reduction in phlebotomy rates, improvement in hemoglobin, white cell and platelet counts, reduction in hydroxyurea (HU) dose, and reduction in spleen size. The secondary endpoints include the pharmacokinetics and pharmacodynamics of CEP-701 and the safety of CEP-701 treatment in patients with JAK2 V617F-positive PV and ET. This is a multicenter study with an anticipated enrollment of 40 PV and ET patients. Inclusion criteria include JAK2 V617F-positive PV and ET patients; patients with PV either have a neutrophil count greater than 7,000/ul or are receiving HU, while ET patients are receiving concomitant HU. Other inclusion criteria include an ECOG performance status of 0, 1 or 2, and 18 years of age or older. Exclusion criteria include the active use of anegrelide or interferon, or a recent history of venous or arterial thrombosis. This is an 18 week trial with an optional 1 year extension period; doses will escalate from 80 mg twice daily to a maximum of 120 mg twice daily. To date, 20 subjects, 11 PV and 9 ET, comprised of 11 females and 9 males, ages 34 to 74, have enrolled. Approximately 27% of the PV patients were taking HU. The most common adverse events have been gastrointestinal (GI) and constitutional in nature. No related serious adverse events have been observed. Five patients have discontinued study participation, all for adverse events: 1 due to disease progression, 1 leg cramps, and 3 GI. To date, 7 patients have completed 18 weeks of therapy and 6 of these patients will continue to receive CEP-701 on the extension phase of the trial. Five of 8 subjects with splenomegaly have responded with reductions in spleen size evident within 6 weeks of therapy initiation. Updated results on current and future patients will be presented at the meeting.

A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 98-98 ◽  
Author(s):  
Neil P. Shah ◽  
Patrycja Olszynski ◽  
Lubomir Sokol ◽  
Srdan Verstovsek ◽  
Ronald Hoffman ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Reversible Inhibitor ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Costal Margin ◽  
Spleen Size ◽  
Activating Mutation

Abstract JAK2 V617F has been identified as a constitutive activating mutation in approximately half of patients with myelofibrosis (MF). MF, a myeloproliferative disorder comprised of primary myelofibrosis and the clinically indistinguishable entities of post-polycythemia vera or post essential thrombocythemia MF, has been reported to have a median survival of 4 years [Dupriez et al. (1996) Blood88:1013–18]. No effective therapies exist for patients with MF. XL019 is a potent, highly selective and reversible inhibitor of JAK2 which may have utility in treating MF, by ameliorating hepato-splenomegaly, constitutional symptoms, and progressive anemia. The objectives of this phase 1 study include safety evaluation, preliminary assessments of efficacy using International Working Group (IWG) response criteria for MF, and evaluation of pharmacokinetic and pharmacodynamic endpoints. Pharmacodynamic evaluations include quantitative PCR for peripheral blood JAK2 V617F allele burden and erythropoietin-independent colony formation. In addition, plasma and fixed blood samples are being collected to evaluate changes in protein biomarkers and JAK2 signaling pathways. To date, XL019 has been studied in 21 patients over multiple dose levels ranging from doses of 25 mg to 300 mg using different schedules of administration (3 weeks on, 1 week off; QD; and QMWF). Median age was 64 years (range, 47–87 years) and 16 patients (76%) carried the JAK2V617F mutation. Additionally, one patient had a MPLW515F mutation in the absence of a JAK2 mutation. No treatment-related hematologic adverse events (i.e. thrombocytopenia, anemia, neutropenia) have been observed to date. Reversible low-grade peripheral neuropathy (PNP) was observed in 7/9 patients treated at daily doses of ≥100 mg (Grade 1: 5 patients; Grade 2: 2 patients). XL019 doses below 100 mg using 2 different dosing schedules are currently being evaluated. To date, XL019 has resulted in reductions in splenomegaly and leukocytosis, stabilization of hemoglobin counts, improvements in blast counts, and resolution or improvement in generalized constitutional symptoms. The median spleen size in 15 patients measured below the costal margin by palpation was 14cm (range, 3–26cm). Three of 15 patients with palpable splenomegaly at baseline were JAK2 V617F mutation negative and did not experience spleen size reduction. Twelve of 12 (100%) evaluable patients with an activating mutation (JAK2 V617F: 11 patients; MPLW515F: 1 patient) experienced reduction in spleen size and 5 (42%) had a ≥50% decline from baseline. Ten of 11 patients with JAK2V617F activating mutations and baseline constitutional symptoms, reported improvements in generalized constitutional symptoms which include pruritus and fatigue. No significant non-hematologic or hematologic toxicity has been observed at the current dose level. On 25 mg dosing schedules, no signs of PNP have been observed with a follow-up period of up to 4 months. Overall, XL019 has demonstrated encouraging clinical activity and is generally well tolerated.

