Four Weeks Administration Schedule of Ropeginterferon Alfa-2b (AOP2014/P1101) in Polycythemia Very Patients Allows Maintaining of Efficacy with Favorable Toxicity Profile in the Phase I/II Peginvera Stud

Abstract Background Ropeginterferon alfa-2b (AOP2014/P1101) is a novel long-acting pegylated IFN-alpha-2b, consisting predominantly of only one isoform, leading to longer half-life and exposure time. Reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with polycythemia vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design The PEGINVERA study (NCT01193699) is the phase I/II single arm dose escalation study with cohort extension after defining the MTD. 51 patients with PV who could be either cytoreduction therapy naive or pre-treated were included. Ropeginterferon alfa-2b was administered subcutaneously in a dose range of 50-540 µg every two weeks. Main objectives were definition of the maximum tolerated dose as well as observation long term safety and efficacy in terms of normalization of blood parameters and molecular abnormalities. The option to switch to an "once every four weeks" schedule has been implemented by the amended protocol for patients who responded well to the treatment and participated in the study for longer than one year. The dose of the study drug had to remain unchanged after the switch, resulting in a decrease of the overall exposure to the drug. Outcomes of this switch are presented here. Results 44 patients (period A, median exposure duration 37 weeks, mean monthly dose 505 µg), eligible for the analysis, i.e. being treated in the maintenance setting, were dosed every two weeks based on the Phase II dosing rules prior the amendment. 33 patients (period B, median exposure duration 12 weeks, mean monthly dose 432 µg) were dosed every two weeks beyond the first year and, showing benefit from treatment, have been assessed as eligible for the switch. 28 patients (period C, median exposure duration 93 weeks) were then switched to dosing once every four weeks (mean monthly dose 203 µg). Blood parameters were normalized and remained stable following one year of treatment and could be maintained after the switch (hematocrit, median in % - period A: 42.7, period B: 42.9, period C: 42.8; WBC, median in G/l - period A: 5.6, period B: 5.3, period C: 5.8; platelets, median in G/l - period A: 252, period B: 217, period C: 210). Spleen length stayed stable within the normal range following the switch in the majority of patients (mean, in cm - period A: 11.6, period B: 8.8, period C: 11.1). Complete hematological response could be maintained in 57% of patients in period A, in 38% of patients in period B and in 50% of patients in period C, while for partial hematological responders the results were 71%, 54% and 57%, respectively. Molecular response improved continuously over time, being maintained at the best individual level in 38% of period A patients, compared to 53% of period B and 69% of period C patients. Comparison of patient discontinuations between the arms revealed the following rates: 5(11%) in the period A, 5(15%) in the period B and 3(11%) in the period C, while the mean numbers of adverse events per patient treatment week was 0.15, 0.27 and 0.09 respectively. There were no new drug-related SAEs occurring in the period C. Conclusions This explorative data re-confirm the feasibility to administer ropeginterferon alfa-2b once every four weeks, while efficacy was maintained compared to the biweekly application schedule. Reduced injection frequency is not associated with a lack or loss of response, but clearly improves tolerability. Finally, continuous reduction of the JAK2 allelic burden indicates that duration of interferon treatment rather than the absolute dose level is an important variable inducing molecular responses. The here presented findings support the idea that interferon alpha effects in PV are pleiotropic, such as induction of immune-surveillance, which may be sufficiently maintained also at lower ropeginterferon alfa-2b levels. Disclosures Buxhofer-Ausch: AOP Orphan: Research Funding. Gisslinger:Geron: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau; Sanofi Aventis: Consultancy. Thaler:AOP Orphan: Research Funding. Schlögl:AOP Orphan: Research Funding. Gastl:AOP Orphan: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kralovics:AOP Orphan: Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees. Ban:AOP Orphan: Research Funding. Egle:AOP Orphan: Research Funding. Melchardt:AOP Orphan: Research Funding. Burgstaller:Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria; Novartis: Honoraria; AOP Orphan Pharmaceuticals: Honoraria, Research Funding. Willenbacher:AOP Orphan: Research Funding. Zörer:AOP Orphan: Employment. Ammann-Mwathi:AOP Orphan: Employment. Kadlecova:AOP Orphan: Consultancy. Zagrijtschuk:AOP Orphan: Employment. Klade:AOP Orphan: Employment. Greil:Novartis: Honoraria; Astra-Zeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Sanofi Aventis: Honoraria; GSK: Research Funding; Celgene: Consultancy; Pfizer: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Ratiopharm: Research Funding; AOP Orphan: Research Funding.

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Switch from Every Two Weeks to Every Four Weeks Administration Schedule of AOP2014, an Innovative Pegylated Interferon Alpha, in Polycythemia Very Patients Allows Maintaining of Efficacy with Improved Toxicity Profile in Phase I/II Study

Blood ◽

10.1182/blood.v124.21.3177.3177 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3177-3177

Author(s):

Heinz Gisslinger ◽

Veronika Buxhofer-Ausch ◽

Josef Thaler ◽

Ernst Schloegl ◽

Guenther A. Gastl ◽

...

Keyword(s):

