scholarly journals Clinical Characteristics and Outcomes of AML Patients Treated with Frontline CPX 351 or HMA/Venetoclax: A Single Institution's Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1252-1252
Author(s):  
Aleksander L. Chojecki ◽  
Justin Arnall ◽  
Danielle Boselli ◽  
Kristyn Y. DiSogra ◽  
Allison Karabinos ◽  
...  
Keyword(s):  
Research Funding ◽  
Clinical Characteristics ◽  
Treatment Options ◽  
Standard Of Care ◽  
Response Rates ◽  
Similar Response ◽  
Refractory Disease ◽  
Newly Diagnosed ◽  
Frontline Treatment ◽  
To Receive

Abstract Introduction: Treatment options for newly diagnosed patients (pts) with acute myeloid leukemia (AML) have historically been limited. The combination of a hypomethylating agent and venetoclax (HMA/Ven) has emerged as standard of care treatment for elderly and/or unfit pts with newly diagnosed AML. Liposomal cytarabine/daunorubicin (CPX-351) has also become standard of care therapy for pts with AML with myelodysplasia related changes or therapy-related AML. Despite being an intensive regimen, CPX-351 may have a more favorable toxicity profile compared to other intensive regimens. As a result, CPX-351 may be offered to older fit pts who may not have been candidates for traditional induction regimens. As the landscape for frontline treatment options evolves, there are now overlapping pt populations who may be eligible for either frontline treatment option. A retrospective study that included clinical trial pts demonstrated similar response rates in pts treated with HMA/Ven and CPX-351 (Asghari Blood 2019). Similarly, a study of secondary AML pts receiving HMA/Ven and CPX-351 showed no difference in remission rate or survival (Salhotra Am J Hematol 2021). There remains a shortage of data describing clinical characteristics of pts selected for and treated with standard-of-care HMA/Ven and CPX-351. We present a study on our center's experience. Methods: The purpose of this study was to evaluate the clinical characteristics and outcomes of adult pts with newly diagnosed AML who were treated with either CPX-351 or HMA/Ven as initial therapy. Consecutive pts treated with either of these two induction therapies between August 2017 and June 2021 were evaluated retrospectively. Pts were eligible for response evaluation if they received at least 3 doses of CPX-351 or 28 days (1 cycle) of venetoclax ("response cohort"). All pts treated with CPX-351 or HMA/Ven were included in survival analysis ("survival cohort"). Response assessment is based on ELN-2017 criteria. Pt characteristics were described and compared using Fisher's Exact tests. Kaplan-Meier methods were used to summarize overall survival, and log-rank tests were used for the comparison of frontline therapies. Cox proportional-hazards regression estimated hazard ratio (HR), 95% confidence interval (CI), and interactions between frontline therapy and age at induction start. Results : A total of 79 pts were identified receiving frontline HMA/Ven or CPX-351; 61 pts (77%) were evaluable for response. Of the response cohort, 21 (34%) were treated with CPX-351 and 40 (66%) with HMA/Ven; pt characteristics are described in Table 1. CPX-351 pts were younger at start of induction (P<0.001); many pts in both treatment groups had unfavorable ELN risk scores at diagnosis (CPX 43%, HMA/Ven 41%; P>0.99). 33% and 23% of the HMA/Ven cohort achieved CR and CRi respectively; in the CPX-351 cohort 57% and 5% achieved CR and CRi respectively. A greater fraction of CPX-351 pts proceeded to allogeneic stem cell transplant than HMA/Ven pts (67% vs 23%; P<0.001). No differences were detected in achievement of MRD negativity by flow cytometry (P=0.51) or molecular profile (P=0.52). Median follow-up for all pts was 18.9 months; 42 deaths occurred. Differences in survival between the frontline therapies were not detected in the survival cohort (HR, 1.31; 95% CI, 0.67 to 2.57; P=0.43) nor the response cohort (HR, 0.97; 95% CI, 0.45 to 2.09; P=0.93); these results were unaffected by adjustments for age at induction, ELN risk score, and transplant status. 8 pts who initially received CPX-351 and had refractory disease later went on to receive HMA/Ven reinduction; 2 achieved CRi, 2 MLFS, 3 Refractory and 1 Death in Aplasia. 1 pt who initially received HMA/Ven with refractory disease went on to receive CPX-351. This pt was refractory to CPX-351. Conclusion: HMA/Ven and CPX-351 are effective frontline treatment options with similar response rates and survival outcomes in newly diagnosed adults with AML. Pts treated with CPX-351 were younger and more likely to proceed with allogeneic transplantation, in line with standard practice. Though there was heterogeneity in pt populations, age did not appear to affect outcomes. As the landscape for standard-of-care upfront treatment for AML continues to evolve, further studies are warranted to determine optimal therapy selection and sequencing. Figure 1 Figure 1. Disclosures Arnall: Novo Nordisk: Speakers Bureau. Symanowski: Carsgen: Consultancy; Immatics: Consultancy, Other: DSMB Member; Eli Lilly: Consultancy, Other: DSMB Member. Avalos: JUNO: Membership on an entity's Board of Directors or advisory committees. Copelan: Amgen: Consultancy. Grunwald: Cardinal Health: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Agios: Consultancy; Janssen: Research Funding; PRIME: Other; Karius: Consultancy; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Blueprint Medicines: Consultancy; Gilead: Consultancy; Incyte: Consultancy, Research Funding; Amgen: Consultancy; Med Learning Group: Other; Sierra Oncology: Consultancy; MDEdge: Other; PER: Other; Trovagene: Consultancy; Stemline: Consultancy.

