13 research outputs found
IDENTIFYING INFLUENCERS FOR PSYOP
Social media has become one of the primary modes of communication throughout the world, especially in developed countries. Nearly every user of social media in its various forms or applications has an audience he or she can influence and a set of influencers from which he or she receives information. U.S. Psychological Operations (PSYOP) personnel focus on influencing foreign target audiences in their audience’s own language but have been slow to adapt to the use of social media as a means of influence. Drawing from principles used in influencer marketing, we ask, How can U.S. PSYOP forces and their partners best identify social media influencers with whom they can partner in their effort to change the behavior of foreign target audiences? Through this study, we identified the main factors for influence on social media using both quantitative and qualitative analysis and developed a decision-making tool to identify the key communicators, in particular social media influencers, who can elicit the desired behavioral change in a target audience. The seven-category influencer scorecard we created provides a low-tech, situationally adaptable method for identifying influencers with whom U.S. PSYOP can partner to execute a PSYOP series.Major, United States ArmyMajor, United States ArmyApproved for public release. Distribution is unlimited
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Eligibility Criteria Are Not Associated with Expected or Observed Adverse Events in Randomized Controlled Trials (RCTs) of Hematologic Malignancies
Abstract
Background: RCTs play a key role in advancing treatment for hematologic malignancies and are often a requisite for regulatory approval. To maximize this potential for registration, eligibility criteria for RCTs may be overly restrictive so as to avoid toxicities that may be attributed to the study drug. We hypothesized that RCTs in hematologic malignancies exclude patients (pts) irrespective of adverse events (AEs) that would be expected based on drug class, or that are ultimately observed.
Methods: We searchedjournals with an impact factor ≥5 for therapeutic phase II and III hematologic malignancy RCTs in adults published from 01/10 to 01/15. Trial eligibility criteria were extracted from clinicaltrials.gov, the International Standard Randomized Controlled Trial Number (ISRCTN) registry, or the protocol, when available. AEs were collected from package inserts or published manuscripts for the following drug classes: alkylators, antimetabolites, anthracyclines, topoisomerase inhibitors, microtubule inhibitors, proteasome inhibitors, and monoclonal antibodies. Toxicities of these drug classes were compared to corresponding trial exclusion criteria using the exact binomial test. We examined reported AEs occurring in ≥10% of subjects within trials, the threshold applied in medication labels. Poisson distributions, with means = 10% of sample sizes of studies (with exclusion criteria), were assumed in calculating the binomial probability for each AE; we considered AEs relevant to the most commonly used organ function exclusion criteria: hepatic, kidney, cardiac, and neurological.
Results: Of 252 full publications identified, 91 (36%) were not RCTs; 27 (11%) were pediatric; 23 (9%) did not meet other inclusion criteria, and 13 (5%) were "kin" publications of the same trial, leaving 98 trials in the final analysis. Of these, 32 (33%) were leukemia trials, 27 (28%) were lymphoma, 34 (35%) were multiple myeloma, and 5 (5%) were myelodysplastic syndromes or myelofibrosis. The majority of studies were phase III (n=77, 79%), multi-center (n=92, 94%), and/or multi-national (n=63, 64%). Of the 98 trials, 12 (12%) contributed pivotal registration data leading to a label change or new approval for 8 drugs.
Key trial exclusion criteria were medical comorbidities (e.g. active or prior cancer, previous cardiac conditions, HIV infection, hepatitis, or psychiatric disease, in 97% of studies); inadequate organ function (in 89%), and poor performance status (in 67%). Exclusion criteria relevant to baseline organ function did not reflect established safety profiles, as the proportion of studies excluding pts with specific organ dysfunction was significantly greater than the proportion of drug classes with known hepatic (85/98 [87%] vs. 75%; P=.007), cardiac (73/98 [74.5%] vs. 62.5%; P=.02), and renal (72/98 [73.5%] vs. 50%; P<.0001) toxicities. Conversely, the proportion of studies excluding patients with neurological deficits was lower than the proportion of drug classes with known neurological toxicities (22/98 [22%] vs. 50%; P<.0001).
