Clinical Characteristics and Cardioavscular Events in Patients with Esential Thrombocythemia with <10% Vs. ≥10% JAK2 V617F Allele Burden

Introduction The clinical characteristics, treatment, cardiovascular events (CVE) and evolution of patients diagnosed with JAK2 V617F positive essential thrombocythemia (ET) with low allele burden (LAB) are scarcely studied. Its presence in people without a confirmed diagnosis of malignant hemopathy is called clonal hematopoiesis of uncertain significance (CHIP) and confers higher risk of developing CVE. The objective of this study was to compare the clinical characteristics and CVE of a series of JAK2 V617F-positive ET patients with <10% (LAB) vs. ≥10% allele burden (HAB), from the GEMFIN (Grupo Español de Enfermedades Mieloproliferativas Crónicas Filadelfia Negativas) Group. Methods From the database of the GEMFIN group, 410 ET patients were JAK2 V617F positive, 89 (21.7 %) with LAB and 321 (78.3%) with HAB. The clinical characteristics, treatment (cytoreduction, antiagregation, anticoagulation, JAK inhibitor), CVE (before, at and after diagnosis) and evolution to myelofibrosis (MF) or acute myeloid leukemia (AML) of these two groups of patients were compared. Results LAB and HAB groups did not significantly differ regarding the main clinical characteristics (i.e cardiovascular risk factors [CVRF] and International Prognostic Score for Thrombosis in Essential Thrombocythemia [IPSET] score) except for the median platelet count: LAB 636 x109/L [436- 2500] vs HAB 687 x109/L[440-1980L], p=0.035). CVE after diagnosis of ET were more frequent in patients with HAB (41/137, 30%) than in patients with LAB (5/48, 10%), p=0.007. Only one LAB patient with CVE had JAK2 allele burden >5%. Treatments received by both groups were not significantly different. None of the patients from both groups progressed to AML, whereas 1/48 vs. 6/137 of patients evolved to MF. Median follow-up of patients with LAB and HAB was 3.4 years [0.1-17.7] and 4.3 years [0.1-27.8], respectively (Table 1). Conclusions In these series of ET patients from the GEMFIN group, patients with LAB had significantly lower median platelet count at diagnosis and less CVE after diagnosis than patients with HAB, although CVRF and IPSET scores and treatment approach were similar. The clinical behavior of LAB patients may resemble that of individuals with CHIP. The therapeutic algorithm of ET patients with LAB may be somehow different than that of patients with HAB and therefore, might be revised. Disclosures Bellosillo: Astra-Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biocartis: Honoraria; Merck-Serono: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman â€"La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; ThermoFisher: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; BMS: Honoraria. Hernandez Boluda:Incyte: Other: Travel expenses paid. Pérez:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Imetelstat Rapidly Induces and Maintains Substantial Hematologic and Molecular Responses in Patients with Essential Thrombocythemia (ET) Who Are Refractory or Intolerant to Prior Therapy: Preliminary Phase II Results

Blood ◽

10.1182/blood.v120.21.179.179 ◽

2012 ◽

Vol 120 (21) ◽

pp. 179-179 ◽

Cited By ~ 4

Author(s):

Gabriela M. Baerlocher ◽

Elisabeth Oppliger Leibundgut ◽

Christina Ayran ◽

Martha Blaney ◽

Bart Burington ◽

...

Keyword(s):

Platelet Count ◽

Maintenance Therapy ◽

Progenitor Cells ◽

Board Of Directors ◽

Essential Thrombocythemia ◽

Research Funding ◽

Jak2 V617f ◽

Advisory Committees ◽

Allele Burden ◽

Prior Therapy

Abstract Abstract 179 Background: Myeloproliferative neoplasms (MPNs), such as essential thrombocythemia (ET), are driven by neoplastic progenitor cells. The JAK2 V617F mutation can be detected in approximately 50% of patients (pts) with ET, and the JAK2 V617F allele burden can be used to measure the treatment-induced molecular response (MR) over time. Telomerase is upregulated in neoplastic progenitor cells and sustains indefinite replication. Imetelstat is a first in class, potent, specific inhibitor of telomerase which selectively distributes to bone marrow and inhibits thrombopoiesis. In vitro studies demonstrate that imetelstat selectively inhibits spontaneous megakaryocytic colony-forming unit (CFU-Meg) growth from the blood of pts with ET but not from healthy individuals. Phase I studies have demonstrated that imetelstat inhibits telomerase activity in pts at doses of 7.5 mg/kg and above. Therefore, unlike conventional cytoreductive therapy and JAK2 kinase inhibitors, imetelstat may be uniquely able to selectively inhibit proliferation of neoplastic clonogenic cells in pts with ET and modify the biology and progression of the disease. Methods: A phase II study enrolled pts with ET who had failed or were intolerant to at least one prior therapy, or who refused standard therapy. Pts were treated with imetelstat 7.5 mg/kg or 9.4 mg/kg IV weekly. After attainment of best platelet response in the induction phase, maintenance dosing with imetelstat was commenced with dosing based upon platelet count. Primary endpoint was best overall hematologic response (HR) with complete response (CR) defined as platelet count <400 × 103/μl maintained for at least 4 consecutive weeks in the absence of new thromboembolic events. A key secondary endpoint was rate of MR in patients with JAK2 V617F molecular mutations. JAK2 V617F allele burden was measured by allele-specific quantitative real-time PCR with a limit of detection of 0.1%. CFU-Meg growth pre- and post-treatment and tolerability were also assessed. Results: As of July 9, 2012, 13 pts were treated. Median age was 60 yrs (range 21–83) with a median of 2 prior treatments (range 1–3). Median years since initial diagnosis were 5.8 (range 0.3 to 24.9) and initial platelet count was 809 × 103/μl (range 601 to 1359 × 103/μl). Best overall HR was 100%, with 11 of 13 pts achieving a confirmed CR after a median of 6.1 weeks (range 5.1 to 14.1 wks). Twelve of 13 pts remain on maintenance therapy (median time on study 26.1 weeks) and despite transient elevations of platelets above best response, pts continue to be responsive to imetelstat. Four pts have reached 1 year of therapy and continue to be treated with ongoing HR. Dosing frequency on maintenance therapy was generally reduced with time. A substantial decrease in JAK2 V617F allele burden was demonstrated in all 5 JAK2 V617F-positive pts (mean allele burden reduction of 82%; range of 59–94%, see table below). Four pts who were eligible for MR assessment by LeukemiaNetcriteria (initial JAKV617F allele burden >10%) reached molecular partial responses (PR): one pt after 12 weeks, which has been maintained through 1 year, and 3 other pts at 24, 36 and 48 weeks of therapy. One additional pt with JAK2 V617F levels of 4.8% prior to therapy has also had a 75% reduction after 12 weeks of treatment. A reduction in the spontaneous growth of CFU-Meg was also observed in the 2 pts tested, with 93% and 96% reduction from baseline, respectively. Long-term administration of imetelstat was generally well tolerated. Common adverse events reported on therapy were mild to moderate gastrointestinal toxicities, reductions in neutrophil counts, and fatigue. Conclusions: Imetelstat rapidly induces and maintains hematologic responses in pts with ET who have failed or are intolerant to conventional therapies. Importantly, substantial MR is observed in all JAK2 V617F-positive pts and inhibition of the neoplastic clonogenic growth ex-vivo is demonstrated. The reduction in JAK2 V617F allele burden and cytokine-independent growth of CFU-Meg suggests that imetelstat has a relatively selective inhibitory effect on the growth of the neoplastic clone(s) which drive ET and has the potential to modify the underlying biology of MPNs. Additional data will be presented from this ongoing study. Disclosures: Baerlocher: Geron Corporation: Research Funding. Oppliger Leibundgut:Geron Corporation: Research Funding. Ayran:Geron Corporation: Employment. Blaney:Geron Corporation: Employment. Burington:Geron Corporation: Employment. Morfeld:Geron Corporation: Employment. Odenike:Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Reddy:Geron Corporation: Employment. Roeth:Geron Corporation: Research Funding. Stuart:OncoMed Pharmaceuticals: Consultancy; Geron Corporation: Consultancy, Employment.