scholarly journals Real Life Treatment Alterations of Frontline Therapies in Classic Hodgkin's Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Samer Al Hadidi ◽  
Ranjit Nair ◽  
Raphael E Steiner ◽  
Sairah Ahmed ◽  
Paolo Strati ◽  
...  
Keyword(s):  
Treatment Response ◽  
Research Funding ◽  
Brentuximab Vedotin ◽  
Hodgkin's Lymphoma ◽  
P Value ◽  
Refractory Disease ◽  
Newly Diagnosed ◽  
Time To Event ◽  
Grant Support ◽  
Frontline Treatment

Introduction Classic Hodgkin's lymphoma (cHL) is a highly curable lymphoid malignancy. Most of the patients receive either bleomycin or brentuximab vedotin (BV) based therapies as a frontline treatment. Treatment alterations are common and can be related to toxicity, patient's preference, and/or clinical evidence of response. The aim of our study is to explore the frequency and characteristics of treatment alterations, especially bleomycin and BV, in frontline therapies used in newly diagnosed cHL. Methods This single center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Patients' charts were reviewed to assess frequency of treatment discontinuation at the time of frontline therapy and underlying reasons for any treatment alterations. The primary aims were to assess the frequency of treatment alterations and its effects on overall survival (OS), and progression-free survival (PFS). Descriptive statistics including mean, standard deviation, median, and range for continuous variables such as age, and lab measurements, and frequency counts and percentages for categorical variables such as race, gender, and response were analyzed. The Kaplan-Meier method was used for time-to-event analysis including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses. Results In the studied period, 644 patients met the inclusion criteria. The median age at diagnosis was 33 years (range:9-85) with 52% males. Advanced stage (stages III and IV) occurred in 45% of patients. Ninety-seven percent of patients had 0-1 Eastern Cooperative Oncology Group (ECOG) performance status. Histological subtype was predominately nodular sclerosis (83%). International prognostic index at the time of diagnosis was ≥4 in 13% of patients. Most of the patients received doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) based therapy (77%). Other therapies included brentuximab vedotin (BV)(13%) and checkpoint inhibitors (CPIs) (6%, as a part of clinical trial). Patient's demographics are outlined in Table.1. Treatment alteration, which included either addition or omission of drug/s, occurred in 26% of patients. The most common discontinued drugs were bleomycin (79%), and BV (15%). Of the patients who were started on ABVD based therapy, the frequency of bleomycin discontinuation was 26% (116 of 455 patients). The most common reasons for bleomycin discontinuation were: treatment response as per the RATHL study (49%), pulmonary toxicity (27%) and other treatment-related toxicity (9%). Of the patients who were started on frontline BV based therapy, the frequency of BV discontinuation was 26% (20 of 78 patients). The most common reasons for BV discontinuation were: peripheral neuropathy (65%), skin rash (10%) and other treatment-related toxicity (25%). Patients who discontinued bleomycin due to adverse events (AEs) had a higher chance of primary refractory disease at the end of frontline treatment (19% vs. 15%, p-value: 0.005) while patients who discontinued bleomycin due to treatment response had similar rates of primary refractory disease (13% vs. 15%, p-value: 0.57). The median cycles number of bleomycin based therapy were the same (6 cycles) among all the groups (those who continued bleomycin without AEs or discontinuation, patients who discontinued bleomycin for treatment response and patients who discontinued bleomycin for AEs) . Patients who discontinued BV due to AEs had similar outcome to the patients who continued the treatment without alterations. Conclusions Frontline treatment alterations in cHL are common. Positron emission tomography treatment response based bleomycin discontinuation was not associated with worse PFS or OS. However bleomycin discontinuation secondary to AEs was associated with a statistically significant higher rate of primary refractory disease and subsequent worse PFS and OS. BV discontinuation secondary to AEs didn't result in worse outcomes. Disclosures Parmar: Cellenkos Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.Iyer:CRISPR:Research Funding;Spectrum:Research Funding;Merck:Research Funding;Afffimed:Research Funding;Rhizen:Research Funding;Seattle Genetics, Inc.:Research Funding;Legend Biotech:Consultancy;Daiichi Sankyo:Consultancy;Trillium:Research Funding;Curio Biosciences:Honoraria;Target Oncology:Honoraria.Nieto:Affimed:Consultancy, Other: Grant Support;Novartis:Other: Grant Support;Secura Bio:Other: Grant Support;Astra Zeneca:Other: Grant Support.Chuang:Sage-Evidence=Based Medicine & Practice:Consultancy.Wang:Lu Daopei Medical Group:Honoraria;Pulse Biosciences:Consultancy;Molecular Templates:Research Funding;BioInvent:Research Funding;VelosBio:Research Funding;Beijing Medical Award Foundation:Honoraria;Juno:Consultancy, Research Funding;Oncternal:Consultancy, Research Funding;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;InnoCare:Consultancy;Loxo Oncology:Consultancy, Research Funding;Verastem:Research Funding;Acerta Pharma:Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;MoreHealth:Consultancy;OncLive:Honoraria;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Nobel Insights:Consultancy;Guidepoint Global:Consultancy;Dava Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Targeted Oncology:Honoraria.Lee:Celgene:Research Funding;Guidepoint Blogal:Consultancy;Bristol-Myers Squibb:Consultancy, Research Funding;Aptitude Health:Speakers Bureau;Oncternal Therapeutics:Research Funding;Seattle Genetics:Research Funding;Takeda:Research Funding.

Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs) on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2768-2768 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Francois Guilhot ◽  
Chao Zhu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Response Rates ◽  
Similar Response ◽  
Medical Procedure ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Reductions

Abstract Abstract 2768 Background: 24-month follow-up of pts with newly diagnosed CML-CP in the DASISION trial demonstrated both a high rate of complete cytogenetic response (CCyR) with dasatinib (D) and higher and faster rates of major molecular response (MMR) with D over imatinib (IM), supporting the use of D 100 mg once daily as a first-line treatment option for newly diagnosed CML-CP. Discontinuations due to adverse events (AEs) occurred in 7% with D and 5% with IM. Median dose intensity for D and IM were 99.5 mg/day and 400 mg/day, respectively (Kantarjian JCO 2011:29;Abs 6510). A retrospective analysis of pts from DASISION was performed to evaluate the impact of dose reductions and interruptions due to AEs on efficacy of D or IM in newly diagnosed CML-CP. Methods: Pts with newly diagnosed CML-CP received D 100 mg QD (N=258) or IM 400 mg QD (N=258). The primary endpoint was confirmed CCyR by 12 months. In DASISION, up to two dose reductions were permitted for AEs; dose reduction levels were 80 mg/50 mg for D and 300 mg/200 mg for IM. Dose interruptions were permitted for management of AEs. Upon resolution or improvement of AEs to ≤ Grade 1, pts could resume therapy at an appropriate dose based on initial severity of the AE. Efficacy was evaluated for pts with or without dose reductions and/or interruptions due to AEs at any time. Efficacy was also evaluated for pts with first dose interruption and/or reduction due to AEs within ≤6 or >6 months of their first dose who remained on treatment for at least 6 months, in order to reduce selection bias of pts with longer duration of therapy. Pts with dose reduction and/or interruption for reasons other than AEs (dosing error, medical procedure) were excluded from all analyses. Results: 134 D pts (52%) and 92 IM pts (36%) had dose reduction and/or interruption for AE management at the DASISION 24-month update. First dose reduction and/or interruption due to non-hematologic AEs occurred in 59 (23%) D and 40 (16%) IM pts and hematologic AEs in 75 (29%) D and 52 (20%) IM pts. Pts with dose reduction and/or interruption for reasons other than AE management were excluded, including 21 (8%) D pts and 19 (7%) IM pts. The median duration of first dose interruption due to AEs was approximately 2 weeks on both arms. CCyR and MMR rates with D were comparable whether pts did or did not have their dose reduced and/or interrupted at any time (Table). D pts who had dose reduction and/or interruption had generally higher rates of responses than IM pts overall and in those without an IM dose reduction and/or interruption. The timing of dose reduction and/or interruption appeared to have a potential impact as response rates were higher when dose reduction and/or interruption occurred >6 months after the first dose of either drug (Table). CCyR and MMR rates with D remained higher than with IM when dose reduction and/or interruption occurred ≤6 months from first dose. Similarly, both CCyR and MMR were higher for D than with IM if dose reduction and/or interruption occurred >6 months from the first dose. Conclusions: Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Quintas-Cardama:Bristol-Myers Squibb: Honoraria. Guilhot:Novartis: Honoraria; Bristol-Myers Squib: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Zhu:Bristol-Myers Squibb: Employment. Hong:Bristol-Myers Squibb: Employment, Equity Ownership. Cain:Bristol-Myers Squibb: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

