scholarly journals Maintenance Treatment with Guadecitabine (SGI-110) in High Risk MDS and AML Patients after Allogeneic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-30
Author(s):  
Betul Oran ◽  
Gheath Alatrash ◽  
Amin M. Alousi ◽  
Rohtesh S. Mehta ◽  
Chitra Hosing ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Study Drug ◽  
Bone Marrow Suppression ◽  
Efficacy And Safety ◽  
Disease Relapse ◽  
Interim Analyses ◽  
Grade 3 ◽  
Count Recovery

Background: Disease relapse remains to be the one of the major reasons of treatment failures after allogeneic stem cell transplantation (allo-SCT) in AML and MDS patients (pts). SGI-110 is a next generation hypomethylating agent that molecularly is a dinucleotide derivative of decitabine and therefore a more potent inhibitor of DNA methyltransferase activity. We present interim results of a single arm phase II trial evaluating the efficacy and safety of SGI-110 in AML/MDS pts. to improve transplant outcomes. Methods: In this study, there are 3 treatment cohorts defined by disease status after transplant with different primary outcomes of interest. Cohort 1 includes AML/MDS pts. with morphological relapse after transplant; cohort 2 pts with minimal residual (MRD) and cohort 3 pts with no evidence of disease. As of June 2020, 54 pts have enrolled. Herein, we report the interim analyses of 22 pts treated in cohort 3 and received SGI-110 as post-transplant maintenance while in remission. Other cohorts' results will be reported separately. The maintenance cohort includes high risk AML/MDS pts aged 18-75. High risk MDS is defined as having (1) poor or very poor cytogenetics by revised-IPSS or (2) monosomal karyotype or (3) bone marrow blast count > 5% before transplant; high risk AML as (1) adverse risk group by European LeukemiaNet (ELN) or (2) presence of MRD or active disease at transplant. Therapy-related AML/MDS is included. Pts. are excluded in the presence of (1) active acute graft versus host disease (GvHD), (2) uncontrolled systemic infection, or (3) concurrent use of systemic immune suppressive other than calcineurin inhibitors and sirolimus. The study intervention includes SGI-110 given as 30 mg/m2/day subcutaneously for 5 consecutive days every 28 days until completion of 12 cycles, disease relapse, or experience of unacceptable toxicity. SGI-110 is initiated between 42 to 100 days following allo-SCT if there is adequate engraftment with absolute neutrophil count >/= 1.0 x 109 /L; platelet >/= 50 x 109 /L and no documented evidence of relapse. Treatment delays up to 70 days and dose reductions are allowed per protocol. The primary endpoint for this cohort is relapse-free survival (RFS) time defined as either time to disease progression or death whichever happened first. The maximum planned sample size is 40. Results: As of June 2020, 22 pts were enrolled; M/F, 12/10, median age, 62 (range 18 to74). Of 11 AML pts., ELN risk category was adverse in 8, intermediate in 2 and favorable in 1. Of 11 MDS pts, 6 had poor/very poor and 4 good and 1 intermediate risk cytogenetic abnormalities by revised-IPSS. Of 22, 6 were in complete remission with count recovery at transplant. Median time to initiation of first cycle of maintenance with SGI-110 was 59.5 days (range, 43 to 114 days). So far, 14 pts of 22 were taken off the study; 6 due to disease relapse, 4 completed planned 12 cycles of treatment, 1 lost insurance, 1 withdrew the consent, 1 had travel issues due to COVID19 pandemic and 1 had pulmonary complications unrelated to study drug. Currently, 8 remain to be on the study. Median number of treatment cycles administered have been 4 (range, 1 to 12). Of 22, 7 pts. required the SGI-110 dose to be reduced down to 20 mg/m2/dayX5 days and 1 patient to 20 mg/m2/dayX3 days to be able to continue the treatment. At a median follow-up of 13.1 months for survivors (n=17), RFS and overall survival at 1-year was 66.3% (95% confidence interval (CI)=42% to 82.3%) and 88.9% (95%CI=61.8 to 92.2%) respectively (Figure) During the study, 353 AEs observed with 125 cycles of SGI-110 treatments. Of 353, 287 (81.3%) were attributable to SGI-110 and 133 of 287 (46.3%) were grade 3 or higher in severity. Most of the grade 3 or higher AEs were related with bone marrow suppression; 71 (25%) thrombocytopenia, 64 (22%) neutropenia, 67 (23%) leukopenia and 8 (2%) anemia. Of 22 pts, 15 had grade 4 neutropenia at least once and 8 pts grade 4 thrombocytopenia. There was 18 episodes of infectious AEs and 11 of 18 were grade 3-4. There were no grade 5 AEs observed attributable to study drug. Conclusion: SGI-110 led to frequent grade 3-4 BM suppression in high risk AML/MDS pts when given as maintenance therapy after allo-SCT. However, bone marrow suppression was not associated with increased risk of infection and it was temporary with count recovery. The efficacy of SGI-110 has been promising with 1-year RFS of 66.3%. The study currently is ongoing. Disclosures Oran: Celgene: Consultancy; Arog Pharmaceuticals: Research Funding; ASTEX: Research Funding. Alousi:Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Mehta:CSL Behring: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing:NKARTA Inc.: Consultancy. Popat:Bayer: Research Funding; Novartis: Research Funding. Keer:Astex Pharmaceuticals, Inc.: Current Employment. Champlin:Actinium: Consultancy; Genzyme: Speakers Bureau; Omeros: Consultancy; Cytonus: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Takeda: Patents & Royalties; Johnson and Johnson: Consultancy. OffLabel Disclosure: The abstract presents interim analyses of a clinical trial investigating efficacy and safety of SGI-110 used as maintenance therapy in high risk AML and MDS patients after transplant.

Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3286-3286 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Anna Turkina ◽  
Dong-Wook Kim ◽  
Bernadeta Ceglarek ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2823-2823 ◽  
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.

Activity and Tolerability of Azacitidine in Patients Who Relapse after Allogeneic Stem Cell Transplantation (allo-SCT) for Acute Myeloid Leukemia (AML) and Myelodysplasia (MDS): a Survey from the European Society for Blood and Marrow Transplantation (EBMT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2506-2506 ◽  
Author(s):  
Charles Craddock ◽  
Myriam Labopin ◽  
Mohamed Houhou ◽  
Marie Robin ◽  
Juergen Finke ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
Multivariable Analysis ◽  
Unrelated Donor ◽  
Disease Relapse ◽  
Post Transplant ◽  
Significant Difference ◽  
Grade 3

Abstract Disease relapse is the most common cause of treatment failure after allo-SCT for high risk AML and MDS. Treatment options for patients with recurrent disease are extremely limited and re-induction chemotherapy, when administered, is often either poorly tolerated or ineffective. Azacitidine (AZA) is a DNMT inhibitor which is well tolerated and clinically active in high risk AML/MDS. Of interest AZA also up-regulates the expression of tumor antigens and plausibly augments a graft-versus-leukemia effect. A number of small studies have suggested clinical activity of AZA in patients who relapse after an allograft for AML/MDS but both overall response rate and predictors of response remain unknown. We report the first systematic study of the activity and tolerability of AZA in patients who relapsed after allo-SCT for AML/MDS. 204 patients who relapsed at a median of 6.5 months (range, 1-49) after an allograft for AML (n=130) or MDS (n=74) were studied. The median age was 58 years (range 22-76). 89 patients were transplanted using a matched sibling donor and 115 from an adult unrelated donor. 47 patients received a myeloablative and 157 a reduced intensity conditioning regimen. AZA was administered for 5-7 consecutive days every month. The median duration of AZA treatment was 68 days (inter-quartile range 24-154 days). 66 patients received additional donor lymphocyte infusions (DLI) at a median of 43 days after commencement of AZA. AZA was well tolerated in the majority of patients. 57 patients developed Grade 3-4 non-hematological toxicities 47 of which were infectious complications and likely also attributable to relapsed disease. 4 patients developed Grade 3-4 acute GVHD after AZA treatment. 45 (22%) patients achieved a complete remission (CR) or partial remission after AZA administration at a median of 114 days after commencement of treatment. 31 (15%) patients achieved a CR. The median number of courses of AZA to achieve a clinical response was three. In multivariable analysis the only significant factor determining improved response to AZA was relapse occurring more than 12 months post-transplant. The median overall survival (OS) for all patients was 6 months after the commencement of AZA therapy. In patients who achieved a CR the 2 year OS after commencement of AZA was 38.5% versus 11% for the whole population (p= 0.001). In multivariable analysis OS was determined by the occurrence of disease relapse more than 6 months post-transplant and achievement of a CR after AZA therapy. Of note, there was no significant difference in response rates to AZA between patients with relapsed AML or MDS. Concurrent administration of DLI did not improve either response or survival rates. In conclusion, these data confirm the ability of AZA to salvage a proportion of patients with AML or MDS who relapse after an allogeneic SCT and identify prognostic factors of response. The response and survival rates achieved with salvage AZA are comparable to those previously reported with either intensive chemotherapy or DLI. We conclude AZA represents an important and relatively well-tolerated new treatment option in the management of selected patients with AML and MDS who relapse after allo-SCT. Disclosures Craddock: Celgene: Grants Other, Honoraria. Kroger:Celgene: Research Funding. Mohty:Celgene: Research Funding.

The Safety and Activity of BMS-906024, a Gamma Secretase Inhibitor (GSI) with Anti-Notch Activity, in Patients with Relapsed T-Cell Acute Lymphoblastic Leukemia (T-ALL): Initial Results of a Phase 1 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 968-968 ◽  
Author(s):  
Patrick A. Zweidler-McKay ◽  
Daniel J. DeAngelo ◽  
Dan Douer ◽  
Hervé Dombret ◽  
Oliver G. Ottmann ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Mutation Status ◽  
Response Data ◽  
Notch Receptors ◽  
Equity Ownership ◽  
Grade 3 ◽  
Count Recovery