Phase I ◽

Interferon Alpha ◽

Exposure Duration ◽

Research Funding ◽

Blood Parameters ◽

Phase Iii ◽

Long Term Treatment ◽

One Year ◽

Monthly Dose

Abstract Background AOP2014 is a next generation long-acting pegylated IFN-alpha-2b, consisting predominantly of only one isoform, as opposed to other commercially available pegylated interferons. Due to this property, reduced dosing frequencies, better tolerability, improved compliance and more favorable long-term treatment outcomes in patients with Polycythemia Vera (PV) are expected. The drug has Orphan designation by EMA and FDA and is currently in the phase III stage of development. Study design This phase I/II single arm dose escalation study with cohort extension included 51 patients with PV who could be either cytoreduction therapy naive or pre-treated. AOP2014 was administered subcutaneously in a dose range of 50-540 mcg every two weeks. Main objectives were to define the maximum tolerated dose as well as observe the long term safety and efficacy in terms of normalization of blood parameters and molecular abnormalities (results were already presented at the ASH 2013 annual meeting by Gisslinger et al). The option to switch to an "once every four weeks" schedule has been implemented by the amended protocol for patients who responded well to the treatment and participated in the study for longer than one year. The dose of the study drug had to remain unchanged after the switch, resulting in a decrease (by approx. the half) of the overall exposure to the drug. Outcomes of this switch are presented here. Results Patients (period A, median exposure duration 34 weeks, mean monthly dose 484 mcg) were dosed every two weeks based on the Phase II dosing rules prior having switch option. 33 patients (period B, median exposure duration 12 weeks, mean monthly dose 413 mcg) were dosed every two weeks beyond the first year and, showing benefit from treatment, have been assessed as eligible for switch. 28 patients (period C, median exposure duration 42 weeks) were then switched to once every four weeks schedule (mean monthly dose 221 mcg). Blood parameters were normalized and remained stable following one year of treatment and could be maintained after the switch (hematocrit, median,% - period A: 43, period B: 43, period C: 42; WBC, median, G/l - period A: 6.1, period B: 5.9, period C: 5.7; platelets, median, G/l - period A: 246, period B: 211, period C: 204). Spleen length stayed stable within the normal range following the switch in the majority of patients either (mean, in cm – period A: 11.4, period B: 8.3, period C: 10.3). Complete response as best individual response could be maintained in 42% from the period A, 55% in the period B and 67% of the period C patients, while for the partial hematological responders the results were 60%, 71% and 67%, respectively. Molecular response improved continuously over time, being maintained at the best individual level in 31% of period A patients, compared to 42% of period B and 75% of period C patients. Decrease of application frequency and total dose exposure led to decrease of the occurrence of all/drug related AEs (measured as mean count of adverse events [AE] per patient week exposure) to 0.17/0.09 (arm A) from 0.3/0.09 (arm B) and 0.08/0.03 (arm C). Conclusions This explorative data from endpoints pre-defined in the prospective study demonstrate the feasibility to further reduce the frequency of AOP2014 administration to once every four weeks in responding patients, previously treated every two weeks. Reduced injection frequency is not associated with a lack of- response, but clearly improves tolerability. Finally, continuous reduction of the JAK2 allelic burden indicates that duration of interferon exposure rather than dose of interferon is an important variable inducing molecular responses. The here presented findings support the idea that interferon alpha effects in PV are pleiotropic, such as induction of immune-surveillance, which is continuously maintained at lower AOP2014 levels. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Research Funding. Buxhofer-Ausch:AOP Orphan Pharmaceuticals AG: Research Funding. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding. Schloegl:AOP Orphan Pharmaceuticals AG: Research Funding. Gastl:AOP Orphan Pharmaceuticals AG: Research Funding. Wolf:AOP Orphan Pharmaceuticals AG: Research Funding. Kralovics:AOP Orphan Pharmaceuticals AG: Research Funding. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding. Strecker:AOP Orphan Pharmaceuticals AG: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Melchardt:AOP Orphan Pharmaceuticals AG: Research Funding. Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Willenbacher:AOP Orphan Pharmaceuticals AG: Research Funding. Zoerer:AOP Orphan Pharmaceuticals AG: Employment. Kadlecova:AOP Orphan Pharmaceuticals AG: Consultancy. Zagrijtschuk:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.

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Long-Term Outcome Following B-Cell Depletion Therapy with Rituximab In Children and Adults with Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v116.21.72.72 ◽

2010 ◽

Vol 116 (21) ◽

pp. 72-72 ◽

Cited By ~ 1

Author(s):

Vivek L. Patel ◽

Matthieu Mahévas ◽

Roberto Stasi ◽

Susanna Cunningham-Rundles ◽

Bertrand Godeau ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Initial Response ◽

Response Rates ◽

Advisory Committees ◽

Term Outcome ◽

Long Term Outcome ◽

One Year

Abstract Abstract 72 Background: Studies of B-cell depletion using Rituximab in adults with ITP report responses lasting at least one year in almost all of the 30–40% of patients with complete responses (CR: platelet count >150 × 109/l) and also a small fraction of patients with partial responses (PR: platelet count 50–150 × 109/l). However data describing patients with ITP who are relapse-free and off-treatment beyond 1–2 years from initial Rituximab are almost entirely anecdotal and comparable response data are even less available for children. This study assessed the duration of unmaintained platelet response following rituximab treatment in 72 adults and 66 children with ITP, all of whom had had at least an initial response to rituximab. Long-term outcome was estimated from these data. Methods: Seventeen published studies including 486 patients, 376 adults and 110 children, were used to obtain the initial response rates to standard-dose rituximab treatment (375mg/m2 weekly for 4 weeks) in adults and children. Only 1 included study did not use the standard dose of rituximab. The Godeau study (Blood, 2008) was used to estimate the one-year response rate in adults with ITP. Only those adults whose responses persisted at least one year had follow up assessed whereas children who demonstrated even ephemeral responses were included. Only verified counts were used in this IRB-approved multicenter study. Results: 138 subjects with CR's or PR's after rituximab were included. All patients had starting platelet counts <30×109/l and 131 (95%) had ITP of > 6 months duration. Thirty-three (24%) had undergone splenectomy. Using the data from prior publications to obtain the initial response rates, children had a 56% initial response rate to rituximab treatment and adults had a 57% rate. Taking initial responders and then using the Godeau data for adults and Kaplan-Meier analysis of our data for children, 38% one-year response rates were obtained for both children and adults treated with rituximab. Both age groups also showed remarkable similarity at two years with 30% relapse-free response rates. However, all of the 26 eligible children maintained their response beyond two years whereas adults continued to relapse. Therefore the five-year response rate was 30% for children and only 21% for adults. Sex, duration of ITP, and age among adults did not affect long-term outcome. The rate of relapse was almost identical for splenectomized patients and non-splenectomized ones but the splenectomized patients appeared to relapse sooner (Figure). Patients with CR's (55 of the 72 adults with responses lasting at least one year were CR's) had better long-term outcomes than did patients with PR's even more than one year from initial treatment. B-cells returned significantly sooner to higher levels in subjects who relapsed compared to those whose responses were ongoing. No clinical long-term toxicity was observed but 2 patients were identified to have mild hypogammaglobulinemia > 30 months from initial treatment. Conclusions: In summary, only approximately 1 in 5 adults treated with rituximab will have an at least five-year relapse-free response rate which is disappointingly low; children have only a slightly higher five-year relapse-free response rate. A pilot study to improve outcomes using either R-CVP or double dose rituximab was unsuccessful (Hasan, Am J Hematol,2009) Current efforts to improve long-term response rates have focused on the combination of high dose dexamethasone and rituximab (or even by providing maintenance treatment with rituximab). A better understanding of the mechanism of effect of rituximab in patients with ITP might allow an improved treatment strategy to be developed. Fortunately, the toxicity of rituximab treatment in patients with uncomplicated ITP appears to be low; however, yearly testing for immunoglobulins for a minimum of five years might be appropriate. Disclosures: Neufeld: Novartis. Inc: Research Funding. Shenoy:Novartis Oncology: Honoraria. Bussel:Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy.

