bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistent high-risk opioid use in lymphoma survivors following treatment.
Authors: Stafford Katherine Ann , Kumar Anita J. , Pate Virginia , Loren Alison W. , Kinlaw Alan 
Published: June 2022

6585 Background: Opioid analgesia has an important role in treating cancer pain but can place survivors at risk for long-term adverse effects, including misuse, abuse, and overdose. While opioid use has been studied in surgical oncology patients, little is known about long-term use and outcomes for patients with hematologic malignancies who primarily receive non-surgical treatment. We evaluated the association between opioid use during lymphoma treatment and persistent high-risk opioid use. Methods: We conducted a retrospective cohort study using IBM Watson Health MarketScan Commercial Claims and Encounters Data from 2000-2019, containing claims for employer-sponsored privately insured individuals in the US. We identified opioid-naïve adults age 18-64 years at their first diagnosis of Hodgkin (HL) or Non-Hodgkin lymphoma (NHL) who had outpatient cancer therapy lasting 90-240 days (including ≥3 episodes of outpatient chemotherapy). Using outpatient pharmacy claims, we categorized each patient’s opioid exposure during cancer treatment to no exposure, moderate [1-7 days supply], or high [ > 7 days supply]. Follow-up began 60 days after patients’ final cancer treatment and continued up to 365 days or until an outcome or censoring event. High-risk opioid use was defined as ≥120 days cumulative supply, ≥3 consecutive months of opioid prescriptions, or a prescription with ≥90 morphine milligram equivalents per day. We used time-to-event methods to estimate cumulative incidence and hazard ratios across exposure groups. Results: There were 4380 opioid-naïve lymphoma patients in the cohort. 42.5% had HL and 57.5% had NHL. Median age at diagnosis was 46 years (IQR 32-56) and median treatment duration was 147 days (IQR 112-166). 55.0% of patients were male. During cancer treatment, 42.8% of patients had no opioid exposure, 28.1% had moderate, and 29.1% had high. Among the no-opioid-exposure group, the 1-year cumulative incidence of high-risk opioid use was 1.7%. Compared to this no-exposure group, the hazard ratios for moderate and high exposure were 2.6 (95% CI 1.5-4.6) and 9.0 (95% CI 5.6-14.4), respectively, after adjustment for cancer treatment duration, age, cancer type, and calendar time. A sensitivity analysis comparing patients diagnosed 2000-2009 vs. 2010-2019 found that hazard ratios remained consistent between the two time periods; however, there was a decrease in the absolute incidence of high-risk opioid use by approximately half. Conclusions: In this cohort study of opioid-naïve lymphoma patients, higher opioid exposure during cancer treatment was associated with a higher likelihood for persistent high-risk opioid use in the year following cancer treatment. The absolute incidence of high-risk opioid use decreased over time and may be due to increased awareness of the opioid epidemic. Close clinical follow-up in the post-treatment period may be warranted for patients at high risk of adverse outcomes.
Time at home among older adults with acute myeloid leukemia based on treatment intensity: A SEER-Medicare analysis.
Authors: Richardson Daniel R. , Zhou Xi , Jensen Christopher Edward , Reeder-Hayes Katherine Elizabeth , Lund Jennifer Leigh , Baggett Christopher 
Published: June 2022

6586 Background: Older adults with acute myeloid leukemia (AML) have identified time at home (TAH) as a critical outcome when deciding on treatment. No study to date has fully explored TAH for older adults with AML. Methods: We identified a cohort of adults age ≥66 years with a new diagnosis of AML from the SEER-Medicare linked database from 2004-2016. Individuals were stratified into high-intensity chemotherapy [HIC] v. hypomethylating agent [HMA] v. other using claims. The primary outcome was TAH, quantified by subtracting the total number of person-days spent in hospitals and skilled nursing facilities from the number of person-days survived. Demographics, comorbidities, frailty, and transfusion dependence were considered covariates. Results: 7,946 adults were included. 2,824 (36%) received HIC, 2,542 (32%) HMA, and 2,580 (33%) other. Mean age was 75 years (HIC: 73; HMA: 78; other: 76). The cohort was predominantly White (88%, Black 5%; Asian 3%; Hispanic 1%) and male (57%). Median survival was 7 months (HIC: 9; HMA: 8). Median total TAH was 151 days (Mean 426, Range 0-1825). Adults receiving HIC spent less time at home and more time hospitalized than those receiving HMAs each month in the first year (Table). Differences in TAH between HIC and HMA cohorts were most pronounced in the first 3 months (1st: 49.5% v. 86.5%; 2nd: 68.2% v. 84.1%; 3rd: 77.3% v. 86.8%). Total TAH over 12 months was lower for those receiving HIC v. HMA (51.7% [187 days] v. 56.9% [205 days]). Transfusion dependence (≥ 1/month) was associated with decreased TAH at 1 month (OR 0.81, p<0.001) and 12 months (OR 0.90, p=0.04). Other covariates were not associated with TAH. Conclusions: Although intensive chemotherapy resulted in slightly longer survival, older adults treated with HMAs had more time at home. Treatment decision-making should incorporate patient preferences for prolonging survival v. increasing time at home. The effect of new treatments (eg, venetoclax) on time at home should be evaluated in future studies. [Table: see text]
Challenges and outcomes of treating acute myeloid leukemia (AML) in resource-constrained settings.