Abstract Background: Activating mutations in Notch receptors are found in multiple hematopoietic malignancies, including > 50% of patients with T-ALL, making it the most common genetic abnormality in this disease. GSIs block activation of Notch receptors and limit growth and survival in pre-clinical T-ALL models. However, various GSIs evaluated in clinical trials have had on target toxicities and have not been reported to show significant responses. CA216002 is a multicenter phase 1 trial designed to assess the safety of a novel intravenous GSI BMS-906024 in patients with relapsed or refractory T-ALL and T-cell lymphoblastic lymphoma (T-LL). We are presenting the initial toxicity profile and response data on this trial. Methods: Adults with relapsed/refractory T-ALL or T-LL were enrolled and received BMS-906024 intravenously weekly at doses of 0.6 mg, 4 mg, and 6 mg. Due to the rapid progression of T-ALL in many cases, administration of glucocorticoids or other agents was permitted and dosing guidelines for dexamethasone were provided in the protocol. Results: As of July 2, 2014, safety and response data are available on 25 patients (age 18-74 yrs) with relapsed/refractory T-ALL/T-LL that received at least one dose of BMS-906024, at doses of 0.6 mg (n=1), 4 mg (n=10), and 6 mg (n=14). Seven patients did not complete the first 4-week cycle due to rapid disease progression or disease-related death (n=5), infusion reaction (n=1), or an unrelated adverse event (n=1). Safety: The drug-related grade 3-5 adverse events included grade 4 events of anemia, hypophosphatemia, and thrombocytopenia, and grade 3 events of diarrhea, febrile bone marrow aplasia, hepatotoxicity, hypophosphatemia, pancytopenia, and tumor lysis syndrome (n=1 each). Drug-related diarrhea was common (n=11, 44%), consistent with expectations for Notch inhibition, but was generally grade 1-2 with only one grade 3 event. One dose-limiting toxicity involving grade 3 elevations of ALT and AST without bilirubin elevation (reported as grade 3 hepatotoxicity) occurred at the 4 mg dose level. One death not related to disease progression occurred, due to GI and post-surgical hemorrhage associated with pancytopenia; hemorrhage was considered not related, but pancytopenia was considered related to study drug. Responses: Eight patients (32%; 4 at 4 mg and 4 at 6 mg) had at least 50% reduction in bone marrow (BM) blasts, including one formal CR and one PR (both at 6 mg), and three of these eight had 98-100% clearance of BM blasts. (One patient, marked “*” below, began the study with 0.1% BM blasts and is not included in the eight.) The patient who achieved a CR began the study with 85% BM blasts and an absolute peripheral blood (PB) blast count of 38 k/mcL. By the end of the first cycle the BM and PB were cleared of blasts, and by the end of the second cycle there was count recovery. This patient received dexamethasone during the first cycle only, and left the study after 3 cycles in CR for an allogeneic transplant. The patient who achieved a PR began with 32% BM blasts, and by the end of the first cycle the BM blasts had decreased to 7% with improvement in ANC. The additional six patients with 50-100% decreases in BM blasts had residual lymphadenopathy, had incomplete count recovery or failed to meet other criteria which prevented them from being considered CR or PR based on the protocol definitions. One of these six patients also received hydroxyurea beginning on study day 16. Biomarkers: The figure shows change in BM blasts in 12 patients with paired BM assessments and Notch mutation status available. BM responses occurred in both Notch mutant and wildtype patients. Conclusions: Overall 8 of the 25 patients (32%) showed at least 50% reduction in BM blasts including one CR and one PR. Although the contribution of concurrent glucocorticoid therapy to the improvement in some patients is not clearly defined, the multiple responses on this trial suggest anti-leukemia activity of BMS-906024. This represents the first Notch targeting trial leading to multiple responses in relapsed/refractory T-ALL. BMS-906024 was relatively well tolerated, with minimal diarrhea in this population. The weekly dosing of this long-acting GSI shows promise for targeting Notch in T-ALL. Pharmacokinetic and additional biomarker data will be presented. Figure 1 Figure 1. Maximum Percent Reduction from Baseline of BM Blasts in Patients with Paired BM Assessments and Known Mutation Status Disclosures Zweidler-McKay: BMS: Research Funding. Off Label Use: BMS-906024 is in early Phase I clinical trials, and does not yet have an FDA-approved indication.. Douer:BMS: Research Funding. Ottmann:BMS: Consultancy, Honoraria, Research Funding. Vey:BMS: Honoraria. Thomas:BMS: Research Funding. Zhu:BMS: Employment. Huang:BMS: Employment, Equity Ownership. Bajaj:BMS: Employment. Fischer:BMS: Employment, Equity Ownership.

Patterns and Management of Selected Adverse Events of Adult Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) From the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1115-1115
Author(s):  
Philipp D. le Coutre ◽  
Bernadeta Ceglarek ◽  
Anna Turkina ◽  
Dong-Wook Kim ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Drug Therapy ◽  
Research Funding ◽  
Concomitant Medication ◽  
Kinase Inhibitor ◽  
Study Drug ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
First Occurrence ◽  
Grade 3

