19 research outputs found
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
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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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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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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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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