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Outcome and Prognostic Factors in Patients with Mantle Cell Lymphoma Relapsing After Autologous Stem Cell Transplantation: A Retrospective Study of the EBMT

Blood ◽

10.1182/blood.v120.21.474.474 ◽

2012 ◽

Vol 120 (21) ◽

pp. 474-474 ◽

Cited By ~ 1

Author(s):

Sascha Dietrich ◽

Herve Finel ◽

Ariane Boumendil ◽

Irit Avivi ◽

Liisa Volin ◽

...

Keyword(s):

Prognostic Factors ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Salvage Chemotherapy ◽

Refractory Disease ◽

Advisory Committees ◽

Mantle Cell ◽

One Year

Abstract Abstract 474 BACKGROUND: Autologous stem cell transplantation (autoSCT) is considered as standard treatment for non-frail patients with mantle cell lymphoma (MCL). However, little is known about outcome of MCL recurrence after autoSCT. We therefore conducted a retrospective analysis of patients with MCL who failed autoSCT using the EBMT database. PRIMARY OBJECTIVE was to analyse outcome and prognostic factors after relapse following autoSCT for MCL in the rituximab era. PRIMARY ENDPOINT was overall survival (OS) from relapse. ELIGIBLE were patients aged 18 years or more who relapsed following an autoSCT for MCL performed between 2000 and 2010 and who were registered with the EBMT. Centres were contacted to provide additional information on relapse treatment. STATISTICAL ANALYSIS was based on log-rank comparisons and multivariable testing using Cox regression models. RESULTS: 1054 patients meeting the eligibility criteria could be identified in the EBMT registry. Of these, a full data set could be retrieved for 382 patients. Sixteen patients had to be excluded due to loss of follow up (n=7), wrong diagnosis (n=6), or falsely reported relapse (n=3). Median age at autoSCT of 366 evaluable patients was 59 years (range: 37 to 76), 290 patients (79%) were men. 64% had undergone autoSCT as part of 1st-line therapy; 68% and 49% had documented exposure to rituximab (RTX) and high-dose ara-C (HA) before autoSCT; and 12% had had refractory disease at autoSCT. Median time from autoSCT to relapse was 20 months (range: 0.4 to 117). 21 relapses (6%) occurred beyond 5 years after autoSCT. With a median observation time of 37 months (95% CI 32–43), median OS after relapse of the whole study group was 20 months. By univariate analysis, a long (>12mo) interval between autoSCT and relapse (p<0.001; HR 0.26; Figure 1A), 1st-line autoSCT (p=0.006; HR 0.7) refractory disease at autoSCT (p<0.001, HR 2.0) and more recent year of relapse (p<0.001, HR per year 0.9) significantly influenced OS from relapse, whereas age, gender, RTX and HA exposure did not. By multivariate analysis refractory disease at autoSCT (p<0.001, HR=2.14), remission duration after autoSCT (p<0.001 HR per 3 months 0.88) and calendar year of relapse (p<0.03, HR per year 0.93) were confirmed to be predictors for OS. In addition, HA exposure prior autoSCT adversely affected OS from relapse (p=0.06, HR 1.38). Salvage chemotherapy after relapse resulted in only 31% complete responses and 29% partial responses, whereas 40% of patients have been refractory to first salvage chemotherapy. 83 patients (23%) received an allogeneic SCT (alloSCT), whereas only 7 patients (2%) received a second autoSCT after relapse. Median time after relapse to second SCT was 7 months (range: 1 to 40). Survival after relapse for patients who received a second autoSCT was poor with no long-term survivor. AlloSCT performed for late relapse (>12mo) after autoSCT was associated with superior OS compared to patients who received an allograft upon a shorter remission duration after autoSCT (5-year OS from alloSCT 50% vs 0%; p=0.001; Figure 1B). Achievement of CR before alloSCT (p=0.05 HR=0.5), but not donor source, T-cell depletion or conditioning intensity affected OS after alloSCT. CONCLUSIONS: Patients with MCL who relapse within one year after autoSCT have an extremely dismal outcome even with alloSCT. In contrast, about half of the patients who have MCL recurrence beyond one year after autoSCT and can undergo salvage alloSCT enjoy long-term survival. It remains to be shown if a similarly good outcome can be achieved without alloSCT in this favourable selection of patients. A 2nd autoSCT does not appear to be a promising option in patients with MCL failing a 1st autoSCT. Disclosures: Walewski: Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Cephalon: Research Funding.

