bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementation of a precision medicine thoracic (PREDICT) service using reflex testing in a large academic-community practice network.
Authors: Bruno Debora S. , Donner Andrea Lynn , Kopp Shelby Rose , Yoest Jennifer , Mneimneh Wadad , Margevicius Seunghee , Shanahan John , Fu Pingfu , Hsu Melinda Laine , Dowlati Afshin , Sadri Navid
Published: June 2022

6572

Background: Broad genomic testing is necessary for treatment of patients with stage IV non-small cell lung cancer (NSCLC). This quality improvement initiative aims to implement a precision medicine service for NSCLC patients at a hybrid academic-community practice oncology network. Methods: Following IRB approval, network tumor registries were queried for retrospective newly diagnosed stage IV NSCLC from 01/2016 through 12/2018. PREDICT was implemented in 08/2021. It consists of: 1) system-wide reflex testing of newly diagnosed stage IV NSCLC patients by an in-house solid tumor focused assay (hybrid DNA/RNA next-generation sequencing (NGS) panel previously reported) and PD-L1 testing, 2) PREDICT navigator, 3) molecular tumor board (MTB), 4) integrated information portal for real-time updates on samples processing, results and treatment recommendations by the MTB. We compared prospective data (08/2021 through 01/2022) after PREDICT with retrospective practice assessment. Comparisons between the groups were conducted using independent samples t-test / Wilcoxon rank sum test for continuous variables and Chi-square test/Fisher’s exact test for categorical variables. Results: Of 861 retrospective patients identified in the compiled registry of stage IV NSCLC, 626 were eligible. Since PREDICT launch in 08/2021, 103 eligible prospective patients have been identified. Prospective patients are slightly older (mean age 70.9 vs 68 years old; p = 0.013), with no other significant demographic or clinical differences identified. Rates of NGS testing obtained within 90 days of biopsy date (BxD) increased significantly (94.1% vs 60.8%; p < 0.0001) after PREDICT. Turnaround times (TAT) from BxD to test results were significantly shorter for both NGS (12 vs 18 days; p < 0.0001) and PD-L1 (7 vs 10 days; p = 0.007) after PREDICT. A trend towards higher rates of actionable alterations (EGFR, ALK, ROS1, RET, BRAF, MET14 skipping, NTRK1/2/3) was noted: 19.6% vs 13% (p = 0.071). Targeted therapy use increased from 6.8% to 15.6% (p = 0.002) in the overall cohort. No differences in time to treatment initiation (TTI) after PREDICT have been identified to this point, with a median of 34 and 35 days for the prospective and retrospective groups, respectively. Conclusions: Implementing a precision medicine service for thoracic oncology patients has led to significantly higher rates of NGS testing for patients with stage IV NSCLC in a large hybrid academic-community practice network. Launching of this initiative resulted in significantly shorter TAT for both NGS and PD-L1 test results. A trend towards higher rates of actionable alterations has been identified. Targeted therapy use has increased significantly overtime, potentially due to higher availability of precision medicine drugs in the current era.
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]
Efficacy and safety of venetoclax in combination with azacitidine or decitabine in an outpatient setting in patients with untreated acute myeloid leukemia.
Authors: Manda Sudhir , Anz Bertrand Marquess , Benton Christopher , Broun E. Randolph , Yimer Habte Aragaw , Melear Jason M. , Cruz Jose C. , Fanning Suzanne , Sharman Jeff Porter , Kang Kingston , Svensson Anders , Pai Madhavi , Geils George F. , Renshaw John Scott , Donnellan William Bruce
Published: June 2022