scholarly journals Newly Diagnosed Myeloma in 2020

2020 ◽  
pp. e144-e158 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Touzeau ◽  
Ravi Vij ◽  
Scott R. Goldsmith ◽  
Ashley E. Rosko
Keyword(s):  
Older Adults ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Newly Diagnosed ◽  
New Agents ◽  
Specific Patient ◽  
Clinical Endpoints ◽  
Frontline Treatment ◽  
Treatment Tolerance

Over the last few years, there has been great progress in the treatment of multiple myeloma (MM), with many new agents and combinations having been approved and being now routinely incorporated into treatment strategies for newly diagnosed patients. As a result, patients are experiencing benefits in terms of survival and better tolerance. However, the multitude of treatment options also presents a challenge to select the best options tailored to the specific patient situation. Frontline autologous stem cell transplantation (ASCT) is the standard of care for fit patients younger than age 71 who are newly diagnosed with MM, and triplet combinations are the backbone of induction therapy before ASCT. Post-transplant consolidation and prolonged lower-intensity maintenance are two strategies that have been used to deepen responses and delay progression. For older patients not eligible for ASCT, lenalidomide (len) is increasingly being used as part of frontline therapy, and current approaches are now targeting combinations of anti-CD38 antibodies. Strategies for selecting therapeutic regimens for older adults newly diagnosed with MM can be augmented with use of predictive tools to better capture physiologic age and estimate treatment tolerance. Here we review a decade of trials identifying clinical endpoints and toxicities relevant for the frontline treatment of younger patients and older adults.

scholarly journals A Phase II Trial to Compare Allogeneic Transplant Vs. Standard of Care for Severe Sickle Cell Disease: Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 1503

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4592-4592
Author(s):  
Mary Eapen ◽  
Donna S Neuberg ◽  
Adam M. Mendizabal ◽  
Kristen E. Stevenson ◽  
Joseph H. Antin ◽  
...  
Keyword(s):  
Research Funding ◽  
Treatment Options ◽  
Standard Of Care ◽  
Hla Typing ◽  
Unrelated Donor ◽  
No Donor ◽  
History Of ◽  
Matched Sibling ◽  
The Difference ◽  
To Receive

Background: Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for sickle cell disease (SCD). A pilot trial confirmed the suitability of a myeloablative conditioning regimen (busulfan/fludarabine/r-ATG) for HLA-matched sibling and unrelated donor HCT for severe SCD. This led to the current phase II trial funded by the NHLBI. The primary aim is to determine the efficacy of treatment options (HCT vs. standard of care) for adolescents and young adults with severe SCD (NCT02766465). Study design and Treatment: This is a "biologic assignment" trial in which subjects with an HLA-matched sibling or HLA-matched unrelated donor are assigned to a donor arm (expected to receive HCT). Those without a suitable donor are assigned to a no-donor arm and expected to receive current therapies for SCD at the discretion of their provider. Although randomization is the gold standard for comparing treatments, such an approach for a rare disease is not feasible for the following reasons: 1) timely completion of the trial (~30% expected to identify a matched sibling and ~20%, a matched unrelated donor) and 2) accrual is challenging when the two arms of a randomized trial have markedly disparate treatments (i.e., one arm is an intervention with about 10-20% upfront mortality vs. the other arm also expected to have mortality risks but accepted as a consequence of disease). While we expect some to decline HCT (donor arm) or proceed to a mismatched related or unrelated donor HCT (no-donor arm), through education /counselling prior to consent, we anticipate <5% cross-over. Major Inclusion Criteria: Age 15 - 40 years with SCD (stroke or neurologic deficit, recurrent vaso-occlusive crisis, acute chest syndrome, high impact chronic pain or tricuspid regurgitant jet velocity ≥2.7m/second. Subjects who already have a suitable donor are excluded. Statistical Methods: Subjects are screened for eligibility and enrolled without knowing their biological assignment. HLA typing of the subject and donor search can be undertaken only after enrollment. Treatment arm assignment, (donor or no-donor arm) has to occur within 6 months of enrollment. We hypothesize that subjects on the donor arm will exert an early impact on survival and that survival will plateau by 1-year. Those on the no-donor arm are expected to follow the natural history of their disease with risk of premature mortality. A non-inferiority framework was chosen to test the non-inferiority of the donor arm compared to the no donor arm. The non-inferiority margin of 0.20 was chosen to establish that the difference in the proportion of subjects surviving at 2 years between the donor arm is no more than 0.20 worse than the no donor arm. If we reject the non-inferiority null hypothesis with a one-sided test, we will declare that the non-inferiority margin is met and that the difference in the probability of 2-year survival between the donor and no-donor arm is no more than 20%. Endpoints: The primary endpoint is the estimate of overall survival at 2-years after enrollment. Regardless of treatment received subjects will remain in their assigned treatment arm for analysis of survival (intent-to-treat principle). Secondary endpoints include comparison of occurrence of sickle related events in both treatment groups over 2 years (pulmonary hypertension, cerebrovascular, renal, avascular necrosis, leg ulcer), and functional assessment (6-minute walk distance test, 28-day e-pain diary [mean pain intensity] and HRQoL. Exact logistic regression will be used to estimate an odds ratio of such events, assuming that at least one such event occurs on study in each of the treatment arms, controlling for other patient-related characteristics and individual history of the event of interest. The trial is on-going and has met ~55% of projected accrual. Obstacles to accrual include: physician bias, subjects were not aware of a curative option for their disease, payment for HCT on a clinical trial in some US states despite meeting the Center for Medicare/Medicaid Services (CMS) requirement for coverage with evidence determination (CED), prior HLA typing and knowledge regarding donor availability, competing treatment options and the fact that substantial numbers of potentially eligible subjects are followed in the community and lack access to academic sites. Overcoming obstacles took ~2 years. The trial is now at "steady state accrual" and expected to complete accrual in ~18-24 months. Disclosures Neuberg: Celgene: Research Funding; Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership. Stevenson:Celgene: Research Funding. Waller:Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Walters:Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy.

scholarly journals OP0173 IMMUNOMODULATION CO-THERAPY WITH PEGLOTICASE: DATABASE TRENDS 2014-2019

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 108.2-108
Author(s):  
B. Lamoreaux ◽  
M. Francis-Sedlak ◽  
K. Svensson ◽  
R. Holt
Keyword(s):  
Case Series ◽  
Standard Of Care ◽  
Response Rates ◽  
Therapeutic Benefit ◽  
Azathioprine Therapy ◽  
Claims Database ◽  
Immunomodulating Therapy ◽  
Therapeutic Benefits ◽  
To Receive ◽  
Medical Claims Database

Background:Pegloticase is a PEGylated biologic therapy for patients with uncontrolled gout who have not improved on or could not tolerate conventional urate-lowering therapies.1All biologics have the ability to engender anti-drug antibodies (ADAs) and it is known that some patients given pegloticase develop ADAs that cause them to stop treatment prior to recieving a complete course of therapy.2-3In other rheumatic autoimmune diseases, DMARDs such as methotrexate or azathioprine are used as standard of care to prevent the development of ADAs to biologics. These DMARDs often allow patients to remain on biologic therapies longer and recieve the full therapeutic benefits while minimizing adverse events.4While pegloticase has been used traditionally as monotherapy, recent case series have demonstrated the therapeutic benefit of immunomodulator co-administration, allowing more patients to receive a full course of pegloticase therapy.5-6Little has been published on how widespread this practice is and whether it has changed over time.Objectives:To examine medical claims database from 2014-2019 for trends in immunomodulating therapies being co-prescribed with pegloticase.Methods:An IQVIA claims database (November 2014 to October 2019) representing 1.3 billion claims, covering 30 million patients diagnosed with gout or CKD, was utilized to search for patients who had received pegloticase. Patients who had recieved pegloticase were classified as having been on an immunomodulating co-therapy if they were prescribed methotrexate or azathioprine within 60 days before or after initiation of their first pegloticase infusion.Results:We found relatively steady low rates of immunomodulation co-therapy with pegloticase from 2014 through 2018 ranging from 1% in 2016 to 4% in 2018 (Figure 1). In 2019 however, the proportion of pegloticase patients that were co-treated with methotrexate or azathioprine therapy increased to 15%. Most patients were started on immunomodulating therapy 20 days before to 10 days after initiation of pegloticase. Methotrexate was the more frequently used immunomodulaton co-therapy as compared to azathioprine.Conclusion:We found evidence of a relatively dramatic increasing initiation of immunomodulation therapy with pegloticase beginning soon after a November 2018 presentation of a case series which demonstrated improved response rates of pegloticase when co-administered with methotrexate. These data indicate that clinicians began to more frequently employ a strategy of DMARD co-treatment with pegloticase in 2019 to improve response rates to this important gout medicine.References:[1]Sundy JS, et al.JAMA2011;306:711-20.[2]Abeles AM.Arthritis Research & Therapy2014, 16:112[3]Strand V, et al.BioDrugs2017; 31:299–316.[4]Krieckaert CL, et al.Arthritis Res Ther2010;12:217.[5]Botson J and Peterson J.Ann Rheum Dis.2019; 78: A1289.[6]Bessen SY, et al.Semin Arthritis Rheum.2019;49:56-61.Disclosure of Interests:Brian LaMoreaux Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Megan Francis-Sedlak Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Karl Svensson Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics, Robert Holt Shareholder of: Horizon Therapeutics, Employee of: Horizon Therapeutics

scholarly journals Long Term Outcome of Lenalidomide-Dexamethasone (Rd) Vs Melphalan-Lenalidomide-Prednisone (MPR) Vs Cyclophosphamide-Prednisone-Lenalidomide (CPR) As Induction Followed By Lenalidomide-Prednisone (RP) Vs Lenalidomide (R) As Maintenance in a Community-Based Newly Diagnosed Myeloma Population: Updated Analysis of EMN01 Phase III Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 901-901
Author(s):  
Sara Bringhen ◽  
Massimo Offidani ◽  
Pellegrino Musto ◽  
Anna Marina Liberati ◽  
Giulia Benevolo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase Iii ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Community Based ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Grade 3 ◽  
To Receive

Abstract Introduction : Rd and MPR showed to be effective combinations in elderly newly diagnosed multiple myeloma (NDMM) patients (pts). Cyclophosphamide is a less toxic alkylating alternative agent. EMN01 is the first trial to formally compare these three different Lenalidomide-based combinations. Maintenance with Lenalidomide has been recently approved in patients eligible for autologous stem cell transplant (ASCT). Few data are available about the best combination as maintenance in patients not eligible for ASCT. Methods : 662 pts with NDMM were randomized to receive 9 28-day cycles of Rd (lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those &gt;75 years), MPR (lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in &gt;75 years pts; prednisone 1.5 mg/Kg for 4 days) or CPR (lenalidomide 25 mg/day for 21 days; cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day in &gt;75 years pts; prednisone 25 mg every other day). After induction, pts were randomized to receive maintenance with lenalidomide alone (R; 10 mg/day for 21 days) or with prednisone (RP; R, 10 mg/day for 21 days and P, 25 mg every other day), until disease progression. Results : Pts characteristics were well balanced in all groups; 217 pts in Rd, 217 in MPR and 220 in CPR arms could be evaluated. After a median follow-up of 63.7 months, median PFS was 23.2 months in MPR, 18.9 months in CPR and 18.6 months in Rd (MPR vs CPR p=0.02; MPR vs Rd p=0.08). Median overall survival (OS) was 79.9 months in MPR, 69.4 months in CPR and 68.1 months in Rd (MPR vs CPR p=0.98; MPR vs Rd p=0.64). The most common grade ≥3 adverse event (AEs) was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd pts (p&lt;0.0001). Grade ≥3 non hematologic AEs were similar among arms. At the end of induction, 402 pts were eligible for maintenance, 198 in the RP and 204 in the R groups. PFS from start of maintenance was 22.2 months in the RP group and 17.6 in the R group, with 20% reduced the risk of death/progression for pts receiving RP maintenance (HR 0.81, p=0.07; Figure 1). A subgroup analysis was performed to determine the consistency of RP vs R treatment effect in different subgroups using interaction terms between treatment and cytogenetic abnormalities, ISS, age, sex, induction treatment and response before maintenance (Figure 1). No difference in OS was observed (HR 1.02, p=0.93) but the OS analysis was limited by the low number of events. Median duration of maintenance was 23.0 months in RP pts and 20.5 months in R pts, 14% and 13% of pts discontinued due to AEs, in RP and R groups, respectively. Conclusion : This phase III trial compared 2 different Lenalidomide-containing induction regimens and 2 different Lenalidomide-containing maintenance regimens in an elderly community-based NDMM population. MPR prolonged PFS by approximately 5 months, yet the higher incidence of hematologic toxicity should be carefully considered. The addition of low-dose prednisone to standard lenalidomide maintenance reduced the risk of death/progression by 20%, with a good safety profile. Updated results will be presented at the meeting. Disclosures Bringhen: Mundipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Karyipharm: Membership on an entity's Board of Directors or advisory committees. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Celgene: Honoraria; Janssen: Honoraria. Gaidano: Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. De Sabbata: Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Binding Site: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Genmab A/S: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Employment, Equity Ownership, Honoraria, Research Funding. Hájek: Amgen, Takeda, BMS, Celgene, Novartis, Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; Pharma MAR: Consultancy, Honoraria. Boccadoro: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

scholarly journals Results of the Phase 1b Dose Escalation Study of OPB-111077, Decitabine, and Venetoclax for the Treatment of Newly Diagnosed or Relapsed/Refractory AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Lindsay Wilde ◽  
Ubaldo Martinez-Outschoorn ◽  
Neil Palmisiano ◽  
Gina Keiffer ◽  
Margaret Kasner
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Acid Metabolism ◽  
Pharmaceutical Research ◽  
Refractory Disease ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Otsuka Pharmaceutical ◽  
Refractory Aml