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Effect Of Treatment With The JAK2-Selective Inhibitor Fedratinib (SAR302503) On Bone Marrow Histology In Patients With Myeloproliferative Neoplasms With Myelofibrosis

Blood ◽

10.1182/blood.v122.21.2823.2823 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2823-2823 ◽

Cited By ~ 3

Author(s):

Catriona HM Jamieson ◽

Robert P Hasserjian ◽

Jason Gotlib ◽

Jorge E. Cortes ◽

Richard M. Stone ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Phase I ◽

Board Of Directors ◽

Clinical Benefit ◽

Research Funding ◽

Selective Inhibitor ◽

Advisory Committees ◽

Grade 3

Abstract Introduction Fedratinib, a JAK2-selective inhibitor, demonstrated clinical benefit through a reduction in splenomegaly and symptoms in patients with myelofibrosis (MF), including post-polycythemia vera MF (post-PV MF), post-essential thrombocythemia MF (post-ET MF) and primary MF (PMF), in Phase I and II studies (J Clin Oncol 2011;29:789; Haematologica 2013;98:S1113). Bone marrow fibrosis (BMF) has been associated with splenomegaly and cytopenias (Ann Hematol 2006;85:226). Hence, stabilization and/or reversal of BMF remain important therapeutic goals. This report represents an exploratory analysis of sequential BMF data from patients with MF in an open-label Phase I/II study to evaluate the long-term effects of orally administered fedratinib (TED12015; NCT00724334). Methods Patients with intermediate or high-risk MF (Mayo Prognostic Scoring System) received fedratinib therapy in consecutive cycles (1 cycle = 28 days) as long as they derived clinical benefit. Bone marrow trephine biopsies were performed at baseline and after every 6 cycles. Hematoxylin and eosin, reticulin, and Masson's trichrome staining of core biopsy slides were used to grade BMF on a scale from 0 to 3 using the 2008 WHO MF grading criteria. BMF was graded independently in a blinded fashion by 3 hematopathologists. BMF grades were established as long as at least 2 of the 3 pathologists agreed independently. Changes in BMF grade from baseline were categorized as improvement (≥1 grade reduction), stabilization (no change), or worsening (≥1 grade increase). Results Of the 43 patients enrolled in the TED12015 study, the median fedratinib dose received was 473 (range 144–683) mg/day and median treatment duration was 32.3 (range 7–61) cycles. Bone marrow biopsies at baseline and at least one other time point were available for 21/43 (49%) patients, whose baseline characteristics were: median age 61 years (range 43–85); 57% male; 38% high-risk MF by WHO 2008 criteria (Leukemia 2008; 22:14); and 90% JAK2V617F positive. A consensus grade was achieved for 96% of the samples. At baseline, 2, 10, and 9 patients had grade 1, 2, and 3 BMF, respectively. Changes in BMF grade from baseline are shown in the figure. BMF improvement with 1 grade reduction was observed in 8/18 (44%) patients at Cycle 6. By Cycle 30, 4/9 (44%) evaluable patients had BMF improvement, including 2 patients with improvement by 2 grades and 2 patients with improvement by 1 grade. Of patients with Grade 3 BMF at baseline, 6/9 (67%) exhibited 1 grade improvement at Cycle 6. Two patients had 2 grades of BMF reduction from baseline during treatment (grade 3 to 1, and grade 2 to 0, both at Cycle 12), and the latter achieved a complete clinical remission at Cycle 30 assessed by IWG-MRT response criteria. The two patients who experienced complete reversal of BMF to grade 0 (one from grade 2 and one from grade 1) had normalization of not only hemoglobin level but also white blood cell and platelet counts at Cycle 18. Conclusions These exploratory analyses suggest that a proportion of patients treated long-term with fedratinib demonstrate stable or improved BMF. The disease modifying impact of fedratinib on BMF changes will be further assessed in a randomized, placebo-controlled Phase III clinical trial (JAKARTA; NCT01437787). This study was sponsored by Sanofi. Disclosures: Jamieson: J&J, Roche: Research Funding; Sanofi: Membership on an entity’s Board of Directors or advisory committees. Hasserjian:Sanofi, Inc: Consultancy. Gotlib:Sanofi: Travel to EHA 2012, Travel to EHA 2012 Other; Sanofi: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Thiele:AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Consultancy; Novartis, Shire: Research Funding; AOP Orphan Pharmaceuticals, Incyte, Novartis, Shire, Sanofi: Honoraria. Rodig:Ventana/Roche Inc.: Research Funding; Daiichi-Sankyo/Arqule Inc., Ventana/Roche Inc., Shape Pharmaceuticals Inc.: Consultancy. Patki:Sanofi: Employment. Wu:Sanofi: Employment. Wu:Sanofi: Employment. Pozdnyakova:Sanofi: Honoraria; Sanofi: Consultancy.

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Hepatobiliary and Thromboembolic Events during Long-Term E.X.T.E.N.Ded Treatment with Eltrombopag in Adult Patients with Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v128.22.1368.1368 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1368-1368

Author(s):

Mansoor N. Saleh ◽

James B Bussel ◽

Raymond SM Wong ◽

Balkis Meddeb ◽

Abdulgabar Salama ◽

...

Keyword(s):