7044

Background: Venetoclax (Ven), a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine (Aza) or decitabine (Dec) is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients (pts) who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated Ven + HMA in an inpatient setting due to concerns of tumor lysis syndrome (TLS). This Phase 3b, single-arm, multicenter, open-label study (NCT03941964) evaluated the efficacy and safety of Ven + HMA in a US community-based outpatient setting. Methods: Pts with ND AML who were ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed an appropriate candidate for outpatient initiation of Ven + HMA by the investigator were eligible. Pts received Ven (400 mg) in combination with Aza (75 mg/m2) or Dec (20 mg/m2) for up to 6 cycles during the study period. Pts could continue receiving commercially acquired Ven after the study period. All pts received TLS prophylaxis. The primary endpoint was the composite complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) per modified International Working Group criteria. Secondary endpoints included CR or CRi rates and transfusion independence (TI). TLS was assessed per Howard criteria (Howard. N Engl J Med. 2011;364:1844). Results: At the 19 Oct 2021 cutoff date, 60 pts were enrolled and treated (Ven + Aza, n=30; Ven + Dec, n=30). Efficacy outcomes are shown in the Table. The composite CR rate was 58%. CR and CRi rates were 13% and 45%, respectively. Most pts (>50%) maintained TI, and 41% and 57% of pts dependent on red blood cells or platelets, respectively, converted to TI. Bone marrow blast clearance was achieved in 42 pts (70%) at a median 26 days after treatment initiation. The most common (≥50%) AEs were anemia (75%), neutrophil count decrease (55%), white blood cell count decrease (52%), and nausea (50%). Serious AEs occurred in 67% of pts, most commonly (≥15%) febrile neutropenia (28%) and sepsis (15%). Two pts (3%) had TLS; neither event led to treatment discontinuation. Of pts who achieved blast clearance, 12/42 (29%) had a new event of myelosuppression post-blast clearance and prior to the next cycle. Conclusions: The results of this US community-based study indicate that Ven + HMA is an effective treatment option for pts with ND AML and, with appropriate TLS prophylaxis and monitoring, can safely be initiated in an outpatient setting. Clinical trial information: NCT03941964. [Table: see text]
Incorporating patient-reported outcome data into a hematopoietic cell transplant survival calculator.
Authors: Shaw Bronwen E. , Flynn Kathryn E. , Cusatis Rachel , D'Souza Anita , Hamilton Betty Ky , Horowitz Mary M. , Mattila Deborah , Phelan Rachel , Lee Stephanie , Brazauskas Ruta
Published: June 2022

7045

Background: The Center for International Blood and Marrow Transplant Research (CIBMTR) provides a validated 1-year Overall Survival (OS) calculator to estimate outcomes for individual patients prior to allogeneic Hematopoietic Cell Transplant (HCT) to inform risk. The calculator considers pre-HCT clinical and demographic characteristics, but not patient-reported outcome (PRO)s. Pre-HCT PRO scores have been associated with OS. We hypothesized that adding the baseline PRO score to the calculator will enhance its performance in predicting OS. Methods: In addition to established covariates,we considered pre-HCT PRO scores, collected on five (published) prospective randomized clinical trials performed through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Measures used were the SF36 physical component score (PCS) and mental component score (MCS), and the FACT-BMT Trial outcome index (TOI). We also investigated inclusion of a single question from the SF36: In general, would you say your health is: excellent/very good/good vs fair/poor. Patients were ≥18. Results: 1,033 patients were included, 341 (33%) completed only the SF36, 339 (33%) only the FACT-BMT and 353 (34%) both, per study design. HCT occurred 2004-2014, and the population was diverse with respect to disease, stage, demographics, and transplant characteristics. When adjusted for clinical characteristics, the PCS was significantly predictive of mortality (HR=0.88, 95%CI 0.81-0.96, p=0.0021), while the MCS and TOI were not. The single general health question was also significantly associated with mortality (HR=0.52, 95%CI 0.35-0.74, p=0.0004). Addition of PRO scores to the calculator did not result in a significant change in the model’s predictive ability as measured by Harrell’s concordance statistic (Table). Conclusions: In this large analysis, we confirmed the significant, independent association of pre-HCT PRO scores with OS. We showed, for the first time in this setting, that a single general health question is as accurate as the full SF36 measure for predicting survival, but we did not find support for the hypothesis that adding PROs to the calculator improved its performance. Estimates of baseline PRO measure effect on mortality and model concordance statistics at 1-year post-HCT. [Table: see text]
Non-myeloablative allogeneic blood or marrow transplantation (AlloBMT) with post-transplant cyclophosphamide (PTCy) for peripheral T-cell lymphoma (PTCL): Improved outcomes with peripheral blood (PB) allografts and increased total body irradiation (TBI) to 400 cGV.
Authors: Sterling Cole Harris , Hughes Michael Sang , Tsai Hua-Ling , Fuchs Ephraim Joseph , Yarkony Kathryn , Varadhan Ravi , Gladstone Douglas Edward , Swinnen Lode J. , Jones Richard J. , Wagner-Johnston Nina D. , Ambinder Richard F.
Published: June 2022