scholarly journals How I treat polycythemia vera

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 275-284 ◽  
Author(s):  
Francesco Passamonti
Keyword(s):  
Polycythemia Vera ◽  
Myeloproliferative Neoplasms ◽  
Phase 1 ◽  
Signal Transduction Pathway ◽  
Jak2 V617f ◽  
Prior History ◽  
Oncogenic Mutations ◽  
Clinical Presentations ◽  
History Of ◽  
Disease Stratification

Abstract Polycythemia vera (PV) is a clonal disorder characterized by unwarranted production of red blood cells. In the majority of cases, PV is driven by oncogenic mutations that constitutively activate the JAK-STAT signal transduction pathway, such as JAK2 V617F, or exon 12 mutations or LNK mutations. Diagnosis of PV is based on the WHO criteria. Diagnosis of post-PV myelofibrosis is established according to the International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria. Different clinical presentations of PV are discussed. Prognostication of PV is tailored to the most frequent complication during follow-up, namely, thrombosis. Age older than 60 years and prior history of thrombosis are the 2 main risk factors for disease stratification. Correlations are emerging between leukocytosis, JAK2(V617F) mutation, BM fibrosis, and different outcomes of PV, which need to be confirmed in prospective studies. In my practice, hydroxyurea is still the “gold standard” when cytoreduction is needed, even though pegylated IFN-alfa-2a and ruxolitinib might be useful in particular settings. Results of phase 1 or 2 studies concerning these latter agents should however be confirmed by the ongoing randomized phase 3 clinical trials. In this paper, I discuss the main problems encountered in daily clinical practice with PV patients regarding diagnosis, prognostication, and therapy.

Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7508-7508 ◽  
Author(s):  
Farhad Ravandi ◽  
Roland B. Walter ◽  
Marion Subklewe ◽  
Veit Buecklein ◽  
Mojca Jongen-Lavrencic ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Residual Disease ◽  
Phase 1 ◽  
Dose Range ◽  
Dose Schedule ◽  
Cell Transplant ◽  
Dependent Manner ◽  
Dose Escalation Study ◽  
Hematopoietic Stem ◽  
Prior Therapy

7508 Background: In this open label phase 1 dose escalation study, safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of AMG 330 were evaluated in patients (pts) with R/R AML (NCT#02520427). Methods: AMG 330 was evaluated as a continuous IV (cIV) infusion using a 3+3 design. Response was assessed per revised IWG criteria. Each cycle (2–4 weeks duration) was followed by an infusion-free interval. Eligible pts were ≥18 y/o with > 5% blasts in bone marrow and ≥1 line/s of prior therapy. Results: As of December 10, 2019, 55 pts (median age, 58.0 [18.0–80.0] years) were enrolled in 16 cohorts. AMG 330 was administered on 4 schedules (0–3 dose steps) prior to the target dose (TD, 0.5–720 µg/day). Dose steps were implemented in the dose schedule design based on the adverse event (AE) profile. Across all schedules, 55 (100%) pts reported treatment-emergent AEs (any grade). AMG 330–related AEs reported in 49/55 (89%) pts included cytokine release syndrome (CRS; 67%; ≥ grade 3 in 13%), (60%) and nausea (20%) as the most frequent AEs. CRS was reversible and occurred in a dose/schedule-dependent manner mostly within the first 24 hours of administration of triggering AMG 330 dose. The frequency and severity of CRS correlated with the dose level and leukemic burden at baseline. AMG 330 exhibited dose-dependent increase in steady state exposures over the studied dose range with clinical PK profile consistent with cIV administration. Eight of 42 evaluable pts responded: 3 complete remissions (CR; including 1 CR with negative measurable residual disease reported after data snapshot), 4 CR with incomplete hematologic recovery, and 1 morphologic leukemia free state. Seven responders who achieved CR/CRi received a TD equal or above the minimal efficacious dose of 120 μg/day. Among analyzed CR/CRi responders, 4/6 (67%) had adverse cytogenetic risk profile, 3/6 (50%) had ≥4 lines of prior therapy and all had relapsed disease. Responders had higher AMG 330 exposures and 3 responders treated with ≥600 μg/day TD remain in CR/CRi: 1 patient for > 5 months after cycle 1, 1 patient bridged to hematopoietic stem cell transplant after cycle 4 and 1 patient is in cycle 3. Preliminary response assessment showed a correlation with lower tumor burden at baseline with a trend towards higher CD8+ lymphocyte count and E:T ratio. Conclusions: AMG 330 dosed up to 720 μg/day provided early evidence of acceptable safety profile, drug tolerability and anti-leukemic activity, and supports further dose escalation. Clinical trial information: NCT02520427 .