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Adult Patients ◽

Phase Iii ◽

First Year ◽

Thromboembolic Events ◽

Advisory Committees ◽

Platelet Counts

Abstract Introduction: ITP, characterized by a reduction in platelets leading to thrombocytopenia, which persists for >12 months is considered chronic (cITP). Eltrombopag is an oral thrombopoietin receptor agonist approved for treatment of patients with cITP aged ≥1 year refractory to other treatments (eg corticosteroids, immunoglobulins). The recently completed Phase III EXTEND (Eltrombopag eXTENded Dosing) study was a global, open-label, extension study of patients with cITP, who received eltrombopag or placebo in prior eltrombopag clinical studies. The primary objective of EXTEND was to describe the long-term safety and tolerability of eltrombopag treatment in these patients. Here, we examine the occurrence of hepatobiliary and thromboembolic events (TEEs) as adverse events (AEs) of special interest in this study. Methods :Adult patients (≥18 years old) diagnosed with cITP according to ASH/BCSH guidelines were enrolled and received eltrombopag starting at 50 mg/day. Dose was titrated to 25-75 mg per day or less often as required, based on individual platelet count responses (targeted range ≥50-200x109/L). Patients who received 2 years of treatment and transitioned off eltrombopag due to commercial availability of eltrombopag were considered to have completed the study, whether or not they continued treatment with eltrombopag. The primary endpoint included detection and documentation of investigator-reported AEs, which included hepatobiliary AEs and TEEs. Analyses were conducted using the safety population, defined as all subjects who entered the study and had taken at least one dose of the study medication. Results:302 patients were enrolled and received at least one dose of eltrombopag: 67% were female; 38% splenectomized; 49% aged 18-49 years. Median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day. Overall, 259/302 (86%) achieved platelet counts of ≥50×109/L at least once during the study and 126/248 (51%) patients maintained continuous platelet counts ≥50×109/L for at least 31 weeks. Incidence of bleeding symptoms (WHO grades 1-4) generally decreased over time in patients with available data, from 57% (n=171/302) at baseline to 16% at 1 year (n=13/80), and 21% (12/58) at 2 years. 45 (15%) patients experienced at least one hepatobiliary AE, with the highest incidence within the first year of treatment (Figure A). AEs of increased ALT or AST led to the discontinuation of five and three patients, respectively and four patients discontinued due to an AE of increased blood bilirubin. Nine patients experienced ALT and/or AST >3 x upper limit of normal (ULN) and total bilirubin >1.5xULN. 19 (6.3%) patients experienced a total of 23 TEEs. Most events occurred in the first year (Figure B), and none after year 4. TEEs included deep vein thrombosis (n=6), cerebral infarction (stroke) [n=3], myocardial infarction (n=4), transient ischemic attack (n=2), others (n=8, 1 occurrence of each). A clear association with elevated platelet counts was not observed. Platelets >200x109/L at the time of the TEE were recorded in 8/19 patients; 6/19 experienced the TEE at or shortly after achieving their maximum platelet count. In total, 10 patients discontinued because of TEEs. Conclusions: Long-term treatment with eltrombopag in patients with cITP led to sustained platelet increases and reduced bleeding symptoms. The highest incidences of hepatobiliary AEs and TEEs occurred during the first year of treatment, though several events were recorded after 3 years of therapy. Long-term eltrombopag therapy was well-tolerated with a positive benefit-risk relationship in adults with cITP, with decreasing events after the first year of treatment. Disclosures Saleh: GSK: Consultancy, Research Funding, Speakers Bureau. Bussel:Amgen, Novartis & GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingleheim, Prophylix Pharma, Protalex, Rigel Pharmaceuticals: Research Funding; Momenta Pharmaceuticals, Novartis, Prophylix Pharma, Protalex, Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; UptoDate: Patents & Royalties; Physicians Education Resource: Speakers Bureau. Wong:Bayer, Biogen-Idec and Novartis: Consultancy; Bayer, Biogen-Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, and Roche: Research Funding; Biogen-Idec and Novartis: Membership on an entity's Board of Directors or advisory committees. El-Ali:Novartis: Employment. Quebe-Fehling:Novartis: Employment.

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Final Overall Survival Results of a Randomized Trial Comparing Bortezomib Plus Pegylated Liposomal Doxorubicin with Bortezomib Alone in Subjects with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.3448.3448 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3448-3448

Author(s):

Robert Z. Orlowski ◽

Arnon Nagler ◽

Pieter Sonneveld ◽

Joan Bladé ◽

Roman Hajek ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

Phase Iii ◽

Advisory Committees ◽

Grant Support ◽

Johnson Pharmaceutical Research

Abstract Introduction Previous results of an open-label, randomized, controlled, multicenter phase III study (DOXIL-MMY-3001) demonstrated that bortezomib+pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in treating subjects with relapsed or refractory multiple myeloma (MM) whose disease had failed one or more lines of prior therapy. The risk of developing disease progression was significantly reduced by 45% with bortezomib+PLD (median time to progression (TTP) with bortezomib+PLD: 9.3 months, bortezomib: 6.5 months; HR=1.82, 95% confidence interval (CI) [1.41, 2.35]; p=0.000004). In the interim analysis, the 15-month overall survival (OS) rate for bortezomib+PLD was 76% (95% CI [70%, 83%]) compared with 65% (95% CI [58%, 73%]) for bortezomib alone (p=0.03)(Orlowski et al JCO 25: 3892-3901, 2007). A protocol-defined analysis of the final survival data of this study is provided here. Methods Subjects with confirmed MM, ECOG status 0 to 1, platelets ≥75,000/mm3, hemoglobin ≥8.0 g/dL, absolute neutrophils ≥1,000/mm3, and creatinine clearance ≥30 mL/min were randomized to bortezomib (bortezomib 1.3 mg/m2, intravenous, days 1, 4, 8, and 11 of an every 21-day cycle), or bortezomib+PLD (same bortezomib+PLD 30 mg/m2 intravenous on day 4). Randomization was stratified according to serum β2-microglobulin levels (≤2.5, >2.5 and ≤5.5, or >5.5 mg/L) and response to prior treatment (response followed by progression, or primary refractory). The primary endpoint was TTP; secondary efficacy endpoints included overall survival, progression-free survival (PFS) and overall response rate (complete response [CR] + partial response [PR]). Results A total of 646 subjects (bortezomib+PLD: 324; bortezomib: 322) were randomized between December 2004 and March 2006. In the pre-planned interim analysis, the study met its primary and other secondary end points. The study continued for long-term survival follow-up. At the clinical cutoff of 16 May, 2014, for the final survival analysis with a median follow-up of 103 months, 79% of subjects were dead (bortezomib+PLD: 253 [78%]; bortezomib: 257 [80%]), 6% withdrew consent, 4% were lost to follow-up, and 11% were still alive. Median OS in bortezomib+PLD–treated subjects was 33.0 months (95% CI [28.9, 37.1]) versus 30.8 months (95% CI [25.2, 36.5]) in bortezomib-treated subjects (HR=1.05, 95% CI [0.88, 1.25]; p=0.6068). The types of salvage therapies utilized included dexamethasone (49.1%), thalidomide (31.0%), cyclophosphamide (28.5%), melphalan (22.9%), lenalidomide (21.8%), bortezomib (20.4%) and doxorubicin (8.0%), which were well-balanced between the two treatment groups. Conclusion Despite inducing a superior TTP, long-term follow-up revealed that PLD+bortezomib-treatment did not improve the OS compared with bortezomib alone in subjects with relapsed or refractory MM. The inability to confirm the early survival advantage may be due to the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase III trials. Disclosures Orlowski: Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Orthobiotech;: Consultancy. Bladé:Celgene: Grant support, Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Grant support Other, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hajek:Janssen: Honoraria; Celgene: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Spencer:Hospira: Research Funding. Robak:MorphoSys AG: Research Funding. Dmoszynska:Johnson & Johnson Pharmaceutical Research & Development: Research Funding. Horvath:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Research Funding. Sutherland:OrthoBiotech: Consultancy. Xiu:Johnson & Johnson Pharmaceutical Research & Development: Consultancy, Employment, Equity Ownership. Parekh:Johnson & Johnson Pharmaceutical Research & Development: Employment, Equity Ownership. Miguel:Janssen Cilag: Consultancy, Honoraria.

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Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma:Â a Phase II Trial (GOAL)

Blood ◽

10.1182/blood-2018-99-116670 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1678-1678 ◽

Cited By ~ 1

Author(s):

Georg Hess ◽

Andreas Hüttmann ◽

Julia Meissner ◽

Reinhard Marks ◽

Martin Dreyling ◽

...

Keyword(s):

Adverse Events ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Median Number ◽

Phase Iii ◽

Advisory Committees ◽

Phase Iii Trial ◽

Grade 3 ◽

One Year

Abstract Background: A substantial proportion of patients fail first line treatment of diffuse large B-cell lymphoma. Currently available salvage therapies are often ineffective and cannot be tolerated, especially for elderly patients. Thus, probably less than 25% of patients achieve a long lasting remission. Regimens like gemcitabine/oxaliplatin, or bendamustin, both in combination with rituximab are available for elderly or after failure of HDT, however induce only short lived responses. Obinutuzumab (GA101) is a type II anti-CD20 antibody, with preclinical evidence of superiority over rituximab in xenograft models of MCL and DLBCL. Recently a large phase III trial failed to show a benefit in patients with untreated DLBCL, although a subset analysis showed a potential benefit in a subset GCB DLBCL of patients, its value in relapsed disease is not yet finally determined. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclines from relapse treatments. With pixantrone, a drug related to anthracyclines, a re-exposition against this drug class has been shown to be feasible, a best EOT-ORR of 37% (20% CR/CRu) was observed in a phase III trial. We thus initiated a trial combining both agents for the first time. The trial has opened in Q3/2015 and recruitment of 70 patients is completed as of 7/2018. Primary endpoint is the ORR, secondary endpoints being safety, PFS and OS. We report about available data after enrollment of the last patient. Methods: this is a multicenter, national, prospective trial. Main inclusion criteria: histologically proven DLBCL, FL grade IIIb or transformed iNHL (20% Quorum), no curative option available, relapsed and measurable disease, ECOG < 3, sufficient BM reserve, no severe concomitant diseases and given informed consent. There was no upper limit of prior treatment lines. Treatment consisted of up to 6 cycles of pixantrone 50mg/m² day 1, 8 and 15 of each cycle, obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. Interim staging was scheduled after 3 cycles. Results: Basic data are available of 67 patients, all were caucasian, 37 were female the other 30 male and median age was 75 years. Most of the patients suffered from DLBCL (49 pts, 68%), 68% had advanced stage at diagnosis and the median secondary IPI was 3. Data collection is ongoing, until now data of 32 patients are fully available and updated results will be presented. Median number of prior therapies was 2 (1 to 6). Treatment seemed to be well tolerated, median number of cycles applied was 3, pre-mature stop of treatment was primarily based on progression. Response evaluation: at this time 13/32 (40.6%) evaluable patients responded with 5 patients achieving CR/CRu (15.6%) and 8 a PR. One year after initiation of treatment 54% of patients remained alive. Median follow up is 8.2 months. Median PFS and OS is 82 day and not reached, 1 year PFS and OS are 37% and 54%, respectively, no patient experienced relapse if the patient remained free from relapse at one year. Observed toxicity was predominantly hematologic. The following hematologic grade 3/4 adverse events were observed: leukopenia (9.4%) neutropenia (75%), thrombocytopenia (12.5%). The febrile neutropenia rate was 6.3%. Non-hematologic grade 3/4 adverse events were very rare, no single side effect was observed with a frequency of 5% or more. Summary: the combination of Obinutuzumab and Pixantrone is feasible and safe. Early response rates are interesting. Importantly, although some patients experience progress early, a promising proportion shows long lasting remissions. Molecular analyses are ongoing, as well as a detailed analysis on the impact of factors such as of number of prior treatments, status at inclusion. Figure. Figure. Disclosures Hess: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Marks:BMS: Honoraria; Merck: Honoraria; Servier: Honoraria. Dreyling:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Acerta: Consultancy; Sandoz: Consultancy. Keller:Takeda: Consultancy, Research Funding; MSD: Consultancy; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; BMS: Consultancy; Celgene: Research Funding. Ernst:Novartis: Research Funding. Viardot:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria. Lenz:Novartis: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria.

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Long-Term Efficacy and Safety of Ropeginterferon Alfa-2b in Patients with Polycythemia Vera — Final Phase I/II Peginvera Study Results

Blood ◽

10.1182/blood-2018-99-118584 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3030-3030 ◽

Cited By ~ 3

Author(s):

Heinz Gisslinger ◽

Veronika Buxhofer-Ausch ◽

Josef Thaler ◽

Ernst Forjan ◽

Ella Willenbacher ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Research Funding ◽

First Year ◽

Molecular Response ◽

Efficacy And Safety ◽

Dosing Regimen ◽

Advisory Committees ◽

Hematological Response

Abstract Background: Ropeginterferon alfa-2b (Ropeg) is a novel long-acting monopegylated IFN-alpha-2b. Due to reduced dosing frequencies, better tolerability and improved compliance, Ropeg may be a favorable treatment option for long-term therapy in patients with polycythemia vera (PV). Study design: PEGINVERA phase I/II (NCT: 2010-018768-18), a prospective, open-label, multicenter study, investigated the efficacy and safety of Ropeg for long-term treatment in 51 patients aged ≥18 years with a confirmed diagnosis of PV, regardless of prior cytoreductive therapy. Following ≥1 year of 2-weekly treatment, patients who responded well to Ropeg were permitted to switch to a 4-weekly dosing regimen. Results: Baseline characteristics of the study cohort and interim safety and efficacy data were presented previously (Gisslinger et al., Blood, 2015). Fifty-one patients were treated: Median exposure to Ropeg was approximately 5.1 years (61 months; range: 0 to 87 months). Patients were treated for a median of approximately 2 years (98.9 weeks; (Q1-Q3: 69.0 - 117.4 weeks) on the 2-weekly regimen and 4 years (207.1 weeks; Q1-Q3: 158.6 - 242.0 weeks) on the 4-weekly regimen. The best observed individual hematological response for patients in the efficacy analysis set (FAS) was a complete hematological response for 27/42 (64.3%) and a partial response for 14/42 (33.3%) patients. Patients required a median of 34 weeks (Q1-Q3: 10-96 weeks) treatment to achieve a complete hematological response, and 10 weeks (Q1-Q3: 10-20 weeks) to achieve any hematological response. Switch from 2 to 4-week dosing regimen had no apparent effect on maintenance of response. With respect to JAK-2 allele burden, the best observed individual molecular response was a complete response for 12/42 (28.6%) patients and a partial response for 19/42 (45.2%) patients. Lowest JAK-2 values relative to baseline are presented by patient in Figure 1. Patients required a median of 82 weeks (Q1-Q3: 44-115 weeks) treatment to achieve a complete molecular response and 34 weeks (Q1-Q3: 18-55 weeks) treatment to achieve any molecular response. Irrespective of dosing regimen, molecular responses tended to increase over time. Most patients reported at least one adverse reaction (AR) to treatment (409 ARs in 48/51 [94.1%]); however, the majority (296 in 44 [86.3%] patients) were mild; 102 (in 34 [66.7%] patients) were moderate and 11 (in 10 [19.6%] patients) were severe. The most frequently reported ARs (frequency >20%) were arthralgia, influenza-like illness and fatigue. Twelve serious treatment emergent adverse events (TEAE) reported by 8/51 patients (15.7%) were considered to be treatment related: 2 events of depression, 2 of positive anti-thyroid antibodies, and one each of acute stress disorder, increased antinuclear antibodies, arthralgia, atrial fibrillation, fatigue, influenza-like illness, pyrexia, and increased transaminases. 25 patients completed the trial. The majority of discontinuation due to TEAE (13/21 patients) occurred in the first year, when the recommended slow up-titration of Ropeg could not be applied because of the maximum-tolerated-dose design. After the first year, only 8 additional patients discontinued because of TEAE. Conclusions: The final results of this phase I/II study of Ropeg in patients with PV support the findings of the pivotal phase III clinical trial (Gisslinger et al., Blood 2015) with respect to safety and efficacy as determined by hematological, clinical and molecular parameters. In addition, these data provide evidence that treatment with Ropeginterferon alfa-2b for up to 7 years is efficacious, well-tolerated and disease-modifying at both the 2 week and 4 week maintenance treatment regimens. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Krauth:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Greil:MSD: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zoerer:AOP Orphan Pharmaceuticals: Employment. Empson:AOP Orphan Pharmaceuticals: Employment. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment.

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Very Long Term Follow up a Phase II Study of Post-Remission Subcutaneous (SC) Azacitidine (AZA) in Patients with AML Post-MDS or Higher-Risk (HR) MDS

Blood ◽

10.1182/blood-2020-137012 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Amina Cherait ◽

Thorsten Braun ◽

Krimo Bouabdallah ◽

Denis Caillot ◽

Agnès Guerci ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Fatal Case ◽

Phase Iii ◽

Long Term Results ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Ambulatory Treatment

Background: Results of the phase III QUAZAR trial suggest that post-remission treatment with an oral form (CC-486) of azacitidine (AZA) can prolong CR duration and overall survival(OS) in AML patients reaching at least PR with intensive chemotherapy (IC) (Wei et al, ASH 2019). Maintenance treatment with subcutaneous (SC) AZA was recently shown to improve DFS in elderly AML (Huls et al, Blood 2019, a study that also included 10% MDS). We report very long term results of a study evaluating SC AZA as post-remission treatment in patients with AML post-MDS or high-risk MDS (HR-MDS) who achieved at least PR after IC, a population known to have short responses with IC. Methods: Inclusion criteria were (1) HR-MDS according to IPSS, or AML after a documented phase of MDS(2) who entered CR, CRi or PR after IC with anthracycline and AraC within 28 days of inclusion (3) ECOG <= 2, absence of infection or organ toxicity from IC (4) no identified donor for allo SCT at inclusion. Dosing of SC AZA was 60mg/m2/d for 5 days every 28 days, with adjustments according to tolerance, and until relapse or toxicity. Results: From July 2006 to June 2009, 51 pts (M:31/F:20) were included. The 46 evaluable pts had achieved CR (n=28), CRi (n=11), and PR (n=7) before study entry. Median age was 66y (range 55-78). Diagnosis at IC onset was MDS (n=13) and AML (n=33), IPSS cytogenetics was normal (n= 28), intermediate (n=10), high (n= 6), and failed (n=2). Median time from diagnosis of MDS to IC was 8 months (range 0.5-101). Median number of AZA maintenance cycles was 7.5 (1-76) in CR pts (>23 cycles in 5 of them) and 4.5 (1-24) in CRi or PR pts (> 23 cycles in 1). Two patients were allografted and censored at allo SCT. Median follow-up was 16.5 months As of May 2020 (cut off date of analysis) median DFS and OS from response were 6.9 m and 16.9 m, respectively (figure). In CR patients, median and 18 months OS were 18.9 months and 58%, versus 12.8 months and 50% in CRi-PR patients (p=0.33) All non allografted patients eventually relapsed. 7 had a response duration >18 months (6 CR patients: 22, 23, 25, 36, 40, and 84 months; 1 CRi patient: 24 months) OS from inclusion was >3 years in 7 patients (CR pts: 150, 126,74, 51, 50,40 months; CRi pt:58 months), in addition to the 2 allografted pts who remained alive in CR at 156+ and 159+ months No baseline factor including cytogenetics, diagnosis at IC onset (MDS vs AML), % bone marrow blasts, age or time from MDS diagnosis to treatment, significantly predicted DFS or OS. AZA dosing in CR patients was escalated in 9 pts to 75mg/m2/d due to good tolerance but had to be reduced in 6 pts, due to GI toxicity (n=1) and cytopenias (n=5). During SC AZA maintenance, 2/28 CR pts developed febrile neutropenia, compared to 4/18 pts in CRi or PR (including 1 fatal case). In the 22 AML post MDS pts who reached CR, DFS and OS were similar to those observed in 46 AML post AML pts included in a previous ALFA study where pts in CR after IC received DNR/IDA-AraC post-remission therapy (Gardin, Blood 2007). Conclusion: In the very long term analysis of this trial in AML post MDS and HR-MDS treated with induction intensive chemotherapy, post-remission therapy with SC AZA alone was associated with a median DFS and OS of 6.9 and 16.9 months, respectively, with some prolonged response. Results appeared similar to those we had reported with intensive consolidation chemotherapy, but using an ambulatory treatment with limited myelosuppression. Figure Disclosures Braun: Daiichy-Sankyo: Honoraria; Servier: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Ades:Celgene/BMS: Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Dose Interruption/Reduction Of Tyrosine Kinase Inhibitors In The First 3 Months Of Treatment of CML Is Associated With Inferior Early Molecular Responses and Predicts For An Increased Likelihood Of Discontinuation Of The 1st Line Agent