7047

Background: The use of PTCy for graft-versus host-disease (GVHD) prophylaxis has revolutionized alloBMT, but there is limited published experience in PTCL. Methods: All patients with PTCL who received a non-myeloablative alloBMT using PTCy-based GVHD prophylaxis between January 2004 and December 2020 at Johns Hopkins Hospital were analyzed. Standard population statistics were used. Results: Sixty-five patients were identified. The median age was 59 years (range, 24-75 years). Lymphoma histology included PTCL-not otherwise specified (n=24), ALK-negative anaplastic large cell lymphoma (n=14), angioimmunoblastic T-cell lymphoma (n=7), enteropathy-associated T-cell lymphoma (n=6), hepatosplenic T-cell lymphoma (n=4), and other (n=10). Eleven patients were in first complete remission (CR1, 17%). The remaining patients were in first partial remission (PR1) or underwent salvage therapy to at least PR prior to transplant. Forty-eight patients received an alloBMT from a haploidentical related donor (74%), 10 from a fully matched donor (15%), and 7 from a mismatched unrelated donor (mMUD, 11%). All patients received non-myeloablative conditioning with fludarabine, cyclophosphamide, and TBI. The graft source was bone marrow (BM) in the first 46 patients (71%). Because of relatively high relapse rates, in 2018 we began using PB and increased TBI from 200 to 400 cGy; the remaining 19 patients (29%) received this regimen. GVHD prophylaxis was PTCy, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. With a median follow up of 2.8 years, the 3-year progression-free survival (PFS) for the entire cohort was 39% (95% confidence interval [CI] 28-54%), and the 3-year overall survival (OS) was 43% (95% CI 31-58%). The cumulative incidence (CuI) of relapse and non-relapse mortality (NRM) at 1 year was 25% (95% CI 14-35%) and 12% (95% CI 4-20%), respectively. Among 29 cases of GVHD (45%), 2 were grade 3-4 acute GVHD (3%) and 3 were severe chronic GVHD (5%). Univariate analysis including age, histology, mMUD, PB/400cGy, and CR1 revealed only PB/400 cGy TBI as a significant predictor of survival, relapse, or NRM. Outcomes by source. Conclusions: AlloBMT with non-myeloablative conditioning and PTCy is safe and well-tolerated in patients with PTCL. Our preliminary data suggest increasing TBI dose to 400 cGy and using PB allografts may offer improved disease control and better survival outcomes, though additional studies are needed to confirm these findings. [Table: see text]
Anti–PD-1 antibody (sintilimab) plus decitabine as first-line treatment for patients with higher-risk myelodysplastic syndrome (MDS): Preliminary results from a single-arm, open-label, phase II study.
Authors: Wang Jing , Li Siqi , Jiang Hao , Chang Ying-Jun , Zhao xiao-Su , Jia jin-Song , Zhu xiao-Lu , Gong li-Zhong , Liu xiao-Hong , Yu wen-Jing , Huang xiao-Jun
Published: June 2022