Thrombopoietin Receptor (MPL) Genotype Modifies the Myeloproliferative Phenotype in a JAK2 V617F Transgenic Mouse Model of Polycythemia Vera.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 964-964
Author(s):  
Jerry L. Spivak ◽  
Donna M Williams ◽  
Brady L. Stein ◽  
Ophelia Rogers ◽  
Tsivia Hochman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mouse Model ◽  
Hematopoietic Stem Cells ◽  
Polycythemia Vera ◽  
Transgenic Mouse ◽  
Gene Dosage ◽  
Jak2 V617f ◽  
Transgenic Mouse Model ◽  
Single Mutation ◽  
Hematopoietic Stem

Abstract Abstract 964 The JAK2 V617F mutation is primarily associated with three chronic myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) but how a single mutation could be responsible for three different disorders is still unresolved. A gene dosage effect was proposed based on the MPD phenotypes in mice with differential expression of a JAK2 V617F transgene, where low expression correlated with an ET phenotype and high expression with a PV phenotype. However, quantitative studies of JAK2 V617F expression in humans revealed significant overlap between PV and ET. Since JAK2 is the cognate tyrosine kinase for the erythropoietin (EPO) and thrombopoietin (TPO) receptors, and JAK2 V617F is expressed in pluripotent hematopoietic stem cells, PV is the ultimate clinical phenotype of the mutation. Furthermore, TPO but not EPO promotes the survival and proliferation of pluripotent hematopoietic stem cells, suggesting that the TPO receptor (Mpl) is essential not only for generating thrombocytosis, but also the stem cell expansion that is characteristic of PV. To examine the role of Mpl in the genesis of the JAK2 V617F MPD phenotype, we manipulated the MPL genotype in a transgenic mouse expressing 13 copies of JAK2 V617F (V617Ftg) (Blood 111:5109, 2009) by breeding these mice with MPL knockout mice (Science265:1445, 1994), which are hematologically normal except for profound thrombocytopenia, to create three genotypes: V617Ftg/MPL wild type (wt); V617Ftg/MPL heterozygote (het), and V617Ftg/MPL knockout (ko). We compared the blood counts, spleen weights, plasma TPO levels, and bone marrow and spleen histology of these three genotypes with each other and with MPL wt, MPL het and MPL ko mice over a 33 week period. Crossbreeding gave the expected genotypes, JAK2 V617F transgene expression was stable in all groups, platelet Mpl expression by immunoblotting correlated with MPL genotype, there was no unexpected mortality, and body weights were not different for any of the genotypes during the observation period. As expected, in V617Ftg/MPL wt mice there was a robust and persistent thrombocytosis (2087 +/− 641 × 106/μL vs 1005 +/− 176 × 106/μL, p<0.001), an erythrocytosis (hemoglobin, 18.3 +/− 1.1 gm % vs 14.9 +/− 0.72 gm %, p <0.001) that peaked at 14-16 weeks but then diminished, and a leukocytosis (16.3 +/− 5.1 × 106/μL vs 12.9 +/−3.4 ×106/μL, p = 0.043) as compared to MPL wt mice. By contrast, in V617Ftg/MPL ko mice, the PV phenotype was virtually abrogated in all cell types as compared to V617Ftg/MPL wt (hemoglobin, 16.1 +/− 0.87 vs 18.3 +/− 1.1, p< 0.001; leukocyte count, 11.3 +/− 2.8 vs 16. 3 +/− 5.1 , p= 0.003, and platelet count, 293 +/− 102 vs 2087 +/− 641, p< 0.001), and not different than their MPL ko counterparts except for a mild erythrocytosis (16.1 +/− 0.9 vs 14.9 +/−, p < 0.001), while in V617Ftg/MPL het mice, erythrocytosis was comparable to the V617Ftg/MPL wt mice and higher than in MPL het controls (17.9 +/− 1.4 gm% vs 14.9 +/− 0.9 gm % p <0.001), but there was only minimal thrombocytosis (1310 +/− 274 × 106/μL vs 1021+/− 241 × 106/μL, p< 0.001), and no leukocytosis (14.8 +/− 4.0 106/μL vs 14.1 +/− 3.7 × 106/μL, p=0.4 ) as compared to the MPL het mice. Marrow and spleen histology reflected the genotype and blood counts and spleen weight was increased equally in all three V617Ftg/MPL genotypes as compared to controls. Plasma TPO was elevated in MPL ko (5530 +/− 1334 pg/mL, p =0.006) and V617Ftg/MPL ko (4201 +/− 736 pg/mL, p = 0.001 ), but not in MPL het mice (723 +/− 720 pg/mL), compared to MPL wt mice (323 +/− 62 pg/mL), while in V617Ftg/MPL wt (163 +/− 52 pg/mL, p < 0.001) and V617Ftg/MPL het mice (176 +/− 56 pg/mL, p < 0.001) plasma TPO was lower than in MPL wt mice. Based on these data, we conclude that MPL genotype is an important modifier of the MPD phenotype in a JAK2 V617F transgenic mouse model of PV, not only for thrombopoiesis but, importantly, also for erythropoiesis and myelopoiesis. We also infer from these data that the impaired Mpl expression observed in human PV may also be a significant modifier of the JAK2 V617F phenotype, either by acting as a dominant-negative with respect to JAK2 V617F activity, or possibly through impaired plasma TPO regulation. Disclosures: No relevant conflicts of interest to declare.