Background: The combination of a hypomethylating agent (HMA) and the Bcl-2 inhibitor venetoclax (VEN) has revolutionized the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML). However, patients treated with this regimen inevitably relapse and subsequent treatment options are limited. Furthermore, the success of this combination in the relapsed/refractory setting has been less impressive. Mechanisms of resistance to HMA/VEN are of great interest, and alterations in leukemic cell metabolism have been implicated. It is hypothesized that drugs that target oxidative phosphorylation (OXPHOS), fatty acid metabolism, and /or amino acid metabolism may be successful in overcoming HMA/VEN resistance. OPB-111077 is a novel, oral, low-molecular-weight compound that was shown in preclinical models to inhibit mitochondrial electron transport and have an inhibitory effect on the growth of AML cells. When given in combination with decitabine, OPB-111077 showed a more potent antitumor effect in a KG-1 tumor-bearing mouse model, thus providing support for conducting clinical trials of this combination. AML cells treated with OPB-111077 and venetoclax have also been shown to have decreased proliferation and increased apoptosis. The effects on proliferation and apoptosis of the combination of OPB-111077 and venetoclax were more pronounced in AML cells that were genetically engineered to increase OXPHOS. These data formed the basis for the development of a clinical trial utilizing the triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML. Herein, we report results from the Phase Ib dose escalation study. Methods: In this phase Ib single center study (NCT03063944), OPB-111077 is administered daily starting on day 1 and continuing throughout the treatment cycle. Decitabine 20mg/m2 is given for 5 days starting on day 4 of cycle 1. Venetoclax 70mg daily (if receiving posaconazole prophylaxis) or 100mg daily (if receiving voriconazole) is started on day 4 and given continuously until day 28. If a response is seen within 2 cycles, treatment continues until toxicity, disease progression, or availability of an alternative therapy. Patients were enrolled in cohorts of escalating dose levels of OPB-111077 using a traditional 3+3 design. The primary objectives were to determine preliminary safety and tolerability as well as maximum tolerated dose (MTD) of OPB-111077. The secondary objective was to measure preliminary efficacy. Correlative studies including metabolomics, ATP measurement, apoptosis, and proliferative assays were performed on samples of blasts and non-cancerous cells that were collected from blood or marrow. Results: As of July 15, 2020, 2 patients with newly diagnosed AML and 7 patients with relapsed/refractory AML were treated with the triplet. Patients received OPB-111077 at 150mg (n=3), 200mg (n=3), and 250mg (n=3). Median age was 73 years (range, 23-79) and 7 patients (78%) were male. The median number of prior systemic anticancer regimens for patients with relapsed/refractory disease was 2 (range, 1-5); no patients had undergone prior stem cell transplant. The median treatment duration has not yet been reached; 3 patients are receiving ongoing treatment. No patients experienced a dose limiting toxicity. The most common Grade ≥3 adverse event (AE) was febrile neutropenia (56%). No patients discontinued due to AEs. No pts experienced tumor lysis syndrome. Three patients died after completing their study treatment, all due to progressive AML. The best overall response to therapy was a complete remission in 2 (22%) patients (1 with newly diagnosed AML and 1 with relapsed/refractory disease). Metabolomics using liquid chromatography/mass spectrometry was performed on paired pre- and post-treatment samples and intracellular metabolic changes in glycolysis and the tricarboxylic acid (TCA) cycle were observed consistent with on-target effects. Conclusion: The triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML was safe and well tolerated, and showed preliminary anti-leukemic efficacy. A planned expansion phase is underway utilizing the 250mg daily dose of OPB-111077. Disclosures Martinez-Outschoorn: Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding.

scholarly journals Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3816-3816 ◽  
Author(s):  
Ryan J. Daley ◽  
Sridevi Rajeeve ◽  
Charlene C. Kabel ◽  
Jeremy J. Pappacena ◽  
Sarah E. Stump ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hypersensitivity Reactions ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

Appendix: Multiple Myeloma Treatment Options for Newly Diagnosed, Relapsed, and Refractory Disease

2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Kimberly Noonan, MS, RN, ANP, AOCN ◽  
Teresa S. Miceli, RN, BSN, OCN ◽  
Patricia Mangan, RN, MSN, APRN-BC ◽  
Sandra Rome, RN, MN, AOCN, CNS
Keyword(s):  
Multiple Myeloma ◽  
Treatment Options ◽  
Refractory Disease ◽  
Newly Diagnosed