Authors: Dangudubiyyam Sri Krishna Sahitya Srikrishna , Dhawan Rishi , Swaminathan Anusha , Stitha Pragna , Naik Ramavath Devendra , Aggarwal Mukul , Kumar Pradeep , Dass Jasmita , Viswanathan Ganesh , Tyagi Seema , Seth Tulika , Mahapatra Manoranjan 
Published: June 2022

7014 Background: Acute myeloid leukemia (AML) is a heterogeneous disease. Improvement in supportive care, has considerably improved AML induction outcomes, decreasing induction deaths to <5% in recent studies. However, induction deaths during AML treatment in resource constraint settings remains as high as 25% in young adults. In this study we explore various challenges encountered in treating AML patients in one of the largest public sector teaching hospitals in India. Methods: Consecutive patients diagnosed with AML and registered in our clinic from January 1, 2018 to December 31, 2019, were included. Results: Of 316 patients diagnosed with AML, only 181 (57%) were able to get admitted to our institute for remission induction treatment. Median time from diagnosis to treatment initiation was 9.5 days (range, 0-232 days). Almost half (N=88; 49%) of admitted patients had infections at the time of admission. Among these, 31 (35%) had invasive fungal infection; 14 possible, 15 probable, and 2 proven. Fifty-two (29%) patients died prior to starting their remission induction therapy. Induction mortality in our cohort is 40%. Primary induction failure and primary refractory disease were noted in twenty (18%), and 5 (4%) patients respectively. Only 1 patient was able to get all three high dose cytarabine (HIDAC) consolidations on time. Median time to first HIDAC was 39.5 days (range, 28-91). Of 83 patients who were candidates for consolidative allogeneic hematopoietic cell transplantation (HCT), only ten (12%) patients were able to get transplanted. Median time to HCT from CR1 was 3.8 months (range, 1.89-12.8). The median event free survival (EFS) was 1.7 months (95%CI, 1.03-2.5) and median overall survival was 2.5 months (95%CI, 1.6-3.6). The median EFS in favourable risk, intermediate risk and adverse risk AML was 3.6 months, 3.7 months, and 3.4 months respectively. Likewise the median OS was 8.8 months, 11.8 months and 7.4 months in the three risk strata respectively. Conclusions: Outcomes of AML treatment in our cohort are discordant with that reported from the West. Our study identifies various challenges in treating AML in resource-constraint setting. Strategies need to be formulated to overcome these challenges. [Table: see text]
Navitoclax plus ruxolitinib in JAK inhibitor-naive patients with myelofibrosis: Preliminary safety and efficacy in a multicenter, open-label phase 2 study.
Authors: Passamonti Francesco , Foran James M. , Tandra Anand , De Stefano Valerio , Fox Maria Laura , Mattour Ahmad Hatem , McMullin Mary Frances , Perkins Andrew , Rodriguez-Macias Gabriela , Sibai Hassan , Qin Qin Q. , Potluri Jalaja , How Jonathan B. 