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Distinct Clinical, Laboratory, and Molecular Features of Myeloproliferative Neoplasm Patients Presenting with Splanchnic Vein Thrombosis

Blood ◽

10.1182/blood.v128.22.3121.3121 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3121-3121

Author(s):

Joan How ◽

Stephen T. Oh ◽

Kathryn M. Trinkaus

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Mutant Allele ◽

Jak2 V617f ◽

Continuous Variables ◽

Disease Phenotype ◽

Advisory Committees ◽

Allele Burden ◽

Vein Thrombosis ◽

Cell Counts

Abstract BACKGROUND: Myeloproliferative neoplasms (MPN), including polycythemia vera (PV), essential thrombocythemia (ET), and primary meylofibrosis (PMF), are frequently associated with splanchnic vein thromboses (SVT). Risk factors for SVT in MPN patients differ from risk factors for all-cause thrombosis. This is likely due to differing disease mechanisms at play, and suggest a separate disease phenotype for MPN/SVT patients. While several studies have characterized the features of MPN patients with SVT, a direct comparison of MPN/SVT versus all MPN patients has been lacking. METHODS: We performed a retrospective, cross-sectional analysis of patients at Barnes-Jewish Hospital from 2000-2014 with MPN and SVT. Patients were identified using ICD-9 codes in the electronic medical record. 52 available patients with both MPN and SVT were included. Randomly selected 134 patients with MPNs only were used as controls. Clinical and laboratory variables were compared between the two groups. Quantitative JAK2 V617F allele burdens were available in 20 patients. As continuous variables were not normal in distribution, a Mann-Whitney U test was performed. Non-continuous variables were compared with an N-1 Chi-squared test to accommodate rare events. All p-values were corrected for multiple testing. RESULTS: MPN/SVT patients were significantly younger at time of MPN diagnosis (median age 47 vs 57 years, p=0.003). MPN/SVT patients were more likely to have splenomegaly (83% vs 30%, p=0.003), deep vein thrombosis (37% vs 15%, p=0.003), and concomitant thrombophilia (17% vs 2%, p=0.003). MPN/SVT patients had a higher proportion of females (63% vs 54%), but this finding did not reach significance. However, PV/SVT patients had a significantly higher proportion of females compared to PV alone (67% vs 37%, p=0.02). There were no significant differences in JAK2 mutation status, race, smoking status, presence of stroke or coronary artery disease risk factors. MPN/SVT patients had significantly lower hemoglobin (13.1 vs 14.6, p=0.024), hematocrit (39.3 vs 43.5, p=0.027), and platelet count (513 vs 698, p=0.003) at time of MPN diagnosis. When analysis was restricted to PV, only hemoglobin (14.6 vs 17.24, p=0.007) and hematocrit (44.3 vs 50.68, p=0.012) were significantly lower in SVT patients. No significant differences in cell counts were detected in ET and PMF patients. MPN/SVT patients had significantly lower JAK2 mutant allele burdens, with no MPN/SVT patient having an allele burden greater than 10% (p=0.019) (Figure 1). In contrast, mutant allele burdens for MPN patients ranged from 0.1 to 99.7%, with median allele burden being 36.3%. DISCUSSION: This is the first study to directly compare clinical and laboratory features of MPN patients with and without SVT. Our results confirm that MPN/SVT patients are younger, and within PV are more likely to be female. We also demonstrate that MPN/SVT patients have lower cell counts and lower JAK2 mutant allele burdens, findings not previously shown in the literature. MPN/SVT patients are more likely to have splenomegaly, concurrent thrombophilia, and additional DVT. These results indicate that MPN/SVT patients exhibit a disease phenotype distinct from MPN patients without SVTs. While the nature of this study is retrospective and causality cannot be definitively established, the findings of younger age, lower laboratory values, and lower JAK2 allele burden are consistent with the hypothesis that MPN/SVT patients present early in disease. It is possible that in MPN/SVT patients, other environmental and host factors (such as concurrent thrombophilia), in combination with early MPN disease, result in the first manifestation of SVT. These findings have important implications, as investigating the natural course of MPN/SVT patients would allow insight into MPN disease pathogenesis. These findings also suggest that SVTs in MPN patients are not solely mediated by elevated cell counts. In addition, while the presence of the JAK2 V617F mutation likely does affect thrombotic risk, the finding of lower allele burdens in MPN/SVT patients suggests that additional interactions mediate SVT development. These interactions are likely multifactorial and include both environmental and genetic factors. Of particular interest would be the presence of yet unidentified driver mutations present in MPN/SVT patients. Disclosures Oh: Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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Danazol As First-Line Therapy for Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v128.22.5528.5528 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5528-5528

Author(s):

Perla Rocío Colunga-Pedraza ◽

Alejandra Garza-Ledezma ◽

Julia Colunga-Pedraza ◽

Olga Cantu-Rodriguez ◽

Rosa Elena Lozano-Morales ◽

...