Similarly, the number of studies that reported ≥10% patients with a ≥grade 1 toxicity was considerably lower than the number of studies expected, assuming study treatments lead to an AE in 10% of pts (Figure): 19 (22%) vs. 41 (48%) of 85 studies for hepatic AEs (P<.0001); 23 (32%) vs. 35 (48%) of 73 studies for cardiac AEs (P=.003), and 4 (6%) vs. 35 (49%) of 72 studies for renal AEs (P <.0001). Of the 22 studies that excluded pts with peripheral neuropathy, 14 (64%) reported ≥10% of pts with this toxicity, vs. the 11 (50%) expected (P=.95).
Conclusions: The proportion ofRCTs in hematologic malignancies published in high impact medical journals excluding pts with comorbidities and/or organ function abnormalities does not reflect the expected or observed AEs in these patients. This suggests that landmark RCTs, with an eye to registration, may be overly conservative in using restrictive exclusion criteria. The widespread use of these criteria, many of which may not be appropriate given the toxicity profile of the investigational product, may lead to the systematic exclusion of specific patient populations, limiting trial result generalizability.
Disclosures
Kodish: Biogen Idec: Consultancy. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees
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A Phase II Study of CPX-351 As a Novel Therapeutic Approach for Patients with Myelodysplastic Syndromes (MDS) after Hypomethylating Agent Failure
Treatment options are limited for patients (pts) diagnosed with MDS at the time of hypomethylating agent (HMA) failure. One goal is to introduce another line of therapy to reduce tumor burden and enable patients to undergo hematopoietic stem cell transplant (HSCT), which may prolong survival for a subset. CPX-351, has shown better overall response rates and improved overall survival in patients with acute myeloid leukemia with underlying MDS changes compared to 7+3, suggesting that CPX-351 can be used in an MDS patient population. We hypothesized that treating MDS pts, who were failed by HMAs or were intolerant with CPX-351 would overcome HMA resistance.
This is a phase II study of single agent CPX-351 administered at the standard FDA approved dose of 44 mg/m2 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) intravenously on days 1, 3, 5 of the induction cycle. If patients achieve complete remission (CR), marrow CR, partial remission or hematologic improvement per 2006 IWG criteria they will be eligible to continue on to consolidation therapy, which consists of CPX-351 at a dose of 15.4 mg/m2 (daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) every 28 days. Pts can receive up to 4 cycles of consolidation therapy in the absence of toxicity.
The primary objective of the trial is to evaluate the efficacy of CPX-351 as measured by overall response rate (ORR) by IWG 2006 criteria. Secondary objectives include: ,1) determine the time to response (TTR), 2) evaluate the duration of response (DOR), 3) evaluate the event-free survival and the overall survival probability during trial period. Pts are risk stratified into lower vs higher-risk prior to enrollment using the Post-HMA model (Nazha A, et al. Hematologica 2016). Eligibility includes: pts >18 years with primary or secondary resistance to HMA, ECOG performance status < 2 and adequate organ function. Pts are excluded if they have uncontrolled infection or active malignancy. A total of 18 pts will be enrolled to each arm (lower and higher risk).
To date, three pts were enrolled. One with MDS refractory to HMA who achieved complete remission and proceeded with 4 cycles of consolidation. The pt remained in remission 6+ months after the completion of consolidation. Another patient achieved a marrow CR but had a fungal pneumonia and then was taken off the trial (patient choice for going to hospice). The third patient had MDS/MPN, completed induction and achieved stable disease with improvement in platelets and neutrophils. All patients were lower-risk per the stratification model. No unexpected toxicity was observed.
In conclusion, preliminarily CPX-351 is effective in MDS patients after HMA failure who are eligible to receive intensive chemotherapy. The treatment was well tolerated and toxicities were similar to what was observed in pivotal CPX-351 trials. The trial is ongoing and the results will be updated in the meeting.
Disclosures
Nazha: MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Jazz: Research Funding. Mukherjee:Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Carraway:Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC). Gerds:AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Apexx Oncology: Consultancy; Pfizer: Research Funding. Patel:Alexion: Other: educational speaker. Sekeres:Takeda/Millenium: Consultancy; Pfizer: Consultancy; BMS: Consultancy.
OffLabel Disclosure:
CPX-351 in MD
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Determinants of "Fitness" for Intensive Therapy Among Acute Myeloid Leukemia (AML) Patients
Background: Determining which AML patients (pts) are "fit" for intensive chemotherapy (IC), both in real-world scenarios and for clinical trial eligibility (particularly as it relates to regulatory indications) is challenging. While age, AML etiology, and cardiac function have been invoked, these oversimplify the clinical assessment and recommendation for IC vs. Non-IC (NIC). We compared baseline characteristics among pts receiving IC and NIC, and evaluated associations between treatment receipt and pt characteristics. Adjusting for treatment received, pts' attributes were further evaluated for association with overall survival (OS).
