Astarabine, a Pro-Drug of Cytarabine, Is Safe for Patients with Advanced Acute Leukemia. A Phase I/IIa Single Center Study in Relapsed/Refractory or Medically Unfit Patients

Abstract Introduction: Therapy of acute leukemia has not changed significantly over the years. Both acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) typically present or have a second peak in older adults, which often precludes intensive therapy due to associated comorbidities. Astarabine, a construct of cytarabine covalently bound to asparagine, is a pro-drug specifically targeting leukemic blasts which are dependent on an external source of asparagine. Within the blasts, Astarabine is cleaved to cytarabine enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia and, particularly, for medically unfit/older adults otherwise given only supportive therapy. Additionally, targeted killing by Astarabine may be more efficacious and can lead to improved responses in relapsed/refractory patients. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia. Methods: This prospective open label study enrolled patients >18 years of age with relapsed/refractory acute leukemia or those unfit for intensive therapy, as judged by the treating physician. Refractory acute leukemia was defined as a failure to achieve remission following the last administered treatment. Relapsed disease was defined as recurrence after induction and consolidation. The study was approved by the Rambam IRB. Patients were enrolled into 4 Astarabine escalating dose cohorts, each composed of 3 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. Astarabine doses for each infusion, measured as an equivalent to cytarabine dosing, for age ≤50 years were: 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. Astarabine doses for age >50 years were reduced by 50%. Results: The outcome of the first 3 cohorts (9 patients) is reported herein (table 1). Eight patients had AML, of whom 4 had refractory/relapsed and 4 had newly diagnosed secondary AML unfit for intensive therapy, while 1 patient had newly diagnosed ALL. Median age was 80 years (range 27-90). Four patients are alive with a follow-up of 1-10 months, 2 of whom are in continuous CR 4 and 6 months after treatment. Three patients died from disease progression; one died suddenly 7 days after treatment, an event not judged to be treatment-related. No significant adverse events were recorded during or after therapy apart from neutropenic fever. Conclusions: Astarabine, a pro-drug of cytarabine, is safe and very well tolerated, including patients over 80 years of age, and resulted in complete remission in 3 of 9 patients with acute leukemia. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 g/m2. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. Table 1. Patient No. Age in years Diagnosis BM blasts after treatment Outcome Follow-up duration in months Day 14 Day 30 1 75 Refractory AML 90% 83% Died- DP 3 2 81 Refractory AML 64% 70% Died - DP 2 3 27 Refractory AML 37% 60% Alive with disease 6 4 76 Secondary AML 39% 63% Died -DP 4 5 81 Secondary AML 5% 0% Alive in CR 6 6 63 Refractory AML 100% 100% Died -DP 1 7 90 ALL 3% 0.2% Alive in CR 4 8 86 Secondary AML 80% 8% Alive in PR 3 9 80 Secondary AML N/A N/A Died 1 DP: disease progression; PR: partial remission; CR: complete remission; N/A: non-applicable Disclosures Off Label Use: Astarabine, a Pro-Drug of Cytarabine. A noval therapy for acute leukemia. Ben Yakar:BioSight Ltd.: Employment, Equity Ownership. Gengrinovitch:BioSight Ltd.: Employment, Equity Ownership, Patents & Royalties.

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Astarabine, a Novel Leukemia-Targeted Cytarabine Composition Allows, for the First Time, the Delivery of High Cytarabine Doses for Older or Unfit Patients with Acute Leukemia. Results of an Ongoing Phase I/IIa Study

Blood ◽

10.1182/blood.v128.22.1650.1650 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1650-1650

Author(s):

Tsila Zuckerman ◽

Stela Gengrinovitch ◽

Ruth Ben-Yakar ◽

Ron Hoffman ◽

Israel Henig ◽

...

Keyword(s):