Keyword(s):

Platelet Count ◽

Blood Cell ◽

Board Of Directors ◽

Neutrophil Count ◽

Clinical Characteristics ◽

Refractory Anemia ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy

Abstract Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological disorders characterized by ineffective hematopoiesis and variable degrees of peripheral cytopenias. Neither curative nor standard therapy has been available yet for the majority of patients with MDS. Patients with available matched donor may undergo an allogeneic bone marrow transplant with a potential cure rate 30-50%. Danazol is a synthetic anabolic steroid with properties similar to corticosteroids, such as inhibition of interleukin-1 and TNF-α production. Also, has demonstrated activity in immune cytopenias and aplastic anemia but its efficacy in MDS has shown contradictory results. Recently there has been increasing interest in telomere dysfunction in hematological diseases. Short telomeres are the major prognostic risk factor for clonal evolution to myelodysplasia and acute leukemia. Danazol not only prevents telomere loss, but a mean increase occurs with improvement observed early during the course of hormone therapy. In our center with poor access to new strategies and therapies the use of danazol remains as an attractive option for patients with MDS because of its low cost. In this study we aim to document the clinical evolution of patients diagnosed with MDS treated with danazol as first-line therapy in our institution. Methods: We include patients diagnosed with MDS according to WHO criteria treated with danazol between 2005 and 2015. Response was defined as one or more of the following criteria: a rise in the platelet count >25 x 109/I, an increase in hemoglobin >2 g/dl or disappearance of a previous requirement for red blood cell transfusion, or an increase in neutrophil count >0.5 x 109/L. All patients received packed red blood cell and platelet transfusions according to physician criteria. Patients were given intravenous or oral antibiotics as needed as prophylaxis. Criteria for stop danazol included: no response to treatment, toxicity or patient's refusal to continue treatment. Blood counts were preformed at least 1-month intervals for the first 4 months. We compared those who responded versus no responders using the Student's t test or Mann-Whitney U test as corresponded. Results: Forty-two patients with MDS were treated with danazol. Median follow-up was 12 months (range 3-75). Median dose used was 400 mg (range 100-600) orally in two divided doses. Mean duration of treatment for all patients was 6 months (range 3-72 months). The distribution by WHO subtypes included 26 refractory cytopenia with multilineage dysplasia (RCMD) (62%), 6 patients with refractory cytopenia with unilineage dysplasia (RCUD), 6 refractory anemia with excess blasts (RAEB), 2 refractory anemia with ring sideroblasts (RARS) and 1 MDS associated with isolated del(5q). Twenty-four (60%) patients presented clinical response. Response for patients with anemia was 23.8% (10/24), increase in absolute neutrophil count occurred in 36.8% (7/19), and 60% (24/40) presented an increase in platelet count. Time to initial response was 2 months (range, 1-8) while time to better response of 3 month (range, 1-8). Response was not associated to any MDS classification or administrated dose. Toxicity was mild and danazol was not discontinued in any patient. Side effects included three patients with gastrointestinal symptoms, and 4 patients reported weight gain. Median overall survival was 24 months (CI95% 5.1-42). Fifteen patients died (35.7%). Five patients progressed to AML. Conclusion: Different agents have been used in MDS. However, for the majority of patients with MDS no curative treatment exists. In conclusion our data suggest that Danazol may be effective in MDS with minimal toxicity, especially in patients with thrombocytopenia. Response was independent of severity, WHO classification and administrated dose. Table Clinical characteristics of responders versus non-responders Table. Clinical characteristics of responders versus non-responders Disclosures Gomez-Almaguer: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol: 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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MPL SV, a Unique MPN MPL Splice Variant, Provokes a Fulminant Myeloid Leukemia in a JAK2 V617F Transgenic Mouse Model of Polycythemia Vera

Blood ◽

10.1182/blood.v126.23.484.484 ◽

2015 ◽

Vol 126 (23) ◽

pp. 484-484 ◽

Cited By ~ 1

Author(s):

Jerry L. Spivak ◽

Donna Marie Williams ◽

Zhizhuang Joe Zhao ◽

Ophelia Rogers ◽

Amy S. Duffield ◽

...

Keyword(s):

