bluuebunny/crossref_metadata_2025 huggingface dataset:
Prior authorization process improvement for pain medications in an oncology unit: Timely initiation of test claim request form.
Authors: Varghese Susy , Amaram-Davila Jaya Sheela , George Marina C.
Published: May 2020

7050

Background: Oncology patients with extensive metastatic disease and advanced-stage cancer frequently require controlled medications for pain managements. Insurers require Prior Authorization (PA) for high-cost specialty medications including: Hydromorphone, Oxycodone, Oxymorphone, Fentanyl, Nucynta, Lyrica and Lidocaine patch. Failure to obtain PA may delay patient hospital discharge and attainment of discharge medications, increase patient medication costs, increase hospital readmissions and emergency visits, and exacerbate clinical complications. In order to avoid delays, providers must submit a Claim Request (CR) to initiate the PA process. PA usually takes 48-72 hours after the CR is submitted; therefore, timely CR submission in anticipation of discharge is imperative. Baseline rates for initiating CR in a timely manner was 15%. A quality improvement project was conducted to increase provider-initiated CRs for prescribed pain medications requiring PA and to demonstrate a sustainable process, anchored by development of new policy. Methods: The project revised the provider-initiated CR process by implementing the following interventions: The Electronic Medical Record (EHR) was modified to create a ‘quick link’ to facilitate CR form submissions. The link was made available to providers via their dashboard for easy access to the CR form.The medication reconciliation process was revised to require nurses to send reminders to providers for any of the seven discharge medications requiring CR submission for PA. A new component was incorporated into the discharge planning process by discussing PA and CR during interdisciplinary rounds. Providers and nurses were educated about the revised process. Results: Rates for timely CR submission were collected from the EHR biweekly for 3 months post-intervention. Post-intervention, 77% of timely CR claims increased from baseline of 15% to 87%. Due to the timely initiation of CR, some medications were deemed not to require PA, and the percentage of PA requirement reduced from 95% to 55%. In addition, up to 16% of patients had money refunded as a result of timely CR submission. Conclusions: The new process was effective for ensuring an efficient and effective process for patients who require high-cost controlled medications for pain management, reducing waste and providing a quality experience for the patient. As a result of the project, the new process has become policy and is now being used on other units in the institution for additional medications that requires CR and PA.
Improving the delivery of team-based survivorship care after primary breast cancer treatment through a multi-level intervention.
Authors: Wallner Lauren P. , Abrahamse Paul , Radhakrishnan Archana , An Lawrence C. , Griggs Jennifer J. , Schott Anne F. , Ayanian John , Sales Anne , Katz Steven J. , Hawley Sarah T.
Published: May 2020

7056

Background: The delivery of team-based survivorship care after primary cancer treatment remains challenging, in part due to a lack of effective interventions. We developed a multi-level intervention for breast cancer patients and their primary care and medical oncology providers to improve the delivery of team-based survivorship care called ConnectedCancerCare (CCC). CCC includes a patient-facing, personalized mobile website, and tailored feedback letters to providers. Methods: We conducted a pilot randomized controlled trial in a breast oncology clinic to establish the feasibility and acceptability of CCC. Women within one year of completing primary treatment for stages 0-II breast cancer were randomized to CCC (intervention) or a static online survivorship care plan (control). Participants completed online surveys at baseline and 3 months, ascertaining their knowledge about PCP roles in their survivorship care, their communication with their PCP about team-based care, and whether they scheduled a follow-up visit with their PCP. Multiple measures of acceptability were collected among women in the intervention arm (n = 28). Qualitative interviews were conducted at the completion of the study with 5 PCPs, 6 oncology providers, and 10 intervention patients to identify barriers and facilitators to implementing CCC. Results: Among 160 eligible women invited to participate, 66 women completed the baseline survey and were randomized (41% participation rate), and 54 completed the 3-month follow-up survey (83% response rate). Women in the intervention arm found the content of the CCC website to be highly acceptable, with 82% reporting it was easy to use, and 86% reporting they would recommend it to other patients. A greater proportion of women randomized to CCC (vs. control) reported scheduling a PCP follow-up visit (64% vs. 42%) and communicating with their PCP about provider roles (67% vs. 18%). Women in the CCC arm also reported higher mean knowledge scores regarding team-based cancer care (3.7 vs. 3.4). Providers noted challenges to implementing CCC, including integration into electronic medical records, and supporting sustained engagement with CCC over time. Conclusions: Our findings suggest deploying CCC in medical oncology practices is feasible, and the intervention content is acceptable among breast cancer patients. CCC shows promise for improving understanding and communication about provider roles in survivorship care, and facilitating patients to follow up with their PCP early in the survivorship period. Clinical trial information: NCT03618017 .
Real-world outcomes of immune-related adverse events in 2,125 patients managed with immunotherapy: A United Kingdom multicenter series.
Authors: Olsson-Brown Anna Claire , Baxter Mark , Dobeson Caroline , Feeney Laura , Lee Rebecca , Maynard Alec , Mirza Shagufta , Mughal Sohail , Parikh Shefali , Rodgers Lisa Jane , Salawu Abdulazeez , Shotton Rohan , Tinsley Nadina , Zhao Sizheng Steven , Jones Christopher ,   The UK National Oncology Trainee Collaboration for Healthcare Research (NOTCH)
Published: May 2020