7052

Background: Hypomethylating agents (HMAs) are the preferred treatment for untreated patients (pts) with higher-risk MDS, but the survival of pts after HMAs treatment is poor. It has been demonstrated that the PD-1/PD-L1 expression was upregulated by HMAs in MDS pts, providing a strong rationale for combining HMAs with PD-1 antibody for MDS treatment. Therefore, this single-arm, open-label, clinical trial was performed to evaluate safety and efficacy of Sintilimab plus decitabine for pts with higher-risk MDS (ChiCTR2100044393). Methods: Adult pts with higher-risk MDS by the IPSS-R were enrolled. Patients received decitabine 20mg/m2 intravenously daily for 5 days and sintilimab 200mg IV starting on the first and 22nd day of a cycle every 42 days until unacceptable toxicity, relapse, or progression, for a maximum of 8 cycles. The primary endpoint was overall response rate (CR+PR+mCR). Simon’s optimal two-stage design was employed.If five or more pts in stage I (13 pts) achieved ORR, the study would enroll 34 additional pts in stage II (47 pts). Secondary endpoints included safety, and survival outcomes. The relationship between expression levels of immune-checkpoint and efficacy of the combination therapy, as well as other potential biomarkers were also explored via genomic profiling. Results: At data cut-off (January 31, 2022), 21 pts were enrolled with a median follow-up time of 5.8 months. The median age of pts was 64 years (range 30-83), and the other characteristics are summarised in Table.The ORR was 62%,with six pts reaching complete response (CR),four pts reaching marrow CR and three pts achieved marrow CR+ hematologic improvement (HI). In addition,four pts reaching HI. The most common grade 3 TEAEs( > 10%) were febrile neutropenia (76.2%) and pulmonary infection (38.1%). No grade 4 TEAEs and treatment-related deaths occurred. A total of 12 pts （57.1%）experienced immune-related adverse event, including rash (28.6%), pneumonia (9.5%), hypothyroidism (9.5%), elevated serum bilirubin (4.8%) and transpeptidase (4.8%), which were all resolved by glucocorticoid. In these 21 pts, the most frequently mutated genes are ASXL1（28.6%）, RUNX1 (14.3%) and TET2(14.3%). Updated biomarker data will be presented during the ASCO meeting. Conclusions: To the best of our knowledge, this is the first study to evaluate the efficacy and safety of sintilimab plus decitabine in pts with untreated higher-risk MDS. The preliminary results demonstrate that the combination therapy is relatively safe with anti-tumor activity. Clinical trial information: ChiCTR2100044393. [Table: see text]
Long-term utilization and benefit of luspatercept in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) from the MEDALIST trial.
Authors: Fenaux Pierre , Santini Valeria , Komrokji Rami S. , Zeidan Amer Methqal , Garcia-Manero Guillermo , Buckstein Rena , Miteva Dimana , Keeperman Karen , Holot Natalia , Zhang Jennie , Hughes Christina , Rosettani Barbara , Yucel Aylin , Platzbecker Uwe
Published: June 2022