Methods: Adult (≥18 years) AML pts who received IC or NIC at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic and renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariate logistic and Cox regression were used to identify significant prognostic factors for treatment receipt and OS, respectively. The Kaplan-Meier method estimated distributions of OS, which were compared among pt cohorts using the log-rank test. Classification and regression tree (CART) analysis was performed to characterize the best decision process used to select pts for NIC.
Results: Of 1,082 AML pts analyzed, 901 (83.2%) were treated with intensive, cytarabine-based chemotherapy, and 181 (16.8%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. As expected, baseline characteristics were significantly imbalanced between groups; pts receiving NIC were more likely to be older (P<.001), have ≥3 comorbidities (P<.001), another cancer (P=.02), myocardial (P<.001), renal (P=.006) conditions, abnormal renal (creatinine (P=.004), creatinine clearance by Cockcroft-Gault (CrCl, P<.001)), and abnormal liver function (bilirubin (P=.03)). And less likely to have de novo disease (P<.001), favorable ELN risk (P=.008), private insurance (P<.001), and mild cardiac abnormalities (QTc 450-480ms (P<.001), LVEF 50-40% (P<.001)) (Tables 1 & 2).
Multivariable stepwise regression revealed independent associations with the following attributes (favoring NIC over IC): older age (OR=1.10, P1.5xULN vs. normal; OR=3.04, P=.02), renal (CrCl <60 ml/min vs. normal; OR=3.17, P=.002), myocardial conditions (atrial fibrillation/congestive heart failure/coronary artery disease vs. normal); OR=2.33, P=.001) and mild cardiac abnormalities (QTc 450-480ms vs. normal: OR=0.46, P=.01; LVEF 50-40% vs. normal: OR=0.33, P=.03). Clinically, in making decisions about NIC, the first step is age, followed by comorbidity. CART analyses revealed that when a comorbidity is identified, age is then re-assessed; depending upon the type of comorbidity present, various age thresholds determined NIC vs. IC.
With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). OS was significantly different between groups (median OS, NIC vs. IC: 4.9 vs. 20.4 months, P1.5xULN: HR=1.70, P=.01), renal (creatinine >1.5xULN: HR=1.55, P=.001; CrCl480-500ms: HR=1.36, P=.04; LVEF 50-40%: HR=1.38, P=.04) were, however, associated with worse survival.
Conclusions: Age, comorbidities, and organ dysfunction are associated with AML treatment determination. Pts who presented with cancer/renal/myocardial comorbidities and renal/liver dysfunction were more likely to receive NIC, despite the comorbid conditions not having an impact on OS. Further research needs to elucidate the extent to which NIC is the optimal treatment decision for pts exhibiting varying severities of cancer/renal/myocardial comorbidities.
Disclosures
Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:McGraw Hill Hematology Oncology Board Review: Other: Editor; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Advani:Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Gerds:Sierra Oncology: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Abbvie: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees
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Hospital readmission rate for febrile neutropenia (FN) following high dose cytarabine (HiDAC) consolidation chemotherapy for acute myeloid leukemia (AML)
e18513
Background: FN is an anticipated complication of consolidation with HiDAC for AML, though precise descriptions of incidence, type, and severity of infection leading to FN are lacking. Since AML patients (pts) with FN after HiDAC are routinely readmitted to the hospital, there is a likely impact on measures of quality and value in this population. Methods: Our primary aim was to define the rate of FN inpatient readmissions among all HiDAC cycles. Secondary aims included: estimating rates of all-cause readmissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, and identify pts-specific risk factors associated with readmission. Readmission per patient were modeled using Poisson regression, with means proportional to total cycles exposed, and logistic regression for the probability of FN per treatment cycle. Results: We identified 150 AML pts ≥ 18 years of age, who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2016. The median age was 50 (range 19-69); 55% were female and 45% were male. For 417 HiDAC cycles analyzed (87% at 3000 mg/m2), all pts received flouroquinalone prophylaxis and the overall readmission rate was 49% (203/417), of which 86% (174/203) were for FN. Median time to FN hospital admission was 18 days (range 10-22) from the start of HiDAC. Of the 174 FN readmissions, 60% had documented infections. Of these infections, 35% were bacteremia, 29% other bacterial, 24% fungal, 6% sepsis, and 6% viral. Females had higher FN readmission rates (RR 1.7 (1.3, 2.4) p = 0.007), as did pts with higher BMI (RR 1.06 (1.01, 1.09) p = 0.005), while age and HiDAC dose were not associated with readmission. Only 34% of all readmissions were in the absence of a documented infection. Conclusions: The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable. Females and pts with higher BMI were more likely to be readmitted. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality
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The Impact of Comorbidities and Organ Dysfunction Commonly Used for Clinical Trial Eligibility Criteria on Outcome in Acute Myeloid Leukemia (AML) Patients Receiving Induction Chemotherapy
Background: Clinical trial recruitment is hindered by patient (pt), provider, and organizational barriers. The prohibitory impact of specific comorbidity/organ function criteria, however, has not been studied in the AML pt population. While intended to protect pts, trial eligibility criteria, when excessive, exclude pts irrespective of expected toxicities (Statler et al. Leukemia 2017). Yet, research demonstrates adverse events and outcomes are similar among eligible and ineligible AML pts (Statler et al. Blood 2018). We characterized the multi-morbidity prolife of AML pts prior to induction chemotherapy and compared outcomes among those with and without baseline comorbidities/organ dysfunction that have been used in clinical trial eligibility criteria.
Methods: Adult (≥18 years) AML pts who received chemotherapy at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic/renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Univariate associations between dose modifications and pt characteristics were tested using logistic regression. Cox proportional hazards and logistic regression were used to identify significant prognostic factors for overall survival (OS) and complete remission (CR) status per International Working Group criteria. Kaplan-Meier method was used to estimate median OS.
Results: Of 1,082 AML pts analyzed, the median age was 60.6 years (IQR: 50.2, 69.1), 53.1% (n=574) were male, 86.8% (n=939) were white, and 45.7% (n=494) had Medicare insurance. A majority (n=680, [62.9%]) had de novo AML, and 55.3% (n=598) had intermediate-risk disease. Pts were treated with: intensive cytarabine-based (n=901 [83.3%]), or non-intensive (low-dose cytarabine or hypomethylating agents (n=181 [16.7%]). Of those with comorbidities, the most common were vascular (n=540 [49.9%]), endocrine (n=272 [25.1%]), and neurological (n=220, [20.3%]) (Tables 1 and 2).
With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). In multivariate analyses controlling for treatment, age, sex, insurance, number of comorbidities, AML etiology, and ELN risk, the only comorbidity associated with OS was liver disease (HR=1.90, P=.004). However, baseline AST (3xULN vs. normal: HR=1.02, P=.94; >3-5x ULN vs. normal: HR=1.42, P=.30.), ALT (3xULN vs. normal: HR=0.76, p=0.45, >3-5xULN vs. normal: HR=1.58, P=.23) and bilirubin (1.5xULN vs. normal: HR=1.34, P=.08) were not associated with a worse OS. Minor renal dysfunction was also not associated with OS, when measured by creatinine (1.5xULN vs. normal: HR=1.06, P=.52) or creatinine clearance by Cockcroft-Gault (CrCl 84-60 ml/min: HR=0.95, P=.62). Baseline LVEF abnormalities, though, were associated with increased mortality, and as severity increased the effect size increased in a dose-response fashion (50-40%: HR=1.38, P=.04; 480ms: HR=1.36, P=.04; ≥501: HR=1.72, 95%, P=.001).
With the exception of liver comorbidities (OR=0.26, P=.03), our analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction. Comorbidities and liver function abnormalities were also not associated with dose modifications during AML treatment, while pts with clinically significant renal (CrCl ≤ 30 ml/min) and/or cardiac (LVEF ≤50%) abnormalities at baseline did have a higher odds of a dose reduction in univariate analysis.
Conclusions: The majority of AML pts within this cohort (n=953 [88.1%]) presented with at least 1 comorbidity and/or 1 clinically insignificant liver or renal abnormality that could have excluded them from clinical trials. Yet, survival, response, and dose modification outcomes did not significantly differ between pts with and without comorbid conditions or minor liver/renal abnormalities. These results suggest future AML trials may liberalize comorbidity and organ function eligibility criteria, which will likely improve recruitment rates and provide equitable access to investigational products.