Blood ◽

10.1182/blood.v122.21.93.93 ◽

2013 ◽

Vol 122 (21) ◽

pp. 93-93

Author(s):

Jane F Apperley ◽

Richard M Szydlo ◽

Gareth Gerrard ◽

James R McCue ◽

Jamie Wardle ◽

...

Keyword(s):

Board Of Directors ◽

Dose Reduction ◽

Research Funding ◽

Kinase Inhibitors ◽

Randomized Study ◽

Phase Iii ◽

Advisory Committees ◽

Days Of Therapy ◽

The Impact

Abstract In CML, rapid reductions in tumor load, as defined by at least 65% Ph-negativity and/or a RT-qPCR <10%IS at 3 mths, are associated with an improved probability of CCyR and better overall and progression free survivals. However some 15-20% of patients experience cytopenias shortly after starting TKI treatment and are managed by drug interruptions and/or dose reduction. The dilemma is whether these early periods of altered treatment should be considered in the interpretation of the 3 mth results. We investigated the impact of missing days of therapy and average dosing over the first 3 mths on the 3 mth RT-qPCR levels, CCyR at 12 mths and ability to remain on study, in patients treated in a phase III randomized study of imatinib (IM) versus dasatinib (DA) in newly diagnosed patients. RT-qPCR results at 3 mths were available for 585 (IM-292, DA-293) of 632 patients who completed 3 mths of therapy. Patients were divided according to their randomized drug and the amount missed: those who did not miss any days (IM0 [243], DA0 [211]), those who missed 1-14 days (IM1-14 [38], DA1-14 [37]) and those who missed >14 days (IM>14 [11], DA>14 [45]). More patients on DA missed days of dosing (28%) than on IM (17%) with a median number of missed days for DA of 16 (range 1-62) compared to 12.5 (range 1-42) for IM p=0.008. Achievement of a RT-qPCR <10%IS at 3 mths for IM0, IM1-14 and IM>14 was 78.6%, 63.2% and 63.5% p=0.033 and 93.8%, 91.9% and 77.8% for DA-0, DA1-14 and DA>14 respectively p=0.001. Predictably the chance of a RT-qPCR <10%IS at 3 mths is higher with DA than IM but DA is less well tolerated in the early months. RT-qPCR <10%IS at 3 mths occurred in 78.7% and 93. 8% of patients who took more than 95% of the standard doses of IM and DA respectively in contrast to 60% (IM) and 84% (DA) in patients who missed more than 20% of the prescribed doses. Thus missing drug or dose reductions are associated with a reduced chance of achieving a RT-qPCR <10%IS at 3 mths, although the effect is not seen for missing <14 days of DA, and is less marked for reduced average dosing of DA, suggesting that the higher potency of DA compensates for the impact of missing a few days of drug or dose reduction. 107/632 (17%) patients had discontinued the study by 12 mths and RT-qPCR results are available for all remaining patients. Using RT-qPCR <1% (MR2) as a surrogate for CCyR, the 12 mth MR2 rates for patients on IM were 78%, 78% and 90% in the IM0, IM1-14 and IM>14 cohorts p=0.5, and 96%, 88.6% and 79.5% p=0.026 for the DA0, DA1-4 and DA>14 cohorts, confirming superiority of DA over IM for MR2 and the potential impact of missing early doses of DA. Whether this is related to inadequate dosing or whether failure to tolerate the recommended dose is indicative of higher risk disease is not yet clear. We then studied whether missing drug in the first 3 months predicts the ability to stay on trial. The proportion of patients able to take the study drug consistently through mths 3-12 were 91%, 71% and 57% in the IM0/DA0, IM1-14/DA1-14 and IM>14/DA>14 groups respectively. This correlated with discontinuing the study (treatment failure) for 12.5%, 38.1% and 35.7% of patients in the IM0, IM1-14 and IM>14 cohorts and 4.4%, 12.8% and 18.8% in the equivalent DA cohorts. Thus the ability to tolerate daily drug in the first 3 mths predicts future tolerability and efficacy over the subsequent 9 mths and long-term compliance with the first line therapy. RT-qPCR monitoring was provided long-term for all patients entered into the study irrespective of their continuation in the study, so we were able to study the achievement of MR3 at 12 mths in an intention to treat analysis in all patients. With respect to average dosing over the first 3 mths MR3 was seen in 50%, 52.8% and 54.9% p=0.17 of patients who took >95%, 80-95% and <80% of the prescribed dose of IM and 68.1% (>95%), 59.4% (80-95%) and 53.1% (<80%) p=0.038 for the equivalent doses of DA. Similar results were obtained using the number of days of missed drug (data not shown), suggesting that early failure to tolerate IM as 1st line does not impact on subsequent responses as effective alternative therapy is available for the majority of patients. In contract failure to tolerate DA is associated with a reduced chance of MR3 at 12 mths. Patients who experience drug cessation/reduction of either drug in the first 3 mths are less likely to obtain RT-qPCR <10%IS at 3 mths and are more likely to require a change of drug in the longer-term and therefore require close observation during the first year. Disclosures: Apperley: Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Clark:Novartis : Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. O'Brien:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria.

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