Abstract Abstract 1115 Poster Board I-137 Introduction Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML. Data from ENACT are used to characterize the patterns and management of adverse events (AEs) in nilotinib pts with imatinib-resistant or -intolerant CML-CP or -AP. Methods Pts received nilotinib 400 mg twice daily. Safety assessments included monitoring for all AEs and cardiac procedures. The first occurrence of the following AEs were selected on the basis of the following criteria: 1) the most frequently reported hematologic or biochemical laboratory abnormalities; or 2) identified by participating investigators as AEs of interest that may lead to study drug discontinuation: thrombocytopenia, neutropenia, hyperglycaemia, elevated lipase, elevated amylase, hyperbilirubinaemia, elevated alanine transaminase (ALT), and elevated aspartate transaminase (AST). There were no differences observed between the pattern of management between AEs suspected and regardless of study drug relationship as well as all grades vs. grade 3/4. For this reason this analysis covers management of grade 3/4 AEs suspected of study-drug relationship including duration and subsequent management. The following actions taken were reported by the treating physicians: study drug dose adjusted or temporarily interrupted, non-drug therapy given, no action taken, study drug permanently discontinued, concomitant medication taken or hospitalization/ prolonged hospitalization. More than one action was allowed to be selected. Results The AEs experienced by 1,603 pts (1,422 CP and 181 AP) were generally identified during nilotinib treatment and lasted for short durations. The number of the grade 3 and 4 AEs in CP and AP, median time from start of treatment and median duration are reported in Table. For all included AEs, the overall most common action taken for the first occurrence was dose adjustment or temporary interruption with the exception of hyperglycaemia which was most often managed by treatment with concomitant medications (8/11 of hyperglycaemia AEs in CP and 1/2 in AP). In the majority of the biochemical abnormalities other than hyperglycaemia there was no additional action taken. 49/308 (16%) events of thrombocytopenia in CP pts (9 in AP) were managed by non-drug therapy. 31/204 (15%) events of neutropenia in CP pts were managed by concomitant medication (6/33 events in AP). Permanent discontinuation of study drug was infrequently observed (number of pts in CP; AP): thrombocytopenia (25; 7), neutropenia (15; 2), hyperglycaemia (1; 0), elevated lipase (3; 0), elevated amylase (0; no pts), hyperbilirubinaemia (2; 0), elevated ALT (3; 0), and elevated AST (1; 0). Conclusions Based on a large cohort of 1,603 nilotinib pts with CML-CP and CML-AP, nilotinib is well-tolerated. Most study drug-related grade 3/4 AEs could be managed by temporary treatment interruption or dose adjustment, such that permanent discontinuation of study drug due to AEs was infrequent. The only events requiring concomitant medication administration or non-drug therapy were thrombocytopenia, neutropenia, hyperglycaemia and hyperbilirubinaemia. The AE profile observed was predictable and similar to that seen in registration trial. Disclosures le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Ceglarek:Novartis Pharmaceuticals: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Dial:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

Bortezomib, Bendamustine, and Rituximab in Patients with Relapsed or Refractory Follicular Lymphoma: Encouraging Activity in the Phase 2 VERTICAL Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 933-933 ◽  
Author(s):  
Nathan Fowler ◽  
Brad S Kahl ◽  
Peter Rosen ◽  
Jeffrey Matous ◽  
Amanda Cashen ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Clin Oncol ◽  
Board Of Directors ◽  
Research Funding ◽  
High Risk Population ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Abstract 933 Follicular lymphoma (FL) is an incurable, indolent B-cell non-Hodgkin lymphoma. Although survival has improved with the introduction of rituximab (Rituxan®, R), relapse is inevitable and new therapies are needed. Bortezomib (Velcade®, V) plus rituximab is active in relapsed or refractory (rel/ref) FL (de Vos et al, ASH 2006). Bendamustine (Treanda®, B) plus R has also shown activity in rel/ref FL (Robinson et al, J Clin Oncol 2008), and V has been safely combined with B in patients (pts) with advanced multiple myeloma (Fenk et al, Leuk Lymph 2007). The single-arm, multicenter, phase 2 VERTICAL study was conducted to determine the efficacy and safety of V and R in combination with B (VBR) in pts with rel/ref FL. Here we report preliminary phase 2 efficacy and safety findings from pts treated with VBR at doses determined in the dose-escalation phase of this study (Matous et al, ASCO 2009). Pts with rel/ref FL who had received ≥4 prior doses of R (no prior V or B), and had ≥1 measurable tumor mass, no active central nervous system lymphoma, Karnofsky Performance Status (KPS) ≥50%, adequate hematologic, renal, and hepatic function, and no grade ≥2 peripheral neuropathy (PN) were eligible. Pts could receive up to five 35-d cycles of V 1.6 mg/m2 (d 1, 8, 15, 22), B 90 mg/m2 (d 1, 2), and R 375 mg/m2 (d 1, 8, 15, 22, cycle 1; d 1, cycles 2–5). Response was assessed by the investigator using International Working Group criteria (Cheson et al, J Clin Oncol 2007). Adverse events (AEs) were graded using the CTCAE v3.0, and by laboratory assessment of hematologic toxicity. Sixty-three pts received VBR; median age was 58 years, 63% were male and 25% had KPS ≤80%. At diagnosis, 47% had grade 1, 26% grade 2, and 8% grade 3 histology, and 18% unknown histology; 35% had high-risk Follicular Lymphoma International Prognostic Index score. Pts had received a median of 2 prior therapies (range 1–11), and 39% were refractory to their last prior rituximab-containing therapy. The median time from diagnosis was 48 months. As of data cut-off (14 Aug 2009), pts had received a median of 3 cycles (range 1–5); 29 pts remain on therapy and 10 have completed treatment. In the 49 pts with at least one post baseline response assessment, to date, the overall best response rate was 84%; 23 (47%) pts achieved a complete response (CR) and 18 (37%) a partial response (PR). VBR was generally well tolerated, with manageable toxicities. The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%; 3% grade 3), fatigue (65%; 10% grade 3), diarrhea (57%; 3% grade 3), and vomiting (44%; 5% grade 3). Other non-hematologic grade 3/4 AEs that occurred in more than one pt included syncope (n=2; 3%) and PN (see below). Grade 3/4 neutropenia, thrombocytopenia, and anemia were seen in 25%, 6%, and 3% of pts, respectively. Treatment-related serious AEs were reported in 17 (27%) pts, including 3 (5%) with febrile neutropenia and 1 (2%) with grade 3 herpes zoster who did not receive antiviral prophylaxis and discontinued therapy. Of the 17 (27%) pts with treatment-related PN, only 4 (6%) had grade 3 (2 discontinued therapy; no grade 4); PN has resolved in 5 (29%) pts to date. There was one on-study death (cardiac arrest) that was considered treatment-related. Additional follow-up is required to assess long-term outcomes, including progression-free and overall survival. VBR is active in this heavily pre-treated, high-risk population, with high CR rates, and was generally well tolerated. Efficacy and safety data will be updated and reported at ASH. Disclosures: Fowler: Millennium Pharmaceuticals, Inc.: Research Funding. Kahl:Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding. Rosen:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Southern California Lymphoma Group, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen : Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tower Cancer Research Foundation: Employment. Matous:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Amin:Millennium Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncotype DX: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Williams:Milllennium: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Cephalon: Research Funding. Smith:Genentech: Membership on an entity's Board of Directors or advisory committees; Cephalon: Membership on an entity's Board of Directors or advisory committees. Shi:Millennium Pharmaceuticals, Inc.: Employment. Parasuraman:Milllennium: Employment. Cheson:Millennium Pharmaceuticals, Inc.: Consultancy, Speakers Bureau; Cephalon: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau.

PRM-151 in Myelofibrosis: Durable Efficacy and Safety at 72 Weeks

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 56-56 ◽  
Author(s):  
Srdan Verstovsek ◽  
Ruben A. Mesa ◽  
Lynda M Foltz ◽  
Vikas Gupta ◽  
John O. Mascarenhas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Negative Slope ◽  
Computer Assisted ◽  
Jak Inhibitor ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: PRM-151 (PRM) is a recombinant form of pentraxin-2, an endogenous human protein that acts at sites of tissue damage, inducing macrophage differentiation to prevent and reverse fibrosis. 27 patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, or post-polycythemia vera MF and Grade 2 or 3 bone marrow (BM) fibrosis enrolled in the first stage of a 2-stage adaptive trial in which PRM-151 10 mg/kg IV was administered for 24 weeks in four different arms: PRM-151 QW (n=8), PRM-151 Q4W (n=7), PRM-151 QW + ruxolitinib (RUX) (n=6), or PRM-151 Q4W + RUX (n=6). At 24 weeks, reductions in BM fibrosis, improvements in hemoglobin (Hgb) and platelets (PLT), decreases in symptoms (MPN-SAF Total Symptom Score [TSS]), and modest reductions in spleen size by palpation were observed in all arms, with a favorable safety profile (Verstovsek, ASH 2014, Abstract 713). Patients experiencing clinical benefit were allowed to continue beyond 24 weeks. We now report efficacy and safety in 13 patients who have completed at least 72 weeks of treatment. Bone marrow fibrosis status by morphologic WHO grading and computer-assisted image analysis (CIA) are available up to 48 weeks in some patients, as assessed by central hematopathologist reviewers blinded to patient, treatment, and timepoint. BM data through 72 weeks is pending. WHO response was defined as ≥1 grade reduction in MF grade at any time and CIA response was defined as a decrease in the % fibrosis compared to baseline with a negative slope > 1. (Pozdnyakova, EHA 2015, Abstract P677). Baseline Demographics (N=13): Median age 60 (51-76); 46% DIPSS Int-1, 54% DIPSS Int-2; 62% PMF, 15% post-ET MF, 23% post-PV MF; 46% grade 3 BM fibrosis, Hgb < 100 g/L in 38%, PLT < 100 x 109/L in 69% and <50 x 109/L in 38%; 31% JAK inhibitor-naive and 69% received a prior or current JAK inhibitor. Study treatment (N=13): In the first 24 weeks, treatment was PRM-151 QW (n=5), PRM-151 Q4W (n=3), PRM-151 QW + RUX (n=2), PRM-151 Q4W + RUX (n=3). At 28 weeks, treatment changed to PRM-151 QW (n=2), PRM-151 Q4W (n=7), and PRM-151 Q4W + RUX (n=4), with 1 patient stopping RUX for thrombocytopenia. Both PRM-151 QW patients switched to PRM-151 Q4W after 40 and 52 weeks. Two patients missed weeks 64 and 68 due to complications of a motor vehicle accident and abdominal surgery, respectively, but are continuing treatment as of week 72. BM (n=13): 54% had a morphologic response, and 85% had a CIA response. Hgb (g/L): In 5 pts with baseline Hgb < 100, median Hgb increased by 24% from 86 (range 77-97) at baseline to 107 (range 71-113) at Week 72. 3 of 5 patients who were receiving transfusions at baseline became transfusion independent, with durations of 32-60 weeks. (Figure 1) PLT (x 109/L): In 9 pts with baseline < 100, median PLT count increased by 37% from 38 (range 10-89) at baseline to 52 (range 26-159) at Week 72. All 4 patients who were receiving PLT transfusions at baseline became transfusion independent, with durations of 24-44 weeks. (Figure 2) Symptoms (N=13): 69% and 38% of patients had ≥ 50% and 100% reductions from baseline in TSS between 24 and 72 weeks, with durations of up to 48 and 12 weeks, respectively. (Figure 3) Spleen (N= 9 with palpable spleens at baseline): 50% of pts had ≥25% reduction, 2 of whom had ≥50% reduction lasting > 12 weeks. (Figure 4) Safety (N=13): Most common adverse events (AEs) regardless of relatedness were fatigue (4), nausea (3), fever (3), cough (2), diarrhea (2), tooth infection (2), headache (2), upper respiratory infection (2), hyperglycemia (2), and hyperuricemia (2). There were 13 possibly or probably related adverse events in 3 patients from beginning of study through 71 weeks, 11 Grade 1, 1 Grade 2 and 1 Grade 3, with no event occurring in > 1 patient. There were no related serious AEs in these patients. Conclusion: In 13 patients completing at least 72 weeks, PRM-151 treatment was well tolerated, and improvements in Hgb, PLT, symptoms and spleen appeared to increase with longer treatment duration. Disclosures Mesa: Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Pfizer: Research Funding. Foltz:Promedior: Research Funding. Gupta:Incyte Corporation: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Promedior: Research Funding. Mascarenhas:Kalobios: Research Funding; Roche: Research Funding; Promedior: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Hoffman:All Cells, LLC: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding. Silver:Promedior: Research Funding. Pozdnyakova:Promedior: Consultancy. Hasserjian:Promedior: Consultancy. Trehu:Promedior: Employment, Equity Ownership. Salama:Promedior: Consultancy. Gotlib:Allakos, Inc.: Consultancy.

scholarly journals A Phase 1b Study of Eltrombopag and Azacitidine in Patients with High Risk Myelodysplastic Syndromes and Related Disorders

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Alex Sternberg ◽  
Rebecca H. Boucher ◽  
Helen C Coulthard ◽  
Manoj Raghavan ◽  
Dominic J. Culligan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Immune Thrombocytopenic Purpura ◽  
Research Funding ◽  
Thrombocytopenic Purpura ◽  
Platelet Recovery ◽  
Chronic Immune Thrombocytopenic Purpura ◽  
Thrombopoietin Receptor ◽  
Phase 1B ◽  
Grade 3

Background: Azacitidine (AZA) based therapy is a standard of care in IPSS INT-2/High MDS/low blast count AML and CMML-2. Thrombocytopenia is an adverse prognostic factor in MDS; increased severity correlates with haemorrhagic complications and shorter AML progression time, and early platelet recovery after AZA is linked to better outcomes. Accumulation of AZA doses is important to patient response, but initial treatment with AZA can aggravate thrombocytopenia and impact outcome. Eltrombopag (ELT) is a thrombopoietin receptor (TpoR) agonist approved for adult chronic immune thrombocytopenic purpura. ELT has shown efficacy in low risk MDS and reduces thrombocytopenic events in advanced MDS and AML. The ELASTIC trial (ISRCTN05858391) is a single-arm phase 1b dose-finding study examining the safety and tolerability of ELT/AZA in patients with MDS/AML with expansion cohort (n=10) at MTD. We investigated if ELT/AZA would lead to earlier platelet recovery and improve AZA efficacy. Although a Phase 3 study testing ELT/AZA (SUPPORT) was terminated due to futility during the ELASTIC trial, we reasoned that drug sequencing may affect outcome. As ELASTIC patients received an ELT pre-phase, ELASTIC was run to completion. Methods: Patients with IPSS INT-2 or High MDS/CMML-2/AML &lt;30% blasts were treated in a 3+3 trial design in cohorts of ≥3 patients with 25, 50, 100, 200 or 300mg/day ELT. AZA (75mg/m2) was administered for 7 days of a 28 day cycle. All patients received ELT and AZA and were treated for maximum 6 cycles. ELT was administered from day -7 of cycle 1. ELT continued through cycles 1-2 and 4-6 with no ELT during cycle 3. Patients were evaluated after cycle 1 for dose-limiting toxicities (DLTs). The primary outcome was safety and tolerability (including establishing the MTD) of ELT in combination with AZA. Key secondary outcomes were the effect of ELT on platelet counts, platelet transfusions and marrow blast percentage. Full blood count was measured weekly over the first 13 weeks and monthly thereafter; bone marrow was taken on day 8 of ELT and at the end of cycles 3 and 6. Results: Thirty-one patients were recruited from November 2014 to August 2018. Thirty (median age 74, range: 62-86) were evaluable for analysis in the safety population (AML=5, IPSS INT-2 MDS=12, IPSS High MDS=12, CMML-2=1); 1 patient was ineligible post registration. 11/30 (37%) were IPSS good risk, 3/30 (10%) intermediate risk and 14/30 (47%) high risk (2 unknown). ELT was well tolerated up to 300mg (25mg=5, 50mg=3, 100mg=4, 200mg=4, 300mg=14) and was safely combined with AZA. There were no DLTs in the DLT evaluable patients (n=15). The MTD was established as 300mg (n=14). There were 3 SUSARs, 19 SAEs, 28 SARs and 87 episodes of grade 3/4 AEs. There were 16 episodes of grade 3/4 neutropenia and 11 episodes of grade 3/4 anaemia. Five patients discontinued treatment due to toxicity (25mg=2, 300mg=3), 6 due to death (pneumonia=2, disease-related=4, ischaemic heart disease=1) and 1 withdrew. Platelet responses were seen at ELT 50mg and higher. At the MTD, median platelet count at baseline was 37 (IQR: 25-52), rising to 77 (IQR 50-108.5) and 74 (IQR: 32-430) at cycle 2 and 3 respectively. The median platelet nadir was 20.5 (IQR: 11-25) and 42 (IQR 18.5-51.5) after cycle 1 and 2 dropping to 20 (IQR: 9-160) after cycle 3 when ELT was stopped. Mean platelet transfusions did not change with ELT dose. There was no increase in delays to AZA dosing across the ELT dose cohorts. There was no change in bleeding incidents when patients received ELT. Overall, there was no increase in bone marrow blast percentage from baseline. The cycle 3 marrow aspirate was reached by 27/30 (90%) and 11/30 (37%) reached the cycle 6 marrow aspirate. At the end of 3 cycles there were 21 non-responders and 10 responders (CR=3, marrow CR=4, PR=3, SD=9). At the end of 6 cycles there were 22 non-responders and 9 responders (CR=3, marrow CR=4, PR=2, SD=5). 6/14 (43%) treated at the MTD responded while 3/16 (19%) treated at below the MTD responded. Conclusions: The combination of ELT with AZA is safe and tolerable. Clinically meaningful responses in platelets were seen in patients receiving 50mg or more ELT. At the MTD, there was a noticeable drop in platelet nadir in cycle 3 when patients were not receiving ELT. No change in platelet transfusion was identified across cohorts. The results suggest that an ELT pre-phase may improve platelet responsiveness in patients treated with AZA and warrants further exploration. Disclosures Sternberg: Celgene/BMS: Honoraria, Research Funding; GSK/Novartis: Honoraria, Research Funding. Raghavan:Celgene UK: Speakers Bureau. Culligan:Celgene: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; Diiachi-Sankyo: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria. Cargo:Novartis: Honoraria. Vyas:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Astellas: Speakers Bureau; AbbVie: Speakers Bureau. OffLabel Disclosure: Eltrombopag is a second generation thrombopoietin receptor (TpoR) agonist approved for adult chronic immune thrombocytopenic purpura.