Published: June 2022

7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-XL and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 109/L or >150 × 109/L, respectively. RUX was given BID with starting dose based on BL platelet count per local label. The primary endpoint was spleen volume reduction of ≥35% (SVR35) from BL at wk 24. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), bone marrow (BM) fibrosis reduction, and anemia response. Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 pts received NAV+RUX. Median duration of f/u was 6.1 (range, 1.9 ─ 18.6) mos. 28 (88%) pts received NAV 200 mg and 4 (13%) received 100 mg OD. Median age was 69 (44 ─ 83) yrs, and median spleen volume was 1889.08 cm3 (645.6 ─ 7339.6). Median NAV and RUX exposures were 24.1 (5.1 ─ 80.9) and 20.1 (0.1 ─ 80.1) wks, respectively. 31 (97%) pts reported ≥1 AE (Grade ≥3 AEs, 25 [78%]; serious AEs, 6 [19%]). Most common Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). 3 (9%) and 2 (6%) pts reported an AE leading to NAV and RUX discontinuation, respectively, and 2 (6%; 1 PD, 1 cardiac disorder unrelated to NAV) AEs led to death ≤30 days after last NAV dose. SVR35 was achieved by 52% of evaluable pts at wk 24 (SVR35 in INT-2, 50%; HR, 33%) and by 76% at any time on treatment (Table). Median time to first SVR35 was 12.1 (11 ─ 47) wks. Conclusions: The combination of NAV+RUX was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in pts without prior JAK-2 inhibitor exposure. SVR35, TSS50, and BM fibrosis improved over time. Clinical trial information: NCT03222609. [Table: see text]
Magrolimab in combination with azacitidine for untreated higher-risk myelodysplastic syndromes (HR-MDS): 5F9005 phase 1b study results.
Authors: Sallman David Andrew , Al Malki Monzr M. , Asch Adam Steven , Wang Eunice S. , Jurcic Joseph G. , Bradley Terrence J. , Flinn Ian W. , Pollyea Daniel Aaron , Kambhampati Suman , Tanaka Tiffany N. , Zeidner Joshua F. , Garcia-Manero Guillermo , Jeyakumar Deepa , Gu Lin , Tan Anderson , Chao Mark , O'Hear Carol Elaine , Lal Indu , Vyas Paresh , Daver Naval Guastad 
Published: June 2022

7017 Background: Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal overexpressed on cancer cells. CD47 blockade by magrolimab induces macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine (AZA) via upregulation of “eat me” signals. Here we report final Phase 1b data in patients (pts) with untreated HR-MDS (NCT03248479). Methods: Pts with previously untreated intermediate-/high-/very high-risk MDS per IPSS-R received magrolimab IV as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg weekly or Q2W maintenance dose. AZA 75 mg/m2 was administered IV or SC on Days 1–7 of each 28-day cycle. Primary endpoints were safety/tolerability and complete remission (CR) rate. Results: 95 pts (median age 69 years [range 28, 91]) were treated. IPSS-R risk was intermediate, high, or very high in 27%, 52%, and 21%, respectively. MDS was therapy-related in 22%; 26% (n=25) had a TP53 mutation and 62% had poor-risk cytogenetics (27% complex). Median (range) number of cycles was 6 (1, 27). The most common TEAEs included constipation (68%), thrombocytopenia (55%), anemia (52%), neutropenia (47%), nausea (46%), and diarrhea (44%). The most common Grade 3/4 TEAEs included anemia (47%), neutropenia (46%), thrombocytopenia (46%), and WBC count decreased (30%). 6 pts discontinued treatment due to AEs. 60-day mortality was 2%. Median Hb change from baseline (BL) at first post-dose sample was –0.7 g/dL (range –3.1, +2.4). CR and objective response (OR) rates were 33% and 75% with 31% of evaluable OR pts with abnormal cytogenetics at BL having cytogenetic CR. Median time to first OR, duration of CR (DCR), duration of OR, and PFS were 1.9, 11.1, 9.8, and 11.6 mos. OS rates at 12 and 24 mos were 75% and 52%, respectively (median NR with 17.1 mos follow-up for OS). For patients evaluated with sequential WES with a VAF cutoff of 5%, 3 of 3 pts with TP53 mutation who achieved CR had TP53 VAF <5% by C5D1. Favorable outcomes were observed in both TP53 mutant (40% CR, median OS 16.3 months) and wildtype pts (31% CR, median OS NR; Table). Conclusions: Magrolimab+AZA was well tolerated with promising efficacy in pts with untreated HR-MDS including those with TP53-mut and TP53-wt disease. A Phase 3 trial of magrolimab/placebo+AZA (ENHANCE: NCT04313881) is ongoing. Clinical trial information: NCT03248479. [Table: see text]
Acute myeloid leukemia with KMT2Ar and association with risk of bleeding and early mortality.