Bone Marrow ◽

Acute Leukemia ◽

De Novo ◽

Intensive Therapy ◽

High Dose ◽

Newly Diagnosed ◽

Employment Equity ◽

Unfit Patients ◽

Equity Ownership ◽

High Doses

Abstract Introduction: Therapy of acute myeloid leukemia (AML) has not changed significantly during several decades. High-dose cytarabine, although used as the first-line treatment for AML since 1970s and as a second-line treatment for acute lymphoblastic leukemia (ALL), is associated with severe side effects, such as cerebellar toxicity and bone marrow suppression. Hence, while the incidence of AML increases with age, doses of cytarabine are significantly attenuated or the drug is entirely excluded from the regimen used in older adults due to its potential toxicities, particularly in individuals with hepatic or renal dysfunction. Astarabine is a new composition of cytarabine covalently bound to asparagine. It is designed to target cytarabine to leukemic blasts, thus avoiding extramedullary toxicity. Leukemic cells, which are dependent on an external source of amino acids in general and asparagine in particular, due to their high metabolic rate, have a relatively increased uptake of Astarabine. Inside the blasts, Astarabine is cleaved to cytarabine, enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults who otherwise can be given supportive therapy only. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia. Methods: This Phase I/IIa prospective open label study enrolled patients aged ≥18 years with relapsed/refractory or newly-diagnosed acute leukemia unfit for intensive therapy, as judged by the treating physician. The study was approved by the Rambam IRB (approval #0384-11). Patients were enrolled into 6 Astarabine escalating-dose cohorts, each composed of 3-6 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. For cohorts 1-4, Astarabine doses for each infusion were 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. The doses were reduced by 50% for patients >50 years. Since dose limiting toxicity (DLT) was not reached in cohorts 1-4, the study was extended to include cohorts 5 and 6 with daily Astarabine doses of 4.5g/m2 and 6g/m2, respectively, with no dose reduction for patients >50 years old. Results: The outcome of 15 patients is reported herein. Six patients with a median age of 64 years (range 27-81) had refractory/relapsed AML, 9 patients with a median age of 80 years (range 70-90) were newly diagnosed (secondary AML - 6, de-novo AML - 2, de-novo ALL - 1) and unfit for intensive therapy. Astarabine treatment was well-tolerated. Two patients died (one from pneumonia and one from sudden death 2 weeks from end of treatment) before completing 30 days post-treatment and hence were excluded from the outcome analysis. Response to the treatment was observed in the bone marrow of 6 of the 7 newly-diagnosed patients for whom bone marrow analysis was available, 3 of whom had a continuous complete remission (CR) for 4 (ongoing), 8, and 10 months post-treatment, and 3 had a continuous partial remission (PR) for 3,7, and 7 (ongoing) months. The median overall survival (OS) of the patients with CR/PR is 7 months to date (table 1). No significant response was observed in the relapsed/refractory patients, with a median OS of 2.5 months. Twelve patients died from disease progression. Conclusions: Astarabine, a new composition of leukemia-targeted cytarabine, is safe and very well tolerated, even in patients over 80 years of age, resulting in response in 6 of 7 newly diagnosed patients with acute leukemia. To the best of our knowledge, this is the first report permitting high-dose of cytarabine, considered a cornerstone of leukemia therapy, to be given to a population of patients that heretofore did not have this option. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 and 6 g/m2/day. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. Disclosures Zuckerman: BioSight Ltd: Consultancy, Research Funding. Gengrinovitch:BioSight Ltd: Employment, Equity Ownership, Patents & Royalties: Inventor all of the patents. Ben-Yakar:BioSight Ltd: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of all patents.

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BST-236, a Novel Cytarabine Pro-Drug, Enables Safe and Effective Administration of High Dose Cytarabine to Older or Unfit Patients with Acute Leukemia. Results of a Phase I/II Study

Blood ◽

10.1182/blood.v130.suppl_1.893.893 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 893-893

Author(s):

Tsila Zuckerman ◽

Ron Ram ◽

Maya Koren-Michowitz ◽

Luiza Akria ◽

Ron Hoffman ◽

...

Keyword(s):

Acute Leukemia ◽

Phase I ◽

De Novo ◽

High Dose ◽

Newly Diagnosed ◽

Standard Chemotherapy ◽

High Dose Cytarabine ◽

Unfit Patients ◽

Refractory Aml

Abstract Introduction: First line therapy of AML has not changed significantly since the 1970s and still relies on cytarabine as its backbone. Older patients or patients with comorbidities have low tolerability to intensive cytarabine treatment due to increased morbidity and mortality related to its toxicity, such as cerebellar toxicity, bone marrow suppression, gastrointestinal toxicity and infections. Hence, currently available intensive cytarabine treatment is unjustified in this population due to its poor risk/benefit ratio, and therefore, older and unfit AML patients are usually treated with reduced intensity therapy with poor outcomes. BST-236 is a new compound of cytarabine covalently bound to asparagine. It acts as a pro-drug of cytarabine, enabling delivery of high cytarabine doses to leukemia cells with lower systemic exposure to the free drug and relative sparing of normal tissues. As such, BST-236 may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults. The aim of this Phase I/II study was to evaluate the safety and optimal dose of BST-236 in refractory/relapsed or newly-diagnosed acute leukemia patients unfit for standard induction therapy. Methods: Acute leukemia patients, either relapsed/refractory, or older or unfit newly-diagnosed, were enrolled to a prospective open label single arm study. The study included 6 dose-escalating cohorts of patients treated with 6 daily doses of BST-236 administered as a 1-hour intravenous infusion. Cohorts 1-4 enrolled patients age ≥18 years, dosed with 0.5 g/m2, 1.5 g/m2, 3 g/m2 or 4.5 g/m2, respectively, with a 50% dose reduction in each cohort for patients age >50 years. Cohorts 5 and 6 enrolled patients ≥70 years of age, dosed with 4.5 g/m2 or 6 g/m2, respectively (Table 1). Results: Twenty-six (26) patients received at least 2 daily doses of BST-236, twenty-three (23) of them (14 males and 9 females) completed at least one 6-day treatment course, including 2 patients who received 2 courses. Out of the 23 patients who completed at least one treatment course, median age 77 (range 27-90), 6 had relapsed/refractory AML following standard chemotherapy, median age 64 years (range 27-81), 15 were newly-diagnosed AML patients unfit for standard chemotherapy, median age 78 years (range 70-89), including 11 patients (73%) with AML secondary to myelodysplastic disorder (MDS) or myeloproliferative neoplasms, median age 77 years (range 70-89), and 2 patients with de novo ALL, age 79 and 90. BST-236 treatment was well-tolerated and MTD was not reached in this study. Notably, the maximal dose of 6 g/m2/d BST-236 is the molar equivalent of 4 g/m2/d of cytarabine. Moreover, adverse events were mainly hematological "on-target" events, and no neurological events or >grade 2 events such as mucositis, diarrhea, or alopecia were reported in any of the cohorts during treatment or within 30 days of follow up. Assessment of the outcome of cohort 6 is still ongoing and will be available in the coming weeks. The majority of the newly diagnosed AML patients in cohorts 1-5 responded to BST-236 (Figure 1). The overall response and Complete Remission (CR) rates, of the newly-diagnosed AML patients (de novo and secondary to MDS) was 71% and 43%, respectively. Follow up of the Overall Survival (OS) of these patients is still ongoing, and is currently 6.9 months (active) for all responders, 9.2 months (active) for CR patients, and 0.6 months for the non-responders (Figure 2). Notably, 67% of the responding patients had secondary AML, refractory to hypomethylating agents (HMA). No CR was reached in the 6 patients suffering from relapse or refractory AML, and their median OS was 2.3 months (Figure 2). Conclusions: This Phase I/II study demonstrates that BST-236, a cytarabine pro-drug, is able to safely deliver high-dose cytarabine to older and unfit patients (median age 78) with no significant typical cytarabine toxicities other than "on-target" hematological events. Moreover, the general wellbeing of the patients during and after administration, as noted by the treating physicians, was exceptionally improved compared to intensive therapy. The good safety profile, accompanied by the high response rates and significantly prolonged survival of the older and unfit newly-diagnosed population, most of them refractory to HMA, is highly encouraging. A phase II study is planned to confirm these results. Disclosures Zuckerman: BioSight Ltd.: Consultancy. Gengrinovitch: Biosight: Employment. Flaishon: BioSight: Employment. Ben Yakar: Biosight: Employment.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Blood ◽