Disclosures
Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene Corporation: Consultancy, Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees
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A Phase I/II Trial of CPX-351 + Palbociclib in Patients with Acute Myeloid Leukemia
Background
Cytarabine resistance is a major reason for compromised treatment efficacy in acute myeloid leukemia (AML). This may be due to leukemic cells being at different stages in their cell cycle, with some at G0/G1, others in M phase, and only a limited number of cells in the S phase necessary for cytarabine susceptibility. Palbociclib, is a selective CKD4/6 inhibitor that arrests cancer cells in the G0/G1 stage. Preclinical studies have shown that the administration of palbociclib to AML cells in vitro for 48 hours can arrest 91% of the cells in the G0/G1 phase. When these cells proceed to S phase after the cessation of palbociclib, cytarabine-based (S phase dependent) chemotherapy has 30-50% enhanced cytotoxic activity.
We hypothesize that the sequential administration of palbociclib and CPX-351 can enhance its efficacy without added toxicity.
Methods
This is a phase 1 (dose escalation of palbociclib) /II single arm trial of the sequential administration of palbociclib and CPX-351. The trial consists of two components: a phase I, 3+3 design to evaluate the safety with dose escalation of palbociclib in combination with CPX-351 (for patients [pts] with relapsed/primary refractory [R/R] AML, or higher risk newly diagnosed AML); and a phase II to evaluate the overall response rate (ORR) of the combination in newly diagnosed AML pts. Palbociclib was given at dose level 1 (75 mg po) (Figure 1) on day -1 and -2, day 0 rest, followed by CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) on day 1, 3, and 5 along with palbociclib on day 2, 4, and 6 followed by a rest/monitoring period (days 7-35). Patients received 1-2 induction courses of the combination of palbociclib and CPX-351. Inclusion criteria: age 18-65, ECOG performance status (< 2), and adequate organ function. Pts with active infections or malignancies that prevented them from enrollment or with cardiac ejection fractions <45 were excluded. The primary endpoint for phase I was to evaluate the safety of the combination and for phase II to evaluate ORR defined by 2003 IWG criteria.
Results:
In this pre-specified analysis, 9 pts competed phase I (3 received palbociclib at 75 mg, 3-100 mg, and 3- 125 mg). The median age was 48 (range, 30-69), 44% females, and median WBC was 3.5 (range, 0.27-39.7). Cytogenetic analysis included: 2 pts with normal karyotype, 4 pts with complex karyotype, 1 pt with inversion 3, 1 pt with Trisomy 8, and 1 pt (no growth). Four pts had TP53 mutations. There were no reported deaths during induction. Common adverse events were similar to those was observed in pivotal CPX-351 trials. Common grade 3 / 4 side effects possibly related to therapy included: febrile neutropenia in 6 pts, elevated bilirubin in 1 pt, epistaxis in 1 pt, electrolyte abnormalities in 1 pt, and atrial fibrillation in 1 pt. All toxicities resolved during the study period. One pt also experienced grade 2 pericarditis/pericardial effusion (possibly related), which resolved. The ORR among the 8 evaluable pts (1 pt had persistent disease at day 14 and refused to receive re-induction and was taken off the study) was 75%: 5 pts (63%) achieved a CR and 1 pt (12%) had a morphological leukemia-free state.
A total 5 pts enrolled in the phase II trial. Three are evaluable for response, 1 withdrew from the study during induction therapy (pt choice), and one is still receiving therapy. Among the three evaluable pts one (unfavorable cytogenetics with a TP53 mutation) achieved CR, one (unfavorable cytogenetics achieved) CRp, and one (unfavorable cytogenetics) achieved CRi. No induction mortality has occurred to date. The phase II portion of the study is still ongoing.
Conclusions
The sequential combination of palbociclib and CPX-351 is highly effective in pts with R/R and newly diagnosed AML enrolled to this trial. The combination was well tolerated and no added toxicity was observed from palbociclib. The trial is ongoing and an updated enrollment of phase II pts will be presented at the meeting.
Figure
Disclosures
Nazha: MEI: Other: Data monitoring Committee; Jazz: Research Funding; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Mukherjee:Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy. Carraway:BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; ASTEX: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau. Gerds:Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding. Patel:Alexion: Other: educational speaker. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy.