7056

Background: Luspatercept was previously shown to improve anemia in the phase 3 MEDALIST trial of pts with LR-MDS ineligible, intolerant, or refractory to erythropoiesis-stimulating agents (ESAs). Here, we report the long-term clinical value of luspatercept treatment (Tx) in pts from the MEDALIST study including dosing and rates of progression to acute myeloid leukemia (AML) and high-risk MDS (HR-MDS). Methods: Eligible pts were ≥ 18 y of age, had LR-MDS requiring regular red blood cell (RBC) transfusions, and were ineligible/intolerant or refractory to ESAs. Pts were randomized 2:1 to subcutaneous luspatercept or placebo every 3 wk for 24 wk. The primary endpoint was RBC transfusion independence (RBC-TI) ≥ 8 wk during wk 1–24. MEDALIST pts were eligible for enrollment into the long-term follow-up study. Median duration of Tx and cumulative duration of response were determined by Kaplan–Meier (KM) analysis. Total person-years for pts at risk of HR-MDS/AML progression was calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress. Results: As of January 15, 2021, the median duration of Tx was 11.70 (95% CI, 8.97–16.33) mo for luspatercept pts and 5.52 (95% CI, 5.52–5.59) mo for placebo pts. Of those enrolled in MEDALIST, 106/153 (69.3%) pts receiving luspatercept and 64/76 (84.2%) receiving placebo escalated to the maximum dose of 1.75 mg/kg. During the entire Tx phase, RBC-TI ≥ 8 wk was observed in 74/153 (48.4%) and 12/76 (15.8%) pts in the luspatercept and placebo arms, respectively, with a median cumulative duration of response of 80.7 (95% CI, 53.71–154.14) wk and 21.0 (95% CI, 10.86–NE) wk, respectively. During the entire Tx period, RBC-TI ≥ 16 wk was observed in 48/153 (31.4%) and 6/76 (7.9%) pts in the luspatercept and placebo arms, respectively (Table). Among pts randomized to luspatercept, 13/153 (8.5%) progressed to HR-MDS/AML during the entire Tx period, compared with 5/76 (6.6%) for placebo. The total person-years for pts randomized to luspatercept at risk of progressing to HR-MDS/AML was 401.7 y vs 190.9 y for placebo. Conclusions: Pts receiving luspatercept had an extended period of clinical benefit and > 50% of pts continued to receive luspatercept for > 1 y, the majority of whom underwent dose escalations to achieve an optimal response. Pts experienced durable responses with luspatercept, with a median cumulative duration of RBC-TI response of approximately 20 mo. Pts receiving luspatercept also appeared to have a longer time to HR-MDS/AML progression than those receiving placebo.[Table: see text]
Outcomes of classic Hodgkin lymphoma, relapsed within one year of diagnosis, in the era of novel agents.
Authors: Desai Sanjal , Spinner Michael Alexander , David Kevin A. , Bachanova Veronika , Goyal Gaurav , Saba Raya , Dorritie Kathleen Anne , Azzi Jacques Mario , Harris Elyse , Fusco Brendon , Sumransub Nuttavut , Hatic Haris , Ibrahim Uroosa , Iyengar Siddharth , Rappazzo Katherine Cynthia , Baidoun Firas , Orellana-Noia Victor Manuel , Magid Diefenbach Catherine S. , Advani Ranjana H. , Micallef Ivana N. M.
Published: June 2022

7515

Background: Primary refractory disease (PRD) and early relapse (ER) are predictors of poor prognosis in classic Hodgkin lymphoma (cHL). In this multicenter retrospective study, we describe outcomes of PRD and ER in pts with relapsed/refractory (R/R) cHL treated with salvage therapy (ST) and autologous stem cell transplant (ASCT). Methods: Of 14 sites, adult patients with R/R cHL who received ST and underwent ASCT were enrolled. PRD was defined as progression on frontline chemoimmunotherapy or within 6 months of diagnosis. ER was defined as relapse from 6 months-1 yr of diagnosis. Pts who relapsed >1 yr of diagnosis were called late relapses (LR). Study objectives were Overall response rates (ORR), CR rates, PFS, and OS. Results: Of 986 total pts, 160 had PRD, 365 had ER and 461 had LR. Significantly higher number of pts with PRD, but not ER, had bulky disease (41% vs 27%, p<0.01) and B symptoms (53% vs 38%, p<0.001) than LR. Higher proportions of pts with PRD and ER required >1 line of ST (44% vs 30% vs 23%, p<0.001) before ASCT and received BV maintenance (25% vs 24% vs 16%, p<0.05). When adjusted for B symptoms and Bulky disease, PRD and ER had significantly lower ORR (65% vs 76% vs 84%, p<0.001) and CR (37% vs 46% vs 57%, p<0.001) to first ST than LR. Pts with PRD and ER had significantly lower PFS (56.3%, 61.4%, vs 77.6%, p<.0001) and OS (93% vs 89% vs 94%, p=0.01) than LR. In pts with ER, Brentuximab/bendamustine (BBV) and brentuximab vedotin/nivolumab (BV/nivo) had a trend towards higher ORR (92% vs 92% vs 75%) but significantly higher CR (79.2% vs 76% vs 42%, p<0.01) than platinum based chemotherapy (PBC). In pts with PRD, BBV and BV/Nivo had a statistically insignificant trend towards higher ORR and CR than PBC. The table shows 2 yr PFS by type of ST in PRD, ER, LR. There was no difference in PFS by time to relapse in BV/nivo, CPI and miscellaneous agents. BV/Nivo had a significantly higher PFS than PBC in PRD (88% vs 48%, p<0.05) and ER (95% vs 57%, p<0.05). There was no difference in PFS of PBC and other ST in PRD, ER or LR. OS was not significantly associated with type of ST in either group. Conclusions: PRD and ER are associated with lower response to ST and survival after ASCT compared to late relapse. In pts with PRD and ER, BV/Nivo has high ORR and CR and leads to significantly higher PFS comparable to pts with late relapse and may be preferable ST regardless of time to relapse. [Table: see text]
Outcomes by BCL2 and MYC expression and rearrangements in untreated diffuse large B-cell lymphoma (DLBCL) from the POLARIX trial.
Authors: Morschhauser Franck , Jiang Yanwen , Jardin Fabrice , Herrera Alex Francisco , Sehn Laurie Helen , Herbaux Charles , Flowers Christopher , Phillips Tycel Jovelle , López Guillermo Armando , Magid Diefenbach Catherine S. , Gregory Gareth , Kim Austin Injae , Barbui Anna Maria , Balasubramanian Sandhya , Harris Will , Hirata Jamie , Paulson Joseph N. , Lee Calvin , Lenz Georg
Published: June 2022

7517

Background: Overexpression of BCL2 and MYC, and translocation of MYC, BCL2, and BCL6, are associated with poorer outcomes in patients (pts) with DLBCL (Horn et al. Blood 2013). We previously reported progression-free survival (PFS) from POLARIX in subgroups of pts with DLBCL receiving Pola-R-CHP or R-CHOP, including pts with double expressor lymphoma (DEL; favoring Pola-R-CHP: hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.42–0.97), and double- or triple-hit lymphoma (DHL/THL; favoring R-CHOP: HR 3.81, 95% CI 0.82–17.64) (Tilly et al. NEJM 2022). In this prespecified exploratory analysis, we further analyzed immunohistochemistry (IHC) expression status of BCL2, MYC, and rearrangements (R) of BCL2, BCL6 and MYC as independent prognostic markers. We also explored the prognostic impact of DEL within treatment arms. Methods: BCL2 and MYC protein expression were assessed by IHC and identified as IHC+ (≥50% [BCL2]/≥40% [MYC]) or IHC−; MYC-R, BCL2-R, and BCL6-R were detected by fluorescence in situ hybridization (Tilly et al. NEJM, 2022). Exploratory multivariate Cox regression models were adjusted for treatment, stratification factors (IPI, bulky disease, geographic region), age >60 years, cell of origin, and biomarker evaluated, as appropriate. Results: The prevalence, univariate HR, and 2-year (yr) PFS estimates of BCL2+/MYC+ and BCL2-R/ MYC-R/ BCL6-R subgroups are presented (Table) except for BCL6-R, because all 4 PFS events in this subgroup were with Pola-R-CHP. Multivariate analyses results for Pola-R-CHP vs R-CHOP in pts with BCL2+ (HR 0.60, 95% CI 0.43–0.86) and in pts with MYC+ (HR 0.63, 95% CI 0.45–0.89) were similar to results of univariate analyses. Multivariate analyses of other subgroups were not performed due to the low pt number with BCL2-R/ MYC-R/ BCL6-R. While pts with DEL treated with Pola-R-CHP had improved PFS vs pts treated with R-CHOP (HR 0.64, 0.42–0.97), the prognostic impact of DEL vs non-DEL was more pronounced with R-CHOP (univariate HR 1.53, 95% CI 1.06–2.21; multivariate HR 1.29, 95% CI 0.88–1.91) vs Pola-R-CHP (univariate HR 1.10, 95% CI 0.72–1.69; multivariate HR 1.42, 95% CI 0.89–2.28). Conclusions: Multivariate analyses support the benefit of Pola-R-CHP in pts with BCL2+ and MYC+ DLBCL. The poor prognostic impact associated with DEL appears reduced in Pola-R-CHP- vs R-CHOP-treated pts. Clinical trial information: NCT03274492. [Table: see text]