Patients with Polycythemia Vera and Essential Thrombocytosis Have a Higher Risk of Prior or Concurrent Tumors Compared to Patients with Secondary Thrombocytosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3084-3084
Author(s):  
Krisstina Gowin ◽  
Caroline Irene Piatek ◽  
Siamak Saadat ◽  
Karren Cuadra ◽  
Pedram Razavi ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Myeloproliferative Neoplasms ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Age At Diagnosis ◽  
World Health ◽  
Low Grade ◽  
Complication Rates ◽  
Essential Thrombocytosis ◽  
Hematopoietic Stem

Abstract Abstract 3084 Background Polycythemia vera (PV) and Essential thrombocytosis (ET) are chronic myeloproliferative neoplasms (MPNs) that arise from aberrant, clonal hematopoietic stem cells. MPNs are associated with an elevated risk of arterial and venous thrombosis as well as with transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). Diseases causing secondary, or reactive, elevation of the red cell or platelet counts are not considered clonal and do not predispose to the development of hematologic malignancies. Prior reports in patients of European descent suggest as many as 15% of patients with MPNs die of unrelated malignancies, but there is no data suggesting that these malignancies precede the MPN diagnosis. In a large, ethnically diverse population, we investigated whether tumors other than MF or AML (“unrelated tumors”) occurred more commonly among patients with ET and PV than among patients with secondary thrombocytosis. Methods We performed a retrospective chart review of all consecutive patients diagnosed with ET, PV or secondary thrombocytosis (ST) between April, 1992 and June, 2010. Laboratory data and the World Health Organization criteria were utilized to distinguish ET, PV and ST. In addition to demographic and MPN-specific diagnostic data and complication rates, we recorded the prior or concurrent, pathologically-confirmed diagnosis of unrelated tumors, their histology and treatment received. We performed a multivariate, exact logistic regression analysis adjusted for age at diagnosis of MPN, sex, ethnicity, JAK2 mutational status and MPN subtype to determine whether MPN patients are more likely to have had unrelated tumors than ST patients. Results Seventy-six patients with MPNs, 55 with ET and 21 with PV, were compared to 82 patients with ST. The median age at diagnosis in the MPN group was 53.5 years (range 19 –84); it was 46 years in the ST group (range 16 – 87). The majority (57.9%) of the patients with MPNs were Hispanic whites, 21% were Asian, 15.8% were non-Hispanic whites, and 5.3% were Black. Of the 82 patients with ST, 73.2% were Hispanic whites, 9.8% were Asian, 9.8% were Black and 4.9% were non-Hispanic whites. Thrombosis occurred in 12 (15.8%) of the MPN patients and in none of the ST patients. We observed a statistically significantly higher incidence of unrelated tumors in MPN patients (17.1%) as compared to ST patients (1.2%). The multivariate analysis revealed an odds ratio for unrelated tumors among MPN patients of 5.19 (95% CI 1.04 – 22.1, p = 0.038) compared to ST patients. Of the 13 unrelated tumors which were diagnosed among patients with MPN, 11 were diagnosed prior to the MPN diagnosis and included 5 breast cancers (2 treated surgically, 2 treated with surgery, radiation and chemotherapy, 1 treated with surgery and radiation only); 3 neural tumors including 1 meningioma, 1 pituitary macroadenoma, and 1 schwannoma (all treated with surgery alone); 2 hematologic malignancies including a low grade B-cell lymphoma and a rectal MALT lymphoma (1 treated with combination chemotherapy and 1 treated with Rituxan alone); and 1 prostate cancer (treated with hormonal therapy alone). Two patients developed unrelated tumors during the course of their MPN; these included 1 patient with gastrointestinal stromal tumor and 1 with multiple myeloma. Interestingly, the latter patient has maintained a normal platelet count without cytoreductive ET therapy for the 18 months since autologous transplant for his myeloma. Conclusions Patients with PV and ET have a significantly higher risk of having prior or concurrent tumors unrelated to progression of their MPN when compared to patients with ST. Disclosures: No relevant conflicts of interest to declare.

A phase II study of temozolomide and oral VP-16 for adults with recurrent glioma—Final results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1565-1565 ◽  
Author(s):  
D. N. Korones ◽  
M. Benita-Weiss ◽  
T. Coyle ◽  
P. Bushunow ◽  
L. Mechtler ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Low Grade Glioma ◽  
Recurrent Glioma ◽  
Low Grade ◽  
Entire Cohort ◽  
Low Grade Gliomas ◽  
Prior Therapy ◽  
Anaplastic Gliomas

1565 Background: Although temozolomide has proven activity in patients with high and low grade gliomas, many patients do not respond, and for those who do, responses are often short-lived. We therefore undertook a trial of temozolomide in combination with oral VP-16 (etoposide) for patients with recurrent glioma. Methods: Patients were eligible for the study if they had recurrence of a glioma (glioblastoma [GBM], anaplastic glioma, or low-grade glioma), were ≥ 18 years of age, had a WHO score of 0–2, and had not received prior therapy with temozolomide or oral VP-16. All patients received temozolomide, 150 mg/m2/d days 1–5 and oral VP-16, 50 mg/m2/d days 1–12 (based on the maximum tolerated dose established in a previous phase 1 study [Cancer 2003, 97 (8); 1963–68.]). Cycles were repeated every 28 days for up to 12 cycles. All patients received prophylaxis for pneumocystis. Results: Fifty-one patients were enrolled - 32 with glioblastoma, 12 with anaplastic gliomas, and 7 with low-grade glioma. Median age was 52 years (21–76), and 67% were male. Forty-one were enrolled at first and 10 at second recurrence. Fifty had had prior radiation, and 30 of these 50 patients had also received prior chemotherapy. Of the 32 subjects with GBM, 4 had a PR (12.5%), 13 (41%) SD, 13 (41%) PD, and 2 were not evaluable because of deterioration prior to imaging. The median progression-free survival (PFS) was 2 mo. (0–51+ mo), and the 6 mo. PFS was 19%. Of the 12 patients with anaplastic gliomas, 2 had a PR (16%), 7 SD (58%), 2 PD (16%) and one was not evaluable. Their median PFS was 5.5 mo, and the 6 mo. PFS was 50%. Of the seven subjects with low grade gliomas, 4 had a PR, 2 SD, and 1 PD. Their median PFS was 5 mo. (0–12) and 6 mo. PFS was 57%. Of the entire cohort, two patients developed fever and neutropenia and died of pseudomonas sepsis. Another two patients were prematurely withdrawn from the study due to toxicity (one for grade 4 neutropenia and a second for grade 2 diarrhea). Conclusions: In this population of previously treated patients with recurrent glioma, the combination of oral VP-16 and temozolomide has only modest efficacy and significant toxicity. The results of this study suggest that in this setting, the combination offers no advantage over either agent used alone. [Table: see text]

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