OffLabel Disclosure:
Palbociclib in AML CPX-351 in newly diagnosed AM
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Comparison of Very Low-Dose Decitabine to Standard-Dose Hypomethylating Agents in Myelodysplastic Syndromes (MDS)
Abstract
Background: Aberrant epigenetic modifications, fundamental to the pathogenesis of MDS, provide rationale for the use of the so-called hypomethylating agents, decitabine (DAC) and azacitidine (AZA). As depletion of DNA methyltransferase 1 (DNMT1) by these agents is S-phase dependent, episodic dosing used in common practice (SD-DAC; 20 mg/m2 x 5 days, every 28 days, SD-AZA; 75 mg/m2 x 5-7 days, every 28 days) affects only a fraction of the malignant clones. Alternative dosing schedules of decitabine with lower doses given more frequently (LD-DAC; .1-.2 mg/kg SC once/twice weekly) may decrease toxicity and increase response rates by improved hematopoietic differentiation and DNMT1 depletion while avoiding cytotoxicity. Data comparing use of very low and standard-dose DAC or AZA are lacking.
Methods: We compared response, survival, and toxicities of 242 MDS patients (pts) treated at our institution from 9/06-10/13 with LD-DAC (n=39), SD-DAC (n=17), or SD-AZA (n=186). Response was assessed per International Working Group 2006 (IWG) criteria, progression-free (PFS) from date of response, and overall survival (OS) from diagnosis.
Results: There were no significant differences in baseline characteristics, including median age (70 vs. 74 years, P=.93), proportion of patients with ≥5% bone marrow blasts (27% vs. 35%, P=.54), high/very high cytogenetic risk by the Revised International Prognostic Scoring System (IPSS-R, 25% vs. 40%, P=.31), number of pts with comorbidities (44% vs. 29%, P=.38), median time from diagnosis to treatment (14.6 vs. 6.4 months, P=.25) or prior MDS treatment (AZA and/or lenalidomide, 46% vs. 53%, P=.17), between the LD-DAC and SD-DAC groups, respectively. Likewise, the LA-DAC and SD-AZA groups were similar with respect to median age (70 vs. 68 years, P=.15), proportion of patients with ≥5% bone marrow blasts (27% vs. 39%, P=.19), and high/very high cytogenetic risk by the IPSS-R (25% vs. 27%, P=.83). However, pts in the SD-AZA group had a shorter median time from diagnosis to treatment (2.9 vs. 14.6 months, P=.009) compared to LD-DAC.
Median treatment duration was longer in LD-DAC pts compared to SD-DAC (9.1 vs. 3.1 months, P=.0008) with a median cumulative dose of 8.4 mg/kg (range 1.2-41.2) and 350 mg/m2 (range 175-975) for LD-DAC and SD-DAC, respectively. Compared to SD-DAC, the LD-DAC group required more frequent dose reductions/delays (67% vs. 20%, P=.004) and experienced more hematologic toxicity (85% vs. 29%, P< .0001), respectively.
While median time to best response was similar for LD-DAC and SD-DAC (3 vs. 4.1 months, P=.52) there was a trend for higher IWG response rates (30% vs. 18%, P=.06) and lower disease progression rates (18% vs. 41%, P=.06) for LD-DAC compared to SD-DAC. However, this did not translate into a difference in median PFS (11 vs. 7.6 months, P= .34) or OS (23.9 vs. 18.2 months, P=.64, Figure 1). Comparing these results to SD-AZA, while LD-DAC had a longer median treatment duration (9.1 vs. 5.1 months, P=.052) and shorter median time to best response (3 vs. 5.3 months, P=.005) than SD-AZA, response rates were similar (30% vs. 31%, P=.5) and there were no significant differences with respect to median PFS (11 vs. 7.1 months, P=.059) or OS (23.9 vs. 21.1 months, P=.5, Figure 1).
Conclusion: Pts treated with the LD-DAC strategy have a response rate at least equivalent to SD-DAC and SD-AZA, though they required more dose adjustments and receive treatment for a longer time period. Survival was similar for all dosing strategies. Very low-dose DAC is an active treatment approach and will be compared to standard-dose DAC and AZA in an upcoming randomized, prospective trial conducted through the MDS Clinical Research Consortium.
Figure 1 Figure 1.
Disclosures
Off Label Use: Subcutaneous administration of very low-dose decitabine in treatment of MDS
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Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies
Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission.
Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy.
Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death.
Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality.
Disclosures
Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees