Ropeginterferon alfa-2b, a novel IFNα-2b, induces high response rates with low toxicity in patients with polycythemia vera

Key Points The novel IFNα-2b, ropeginterferon alfa-2b, administered once every 2 weeks has low toxicity and induces high and sustained response rates in polycythemia vera patients. Ropeginterferon alfa-2b induces significant partial and complete molecular response rates, as reflected by reduction of JAK2 allelic burden.

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Clonal Dynamics of JAK2V617F and Non-Driver Mutations in Polycythemia Vera and Essential Thrombocythemia Patients Receiving Hydroxyurea Therapy

Blood ◽

10.1182/blood-2021-150491 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3623-3623

Author(s):

Lierni Fernández-Ibarrondo ◽

Joan Gibert ◽

Concepción Fernández-Rodríguez ◽

Laura Camacho ◽

Anna Angona ◽

...

Keyword(s):

Dna Repair ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Research Funding ◽

Evolutionary Dynamics ◽

Driver Mutations ◽

Molecular Response ◽

Increased Risk ◽

Cytoreductive Treatment ◽

Allelic Burden

Abstract Introduction : Hydroxyurea (HU) is the most widely used cytoreductive treatment for patients with essential thrombocythemia (ET) and polycythemia vera (PV) at high risk of thrombosis. It remains unknown whether long-term HU therapy modulates or promotes the acquisition of mutations in non-driver (ND) genes, especially, when assessing hematological (HR) and molecular (MR) response. The objective of the study was to analyze the clonal dynamics of ND genes in HR and MR with HU in a cohort of JAK2V617F-mutated PV and ET patients. Method s: The study included 144 JAK2V617F positive patients (PV n = 73, TE n = 71) receiving HU as first-line cytoreductive treatment. The baseline sample (before HU treatment) and at the timepoint of best molecular response to JAK2V617F were analyzed. The allelic burden of J AK2V617F was assessed by allele-specific PCR and the mutational profile of ND genes was analyzed by next generation sequencing with a custom panel including 27 myeloid-associated genes. HR was defined according to the criteria of the European LeukemiaNet 2009 and MR of JAK2V617F was defined as complete, major, partial and no response (Table I). Results : Median molecular follow-up was 54.1 months for PV and 55.5 months for ET. Patients with PV were more likely to be males (p<0.001), and displayed higher leukocyte count (p<0.001) compared to those with ET. The respective numbers of deaths, leukemic transformations and fibrotic progressions were: 22 (30%), 4 (5%), 6 (8%) for PV cases, and 19 (27%), 1 (1%), 0 (0%) for ET patients. At baseline, a total of 62 somatic mutations in ND genes were detected in 42/73 (57%) PV patients while 58 were detected in 36/71 (51%) ET patients. Complete HR was observed in 102 patients: 44 (60%) PV and 58 (81%) ET. Partial MR in 67 cases: 35 (48%) PV and 32 (45%) ET and major or complete MR in 21 cases: 8 (11%) PV and 13 (18%) ET. The median duration of HU treatment was 45.8 months (range: 17.5-189.5) for PV and 45.6 months (range: 14.6-168.6) for ET. The most frequently mutated genes detected at pre-therapy samples were TET2 (34%), ASXL1 (12%), SF3B1 (7%) and EZH2 (5%) in PV patients, and TET2 (34%), ASXL1 (13%), DNMT3A (13 %) and SRSF2 (5%) in ET patients. No significant differences were observed in the MR (p=0.358) or HR (p=0.917) according to the presence or absence of mutations in ND genes at baseline. Clonal dynamics of DNMT3A, ASXL1, and TET2 (DAT) genes were not modulated by HU therapy to the same extent as JAK2V617F. Disappearance and emergence of additional mutations in DAT genes were observed independently of the molecular response achieved by the JAK2V617F clone. These findings suggest the existence of clones with mutations in ND genes independent from the pathogenic driver clone, and the lack of modulation by HU treatment. Finally, an increase of allelic burden or the appearance of mutations in TP53, a gene related to progression, and in other DNA repair genes (PPM1D and CHEK2) was observed in 14 (19.1%) PV patients and 9 (12.6%) ET cases during HU treatment. However, no increased risk of myelofibrotic transformation or progression to acute myeloid leukemia was observed in these patients. Conclusion s: Pre-treatment ND mutations are not associated with HR and MR to HU in JAK2V617F-mutated patients. 2. The clonal dynamics of ND mutations (decrease, increase, appearance, disappearance) are not related to the evolutionary dynamics of JAK2V617F. 3. An increase or appearance of progression-related mutations in TP53 and/or other genes of the DNA repair pathway such as CHEK2 and PPM1D is observed during HU treatment. Acknowledgments : Instituto de Salud Carlos III-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure 1 Figure 1. Disclosures Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Besses: Gilead: Research Funding. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau.

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Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera

Blood ◽

10.1182/blood-2008-03-143537 ◽

2008 ◽

Vol 112 (8) ◽

pp. 3065-3072 ◽

Cited By ~ 351

Author(s):

Jean-Jacques Kiladjian ◽

Bruno Cassinat ◽

Sylvie Chevret ◽

Pascal Turlure ◽

Nathalie Cambier ◽

...

Keyword(s):

Polycythemia Vera ◽

Residual Disease ◽

Pegylated Interferon ◽

Interferon Α ◽

First Year ◽

Molecular Response ◽

Sequential Samples ◽

Low Toxicity ◽

Pegylated Interferon Alfa

Abstract Interferon-α (IFN-α) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-α-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-α-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-α-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6+ to 18+ months, and persisted after pegylated IFN-α-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-α-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

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High response rates in patients with pancreatic cancer using the novel oral fluoropyrimidine S-1

Oncology Reports ◽

10.3892/or.9.6.1355 ◽

2002 ◽

Author(s):

Kazuhiko Hayashi ◽

Toshihide Imaizumi ◽

Kazumi Uchida ◽

Hidekazu Kuramochi ◽

Ken Takasaki

Keyword(s):

Pancreatic Cancer ◽

Response Rates ◽

High Response ◽

The Novel ◽

Oral Fluoropyrimidine

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Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia

Blood ◽

10.1182/blood-2012-09-455691 ◽

2013 ◽

Vol 121 (11) ◽

pp. 1976-1981 ◽

Cited By ~ 76

Author(s):

Sif Gudbrandsdottir ◽

Henrik Sverre Birgens ◽

Henrik Frederiksen ◽

Bjarne Anker Jensen ◽

Morten Krogh Jensen ◽

...

Keyword(s):

Immune Thrombocytopenia ◽

Response Rates ◽

Sustained Response ◽

Newly Diagnosed ◽

Key Points ◽

Primary Immune Thrombocytopenia

Key Points In newly diagnosed ITP, addition of rituximab to dexamethasone yields higher sustained response rates than dexamethasone alone.

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A Phase II Study of Vorinostat (MK-0683) in Patients with Polycythemia Vera and Essential Thrombocythemia

Blood ◽

10.1182/blood.v120.21.803.803 ◽

2012 ◽

Vol 120 (21) ◽

pp. 803-803 ◽

Cited By ~ 1

Author(s):

Christen Lykkegaard Andersen ◽

Mary Frances McMullin ◽

Elisabeth Ejerblad ◽

Sonja Zweegman ◽

Claire N Harrison ◽

...

Keyword(s):