Authors: Nguyen Daniel , Ning Jing , Qiao Wei , Sasaki Koji , Kantarjian Hagop M. , Short Nicholas James , Cuglievan Branko , Daver Naval Guastad , Dinardo Courtney Denton , Jabbour Elias , Kadia Tapan M. , Borthakur Gautam , Garcia-Manero Guillermo , Konopleva Marina , Andreeff Michael , Ravandi Farhad , Issa Ghayas C. 
Published: June 2022

7026 Background: Acute myeloid leukemia (AML) with rearrangement of KMT2A is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well-defined in this entity. Methods: In a retrospective analysis, we compared causes and rates of early mortality following induction treatment between a cohort of adults with KMT2Ar AML (N=172) and an age-matched cohort of patients (pts) with normal karyotype (NK) AML (N=522). Results: The 30 and 60-day (60d) mortality in pts with KMT2Ar AML were significantly higher compared to those with NK AML, with rates of 10% (17/172 pts) and 15% (26/172 pts) in KMT2Ar AML vs 4% (20/522 pts) and 7% (38/522 pts) in NK AML, respectively ( P=0.004). Among those who died within 60d, the most common contributing cause in KMT2Ar was respiratory failure without a clear infectious etiology in 38% (10/26 pts) vs 11% (4/38 pts) in NK AML ( P=0.01). We found 42% (11/26 pts) with KMT2Ar AML who died within 60d were either diagnosed with or had high clinical suspicion for diffuse alveolar hemorrhage (DAH) that warranted empiric therapy vs 18% (7/38 pts) with NK AML ( P=0.05). Given the high occurrence of DAH in KMT2Ar AML, we set out to quantify bleeding events and recorded major and minor bleeds as defined by the International Society of Thrombosis and Haemostasis. We found 65% (17/26 pts) with KMT2Ar AML had at least one bleeding event vs 32% (12/38 pts) with NK AML ( P=0.01). There was a significantly higher frequent occurrence of major bleeds (rate ratio=6.22; P=0.005) and total bleeding events (rate ratio=4.5; P=0.001) in KMT2Ar AML vs NK AML. KMT2Ar was associated with disseminated intravascular coagulopathy (DIC), as 93% of evaluable pts (14/15 pts) vs 54% (7/13 pts) in NK AML had overt DIC before death. Longitudinal trajectories of DIC parameters of pts who died within 60d showed significantly higher prothrombin time levels ( P=0.008) in KMT2Ar. In a multivariate analysis, KMT2Ar and a monocytic phenotypic were the only independent predictors of any bleeding event in pts who died within 60d (OR 3.5, 95% CI 1.4-10.4, P=0.03; OR 3.2, 95% CI 1.1-9.4, P=0.04). Conclusions: KMT2Ar AML is associated with higher early mortality and an increased risk of bleeding and coagulopathy compared with NK AML. Early recognition and aggressive management of DIC and coagulopathy are important considerations that could mitigate the risk of death during induction treatment.[Table: see text]
Targeting signaling pathways vulnerabilities for the treatment of IKZF1-deleted ph-negative B lymphoblastic leukemia.
Authors: Gupta Rohit , Rogers Jason H. , Long Xin , Aguilar Rogelio , Medrano Geraldo , Reyes Jaime , Redell Michele , Goodell Margaret A. , Rau Rachel E. 