Molecular Response, Efficacy and Safety Analysis of 168 Adult French Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) From the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3293-3293
Author(s):  
Franck Emmanuel Nicolini ◽  
Gabriel Etienne ◽  
Dominique Bordessoule ◽  
Denis Caillot ◽  
Coralie Belanger ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
Study Drug ◽  
Molecular Testing ◽  
Molecular Response ◽  
Average Dose ◽  
Efficacy And Safety ◽  
Response Data ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Abstract 3293 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of Ph+ CML patients (pts) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. The ENACT study, which is a Phase IIIb, open label, multicenter study, was initiated to obtain additional efficacy and safety information in pts with imatinib-resistant or -intolerant CML in CML-CP, CML-AP, or blast crisis (BC) in a clinical practice setting outside of a registration program. Methods: Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Cytogenetic and hematological responses were provided by investigator assessment and monitored according to the current European Leukemia Network (ELN) recommendations. Safety assessments included monitoring for all adverse events (AEs), serious AEs and cardiac procedures. A centralized approach to molecular testing in France facilitated matching of the PCR results to ENACT pts who were monitored for molecular response as a standard of care. BCR-ABL/ABL ratio (in %) were reported on the international scale (IS), French physicians followed the current ELN recommendations and monitored pts by PCR at baseline and every 3 months thereafter. Major molecular response (MMR) was defined as IS ≤ 0.1%. In addition, pts with ≤ 0.003% IS are reported. Confirmed loss of MMR was defined as IS > 0.1% on two consecutive PCR tests in pts previously in MMR Results: A total of 168 French CML-CP pts enrolled in the ENACT study between Jan. 2006 and Oct. 2008 with molecular response data available for 77% of pts. The median age of pts was 57 years, 56% were imatinib-resistant and 43% were imatinib-intolerant as determined by physician assessment. At study completion, 108 (64%) pts were continuing on nilotinib. The main reasons for treatment discontinuation were unsatisfactory therapeutic effect and AEs (16% for both). Median (range) duration of nilotinib exposure was 363 (4–765) days; median (range) average dose intensity was 793 (222–913) mg/day. Dose interruptions and reductions lasting longer than 5 days occurred in 36.9% and 11.9% of pts, respectively, with AEs being the main reason. The majority of nilotinib-related grade 3/4 AEs were hematologic, with thrombocytopenia (22.6%) and neutropenia (14.9%) being the most common. Non-hematologic AEs were mostly grade 1/2, not study drug-related and included fatigue, headache and rash. No incidence of grade 3/4 QT prolongation (QTcF > 500 msec) was observed and no pts experienced study drug-related grade 3/4 pancreatitis or pleural effusion on study. Overall major cytogenetic response (MCyR) and complete hematologic response (CHR) rates were both 54%, which are higher than those observed in the overall ENACT CML-CP cohort at 45% and 43%, respectively. Among the pts with molecular response data, 10 (7.8%) came to the study with MMR, one had a confirmed loss of MMR but subsequently regained MMR. The proportion of pts with post-baseline MMR (regardless of baseline response) was 42% (55 pts); 38% of pts achieved an MMR on study. The proportion of pts with a post-baseline ratio ≤ 0.003% IS was 16% (21 pts). The achieved molecular responses were durable with only 4 pts with confirmed loss of MMR, while another 3 pts met the criteria for loss of response but subsequently regained MMR. Of the 61 pts with CCyR and molecular data available, 72% also achieved MMR (see Table). Conclusions: This analysis of the French CML-CP subset of a large expanded access study further demonstrates that nilotinib is well tolerated and effective in heavily pretreated pts with CML-CP. A majority of pts (72%) with CCyR also had MMR. This data supports the use of nilotinib at 400 mg bid as the recommended dose in French pts. Disclosures: Nicolini: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau. Bordessoule:Novartis Pharmaceuticals: Honoraria. Belanger:Novartis Pharmaceuticals: Employment. Lamy:Novartis Pharmaceuticals: Honoraria. Gardembas-Pain:Novartis Pharmaceuticals: Honoraria. Maloisel:Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Calgene: Research Funding. Rea:Novartis Pharmaceuticals: Honoraria. Johnson-Ansah:Novartis: Consultancy. Lenain:Novartis Pharmaceuticals: Honoraria. Szczudlo:Novartis: Employment. Wang:Novartis Pharmaceuticals: Employment. Duh:Novartis Pharmaceuticals: Research Funding.

scholarly journals Long-Term Sustained Responses Following Ibrutinib Discontinuation after Frontline Therapy with Obinutuzumab Plus Ibrutinib in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Paula A. Lengerke Diaz ◽  
Michael Y. Choi ◽  
Eider F. Moreno Cortes ◽  
Jose V. Forero ◽  
Juliana Velez-Lujan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Combination Regimen ◽  
Grade 3

Single oral targeted therapies have emerged as a standard of care in chronic lymphocytic leukemia (CLL). However, accessibility, side effects, and financial burden associated with long term administration limit their clinical use. Mainly, it is unclear in what clinical situation discontinuation of oral therapy can be recommended. The combination of type II anti-CD20 antibody obinutuzumab-Gazyva® with ibrutinib (GI) has shown a significant progression-free survival benefit in patients (pts) with CLL, including those with high-risk genomic aberrations. We conducted a phase 1b/2, single-arm, open-label trial to evaluate the safety and efficacy of GI as first-line treatment in 32 CLL pts. We report the outcome in pts that discontinued ibrutinib (either after 3 years of sustained complete response (CR) as stipulated in the clinical protocol, or due to other reasons). CLL pts enrolled in this protocol were ≥65 years old, or unfit/unwilling to receive chemotherapy. Pts received GI for six cycles, followed by daily single-agent ibrutinib. The protocol was designed to ensure that pts with a sustained CR after 36 months were allowed to discontinue ibrutinib. The median age was 66 years (IQR 59-73), and 6% of the evaluated pts had 17p deletion. All pts were able to complete the six planned cycles of obinutuzumab. The combination regimen was well-tolerated, and the most common adverse events (&gt;5% CTCAE grade 3-4) were neutropenia, thrombocytopenia, and hyperglycemia. The rate and severity of infusion-related reactions (IRR) were much lower than expected (Grade≥ 3, 3%), and pts without IRR had lower serum levels of cytokines/chemokines CCL3 (P=0.0460), IFN-γ (P=0.0457), and TNF-α (P=0.0032) after infusion. The overall response rate was 100%, with nine pts (28%) achieving a CR, and four pts (12.5%) with undetectable minimal residual disease (uMRD) in the bone marrow, defined as &lt;10-4 CLL cells on multicolor flow cytometry. At a median follow-up of 35.5 months (IQR 24.5-42.7) after starting treatment, 91% of the enrolled pts remain in remission with a 100% overall survival. Sixteen pts have completed a long-term follow-up of 36 months. Six pts showed CR, with three of them achieving uMRD in the bone marrow. Ten of these pts were in PR, and only one had disease progression and started treatment for symptomatic stage I disease with obinutuzumab plus venetoclax. In total, thirteen pts (41%) have stopped ibrutinib, with a median time on treatment prior to discontinuation of 35 months. Five (16%) of these pts had CRs and discontinued after 36 months. Eight additional pts (25%) had PRs and discontinued ibrutinib without being eligible: three pts discontinued prior to 36 months due to toxicities, and five pts discontinued after 36 months (3 due to side effects, and 2 due to financially driven decision). One patient eligible to discontinue ibrutinib, decided to remain on treatment despite sustained CR. After a median follow up time following ibrutinib discontinuation of 8 months (IQR 3.5-17), only two out of 13 pts have progressed (10 and 17 months after Ibrutinib discontinuation). None of the pts that stopped ibrutinib after achieving a CR have shown signs of disease progression. Of note, the pharmaceutical sponsor provided ibrutinib for the first 36 months, after which pts or their insurer became financially responsible. This particular scenario could bias the discontinuation pattern compared to a real world experience. It also provided us with a perspective about diverse factors affecting the treatment choices of pts. In summary, the obinutuzumab plus ibrutinib combination therapy was well-tolerated, with a much lower IRR rate. Efficacy compares favorably with historical controls with all pts responding to therapy, no deaths associated with treatment or disease progression, and a longer than expected time-to-progression after discontinuation of ibrutinib. The rate of ibrutinib discontinuation was higher than reported in the literature, most likely influenced by the protocol design and financial decisions driven by the switch from sponsor-provided ibrutinib to insurance or self-paid medication. Our observations regarding safety, efficacy and lack of disease progression after ibrutinib discontinuation are encouraging, and warrant confirmation in long-term prospective studies. Clinicaltrials.gov Identifier NCT02315768. Funding: Pharmacyclics LLC. Disclosures Choi: AbbVie: Consultancy, Speakers Bureau. Amaya-Chanaga:AbbVie: Ended employment in the past 24 months, Other: Research performed while employed as an investigator of this study at UCSD.. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding.

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