Adverse Effects ◽

Polycythemia Vera ◽

Dose Reduction ◽

Phase Ii ◽

Mutant Allele ◽

Response Rates ◽

Dropout Rate ◽

Molecular Response ◽

Intervention Period ◽

Allele Burden

Abstract Abstract 803 Background: Recent findings lend strong support to the contention that histone deacetylase inhibition may be an important epigenetic therapy in the treatment of patients with myeloproliferative neoplasms and emphasize the need to characterize the efficacy and safety of this novel class of cytoreductive agents. Aims: This study was a non-randomized, open-label phase II multicenter study with sixty-three patients (21 essential thrombocythaemia (ET), 42 polycythemia vera (PV)) included from 15 centers. The primary objective was to investigate, if vorinostat as monotherapy in patients with PV and ET was followed by a decline in clonal myeloproliferation as assessed by conventional disease activity parameters. Secondary objectives included assessment of adverse effects during treatment; changes in bone marrow morphology before and after treatment with vorinostat and to investigate whether treatment with vorinostat influences the JAK2 mutant allele burden as assessed by quantitative PCR. (qPCR) Results: Thirty-one patients (49%) were followed to the end of the intervention period. Eighty-one percent of these had a partial (n=20) – or complete (n=5) hematological response according to ELN criteria. Response rates were found to be independent of JAK-status in ET patients. (P=0.83). A tendency towards less favorable responses was observed among patients with > 1 previous therapies albeit statistically insignificant (P=0.11). For all but two patients, a clinicohematological response was not followed by a histological remission. The prevalence of splenomegaly was lowered from 48% to 24% (P=0.02). A statistically significant reduction of JAK2 mutant allele burden was observed (P=0.006). No JAK2 positive patients experienced a complete molecular response defined as undetectable JAK2V617F by qPCR. No significant correlation between severity of tumor allele burden at inclusion and a more pronounced molecular response to vorinostat was found using a Spearman correlation analysis (rho = 0.16, p = 0.3). The most commonly reported adverse effects (AEs) during the intervention period among patients who completed the protocol were fatigue and gastrointestinal (anorexia, nausea, vomiting, diarrhea, dryness of the mouth). Gastrointestinal symptoms were generally manageable. Seventy percent of included patients experienced hair loss. Seventeen percent experienced renal toxicity (3 pts. grade I, 1 pt. grade II) and 1 pt. (4%) liver toxicity of unknown grade, which resolved after withdrawal of vorinostat. Forty-three percent of included patients required at least one dose reduction due to AE′s. Forty patients (63 % of patients) discontinued study drug before end of study period due to adverse events (65%), unknown (17.5%), withdrawal of consent (7.5%), no response (2.5%), or progression to acute leukemia (7.5%). Response rates for patients who discontinued therapy, however, showed that approximately 50% of patients who discontinued experienced a clinicohematological response providing evidence that toxicity issues were of concern rather than lack of clinical effect. Conclusions: Vorinostat is effective in patients with ET and PV normalizing elevated leukocyte and platelet counts as well as providing a statistically significant reduction of the JAK2 mutant allele burden and splenomegaly. However, vorinostat was associated with a high dropout rate. Considering the heterogeneity and complexity of oncogenic events, involving both deregulated tyrosine kinase activity as well as epigenetic deregulation in MPN-pathogenesis combination therapy (eg. JAK1-2 inhibitors, DNA-hypomethylating agents, interferon-alpha2) may be more efficacious than single agent therapy. This strategy might also allow for dose reduction of single agents and accordingly a decrease in toxicity, which was the major limiting factor for patients adhering to treatment in the present study. Disclosures: No relevant conflicts of interest to declare.

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Results of a 50 patient single-center phase II prospective trial of Lutetium-177 PSMA-617 theranostics in metastatic castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.228 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 228-228 ◽

Cited By ~ 3

Author(s):

Michael Hofman ◽

John A Violet ◽

Rodney J Hicks ◽

Justin Ferdinandus ◽

Sue Ping Thang ◽

...

Keyword(s):