10.1182/blood.v118.21.452.452 ◽

2011 ◽

Vol 118 (21) ◽

pp. 452-452 ◽

Cited By ~ 9

Author(s):

Giuseppe Saglio ◽

Philipp D. LeCoutre ◽

Ricardo Pasquini ◽

Saengsuree Jootar ◽

Hirohisa Nakamae ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Safety Data ◽

Molecular Response ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

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Risk Factors Associated with Earlier Relapse and Death and Treatment Response in Patients with Follicular Lymphoma in Taiwan

Blood ◽

10.1182/blood-2018-99-112347 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5338-5338

Author(s):

Sung-Nan Pei ◽

Kuan-Chih Huang ◽

Ming-Chung Wang ◽

Ching-Yuan Kuo ◽

Ming-Chun Ma ◽

...

Keyword(s):

Risk Factors ◽

Follicular Lymphoma ◽

Disease Stage ◽

Newly Diagnosed ◽

Employment Equity ◽

Factors Associated ◽

Β2 Microglobulin ◽

Tertiary Center ◽

Equity Ownership

Abstract Background: Follicular Lymphoma (FL) has been relatively uncommon in Asia. Information on prognostic risk factors are scarce in the Asian population. We evaluated patients with FL in a tertiary medical center in Taiwan to gain better understanding of real world treatment and risk factors affecting outcome. Purpose: To evaluate clinical outcomes and risk factors associated with outcome in patients with FL in Taiwan. Methods: We conducted a retrospective cohort study using electronic medical records from Kaohsiung Chang Gung Memorial Hospital, a major regional hospital in southern Taiwan, from 01 January 2008 to 31 December 2017. Newly diagnosed patients with FL were enrolled from 01 Jan 2008 to 31 Dec 2013. All eligible patients were followed-up until study end, loss to follow-up or until death, whichever occurred first. Event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Risk factors of EFS and OS were identified using Cox proportional hazards model. A significant association was set at p<0.01. Results: A total of 67 patients with newly diagnosed FL were included in the cohort analysis, accounting for 13.7% (67/489) patients with B cell non-Hodgkin lymphoma during the enrolment period. Median follow-up time was 60 months. At diagnosis, median age was 58 years (range 28-95), 56.7% (38/67) of patients were female, and 68.7% (46/67) had Stage III-IV disease. There were 37.3% (25/67) of patients with bone marrow involvement and 22.4% (15/67) with involvement of more than one extra-nodal site. The percentage of patients with low, intermediate and high-risk FL was 32.8%, 25.4%, 38.8%, respectively by FLIPI-1, and 13.4%, 44.8%, 26.9% by FLIPI-2. 72% (48/67) of patients received first-line treatment with regimens that included rituximab, cyclophosphamide, vincristine, prednisolone ± doxorubicin. Of these, 54.2% (26/48) of patients demonstrated complete response and 37.5% (18/48) had a partial response. A further 22.4% (15/67) patients received other treatments and 6.0% (4/67) patients did not receive any treatment. Progression of disease within 24 months after commencing treatment occurred in 32.8% of patients. The 5-year EFS and OS for all patients were 48.6% and 76.2%, respectively (Figure). A higher relapse rate was associated with the presence of B symptoms (HR 6.1; 95% confidence interval [CI] 2.8-13.2), ECOG score ≥2 (HR 5.7; 95% CI 1.7-19.6), FLIPI-2 score ≥3 (HR 5.5; 95% CI 1.4-20.6), large cell transformation (HR 4.1; 95% CI 1.66-10.6), elevated β2 microglobulin (HR 4.0; 95% CI 1.8-9.1), age >70 years (HR 3.6; 95% CI 1.7-7.5), involvement of more than one extra-nodal site (HR 3.5; 95% CI 1.6-7.6) and elevated LDH (HR 2.5; 95% CI 1.3-5.1) (Table 2). Conclusion: Most patients with FL in this tertiary center in Taiwan were at an advanced disease stage at diagnosis. While the majority responded to conventional chemotherapy, one-half of patients progressed within 5 years. Involvement of extra-nodal sites, B symptoms, older age (>70) higher FLIPI-2 score, elevated β2 microglobulin and ECOG score ≥2 were identified as risk factors for earlier relapse and death. Disclosures Pei: Janssen Research & Development, LLC: Research Funding. Huang:Janssen Research & Development, LLC: Employment. Rothwell:Janssen Research & Development, LLC: Employment, Equity Ownership. Qiu:Janssen Research & Development, LLC: Employment, Equity Ownership. Liu:Janssen Research & Development, LLC: Employment, Equity Ownership.