Platelet Count ◽

Polycythemia Vera ◽

Board Of Directors ◽

Splice Variant ◽

Copy Number ◽

Jak2 V617f ◽

Common Denominator ◽

Wild Type ◽

Advisory Committees ◽

Copy Numbers

Abstract Introduction: The MPN, polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) are clonal stem cell disorders, which share mutations constitutively activating the physiologic signal transduction pathways for hematopoiesis. Although the MPN have different natural histories, they share in common transformation to myelofibrosis and acute leukemia at differing frequencies and not explainable by a specific mutation. Impaired MPL expression, due to incomplete glycosylation is another common denominator amongst the MPN. Significantly, MPL is the only hematopoietic growth factor receptor expressed in MPN HSC, and we have demonstrated that the PV phenotype in a JAK2 V617F transgenic (V617tg) mouse could be abrogated by elimination of MPL or its ligand, TPO. Impaired MPL expression in the MPN cannot be completely explained by receptor-activated down regulation because not all MPN driver mutations directly activate MPL. However, we have discovered another common denominator in the MPN, variant MPL splicing, eliminating 7 amino acids in the MPL N-terminal domain, a common hotspot for both MPL driver and inactivating mutations, which impairs MPL glycosylation and expression. Methods: To determine the role of the MPL splice variant (MPL SV) in MPN pathophysiology, we cloned the full length MPLSV cDNA and created a transgenic mouse (MPLSV tg) using the same VAV promoter as the V617Ftg mouse to ensure hematopoietic cell-specific transcription. The MPLSV tg mice were produced by pronuclear injection of purified MPLSV cDNA into B6SJLF1 mice. Founders were crossed into a C57Bl/6 background, and then were crossed with V617Ftg mice in either an MPL knockout or wild type background. Mice were phenotyped by blood counts and necropsy with morphologic and immunophenotyping of bone marrow and tumor masses. Results: Amongst 19 founder B6SJLF1 mice, 6 expressed the MPLSV transgene with copy numbers ranging from one to 30; single copy number mice had no hematopoietic phenotype but all mice with higher MPLSV tg copy numbers had thrombocytopenia (median platelet count 500,000/µL; range 200- 600,000; wild type, 750,000/µL; 550-950,000). MPLSV tg mice from several different founders bred into a C57Bl/6 background for 6 generations maintained consistent copy numbers, Mendelian ratios and hematopoietic phenotypes with 100% penetrance and an inverse correlation between MPLSV copy number and the platelet count. The number of double transgenic (V617Ftg/MPLSV tg) offspring observed in the MPLSV tg to V617Ftg crosses were slightly lower than expected (20% vs 25%), indicating reduced embryo viability. Four week old V617Ftg/MPLSV tg mice displayed tumorous abnormalities of the head and hips as well as small size and failure to thrive (median weight 8.5 gms; range 8-9; wild type, 13 gms; 10-14), and enlarged spleens (median weight 0.29 gms; range 0.15-0.64; wild type 0.086 gms; 0.05-0.10). Histologically, the V617Ftg/MPLSV tg-associated head and hip abnormalities represented monomorphic myeloid sarcomas extending through the calvarium both extra and intracranially and from the femur into surrounding muscle. Both the marrow and spleen were diffusely infiltrated by large blasts with abundant basophilic cytoplasm, expressing CD34, CD61 and CD117 but lacking CD127, consistent with a myeloid origin. All V617Ftg/MPLSV tg mice either died or required humane sacrifice by 6 weeks. The extramedullary tumor was transplantable in secondary recipients, and flow cytometry-based phenotyping showed that the tumors (both primary and secondary) were CD34, CD117, CD61 and CD71- positive. Penetrance of the leukemia phenotype was 100% in V617Ftg/MPLSV tg from all founder lines with multiple copies of the MPLSV tg, whether in an MPL knockout or wild type background. The leukemia phenotype was never observed with the MPLSV tg alone or with V617Ftg alone despite observation of over 300 V617Ftg mice up to 50 weeks of age. Conclusion: We identified an MPL SV in human MPN that was functional in mice with a dominant-negative effect with respect to platelet production and at the same time synergized with JAK2 V617F to create a fulminant myeloid malignancy. We have recently shown that knockout of MPL or TPO alone abrogates the PV phenotype in the V617Ftg mouse, whereas the MPLSV uniquely drives a highly penetrant and fulminant leukemia, establishing MPL and TPO as targets for mitigation of malignant transformation in the MPN. Disclosures Spivak: Incyte: Membership on an entity's Board of Directors or advisory committees. Moliterno:incyte: Membership on an entity's Board of Directors or advisory committees.

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Ruxolitinib for Patients (Pts) with Polycythemia Vera: Responders Vs Non-Responders As Defined in the Response Trial

Blood ◽

10.1182/blood-2019-128101 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2947-2947

Author(s):

Srdan Verstovsek ◽

Jean-Jacques Kiladjian ◽

Monika Wroclawska ◽

Tuochuan Dong ◽

Alessandro M. Vannucchi

Keyword(s):

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Hematological Parameters ◽

Jak2 V617f ◽

Spleen Volume ◽

Advisory Committees ◽

Allele Burden ◽

To Receive ◽

Response Trial

Introduction: The RESPONSE trial (NCT01243944) compared ruxolitinib (Rux) and best available therapy (BAT) in pts with polycythemia vera (PV) who were intolerant of or resistant to hydroxyurea (HU) according to modified European LeukemiaNET criteria. In the primary analysis, at week (Wk) 32, 60% of (pts) randomized to Rux achieved HCT control (HCT <45%). The present analysis evaluated the effect of baseline characteristics on HCT response at Wk 32, and aimed to determine the long-term clinical efficacy of Rux in pts who did and did not achieve the protocol-defined HCT control (i.e., HCT control responders and non-responders at Wk 32) in RESPONSE at Wk 256. Methods: Adult pts with phlebotomy-dependent PV with splenomegaly, and resistant to or intolerant of HU were enrolled. Pts were randomized to receive Rux (at a starting dose of 10 mg BID) or single-agent BAT (1:1). HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (HCT > 45% and ≥ 3 percentage points higher than baseline or > 48%, whichever was lower; regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In this analysis, a logistic regression model was fitted to identify the significant baseline factors to predict HCT control response at Wk 32. Time to phlebotomy eligibility in the HCT control responders and time from the first phlebotomy eligibility to the second phlebotomy eligibility in the HCT control non-responders were plotted, and the changes in hematological parameters (HCT, WBC and platelet count), spleen volume and allele burden over time, up to Wk 256, were studied in HCT control responders and non-responders who were randomized to Rux treatment arm in RESPONSE. Results: A total of 222 pts were randomized to receive either Rux (n = 110) or BAT (n = 112). Baseline WBC (P=0.0198) and baseline JAK2 V617F allele burden (P=0.0159), were found to be predictors of the HCT response within Rux treated pt group (n = 110). In the HCT responder subgroup of the Rux arm, 23% (15/66) pts needed their first phlebotomy by Wk 256. In the HCT non-responder subgroup of the Rux arm, out of 28 patients who experienced their first phlebotomy between Wk 8 and Wk 32, 64% (18/28) of pts required subsequent phlebotomy by Wk 256, with a median duration of 28.4 Wks (12.7, NA). Pts receiving Rux demonstrated controlled hematologic parameters (HCT, WBC, and platelets) over the course of study, regardless of whether they were HCT control responders and HCT control non-responders at Wk 32. From Wk 48 to Wk 80, 97% HCT control responder pts and 84% HCT control non-responder pts of the Rux treatment arm required no phlebotomies. From Wk 80 to Wk 256, 91% and 68% of the evaluable pts in the Rux treatment arm remained phlebotomy-free for HCT control responders and non-responders, respectively. By Wk 256, spleen volume on an average was reduced from baseline by approximately 35% and 50% for HCT control responders and non-responders, respectively. In pts with available assessments, allele burden on an average was reduced approximately from 80% at baseline to 55% at Wk 256 in the HCT control responders, and approximately from 70% at baseline to 40% at Wk 256 in the HCT control non-responders. Conclusions: The results from present analysis demonstrated that the benefits of the Rux treatment were not limited to pts who achieved HCT control at Wk 32. Patients treated with Rux were able to maintain hematological parameters, spleen volume reduction, and JAK2 V617F allele burden reduction for a longer duration (up to 5 years), regardless of whether they were HCT control responders or non-responders at Wk 32. Disclosures Verstovsek: Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding. Kiladjian:Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding. Wroclawska:Novartis Pharma AG: Employment. Dong:Novartis: Employment. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.