Prostate Cancer ◽

Phase Ii ◽

Targeted Delivery ◽

Prospective Trial ◽

Response Rates ◽

High Response ◽

Beta Radiation ◽

Castrate Resistant Prostate Cancer ◽

Low Toxicity ◽

Castrate Resistant

228 Background: Lutetium-177 (177Lu)-PSMA-617 (LuPSMA) is a radiolabelled small molecule that binds with high affinity to prostate specific membrane antigen (PSMA) enabling targeted delivery of beta-radiation. We have previously reported favourable activity with low toxicity in a 30 patient study in men with metastatic castrate-resistant prostate cancer (mCRPC) and now report updated results including a twenty patient extension cohort. Methods: In this phase II trial, 50 pts with PSMA-avid mCRPC who had progressed after standard therapies received up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response (PCWG2) and toxicity (CTCAE v4). Other endpoints included imaging response, PSA PFS and OS. Cut-off for analysis 5 Oct 2018. Results: 76 men were screened to identify 50 patients eligible for treatment. Median PSA doubling time was 2.6 months. The majority of patients had received prior docetaxel (84%), cabazitaxel (48%), and abiraterone and/or enzalutamide (90%). The mean administered radioactivity was 7.5 GBq/cycle. PSA decline ≥ 50% was achieved in 32 of 50 patients (64%, 95% CI 50-77%), including 22 patients (44%, 95% CI 30-59%) with a PSA decline ≥ 80%. 27 patients had measurable soft tissue at baseline and 56% of these patients had a partial or complete response by RECIST 1.1. The most common toxicities attributed to LuPSMA were transient G1-2 dry mouth in 68%, G1-2 nausea in 48%, and G1-2 fatigue in 36%. G3-4 toxicities attributed to LuPSMA were infrequent with thrombocytopenia in 10% and anaemia in 10%. Median PSA PFS was 6.9 months (95% CI 6.0-8.7) and median OS was 13.3 months (95% CI 10.5-18.0). Upon subsequent progression, further LuPSMA was administered to 14 patients (median 2 cycles commencing 359 days from enrolment); PSA ≥ 50% response occurred in 9 patients (64%). Conclusions: This expanded 50 patient cohort confirms high response rates and low toxicity with LuPSMA in men who had progressed after standard therapies. In patients who subsequently progressed and were administered further LuPSMA, high response rates were also observed. These results have provided the basis for randomised controlled trials currently underway. Clinical trial information: ACTRN12615000912583.

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Bortezomib-based antibody depletion for refractory autoimmune hematological diseases

Blood Advances ◽

10.1182/bloodadvances.2016001412 ◽

2016 ◽

Vol 1 (1) ◽

pp. 31-35 ◽

Cited By ~ 24

Author(s):

Sumita Ratnasingam ◽

Patricia A. Walker ◽

Huy Tran ◽

Zane S. Kaplan ◽

James D. McFadyen ◽

...

Keyword(s):

B Lymphocytes ◽

Plasma Cells ◽

Proteasome Inhibition ◽

Response Rates ◽

High Response ◽

Hematological Diseases ◽

Key Points ◽

Conventional Immunosuppression ◽

Immunomodulatory Properties

Key Points Proteasome inhibition has pleiotropic immunomodulatory properties and is cytotoxic to antibody-producing B lymphocytes and plasma cells. Bortezomib yields high response rates in antibody-mediated autoimmune hematological diseases refractory to conventional immunosuppression.

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Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study

Blood ◽

10.1182/blood-2014-03-563759 ◽

2014 ◽

Vol 124 (1) ◽

pp. 63-69 ◽

Cited By ~ 86

Author(s):

Sara Bringhen ◽

Maria Teresa Petrucci ◽

Alessandra Larocca ◽

Concetta Conticello ◽

Davide Rossi ◽

...

Keyword(s):

Multiple Myeloma ◽

Elderly Patients ◽

Response Rates ◽

Complete Response ◽

Phase 2 ◽

Newly Diagnosed ◽

Multicenter Phase ◽

Phase 2 Study ◽

Key Points ◽

Low Toxicity

Key Points This is the first study of carfilzomib-cyclophosphamide-dexamethasone in elderly patients with newly diagnosed multiple myeloma. Carfilzomib-cyclophosphamide-dexamethasone induced high complete response rates and was associated with low toxicity.

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Impact of complete molecular response on survival in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia

Blood ◽

10.1182/blood-2016-03-707562 ◽

2016 ◽

Vol 128 (4) ◽

pp. 504-507 ◽

Cited By ~ 87

Author(s):

Nicholas J. Short ◽

Elias Jabbour ◽

Koji Sasaki ◽

Keyur Patel ◽

Susan M. O’Brien ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Molecular Response ◽

Long Term Outcomes ◽

Key Points ◽

Complete Molecular Response ◽

Philadelphia Chromosome Positive

Key Points In patients with Ph+ ALL, achievement of CMR at 3 months is independently associated with improved survival. CMR at 3 months may identify patients with Ph+ ALL who have excellent long-term outcomes without SCT in first CR.

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