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A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy

Blood ◽

10.1182/blood-2019-130635 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3919-3919

Author(s):

William B. Donnellan ◽

Ehab L. Atallah ◽

Adam S. Asch ◽

Manish R. Patel ◽

Jay Yang ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Slow Release ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Naïve ◽

Equity Ownership ◽

Refractory Aml

Background: Aurora kinases (AurK) represent potential targets for anticancer therapy in hematological malignancies and solid tumors. AurK B inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of AurKB, when given as 2-4hr IV on days 1 and 4, offers a prolonged drug exposure in vivo, mimicking the AZD1152 7-day continuous IV infusion. This is an update on the first-in-man dose-escalation study of AZD2811NP in pts with relapsed/refractory AML/MDS or treatment-naïve patients (pts) not eligible for intensive induction therapy (NCT03217838). The primary objectives are to determine the Maximum Tolerated Dose (MTD) and safety profile of AZD2811NP monotherapy and in combination with azacitidine. The secondary objectives are to evaluate the pharmacokinetic (PK) profile, Biologically Effective Dose (BED), and preliminary efficacy (CR, CRi, PR, 6 month OS). Methods: Pts received a 2-hour IV infusion on Day 1 and 4 of each 28-day cycle (Cy) for doses up to 600mg, extending to a 4 h IV infusion for dosages > 600 mg. In the ongoing dose escalation, 3-6 pts have been sequentially enrolled in cohorts ranging from 100 mg to 800 mg per infusion (Day 1 & 4), i.e. from 200 mg to 1,600 mg per cycle in monotherapy setting, according to a modified continuous reassessment method (mCRM) dose escalation design. AZD2811NP was also combined with azacitidine (75 mg day 1 to 7 or the 5-2-2 schedule) starting at an AZD2811NP dose of 400 mg D1 and D4 every 4 weeks. Study treatment was continued until disease progression, intolerability, or when discontinuation criteria were met. Results: Currently, 30 pts have enrolled of which 29 pts (12 females and 17 males) received study treatment in 5 monotherapy cohorts and 2 azacitidine combination cohorts, with ages ranging from 53 to 85 years. Nineteen pts had relapsed/refractory AML, 9 pts had MDS and 1pt had MDS/MPN. Monotherapy cohort 5 (800 mg D1 & D4) and combination cohort 4c (600mg D1 & D4 + Azacitidine) are currently enrolling. Of the 19 pts in monotherapy cohorts 1-5, 18 pts discontinued (due to consent withdrawal [2], early disease related deaths [2], other reason [1], or completed follow up [13; 11 pts after Cy1, 2 pts after Cy2]) and 1 pt is still on therapy. Nine pts were treated in combination with azacitidine, and of these, 3 pts are still on therapy and 6 pts have discontinued AZD2811NP (due to death [1], consent withdrawal [2], or completed follow up [3; 2 pts after Cy2, 1 pt after Cy4]). Adverse events that occurred in ≥ 20% of pts were mainly myelotoxicity, nausea and fatigue. One dose-limiting toxicity (DLT) has been observed in the monotherapy arm (esophageal infection) and one DLT in the combination setting (late neutropenia recovery). Two deaths were due to the underlying disease and 1 due to a serious adverse event of Gr 5 sepsis not related to study drug. AZD2811 total and released blood PK exposure appears broadly dose proportional with a terminal t1/2 of ~ 30-50 hours. Released blood PK exposure is ~ 1% of total PK exposure. Conclusion: AZD2811NP is documented to be well tolerated at doses up to 600 mg on Day 1 & 4 every 28 days in monotherapy setting and up to 400 mg (D1 & 4) in combination with azacitidine. The monotherapy and combination therapy dose escalations are ongoing. Updated results including preliminary efficacy data will be presented. Additional dose finding and expansion cohorts of AZD2811NP in combination with venetoclax are planned. Disclosures Atallah: Pfizer: Consultancy; Helsinn: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy. Yang:AstraZeneca: Research Funding; Agios: Consultancy. Eghtedar:Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Verastem Oncology: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Borthakur:Merck: Research Funding; Oncoceutics: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Xbiotech USA: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Eisai: Research Funding; Novartis: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding. Charlton:AstraZeneca: Employment; GSK: Equity Ownership. MacDonald:AstraZeneca: Employment, Equity Ownership. Korzeniowska:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment, Equity Ownership. Strickland:Sarah Cannon Development Innovations: Employment. Overend:AstraZeneca: Employment, Equity Ownership. Adelman:AstraZeneca: Employment, Equity Ownership. Fabbri:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment, Equity Ownership. Pease:AstraZeneca: Employment, Equity Ownership. Cosaert:AstraZeneca: Employment. OffLabel Disclosure: AZD2811NP, a nanoparticle encapsulated slow-release inhibitor of Aurora Kinase B (AurKB), is an investigational agent in clinical trials for human cancers including AML/MDS.