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Impact of Underlying Mutational Profile, and Changes during Treatment, in MPN Patients Treated with JAK Inhibitors

Blood ◽

10.1182/blood.v126.23.353.353 ◽

2015 ◽

Vol 126 (23) ◽

pp. 353-353

Author(s):

Paola Guglielmelli ◽

Annalisa Pacilli ◽

Giada Rotunno ◽

Francesca Gesullo ◽

Alessandro Pancrazzi ◽

...

Keyword(s):

Platelet Count ◽

Clinical Response ◽

Mutational Analysis ◽

Jak2 V617f ◽

Symptomatic Improvement ◽

Driver Mutations ◽

Jak Inhibitors ◽

Advisory Committees ◽

Allele Burden ◽

Calr Mutations

Abstract Background. Most patients (pts) with MPN derive clinical benefits from treatment with JAK inhibitors (JAKi) but predictors of response or loss of response have not been clearly identified. Aims. To address the impact of underlying mutational profile of driver mutations (JAK2V617F, CALR, MPL), including other genes of JAK/STAT pathway, and "subclonal" (epigenetic, spliceosome) mutations, and their modifications under treatment, on the response to JAKi. Methods. 100 patients with WHO2008-diagnosis of MPN, 39 PV, 14 ET, 64 MF (37 PMF, 27 PPV/PET-MF), were included. 25 (12PV, 13 MF) had received hydroxyurea (HU), 75 (20 PV, 7 ET, 48 MF) a JAKi (67 ruxolitinib, 8 fedratinib). Response criteria were as by IWG-MRT (Blood 2013; 121:4778; Blood 2013; 122:1395). Mutations in 22 genes (JAK1, JAK2, JAK3, EZH2, ASXL1, TET2, IDH1, IDH2, CBL, SRSF2, DNMT3A, NFE2, SOCS1, SOCS2, SOCS3, SH2B3, STAT1, STAT3, STAT5A, STAT5B, SF3B1, U2AF1) were analyzed in blood DNA at baseline (bl) and at the latest available sample by deep sequencing with Ion Torrent-PGM. CALR mutations were analyzed by capillary electrophoresis; JAK2 V617F allele burden was measured by RT-qPCR assays. The nonparametric Wilcoxon rank-sum test, Kaplan-Meier method and Cox regression, were used for statistical analysis. Results. A. Impact of baseline mutational profile. PV and ET:At bl, 17/40 (42.5%) pts had subclonal mutations. Spleen volume reduction (SVR) by IWG-MRT criteria was obtained in 100% of pts without subclonal mutations compared to 66% of those with >1 mutations (P=0.04). Presence of NFE2 mutations uniformly predicted for lack of SVR (P=0.03). Loss of SVR was predicted by ASXL1 mut (67% vs 12% in un-mutated; P<0.05). No correlation of mutations with symptomatic improvement, normalization of leukocyte and platelet count, and control of hematocrit to <45% in PV pts was noticed. A trend to lower pruritus responses were seen in PV pts harboring >1 subclonal mutations (P=0.06). JAK2 V617F homozygous pts were more prone to have platelet count control (81%) compared to heterozygous (30%; P<0.04). MF:At bl, 33/64 (51.5%) pts had subclonal mutations. No correlation of mutations with symptomatic improvement, normalization of leukocyte and platelet count was found. SVR was not predicted by a high molecular risk status (Leukemia 2013;27:1861; Blood 2014;123:2157); however, harboring >1 of the 22 mutations was negatively associated with SVR (P=0.02) (HR 1.9, 95% CI 1.0-4.6). No correlation of JAK2 V617F or CALR mutations, or the allele burden, on SVR or loss of SVR was discovered. B. Changes during treatment. PV and ET:follow-up mutational analysis was performed at median treatment duration of 2.9y HU, 4.7y ruxolitinib, 1.7y fedratinib in 50 pts for driver mutation and 40 pts for subclonal genes. Of HU pts (n=12), 33% each had JAK2 V617F allele burden stable, increased and reduced by >10%. Median reduction of allele burden was -18.3%. 1 pt acquired 2 novel subclonal mutations (ASXL1, EZH2) and 2 showed increased allele burden of ASXL1 and TET2 by >10%. Among JAKi pts (n=30), 20 pts (66.7%) had JAK2 V617F allele burden reduction by a median of -33.3% (-13.6 to -100%), stable in 9. Degree of allele burden reduction was positively correlated with length of JAKi treatment (P=0.04). 1 pt acquired novel ASXL1, 2 pts had increase (ASXL1, EZH2) and 6 pts reduction of >10% of allele burden (4 TET2, 1 DNMT3A, 1 SH2B3). No correlation was seen with clinical response over time. MF: follow-up mutational analysis was performed at median treatment duration of 2.4y HU, 1.9y ruxolitinib, 1.4y fedratinib. HU pts (n=13): of the 7 JAK2 V617F mut, 4 increased and 1 decreased the allele burden, and 1 of 3 CALR mutated reduced allele burden, by >10%. 1 pt acquired CBL mutation, other mutations (n=7) were stable. Among JAKi treated pts, of the 41 JAK2 V617F mutated, 51% showed a median allele burden reduction of -14.8% (-10.5% to -53.9%). Of 10 pts with subclonal mutations at baseline, 4 clones (3 ASXL1 and 1 NFE2) increased and 2 (EZH2, ASXL1) decreased by >10%. Only 1 pt acquired a novel mutation in EZH2. No correlation was seen with clinical response over time. Discussion. These data suggest that only minimal influence on clinical response is provided by driver mutations and their allele burden, or subclonal mutations, in MPN patients receiving JAKi. The clinical relevance of different clone fluctuations over treatment with conventional therapy and JAKi remains to be addressed. Disclosures Vannucchi: Baxalta: Membership on an entity's Board of Directors or advisory committees; Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Disease and Clinical Characteristics of Patients with Essential Thrombocythemia Enrolled in the MOST Study

Blood ◽

10.1182/blood-2018-99-112183 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4306-4306

Author(s):

Abdulraheem Yacoub ◽

Roger M. Lyons ◽

Srdan Verstovsek ◽

Ryan Shao ◽

David Tin Chu ◽

...

Keyword(s):

United States ◽

Observational Study ◽

Board Of Directors ◽

Essential Thrombocythemia ◽

Research Funding ◽

Clinical Characteristics ◽

The United States ◽

Advisory Committees ◽

History Of ◽

Equity Ownership

Abstract Introduction: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by clonal platelet production and an increased risk for thrombotic and hemorrhagic events. Limited real-world data exist regarding the clinical characteristics and treatment patterns of ET in the United States; most prior data have been generated outside the United States. The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, and patient-reported outcomes in patients with specific risk categories of myelofibrosis (MF) or ET in the United States. This analysis describes the clinical characteristics of patients with ET currently enrolled in MOST. Methods: MOST is a multicenter, noninterventional, prospective, observational study in patients with a clinical diagnosis of specific risk categories of MF or ET (NCT02953704). Eligible patients with ET included high-risk patients (≥ 60 years of age and/or a history of thromboembolic events [TEs]), or low-risk patients currently receiving ET-directed therapy. Key exclusion criteria included participation in blinded investigational drug studies, life expectancy ≤ 6 months, or diagnosis of other malignancy. Data regarding disease and clinical characteristics are collected at usual-care visits over a planned 36-month observation period. Patient demographics and clinical characteristics at enrollment were described with descriptive statistics. Results: At data cutoff (May 18, 2018), 793 eligible patients were enrolled from 85 sites since November 29, 2016. The median age at enrollment was 70 (range, 24-95) years, 66.5% were female, and 89.8% were Caucasian. The median time from ET diagnosis to enrollment was 4.2 (range, 0.0-42.1) years with a proportion of patients diagnosed within 1 year (19.5%), 1 to < 5 years (35.0%), 5 to < 10 years (21.7%), or ≥ 10 years (23.8%) of enrollment. Approximately 40% of patients were retired and 42.7% were working full- or part-time at enrollment. A total of 212 patients (26.7%) had a history of TE at the time of enrollment. The type of TE was available for 148 patients, the most common was arterial events (53.4%); 33.1% had venous, and 13.5% of patients had both arterial and venous events. Six hundred and eighty-eight patients (86.8%) were classified as high-risk. Assessments at the time of ET diagnosis, among evaluable patients, included bone marrow biopsy (51.4%; 393/765) and mutational testing (77.2%; 590/764). Three hundred and forty-nine patients had mutation test results reported at the time of diagnosis; of patients with JAK2 V617F test results reported at the time of diagnosis (n = 313), 78.6% were positive for JAK2 V617F (Table 1). Laboratory values and peripheral blood counts were reported for patients with available data (Table 2). The majority of patients (87.9%) had received at least 1 ET-directed therapy prior to enrollment, which in some cases was the same medication the patient was receiving at the time of enrollment. At the time of enrollment, 740 patients (93.3%) were receiving at least 1 current ET-directed therapy, including HU (71.6%; 530/740), anagrelide (13.1%; 97/740), ruxolitinib (4.7%; 35/740), interferon (3.0%; 22/740), and busulfan (0.3%; 2/740). Of 793 patients, the most frequently occurring relevant comorbid conditions were hypertension (52.7%), history of smoking (44.7%), and hyperlipidemia (24.1%). Among 761 patients with ET-related symptoms assessed at diagnosis, the most common symptoms documented by healthcare providers included constitutional (22.9%), vasomotor (16.0%), and spleen-associated symptoms (3.9%), and pruritus (2.6%). Conclusions: Prior real-world data in ET has predominately been generated outside of the United States or has been reported from single institutional experiences. The MOST study will provide a more complete picture of the patient characteristics and outcomes of patients receiving ET-directed therapy in the United States. Ultimately, these data will be important for determining ET treatment gaps and areas of unmet need. Disclosures Yacoub: Cara Therapeutics: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ardelyx, INC.: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Shao:ASH: Membership on an entity's Board of Directors or advisory committees; ASCO: Membership on an entity's Board of Directors or advisory committees. Agrawal:Incyte: Speakers Bureau. Sivaraman:Incyte: Employment. Colucci:Incyte: Employment, Equity Ownership. Yao:Incyte: Employment. Mascarenhas:Celgene: Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Research Funding.

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MPL p.S204P Is a Recurrent Mutation in Essential Thrombocythemia

Blood ◽

10.1182/blood.v126.23.2837.2837 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2837-2837

Author(s):

Carla AL Assaf ◽

Petros Papadopoulos ◽

Laura Guttierez ◽

Sanne Smits ◽

Carlos Graux ◽

...

Keyword(s):

Board Of Directors ◽

Essential Thrombocythemia ◽

Blood Platelets ◽

Growth Curves ◽

Jak2 V617f ◽

Recurrent Mutation ◽

Driver Mutations ◽

Additional Patient ◽

Advisory Committees ◽

Healthy Donors

Abstract Introduction: The JAK2 p.V617F, MPL p.W515K/L and CALR indels occur in a mutually exclusive pattern in 80-90% of cases with Essential Thrombocythemia (ET), but the driver mutations are unknown in the remaining 10-20%. In this study we aimed to identify driver mutations in the latter group of triple negative (TN) ET by exome sequencing of 10 such cases. Results: We found 27 somatic variants, including indels, in 6 out of 10 TN ET patients (range: 1-10 mutations/case; mean: 2,7 mutations/case), none of which were recurrent. In one case, we found a MPL c.610T>C (p.S204P) mutation, which is located in the extracellular domain of the MPLreceptor. By Sanger sequencing of MPL exon 4 in 20 additional TN ET cases, an additional patient with the MPL S204P mutation was identified. Moreover, this mutation was previously reported in one case with idiopathic myelofibrosis1. In order to study the effect of this mutation on the function of MPL, we produced stable Ba/F3 cell lines expressing MPL S204P, MPL W515K or MPL WT, and assessed the dependence of their growth on exogenous thrombopoietin (TPO). Only MPL W515K transduced Ba/F3 cells proliferated in the absence of TPO, but growth of MPL S204P Ba/F3 and of MPL WT Ba/F3 could be rescued by exogenous TPO, indicating the proper surface expression and the functionality of the transduced receptors. The levels of phospho-JAK2 and phospho-STAT5 were low in cytokine-deprived MPL S204P cells but increased upon TPO stimulation. In contrast, phospho-JAK2 and phospho-STAT5 were detectable in MPL W515K transduced Ba/F3 in the absence of cytokines as assessed by Western blotting. Culture of MPL S204P transduced Ba/F3 in the presence of TPO over a range of concentrations (0,01-10 ng/ml) yielded growth curves comparable with MPL WT transduced Ba/F3. Using flow cytometry, we also explored cell surface marker expression on peripheral blood platelets from the two MPL S204P ET patients. Data were compared with healthy donors or ET patients with JAK2 or CALR mutations. MPL S204P ET platelets displayed higher expression of CD61 than platelets from healthy donors or from JAK2 or CALR mutated ET (p<0,01). In addition, there was a trend for higher expression of KIT, CD36 and CD42b on platelets from the MPL S204P ET cases. Moreover, following platelet activation through the protease activated receptor 1, the degranulation response of platelets from MPL S204P ET was decreased in comparison with JAK2 or CALR mutated ET. Conclusion: The MPL S204P mutation is a recurrent mutation in TN ET, with a frequency of 7% (2/30) in this series, but this mutation does not induce TPO-independent growth nor increased TPO-sensitivity in Ba/F3 cells. However, preliminary phenotypic and functional evidence supports the notion that MPL S204P platelets display specific characteristics as compared with JAK2 or CALR mutated ET. The mechanisms by which the MPL S204P mutation influences megakaryopoiesis and platelet function remain to be elucidated. 1. Williams DM, et al. Phenotypic variations and new mutations in JAK2 V617F-negative polycythemia vera, erythrocytosis, and idiopathic myelofibrosis. Exp Hematol 2007; 35: 1641. Disclosures Graux: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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An Individual Patient Supply Program for Ruxolitinib for the Treatment of Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

Blood ◽

10.1182/blood.v120.21.2844.2844 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2844-2844

Author(s):

Giovanni Barosi ◽

Mohan Agarwal ◽

Sonja Zweegman ◽

Wolfgang Willenbacher ◽

Sima Pakstyte ◽

...

Keyword(s):

Polycythemia Vera ◽

Board Of Directors ◽

Essential Thrombocythemia ◽

Research Funding ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Jak2 V617f Mutation ◽

Phase 3 ◽

Advisory Committees ◽

The Us

Abstract Abstract 2844 Background: Myeloproliferative neoplasms, including PMF, PET-MF, and PPV-MF, are a group of clonal stem cell–derived diseases characterized by bone marrow fibrosis, splenomegaly, and debilitating constitutional symptoms. Ruxolitinib (rux), a potent oral JAK1 & 2 inhibitor, demonstrated rapid and durable reductions in splenomegaly and improved MF-related symptoms and quality of life in 2 phase 3 studies (COMFORT-I and -II). Due to unmet medical need, rux has been made available through an individual patient supply program (IPSP) outside the US. Methods: Patients (pts) with PMF, PPV-MF, or PET-MF requiring treatment (as determined by their physician) and classified as high-, intermediate (int)-2–, or int-1–risk with an enlarged spleen were evaluated for eligibility on an individual basis by the sponsor, irrespective of JAK2 mutation status. The starting dose of rux was determined on the basis of baseline platelet count (15 or 20 mg twice daily for pts with platelet counts of 100–200 × 109/L and > 200 × 109/L, respectively) and can be adjusted for efficacy and safety. Dose changes during treatment, adverse events (AEs), and serious AEs (SAEs) are registered throughout the program. Results: To date, 1339 requests have been received from > 800 physicians in 48 countries, including locations in Europe, Latin America, the Middle East, and Asia. The baseline characteristics are shown in the Table for pts whose requests for access were approved (n = 1240). Drug resupply requests are received every ≈ 3 months. Follow-up information, based on the first resupply request, was available for 381/639 (60%) of the pts who were enrolled in the program prior to February 2012; 303 (80%) remain on rux therapy, 37 (10%) have discontinued, 11 (3%) died, and 30 (8%) did not initiate therapy. Spleen response was available for 247 pts (decreased, n = 201; unchanged, n = 39; increased, n = 7). Changes in constitutional symptoms were available for 203 pts (decreased, n = 151; unchanged, n = 49; increased, n = 3). In pts enrolled in the IPSP undergoing rux treatment, most pts who had a decrease in spleen length also had a decrease in symptoms. Dose-modification information was available for 259 pts, of whom 44 had dose increases and 89 had dose decreases. Reasons for dose modifications included efficacy (n = 28), safety (n = 69), and other reasons (n = 36). Safety information was available for 266 pts; 75 reported significant AEs or SAEs as determined by investigators. Enrolled pt characteristics are generally similar to those expected in the overall MF pt population. Thus far, the proportion of pts enrolled in the IPSP with the JAK2 V617F mutation (73%) is higher than that for the general MF population (50%-60%). This may reflect a misconception that JAK inhibition is primarily effective in pts who have the JAK2 V617F mutation, when in fact rux has demonstrated similar efficacy in both pt types in the phase 1/2 251 study and the two phase 3 COMFORT trials. This may also be reflected in the higher proportion of PPV-MF pts in the IPSP than in the general MF population (28% vs 10%-15%), of whom 95% are JAK2 V617 F–positive. Conclusions: Considerable requests for access to rux have been received through the IPSP, highlighting the need for an effective treatment in pts with a range of IPSS risk-assessment scores. The demographics of the IPSP pts are similar to those expected in the overall MF population. Responses and safety patterns observed in the IPSP appear to be comparable to those from the COMFORT trials. Disclosures: Off Label Use: Jakafi™ (ruxolitinib) is indicated in the United States for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. In Canada, JAKAVI ® is indicated for the treatment of splenomegaly and/or its associated symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. This abstract reports on a clinical study conducted outside the US including patients of all risk categories. All patients have provided written informed consent. Zweegman:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Willenbacher:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Raymakers:Novartis: Consultancy. Cantoni:CSL Behring Switzerland: Research Funding; Robapharm/Pierre Fabre Oncology Switzerland: Research Funding; Janssen-Cilag Switzerland: Consultancy; Novartis Oncology Switzerland: Consultancy, Research Funding. Modi:Novartis Pharmaceuticals Corporation: Employment. Khan:Novartis: Employment. Perez:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Gisslinger:AOP Orphan Pharmaceuticals AG: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Lavie:Novartis: Membership on an entity's Board of Directors or advisory committees. Harrison:Sanofi Aventis: Honoraria; YM Bioscience: Consultancy, Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Research Funding.

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Serum Biomarkers Predict Outcomes in Advanced Hodgkin Lymphoma Independent of International Prognostic Score (IPS) and Treatment: Correlative Analysis from a Large North American Cooperative Group Trial

Blood ◽

10.1182/blood.v128.22.2992.2992 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2992-2992 ◽

Cited By ~ 2

Author(s):

Jennifer A. Kanakry ◽

Fangxin Hong ◽

Otoniel Martinez-Maza ◽

Sandra J Horning ◽

Leo I. Gordon ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

Tumor Tissue ◽

Prognostic Score ◽

Serum Marker ◽

Survival Outcomes ◽

Advisory Committees ◽

International Prognostic Score ◽

Pre Treatment

Abstract Introduction: Progress in the treatment of patients with classical Hodgkin lymphoma (cHL) depends on identifying methods to better risk-stratify patients and assess prognosis and treatment response. While prognostic scores based on clinical characteristics have utility, inflammatory markers and signaling proteins may better reflect tumor biology, the microenvironment, or host response and might serve as prognostic factors. Increased expression of tumor-associated macrophage markers in tumor tissue, such as CD68 or CD163, has been shown to be associated with inferior survival outcomes in cHL patients. Blood-based markers are more practical in that specimens are readily and serially obtainable. Such markers, if shown to track with tumor response and/or prognosticate outcomes, can be used throughout treatment and follow-up. Some soluble markers, such as TARC (chemokine (C-C motif) ligand (CCL)-17) and soluble CD163 (sCD163), have been shown to reflect tumor burden and active disease, and markers such as soluble CD30 (sCD30), interleukin (IL)-6, chemokine (C-X-C motif) ligand (CXCL)-10/IP10, and IL-2 receptor have been associated with failure-free survival (FFS). Methods: Newly diagnosed cHL patients with locally extensive or advanced stage disease were prospectively enrolled in the Intergroup E2496 randomized controlled trial, which compared ABVD with Stanford V chemotherapy. A panel of serum cytokines, chemokines, and other soluble markers including TARC, CCL22, CCL24, sCD30, sCD163, CXCL10/IP10, CXCL13, soluble CD14 (sCD14), IL-6, IL-10, IL-12, and IL-13, IL1-receptor antagonist (IL1RA)) were measured in pretreatment serum specimens from 301 cHL patients (out of 854 on study) using multiplex (Luminex) bead array immunoassay (R&D Systems). Serum marker values were log-transformed for all analyses. Epstein-Barr virus (EBV) tumor status was determined by EBER in situ hybridization. A linear regression model was used to assess the association between pre-treatment serum marker levels and baseline clinical characteristics. A stratified Cox proportional hazards regression model was used to evaluate the association between serum marker levels as continuous variables and survival outcomes, including FFS (time from registration to disease progression/relapse or death) and overall survival (OS). Patients were divided into quartile groups based on serum marker levels and Kaplan-Meier curves were constructed with comparison using the stratified log-rank test. Three stratification factors were used in all modeling/testing include: stage I-II bulky vs. stage III-IV; IPS 0-2 vs 3-7; and treatment arms (Stanford V vs. ABVD). Two-sided p-values were reported. Results: Increased pre-treatment levels of CCL24, sCD30, sCD163, IP10, sCD14, IL-6, and IL-10 were associated with the presence of B symptoms, independent of age, tumor histology, and disease stage, in multivariate analysis. Higher sCD163 and IP10 levels were associated with EBV positive tumors and higher TARC, CCL22, and CXCL13 levels were associated with EBV negative tumors, after adjusting for age and histology. Several markers were associated with factors in the International Prognostic Score (Table 1). Adjusting for IPS, stage and treatment arms, high levels of IL1RA, sCD30, sCD163, IP10, and IL-10, were significantly (p<0.05) associated with inferior FFS. While high levels of TARC (p=0.02, hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.79-0.98), and CXCL13 (p=0.04, HR 0.84, 95% CI 0.72-0.99) were associated with better OS, high levels of CD14 (p=0.02, HR 2.2, 95% CI 1.11-4.38), IP10 (p<0.0001, HR 2.22, 95% CI 1.64-3.00) and sCD163 (p=0.0002, HR 2.89, 95% CI 1.65-5.06) were associated with significantly inferior OS (Figure 1). Conclusion: These findings support prior work demonstrating the prognostic significance of markers such as CD163 in cHL tumor tissue with similar findings using a more readily available (blood-based) method of assessment. The study expands upon the number of blood-based markers shown to be prognostic in cHL, and associates high pre-treatment levels of several markers with IPS factors and other baseline clinical characteristics. Further, and most importantly, IP10 and sCD163 predict inferior FFS and OS independent of IPS and treatment. Disclosures Cheson: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; GSK: Research Funding; Seattle Genetics: Research Funding. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding.

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