Published: June 2022

7033 Background: Approximately 20% of children diagnosed with B lymphoblastic leukemia (B-ALL) will suffer a relapse, and most adults with B-ALL have a poor prognosis. Genome-wide association studies of B-ALL patients have identified frequent deletions of the gene IKZF1, encoding the master regulator of lymphoid development, IKAROS. These deletions are associated with therapy resistance, increased risk of relapse, and inferior survival. Currently, how loss of IKAROS function contributes to therapy resistance and increased risk of relapse is not fully understood. We used CRISPR-Cas9 genome editing to develop human B-ALL cell lines with various IKZF1 deletions that genetically and phenotypically recapitulate those occurring in patients. Using these isogenic cell lines, we have previously shown IKZF1 deletion results in cell-intrinsic chemoresistance and increased activation of the JAK/STAT signaling pathway (Rogers, Gupta et al. 2021). Methods: Given JAK/STAT is often dysregulated in poor-prognosis leukemia, we investigated the potential mechanisms of aberrant JAK/STAT activation and the therapeutic potential of targeting JAK/STAT in our engineered cell lines. We treated our cells with SH-4-54 (STAT3/5 inhibitor) or tofacitinib (JAK1 inhibitor) alone and in combination with dexamethasone. To elucidate how loss of IKAROS mediates an increase in JAK-STAT activity, we also performed RNAseq of known pathway regulators, comparing IKZF1 wild-type with IKZF1 knockout. Results: The JAK/STAT negative regulator Suppressor of Cytokine Signaling 2 (SOCS2) was significantly downregulated with IKZF1 deletion, validated by RTqPCR and immunoblotting. We further analyzed publicly-available RNAseq data from > 650 pediatric B-ALL samples, finding that SOCS2 expression is significantly lower in patients with low IKZF1expression (likely corresponding to IKZF1 deletion) compared to those with high IKZF1 expression. When we treated our engineered cell lines with tofacitinib or SH-4-54, IKZF1 wild-type cells were sensitive to each compound, suggesting JAK/STAT signaling plays a vital role in cell survival. In contrast, the IKZF1-deleted cells were relatively resistant to JAK/STAT inhibitors alone. However, in combination with dexamethasone, treatment of cells with sub-IC50 levels of SH-4-54 or tofacitinib resulted in re-sensitization to glucocorticoid-induced apoptosis. Conclusions: Our findings support that IKZF1 deletion leads to a targetable upregulation of the JAK/STAT pathway that, when inhibited, results in relative re-sensitization to dexamethasone. JAK/STAT pathway upregulation in IKZF1 deleted cells may be mediated by decreased expression of SOCS2. These results provide initial promise for targeting these vulnerabilities for the treatment of this poor-prognosis disease.
Long-term outcomes of newly diagnosed CRLF2 rearranged B-cell ALL.
Authors: Senapati Jayastu , Jabbour Elias , Short Nicholas James , Ravandi Farhad , Kebriaei Partow , Kadia Tapan M. , Borthakur Gautam , Pemmaraju Naveen , Garris Rebecca , Bansal Divyam , Konoplev Sergej , Wang Sa A , Wang Wei , Tang Guilin , Patel Keyur P. , Konopleva Marina , Jain Nitin 
Published: June 2022

7040 Background: CRLF2 rearranged B-ALL, a subtype of Ph-like ALL, constitutes a high-risk subset of B-ALL with poor outcomes with chemotherapy. Targeted therapies such as blinatumomab (blina) or inotuzumab (ino) may improve treatment outcomes for these patients (pts). Methods: We retrospectively analyzed pts with newly diagnosed B-ALL (diagnosed between 01/2001 and 12/2021) at our center who had documented CRLF2 overexpression. Initial therapy, including use of ino and blina in CR1 were noted. Outcomes measures included CR/CRi, MRD response, RFS and OS. Results: A total of 76 pts with a median age of 38 years (yrs) (range, 18-80) were identified, of which 70% were males and 81% were of Hispanic ethnicity. All pts had overexpression of CRLF2 documented by flow cytometry or gene expression profile. A subset of pts (n=37) had a concomitant CRLF2 FISH performed with all confirming CRLF2 rearrangement. Baseline disease parameters, treatment and outcomes are detailed in Table. Sixty-five pts (85%) received Hyper-CVAD based induction therapy (HCVAD, n=51; mini-HCVD, n=14) and 11 (15%) received augmented BFM. Among the HCVAD/mini-HCVD treated pts, 37% received blina in CR1 during consolidation at a median of 3.6 months after starting induction therapy, 34% received ino in CR1 (most commonly starting in cycle 1 as part of mini-HCVD + ino regimen) and 22% received both ino and blina in CR1. We focus on the outcomes of 65 pts treated with HCVAD/mini-HCVD. The median follow-up was 18 months (mos). CR/CRi rate after C1 among HCVAD/mini-HCVD treated pts was 52/65 (80%) with 25/47 (53%) MRD evaluable pts achieving MRD-neg post C1. The median RFS and OS was 17.6 and 26.6 mos, respectively. CR/CRp rate after C1 among pts who received mini-HCVD + ino in C1 was 100% (14/14) with 79% MRD-neg. On landmark analysis to the time to blina initiation, blina treated pts had similar RFS and trended for improved OS. A total of 19/65 (30%) had allo-SCT in CR1; all were MRD-neg prior to allo-SCT. Landmark analysis for OS based on time to allo-SCT (6 mos) favored SCT in CR1 (47.2 vs. 17.6 mos, p=0.04). Conclusions: Despite improvements in treatment options, CRLF2 overexpressed B-ALL continue to have inferior outcomes. Earlier initiation of targeted therapies might improve outcomes.[Table: see text]