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Quality-Adjusted Survival for Low-Dose Cytarabine (LDAC) Versus Glasdegib+LDAC Among Newly Diagnosed Acute Myeloid Leukemia Patients Who Are Not Candidates for Intensive Chemotherapy: A Q-TWiST Analysis

Blood ◽

10.1182/blood-2019-126672 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2610-2610 ◽

Cited By ~ 1

Author(s):

Youngmin Kwon ◽

Timothy J Bell ◽

Caitlyn Solem ◽

Joseph C Cappelleri ◽

Courtney Johnson ◽

...

Keyword(s):

Adverse Events ◽

Myeloid Leukemia ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Equity Ownership ◽

Relative Gains ◽

Mean Time ◽

Low Dose Cytarabine

Introduction: The efficacy and safety of glasdegib (a selective oral inhibitor of hedgehog signaling pathway) in combination with low-dose cytarabine (LDAC) was evaluated in a randomized, phase 2 trial of newly diagnosed acute myeloid leukemia (AML) patients (BRIGHT AML 1003; NCT01546038). Patients receiving glasdegib+LDAC experienced statistically significant and meaningful gains in overall survival (OS) compared with patients receiving LDAC alone (median OS [95% CI]): 8.3 months [4.7-12.2] vs 4.3 months [1.9-5.7]). This analysis examined whether quality-adjusted survival improvements were similarly observed using a quality-adjusted time without symptoms of disease progression or toxicities (Q-TWiST) approach to evaluate possible trade-offs between time with adverse events (toxicities), time in relapse/progression (i.e., with symptoms of disease), and 'good' survival (i.e., time without toxicities or symptoms of progression [TWiST]) when comparing regimens. Methods: OS in BRIGHT AML 1003 data, restricted to a follow-up of 20 months, was partitioned into time with toxicity (TOX: grade 3+ adverse events prior to progression), TWiST, and time post-progression (REL). Progression was defined as treatment discontinuation due to insufficient clinical response or death; patients who discontinued for other reasons (including adverse events) were censored at the date of discontinuation unless death occurred within 28 days of discontinuation. Q-TWiST was calculated by multiplying restricted mean time in each state by respective utilities (U) and then summing up the utility-adjusted time. Base case analysis used U(TOX)=U(REL)=0.5 and U(TWiST)=1.0; threshold analyses were performed varying U(TOX) and U(REL) jointly each from 0 to 1. Relative gains in Q-TWiST (i.e., Q-TWiST difference (combination vs LDAC) / OS in LDAC arm) of ≥15% were considered clearly clinically meaningful per the clinical literature. Sensitivity analysis varied the length of follow-up and AE definitions; subgroup analyses were also performed. 95% confidence intervals were obtained using the bootstrap procedure. Results: At 20 months of follow-up, the survival rate for glasdegib+LDAC and LDAC arm was 28.2% and 7.9%, respectively. Glasdegib+LDAC patients (n=78) compared with LDAC patients (n=38) had significantly longer mean time in TWiST (+3.4 [95% confidence interval: 1.8, 5.2] months) and TOX (+0.8 [0.1, 1.6] months), and longer but non-significant REL (+0.3 [-1.9, 2.3] months). Q-TWiST was 4.0 [2.1, 5.8] months longer for glasdegib+LDAC, translating into a 75% relative improvement in quality-adjusted survival relative to LDAC alone. In threshold analyses, absolute and relative Q-TWiST gains ranged from 3.5 to 4.5 months and 66% to 85%, respectively (Table 1). They exceeded the clinically meaningful threshold for gains in Q-TWiST and were statistically significant across all combinations of U(TOX) and U(REL). Results were robust to length of follow-up 6 to 24 month and remained significant when including all adverse events regardless of grade. Discussions/Conclusions: Glasdegib+LDAC is an add-on therapy that has demonstrated significant survival benefits for newly diagnosed AML patients who are unable to receive intensive chemotherapy. While patients can experience a longer time with toxicities from receiving glasdegib+LDAC (as expected since it is given as an add-on therapy), the trade-off can still be favorable as the treatment provides added time spent in 'good' health (i.e., a significantly longer time in TWiST). In the BRIGHT AML 1003 cohort, the relative gains in OS greatly exceeded previously established thresholds for being clearly clinically meaningful, which suggests that the benefits of glasdegib+LDAC vs LDAC alone outweigh the risks. Table 1 Disclosures Kwon: Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Solem:Pharmerit International: Employment; Pfizer Inc.: Research Funding. Cappelleri:Pfizer: Employment, Equity Ownership. Johnson:Pfizer Inc.: Research Funding; Pharmerit International: Employment. Bhattacharyya:Pfizer Inc: Employment, Equity Ownership. Hoang:Pfizer Inc.: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; Takeda: Consultancy, Research Funding; BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

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Vadastuximab Talirine Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood.v128.22.591.591 ◽

2016 ◽

Vol 128 (22) ◽

pp. 591-591 ◽

Cited By ~ 27

Author(s):

Amir T. Fathi ◽

Harry P. Erba ◽

Jeffrey E. Lancet ◽

Eytan M. Stein ◽

Farhad Ravandi ◽

...