Dexamethasone and Individualized Asparaginase Dosing Are Each Associated with Superior Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: Results From DFCI-ALL Consortium Protocol 00-01.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 321-321 ◽  
Author(s):  
Lynda M. Vrooman ◽  
Donna S. Neuberg ◽  
Kristen E. Stevenson ◽  
Jeffrey G. Supko ◽  
Stephen E. Sallan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Multivariable Analysis ◽  
Hazard Ratio ◽  
Induction Treatment ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
To Receive

Abstract Abstract 321 BACKGROUND: The DFCI-ALL Consortium Protocol 00-01 aimed to determine the relative efficacy and toxicity of 1) dexamethasone (DEX) vs. prednisone (PRED) and 2) asparaginase (ASP) with individualized dosing (ID) based on pharmacokinetic measurements vs. standard fixed dosing (FD) based on body surface area, in the treatment of children with newly diagnosed acute lymphoblastic leukemia (ALL). PATIENTS and METHODS: Between 2000 and 2004, 492 eligible patients (pts) ages 1-18 years (yrs) with newly diagnosed ALL enrolled on Protocol 00-01 from 10 institutions. 282 pts were standard risk (SR) and 210 high risk (HR). Post-induction treatment for all patients included 30 weeks of intramuscular E. coli ASP (beginning at week 7) and vincristine/corticosteroid pulses every 3 weeks for 24 months. Pts who achieved complete remission (CR) were eligible for two randomized comparisons: 1) Steroids: Pts were randomized to receive either DEX or PRED given as 5-day pulses every 3-weeks, and 2) ASP: Pts were randomized to receive either FD (25,000IU/m2) or ID (starting dose 12,500 IU/m2) for 30 weeks. Nadir serum ASP activity (NSAA) was assessed every 3 weeks, and ASP doses on the ID arm were adjusted to maintain NSAA between 0.10-0.14 IU/mL. NSAA was assayed centrally by a validated biochemical assay. RESULTS: 473 pts (96%) achieved CR. With a median follow-up of 4.9 years, the 5-year event-free survival (EFS) ± standard error for all 492 pts was 80 ± 2% and overall survival (OS) was 91 ± 1%. Steroid randomization: 408/473 pts (86%) participated in the steroid randomization (DEX: 201, PRED: 207). Pts randomized to DEX had 5-yr EFS of 90 ± 2% compared with 81 ± 3% for PRED (p=0.01) [Table I]. For pts 10-18 yrs of age, there was a significant increase in the rate of osteonecrosis (ON) with DEX, with 5-yr cumulative incidence (CI) of 23% compared with 4.7% for PRED (p=0.02). There was no difference in the 5-yr CI of ON based on steroid type in pts 1-10 yrs of age (DEX: 2.6% vs. PRED: 4.3%, p=0.43). Fractures were also more common in pts 10-18 yrs of age randomized to DEX (p=0.06), but not in younger pts (p=0.25). Infection (positive blood culture or radiographic evidence of invasive fungal disease) developed in 38 pts (18.8%) randomized to DEX compared with 22 pts (10.6%) randomized to PRED (p=0.03). There was no difference in remission death rate based on steroid randomization (DEX 0% vs. PRED 2%, p=0.5). ASP randomization: 384/473 pts (81%) participated in the ASP randomization (FD: 195, ID: 189). Pts randomized to ID had superior EFS with 5-yr EFS of 90 ± 2% compared with 82 ± 3% for FD (p=0.04) [Table I]. There was no difference between the two arms in the frequency of ASP-related allergy (p=0.46), pancreatitis (p=0.66) or thrombosis (p=0.77). There was also no difference by treatment arm in the proportion of pts able to complete at least 25 weeks of ASP (FD: 88% vs. ID: 87%, p=0.76). There was no difference between the two arms in the proportion of pts with non-detectable NSAA, although fewer pts on the ID arm had high NSAA (>0.14 IU/mL). On multivariable analysis, both DEX and ID ASP were independent predictors of favorable outcome (hazard ratio 0.49 for DEX, p=0.02; hazard ratio 0.52 for ID, p=0.04), with no indication of an interaction. Only 5/92 (5%) pts randomized to both DEX and ID ASP experienced an event. CONCLUSIONS: DEX was associated with superior EFS, but also more bone and infectious toxicities, especially in older children/adolescents. Future studies should focus on minimizing DEX toxicity in older pediatric pts without compromising efficacy. ID of ASP was feasible and was associated with superior EFS. The improved EFS with ID was not due to a reduction in ASP-related toxicity or improved tolerability, but was associated with a reduction in the proportion of pts with high NSAA. Disclosures: Supko: Enzon Inc.: Research Funding. Sallan:Enzon Inc.: Research Funding; Enzon Inc.: Contributed to support of an investigator meeting.

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