Keyword(s):

Febrile Neutropenia ◽

Survival Data ◽

Research Funding ◽

Intensive Therapy ◽

Advisory Board ◽

Hypomethylating Agents ◽

Employment Equity ◽

Secondary Aml ◽

Genetics Research ◽

Equity Ownership

Abstract Background Treatment of AML among the elderly is challenging due to intolerance of intensive therapy and greater prevalence of therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used in this setting, but yield suboptimal remission rates and modest survival (Dombret 2015, Kantarjian 2012). Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. In preclinical studies, HMA priming followed by 33A resulted in upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity. Methods A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33Ain combination with an HMA. Eligible patients (ECOG status 0-1) must have had previously untreated CD33-positive AML andhad declined intensive therapy. A single dose level of 33A, 10 mcg/kg,was administered outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003). Results Fifty-three patients (median age 75 years; range, 60-87) have been treated with 33A+HMA. All patients had adverse (38%) or intermediate (62%) cytogenetic risk by MRC criteria; 40 patients (75%) were considered unfit for intensive therapy and 13 patients (25%) declined intensive therapy.Of the patients with secondary AML (23/53, 43%), median age was 77 years (range 60-87) with most of the patients ≥75 years (70%). The median treatment duration is currently 19.3 weeks (range, 2-86) with 13 patients remaining on treatment; no DLTs or infusion reactions were reported. G3 or higher AEs reported in ≥15% of patients were thrombocytopenia (55%), anemia (43%), febrile neutropenia (43%), neutropenia (38%), pneumonia (19%), and leukopenia (17%); no G4 or 5 bleeding events were observed. Other non-hematologic treatment-emergent AEs regardless of relationship to study treatment and reported in ˃25% of patients were fatigue (58%), nausea (47%), constipation (43%), decreased appetite, peripheral edema (40% each), pyrexia (32%), dyspnea (28%), diarrhea (26%), and dizziness (25%). 30- and 60-day mortality rates were 2% and 8% with no treatment-related deaths reported. A total of 37% (90/246) of doses were delayed due to AEs primarily related to myelosuppression (neutropenia 16%, thrombocytopenia 6%, febrile neutropenia 4%).Thirty-six of the 49 efficacy evaluable patients (73%)achieved CR (21, 43%) or CRi (15, 31%); an additional 4 patients were not efficacy evaluable by protocol definition, due to death (n=2) or withdrawal of consent (n=2) before a response assessment marrow could be obtained. Remissions were achieved after a median of 2 cycles (range, 1-4) and were observed in most of the patients with adverse risk disease including antecedent myelodysplasia (16/22, 73%), adverse cytogenetics (15/18, 83%), FLT3/ITD (5/5, 100%), and patients≥75 years (17/26, 65%). Seventeen of 22 efficacy-evaluable patients with secondary AML (77%) achieved CR (11, 50%) or CRi (6, 27%). Of all responding patients, 17 of 36 (47%) achieved MRD negativity by flow cytometry. The median relapse-free survival was 9.1 months (range, 0.1-16.5+) andOS continues to evolve with22 patients (42%) alive with a median follow-up of 10 months. Conclusions The combination of 33A+HMA is well tolerated with no identified pattern of off-target toxicity. Activity with the combination appears markedly improved when compared to the historical experience of HMA monotherapy in this patient population (Table 1). The CR+CRi rate of 73% in older AML patients with poor risk factors in the setting of low early mortality is particularly encouraging. Activity was maintained even in the highest risk patient groups (adverse risk cytogenetics, underlying myelodysplasia, secondary AML, FLT3/ITD). Survival data are evolving and compare favorably to historical controls. CASCADE, a phase 3 trial investigating 33A+HMA v. HMA alone in older AML patients is now enrolling (NCT02785900). Disclosures Fathi: Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Bexalata: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding. Erba:Gylcomimetics: Other: DSMB; Millennium Pharmaceuticals, Inc.: Research Funding; Jannsen: Consultancy, Research Funding; Ariad: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Celator: Research Funding; Juno: Research Funding; Seattle Genetics: Consultancy, Research Funding; Agios: Research Funding; Astellas: Research Funding; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, DSMB, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Stein:Celgene: Other: Advisory Board, Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Seattle Genetics: Research Funding; Novartis: Consultancy. Ravandi:Seattle Genetics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Faderl:JW Pharma: Consultancy; Amgen: Speakers Bureau; Karyopharm: Consultancy, Research Funding; Ambit Bioscience: Research Funding; BMS: Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celgene: Consultancy, Research Funding. Advani:Seattle Genetics: Consultancy, Research Funding. DeAngelo:Baxter: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Kovacsovics:Seattle Genetics: Research Funding. Jillella:Seattle Genetics: Research Funding. Levy:Seattle Genetics: Research Funding; Jansen: Speakers Bureau; Amgen: Speakers Bureau; Millennium: Speakers Bureau. O'Meara:Seattle Genetics: Employment, Equity Ownership. Ho:Seattle Genetics: Employment, Equity Ownership. Stein:Seattle Genetics: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Stemline Therapeutics: Consultancy, Research Funding; Argios: Research Funding; Celgene: Research Funding.

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Bosutinib Vs Imatinib for Newly Diagnosed Chronic Myeloid Leukemia (CML) in the BFORE Trial: 18 Month Follow-up

Blood ◽

10.1182/blood.v130.suppl_1.896.896 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 896-896

Author(s):

Carlo Gambacorti-Passerini ◽

Michael W. Deininger ◽

Michael J. Mauro ◽

Charles Chuah ◽

Dong-Wook Kim ◽

...

Keyword(s):

Board Of Directors ◽

Primary Endpoint ◽

Cumulative Incidence ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Bosutinib is a potent SRC/ABL tyrosine kinase inhibitor approved for treatment of adults with CML resistant or intolerant to prior therapy. Here we compare the efficacy and safety of first-line bosutinib versus imatinib in patients with chronic phase (CP) CML enrolled in BFORE after ≥18 months of follow-up. Methods: BFORE (NCT02130557) is an ongoing, multinational, open label phase 3 study that randomized 536 patients 1:1 to 400 mg QD bosutinib (n=268) or 400 mg QD imatinib (n=268 [3 not treated]). The prespecified primary endpoint was major molecular response (MMR) rate at 12 months in the modified intent-to-treat (mITT) population, defined as Philadelphia chromosome‒positive (Ph+) patients with e13a2/e14a2 transcripts, and excluding Ph- patients and those with unknown Ph status and/or BCR-ABL transcript type (mITT: BOS, n=246; IM, n=241). Efficacy results refer to the mITT population unless otherwise noted. Results: MMR rate was higher with bosutinib versus imatinib at 18 months (56.9% vs 47.7%; P=0.042). Among all randomized patients (ITT) 18-month MMR rates were higher for bosutinib (56.7% vs 46.6%; P <0.02). Earlier analyses (Table) showed complete cytogenetic response (CCyR) rate by 12 months (77.2% vs 66.4%; P=0.0075) was significantly higher with bosutinib versus imatinib. Rates of BCR-ABL1 transcript ratio ≤10% (International Scale) at 3 months (75.2% vs 57.3%), as well as MR4 at 12 months (20.7% vs 12.0%) and MR4.5 at 12 months (8.1% vs 3.3%), were all higher with bosutinib versus imatinib (all P <0.025). By comparison at 18 months, rates of MR4 (24.4% vs 18.3%) and MR4.5 (11.4% vs 7.1%) were consistent with this trend. Also after ≥18 months follow-up, time to MMR (hazard ratio=1.36, based on cumulative incidence; P=0.0079) and time to CCyR (hazard ratio=1.33; P=0.0049) were shorter for bosutinib (Figure). Cumulative incidence of transformation to accelerated/blast phase disease at 18 months was 2.0% and 2.9% for bosutinb and imatinib, respectively, of which 2 bosutinib and 4 imatinib patients discontinued treatment due to transformation. Additional treatment discontinuations due to suboptimal response/treatment failure occurred in 11 (4.1%) and 35 (13.2%) of bosutinib and imatinib patients, respectively. Dose increases happened in 20% of bosutinib-treated and 31% of imatinib-treated pts There were 2 deaths and 9 deaths in the bosutinib and imatinib arms, respectively. One patient taking bosutinib died within 28 days of last dose, while 4 patients taking imatinib died with that period from last dose. Overall survival at 18 months was 99.6% vs. 96.6% for bosutinib and imatinib groups, respectively. Grade ≥3 diarrhea (8.2% vs 0.8%) and increased alanine (20.9% vs 1.5%) and aspartate (10.1% vs 1.9%) aminotransferase levels were more frequent with bosutinib. Cardiovascular, peripheral vascular, and cerebrovascular events were infrequent in both arms (3.4%, 1.9%, and 0.4% bosutinib vs 0.0%, 1.1%, and 0.8% imatinib; grade ≥3: 1.5%, 0%, and 0.4% vs 0%, 0%, and 0.4%). There were no deaths in the bosutinib arm and 1 death in the imatinib arm due to treatment-emergent vascular events. Treatment discontinuations due to drug-related toxicity occurred in 15.3% and 9.4% of bosutinib and imatinib patients, respectively. Conclusion: After 18 months of follow-up,the MMR benefit seen with bosutinib over imatinib was sustained. These results are in line with observations at 12 months where patients taking bosutinib had significantly higher response rates (primary endpoint) and achieved responses sooner than those on imatinib. Safety data were consistent with the known safety profiles. These results suggest that bosutinib may be an important treatment option for patients with newly diagnosed CP CML. Disclosures Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Deininger: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Research Funding; BMS: Consultancy, Research Funding; Gilead: Research Funding; ARIAD: Consultancy; Ariad Pharmaceuticals, Bristol Myers Squibb, CTI BioPharma Corp, Gilead, Incyte, Novartis, Pfizer, Celgene, Blue Print, Galena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Chuah: Avillion: Honoraria; Chiltern: Honoraria; BMS: Honoraria, Other: Travel; Novartis: Honoraria. Kim: Novartis: 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, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Il-Yang: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Milojkovic: Novartis: Consultancy, Honoraria; Incyte: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. le Coutre: BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; ARIAD: Honoraria. García Gutiérrez: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Crescenzo: Pfizer: Employment, Equity Ownership. Leip: Pfizer: Employment, Equity Ownership. Bardy-Bouxin: Pfizer: Employment, Equity Ownership. Hochhaus: Novartis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Ariad: Research Funding; MSD: Research Funding; BMS: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cortes: Sun Pharma: Research Funding; ARIAD: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

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Treatment Patterns Among Newly Diagnosed Multiple Myeloma Patients in the United States Veteran Population (2010-2015)

Blood ◽

10.1182/blood.v128.22.5952.5952 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5952-5952

Author(s):

Kejal Parikh ◽

Shivani Pandya ◽

Safiya Abouzaid ◽

Onur Baser ◽

Lin Xie ◽

...

Keyword(s):

Research Funding ◽

Cox Regression ◽

Treatment Patterns ◽

Novel Therapies ◽

Newly Diagnosed ◽

Employment Equity ◽

Chemotherapy Agent ◽

The Us ◽

Equity Ownership

Abstract Background: Despite a relatively higher incidence in the veteran population, there are few real-world claims-based analyses to describe Multiple Myeloma (MM) treatment patterns among this patient population (Landgren O, Blood, 2006). This study aimed to assess treatment patterns among newly diagnosed MM (ndMM) patients using the US Veteran Health Administration (VHA) data. Methods: This retrospective study identified adult patients with ≥2 claims for MM (ICD-9-CM code: 203.0x) 30 days apart and ≥1 treatment during identification period (1OCT2011-31MAR2015) from the VHA dataset. The initial course of therapy (COT1) date was the index date and included all treatments prescribed within 60 days of this date. Patients were required to have continuous enrollment for 12 months pre- and ≥6 months post-index date unless patients died within 6 months (follow up period), ≥1 full cycle of therapy with a valid COT1 regimen, no evidence of prior MM diagnosis or treatment (including autologous stem cell transplant (ASCT)), and no evidence of ASCT in the follow up period. A subsequent COT (COT2) was defined as the earliest occurrence of: the addition of a new drug or switch in regimen after the first 60 days, restart of a previous regimen after >180-day gap, or a dose increase from maintenance to relapse therapy. Dexamethasone/prednisone[d] which were assumed to be included regardless of whether or not they were observed during the study period did not impact the ongoing COT. Treatment patterns during the follow-up period were initially examined among patients treated with novel (lenalidomide [R] and/or bortezomib [V] with or without chemotherapy agents) and non-novel therapies (≥1 chemotherapy agent, steroid monotherapy) and then compared among those initiating Rd and Vd. Time to next treatment (TTNT) was defined as the duration from initiation of COT1 plus any gaps before COT2. Kaplan Meier and Cox regression analyses were performed to evaluate TTNT and assess the impact of various predictors on TTNT among patients initiating Rd and Vd. Results: Of 1,183 patients that met the inclusion criteria, 55.4% (n=655) were treated with novel therapies and 44.6% (n=528) with non-novel therapies. Among patients treated with novel therapy, the majority initiated Rd (47.8%; n=313) as COT1 followed by Vd (31.2%; n=204), Vd with cyclophosphamide (11.5%; n=75), RVd (6.6%; n=43), Vd with a chemotherapy agent (2.4%; n=16) and Rd with a chemotherapy agent (0.6%; n=4).Rd initiators were significantly older (75.1 vs 70.6 years, p=0.0002) and a higher percentage was white (69.7% vs 47.0%; p<0.0001) than Vd treated patients. While the Charlson Comorbidities Index score did not differ between the two groups (3.6 vs 4.0, p=0.0583), a significantly higher percentage of patients treated with Vd had some comorbidities including hepatitis and renal disease. Among patients with laboratory tests, patients treated initially with Vd had lower hemoglobin (10.8 vs 11.4 g/dl, p=0.0012) and higher serum creatinine (2.3 vs 1.4 mg/dl, p<0.0001) during the pre-index period. The overall average treatment duration in COT1 was significantly longer among patients treated with Rd vs Vd (10.9 vs 7.0 months, p<0.0001). Among patients who were still on active COT1, the mean duration in COT1 was longer among patients treated with Rd than Vd (18.7 vs 13.3 months, p=0.0061). A significantly higher percentage of patients treated with Vd progressed to COT2 (52.5%, vs 26.2% p<0.0001) as compared to Rd. Among patients who progressed to COT2, those treated with Vd had a shorter TTNT compared to Rd (Mean: 9.3 vs 12.8 months, p=0.0049). After adjusting for baseline demographic and clinical factors using Cox regression, TTNT remained significantly shorter for Vd vs those treated with Rd (HR: 2.67, 95% CI: 1.9-3.7, p <0.0001). Conclusion: Slightly over half of MM patients in the US Veteran population were treated with a regimen containing novel therapies; Rd and Vd were the most commonly observed among these. Patients treated initially with Vd had a significantly shorter TTNT compared to those treated with Rd. The difference remained significant after controlling for baseline characteristics including markers for higher disease severity among patients on Vd. Disclosures Parikh: Celgene Corporation: Employment, Equity Ownership, Research Funding. Pandya:Celgene: Research Funding. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Baser:Celgene: Research Funding. Xie:Celgene: Research Funding. Patel:Celgene: Consultancy.

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