7065

Background: Immune-related adverse events (irAE) are a recognised complication of immune checkpoint inhibitor (ICI) therapy. Previous characterisation of irAEs has been limited to clinical trial or registry populations and small case series. Here we present a multi-centre, granular, real-world analysis of the prevalence and outcomes of irAEs experienced by patients managed within a single comprehensive public health service. Methods: A multi-centre retrospective analysis of 2125 consecutive patients treated with ICIs was undertaken across 12 centres. All patients were managed within the UK National Health Service outside of a trial setting between June 2016 and September 2018. Patients received either ICI monotherapy (MT) or combination therapy (CT). Data were collected using a standardised, pre-piloted, collection tool. IrAEs ≥ grade 2 or endocrinopathies of any grade were considered clinically significant and recorded as per the Common Terminology Criteria for Adverse Events (V5) (CTCAE). Descriptive statistics were employed using Stata v15 (College Station, TX). Results: Patients received αPD-1 (1757; 82%), combination αPD-1/αCTLA-4 (285, 13%), αCTLA-4 (51; 2%) and αPD-L1 (31; 1%) immunotherapy for malignant melanoma (961), non-small cell lung cancer (788) or renal cell carcinoma (335). The median age was 66 (MT) and 57 (CT). Clinically significant irAEs occurred in 732 (34%) individuals; 28% (524) on MT and 73% (208) on CT. Colitis (206,10%), thyroiditis (194, 9%), hepatitis (142, 7%) and dermatitis (126, 6%) were most commonly observed. Grade 1 endocrinopathies occurred in 20% (173) of cases. Grade 2 irAEs occurred in 43% (359), grade 3 31% (269) and grade 4 6% (51). The were 3 (0.4%) cases of grade 5 irAE; pneumonitis (2) and hepatitis, all following αPD-1 MT. 93% (680) required corticosteroids with 64% (490) requiring systemic corticosteroids and 11% (80) steroid sparing immunosuppression. 16% (336) of patients had pre-existing autoimmune disease of whom 40% (136) experienced irAEs. IrAEs led to admission in 42% (308) of cases, accounting for 2996 bed days. Length of stay was 7 days (1-67; IQR 4-13). Higher dependency care was required in 0.7% (15) of cases. Colitis (35%, 107) and hepatitis (25%, 77) accounted for the most admissions. Pneumonitis accounted for 3% (66) of irAEs but 12% of admissions. Conclusions: One third of patients experienced a clinically-significant irAE resulting in significant morbidity and admission burden highlighting the need for effective management strategies to optimise patient outcomes.
A randomized controlled trial (RCT) testing a mobile application (app) to identify cancer treatment-related financial assistance.
Authors: Tarnasky Aaron , Tran George Nhat , Nicolla Jonathan , Friedman Fred Andrew Paul , Wolf Steven , Troy Jesse D , Sung Anthony Derek , Shah Kanan , Oury Jakob , Thompson Jillian C , Gagosian Ben , Pollak Kathryn I. , Manners Ian , Zafar Yousuf
Published: May 2020

7073

Background: Insured cancer patients face high treatment-related, out-of-pocket costs. While philanthropic- and pharmaceutical-sponsored financial assistance programs exist, patients are often unaware of them. We developed “Bridge”, a patient-facing app that identified financial assistance programs for which a patient might be eligible based on treatment, disease, insurance, and financial characteristics. We hypothesized that patients in the Bridge study arm would be more likely than controls to apply for and receive financial assistance. Methods: We enrolled patients at a single institution from January 2018-March 2019. Patients were receiving treatment for any cancer, had a life expectancy of ≥6 months, and self-reported out-of-pocket costs. We randomized patients 1:1 to intervention (Bridge) vs. control (financial assistance educational websites). We assessed subjective financial distress with the validated COST measure. Outcomes included application for and receipt of financial assistance. Data on outcomes was collected from the medical record, institutional pharmacy database, and Bridge. We compared patient characteristics between study arms using chi-square and Mann-Whitney-Wilcoxon tests. We used an unadjusted logistic regression model to compare differences in outcomes. Results: We randomized 200 patients and found no significant differences between arms in baseline characteristics (Table). At 6 months from enrollment, patients in the Bridge arm were more likely than controls to apply for financial assistance [35% Bridge vs. 10% control, OR 3.53, 95%CI 1.69-7.34, p < 0.01]. Bridge patients were also more likely than controls to receive financial assistance (30% Bridge vs. 9% control, OR 3.39, 95%CI 1.78-6.46, p < 0.01). Conclusions: Among patients with treatment-related out-of-pocket costs, those who interacted with a financial assistance app were significantly more likely to apply for and receive treatment-related financial assistance. [Table: see text]
Health plan expenditures young adults with newly-diagnosed Hodgkin lymphoma (HL) by care at NCI-designated comprehensive cancer centers (CCC) vs. other treatment sites (non-CCC).
Authors: Wolfson Julie Anna , Bhatia Smita , Ginsberg Jill P. , Becker Laura , Bernstein David , Henk Henry J. , Lyman Gary H. , Nathan Paul C. , Puccetti Diane , Wilkes Jennifer J , Winestone Lena , Kenzik Kelly
Published: May 2020

7081

Background: Patients diagnosed with HL between 22-39y have worse outcomes than younger patients (≤21y); we previously reported that treatment at a CCC mitigates these disparities [Wolfson, Leukemia 2017]. While there is general consensus that CCC care is expensive, expenditures for managing young adults with HL in CCC vs. non-CCC are not known. Methods: Cancer-related expenditures were examined in HL patients diagnosed between 2001-2014 at age 22-39y and treated at CCC and non-CCC sites using commercial insurance claims data (OptumLabs Data Warehouse). Multivariable generalized linear models with log link modeled average monthly health plan paid expenditures, adjusting for sociodemographics, stage, adverse events, pre-existing comorbidities, and diagnostic era. Results: Of the 1501 HL patients, 33% (n = 489) were treated at a CCC. Patients treated at CCC vs. non-CCC did not differ with respect to race, sex, income, diagnostic era or comorbidities (p≥0.3). Mean duration of enrollment was longer in CCC than non-CCC (25 vs. 23 mos; p < 0.001) patients. During the first year after HL diagnosis, total average monthly expenditures were higher in CCC ($9,111) than non-CCC ($7,834, p = 0.001), including those related to inpatient (CCC: $1,790 vs. non-CCC: $1,011; p = 0.001) and outpatient (CCC: $6,971 vs. non-CCC: $6,487; p = 0.001) expenditures. The higher CCC expenditures were associated with higher monthly rates of inpatient admissions (IRR = 1.3, p = 0.001) and outpatient visits (IRR = 1.1, p = 0.02) at CCC. Rates of chemotherapy-related inpatient admissions were higher (IRR = 2.3, p = 0.001) in CCC than non-CCC patients, while outpatient chemotherapy visit rates were lower (IRR = 0.9, p = 0.001) in CCC. During Years 2-3, total average monthly expenditures were higher in CCC ($19,259) than non-CCC ($4,145, p = 0.002) patients. Outpatient expenditures were higher in CCC ($10,164) vs. non-CCC ($2,901, p = 0.001), with higher monthly outpatient visit rates (IRR = 1.7, p = 0.001) at CCC. Conclusions: Inpatient and outpatient cancer-related expenditures in young adults with HL were higher at CCC than non-CCCs. Higher outpatient expenditures at CCC were associated with only higher monthly visit rates. Higher inpatient expenditures were in the setting of higher admission rates, including those related to chemotherapy. Additional work is necessary to understand whether these higher expenditures at CCC are related to supportive care and/or differences in facility structure and billing practices.
Cost-effectiveness analysis of stereotactic ablative radiotherapy in patients with oligometastatic cancer.
Authors: Kumar Abhishek , Straka Christopher Andrew , Vitzthum Lucas , Cherry Daniel R , Courtney Patrick T , Riviere Paul , Murphy James Don
Published: May 2020

7085

Background: The SABR-COMET randomized clinical trial found that stereotactic ablative radiotherapy (SABR) improved outcomes among cancer patients with oligometastatic disease. Yet, the cost of SABR along with the large number of patients with oligometastatic disease raises the important question of value. This study sought to evaluate the cost-effectiveness of SABR compared to standard therapy among cancer patients with oligometastatic disease. Methods: We constructed a Markov model to simulate treatment with stereotactic ablative radiotherapy or standard therapy among patients with oligometastatic cancers. The model derived transition probabilities from clinical trial data to estimate risks of toxicity, disease progression and survival. Healthcare costs and health utilities were estimated from the literature. Cost-effectiveness was estimated with an incremental cost-effectiveness ratio (ICER) defined as dollars per quality-adjusted life year (QALY), with an ICER less than $100,000/QALY considered cost-effective. One-way and probabilistic sensitivity analyses were used to examine model uncertainty. Results: The addition of SABR increased total costs by $54,279 and improved effectiveness by 1.20 QALYs compared with standard therapy, leading to an ICER of $45,162/QALY. The model was sensitive to assumptions about tumor progression, though the model was not sensitive to assumptions about survival or cost of treatment. The cost of SABR would need to increase approximately six-fold from $12,241 to $78,151 before SABR becomes cost-ineffective. Probabilistic sensitivity analyses demonstrated that SABR was the cost-effective treatment option 97.2% of the time. Conclusions: The addition of SABR increased costs and improved quality adjusted survival, overall leading to a cost-effective treatment strategy for patients with oligometastatic cancer.
Phase Ib/II study of the IDH1-mutant inhibitor ivosidenib with the BCL2 inhibitor venetoclax +/- azacitidine in IDH1-mutated hematologic malignancies.
Authors: Lachowiez Curtis Andrew , Borthakur Gautam , Loghavi Sanam , Zeng Zhihong , Kadia Tapan M. , Masarova Lucia , Takahashi Koichi , Tippett George Dono , Naqvi Kiran , Bose Prithviraj , Jabbour Elias , Ravandi Farhad , Daver Naval Guastad , Garcia-Manero Guillermo , Stoilova Bilyana , Vyas Paresh , Kantarjian Hagop M. , Konopleva Marina , Dinardo Courtney Denton
Published: May 2020

7500

Background: Mutations in the isocitrate dehydrogenase-1 gene ( IDH1) result in myeloid differentiation arrest and accumulation of the oncometabolite 2-hydroxyglutarate (2-HG), promoting leukemogenesis. We report a primary safety and efficacy analysis of the IDH1 inhibitor ivosidenib (IVO; 500 mg PO daily D15-continous) combined with venetoclax (VEN; D1-14 per 28-day cycle), with and without azacitidine (AZA; 75mg/m2 D1-7). Methods: Eligible patients age ≥18 with IDH1 mutated myeloid malignancies (high-risk MDS and AML) enrolled into one of three successive cohorts (Cohort 1: IVO+VEN 400 mg, Cohort 2: IVO+VEN 800 mg, Cohort 3: IVO+VEN 400 mg+AZA). Primary endpoints include safety and tolerability and overall response rate (ORR) by revised IWG criteria. Key secondary endpoints include survival endpoints and PK correlates. Results: 19 patients (median age 68) enrolled, 17 with AML: 9 relapsed/refractory AML (R/R; median 1 prior line of therapy), 5 treatment naïve AML, and 3 HMA-failure MDS with secondary AML. Two patients had high-risk MDS. ELN risk was favorable, intermediate, and adverse risk in 37%, 15%, and 47%. Co-mutations included NPM1 (37%), chromatin-spliceosome (32%), methylation (16%), and RAS pathway (21%). Adverse events of special interest included IDH differentiation syndrome (n=4, grade > 3 in 1) and tumor lysis syndrome (TLS; n=2), including one grade 3 TLS event in a NPM1+ patient (successfully managed without hemodialysis). In evaluable patients (n=18), composite complete remission (CRc: CR+CRi+CRh) rates were 78% overall (treatment naive: 100%, R/R: 75%), and 67%, 100%, and 67% by cohort (median time to best response: 2 months). 7 (50%) patients achieving CRc were also MRD negative by flow cytometry. 1 patient had HI without CR/CRi and 1 had a MLFS. 9 (50%) patients remain on study, 3 (17%) proceeded to SCT in CR, 2 were non-responders, and 5 (22%) experienced progressive disease following CRc occurring after a median of 3 months. After a median follow up of 3.5 months, median OS was not reached in treatment naïve patients, and 9.7 months in R/R patients. Conclusions: IVO+VEN +AZA therapy is well tolerated and highly effective for patients with IDH1 mutated AML. Follow up and accrual is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03471260 . [Table: see text]
Development and validation of a pediatric disease risk index for allogeneic hematopoietic cell transplantation.
Authors: Qayed Muna , Kitko Carrie L , Ahn Kwang Woo , Johnson Mariam H , Schultz Kirk R. , Smith Angela R. , Yanik Gregory A , Eapen Mary
Published: May 2020

7503

Background: Characteristics such as disease, disease status and cytogenetic abnormalities impact relapse and survival after transplantation for acute myeloid (AML) and acute lymphoblastic (ALL) leukemia. In adults, these attributes were used to derive the disease risk index for survival. Thus, the current analysis sought to develop and validate a pediatric disease risk index (p-DRI). Methods: Eligible were patients aged <18 years with AML (n=1135) and ALL (n=1228) transplanted between 2008 and 2017 in the United States. Separate analyses were performed for AML and ALL. Patients were randomly assigned (1:1) to a training and validation cohort. Cox proportional hazards model with stepwise selection was used to select significant variables (2-sided p<0.05). The primary outcome was leukemia-free survival (LFS; relapse or death were events). Based on the magnitude of log(HR), a weighted score was assigned to each characteristic that met the level of significance and risk groups were created. Results: Four risk groups were identified for AML and three risk groups for ALL (Table). The 5-year probabilities of LFS for AML were 81% (68-91), 56% (51-61), 44% (39-49) and 21% (15-28) for good, intermediate, high and very high-risk groups, respectively. The 5-year probabilities of LFS for ALL were 68% (63-72), 50% (45-54) and 15% (3-34) for good, intermediate, high risk groups, respectively. Conclusions: This validated p-DRI successfully stratified children with AML and ALL for prognostication undergoing allogeneic transplantation. [Table: see text]
Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: Phase Ib results.
Authors: Sallman David Andrew , Al Malki Monzr , Asch Adam Steven , Lee Daniel Junseung , Kambhampati Suman , Donnellan William Bruce , Bradley Terrence James , Vyas Paresh , Jeyakumar Deepa , Marcucci Guido , Komrokji Rami S. , Van Elk Joanna , Lin Ming , Maute Roy , Volkmer Jens-Peter , Takimoto Chris H.M. , Chao Mark , Daver Naval Guastad
Published: May 2020

7507

Background: Magrolimab (Hu5F9-G4) is an antibody blocking CD47, a macrophage immune checkpoint and don’t eat me signal on cancers. It induces tumor phagocytosis and eliminates leukemia stem cells. Azacitidine (AZA) synergizes with magrolimab by inducing eat me signals on leukemic cells, enhancing phagocytosis. We report Ph1b data including a potential MDS registration cohort. Methods: Magrolimab+AZA was given to untreated intermediate to very high risk IPSS-R MDS and intensive chemo unfit AML patients. A magrolimab priming/intrapatient dose escalation regimen (1-30 mg/kg QW, Q2W Cycle 3+) was used. AZA was dosed 75mg/m2 days 1-7. Efficacy was assessed by IWG 2006 (MDS) and ELN 2017 (AML) criteria. Results: 68 patients (39 MDS, 29 AML) with a median age of 72 were treated with magrolimab+AZA. 19% were intermediate cytogenetic risk with 68% poor risk (13% unknown). 27% were TP53 mutant. The combo was well-tolerated with safety similar to AZA alone. Common treatment-related AEs were anemia (38%), fatigue (21%), neutropenia (19%), thrombocytopenia (18%) and infusion reaction (16%). Treatment-related febrile neutropenia was 1.5%. Only 1 patient (1.5%) discontinued due to an AE. In RBC transfusion dependent patients, 58% of MDS and 64% of AML patients became transfusion independent. 30/33 (91%) efficacy evaluable MDS patients had an objective response (42% CR, 24% marrow CR (4/8 also with HI), 3% PR, 21% HI alone, 9% SD). MDS patient responses deepened on study, with a 56% CR rate in patients with ≥ 6 mo follow-up. In AML, 16/25 (64%) responded (40% CR, 16% CRi, 4% PR, 4% MFLS, 32% SD, 4% PD). In 12 TP53 mutant AML patients, 75% had a CR+CRi (42% CR, 33% CRi, 17% SD, 8% PD). Cytogenetic CR was seen in 35% and 50% of responding MDS and AML patients. 22% of MDS and 50% of AML patients with CR/CRi/marrow CR were MRD negative by flow cytometry. Median duration of response is not reached in either MDS or AML, including TP53 mutant AML, with a median follow-up of 5.8, 8.8 and 9.4 mos, respectively (range: 1.9 – 16.8 mos). 91% of MDS and 100% of AML responding patients are in response at 6 mos. The 6 mo overall survival estimate is 100% in MDS and 91% in TP53 mutant AML patients. Conclusions: Magrolimab is a macrophage targeting immunotherapy that with AZA is well tolerated with durable efficacy in MDS, AML, particularly TP53 mutant, a poor prognostic group. A potential registration single arm MDS cohort is ongoing (NCT03248479). ENHANCE, a randomized Ph3 MDS trial is planned. Additional patients/analyses will be reported. Funded by Forty Seven and CIRM. Clinical trial information: NCT03248479 .
Type of prior genotoxic insult determines the genomic characteristics of therapy-related acute myeloid leukemia.
Authors: Ozga Michael , Blachly James Stewart , Grieselhuber Nicole Renee , Larkin Karilyn T.M. , Walker Alison R. , Bhatnagar Bhavana , Behbehani Gregory , Long Meixiao , Haque Tamanna Zohra , Vasu Sumithira , Zhao Weiqiang , Jones Daniel , Byrd John C. , Mims Alice S. , Saygin Caner
Published: May 2020

7515

Background: Therapy-related AML (tAML) is a long-term complication of cytotoxic cancer therapy. It is characterized by adverse genetics and inferior survival outcomes when compared to de novo AML. A proposed mechanism in tAML pathogenesis includes treatment-induced selection of clones harboring pre-existing mutations (i.e. clonal hematopoiesis, CH). We hypothesize that genotoxic therapies used to treat prior malignancy drive leukemogenesis through different mechanisms leading to unique clonal compositions. Methods: AML patients (pts) treated at The Ohio State University between 2015-2018 were included. Genetic profiling was performed using Miseq Illumina platform with a 49-gene targeted sequencing panel at our clinical laboratory. Results: We studied 337 AML pts (Table), of whom 53% had smoking history. Mutations involving ASXL1 were more common in smokers vs non-smokers (14% vs 5.8%, p= .001), while JAK2 mutations were more common in non-smokers (8% vs 1.2%, p= .003). Regarding specific genotoxic therapies and mutations in tAML, we investigated common CH-associated mutations including DNMT3A, TET2, and ASXL1 (DTA mutations). In tAML pts, those exposed to radiotherapy experienced a higher frequency of DTA (52% vs 27%, p= .05), NPM1 (21% vs 0%, p= .002), and SRSF2 (15% vs 0%, p= .01) mutations, and conversely, a lower incidence of TP53 mutations (21% vs 46%, p= .04). Pts with history of cytotoxic chemotherapy had a lower incidence of DTA mutations, including those who received platinum agents (8% vs 49%, p= .005) and taxanes (7% vs 52%, p< .001), but had a higher incidence of TP53 mutations (75% vs 25%, p< .001 for platinum; 53% vs 25%, p= .04 for taxanes). Similarly, alkylators and anthracyclines were associated with lower incidence of DNMT3A (0% vs 20%, p= .009) and ASXL1 (0% vs 12.5%, p= .04) mutations. Conclusions: Different genotoxic agents demonstrate unique effects in leukemia development. Our data suggest that CH clones with DTA mutations may be enriched with smoking and radiotherapy, while cytotoxic chemotherapy may confer a higher incidence of TP53 mutations. Given the adverse prognosis of TP53 mutated AML, identification of pre-existing CH clones might influence treatment selection in solid tumor pts receiving anticancer therapy. [Table: see text]
Longer-term RBC transfusion reduction in the phase III MEDALIST study of luspatercept in patients (pts) with lower-risk MDS with ring sideroblasts (RS).
Authors: Komrokji Rami S. , Sekeres Mikkael A. , Zeidan Amer Methqal , Fenaux Pierre , List Alan F. , Dezern Amy Elizabeth , Greenberg Peter L. , Savona Michael R. , Jurcic Joseph G. , Verma Amit , Mufti Ghulam J. , Buckstein Rena , Santini Valeria , Laadem Abderrahmane , Ito Rodrigo , Zhang Jennie , Louis Chrystal Ursula , Linde Peter G. , Garcia-Manero Guillermo
Published: May 2020

7518

Background: MEDALIST (NCT02631070) is a randomized, placebo (PBO)-controlled, phase 3 trial evaluating the efficacy and safety of luspatercept, a first-in-class erythroid maturation agent, in pts with anemia due to lower-risk MDS (LR-MDS) with RS (Fenaux & Platzbecker et al. NEJM. 2020;382:140-51). Methods: Pts were aged ≥ 18 years; had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with RS; were refractory, intolerant, or unlikely to respond to ESAs; and required RBC transfusions (≥ 2 units/8 weeks in the 16 weeks prior to randomization). 229 pts were randomized 2:1 to luspatercept (1.0 mg/kg, titration to 1.75 mg/kg) or PBO subcutaneously every 3 weeks. This analysis evaluates long-term transfusion burden reduction with luspatercept in all pts in the MEDALIST trial. Results: As of July 1, 2019, 77/153 (50.3%) and 11/76 (14.5%) pts in the luspatercept and PBO arms, respectively, achieved ≥ 50% RBC transfusion burden reduction for ≥ 24 weeks ( P < 0.0001). The median longest single response episode was 131.6 weeks with luspatercept, and not estimable with PBO due to pts stopping treatment. In Weeks 9–24, mean change from baseline in RBC units transfused was −3.0 (95% CI −3.9, −2.1) vs +0.4 (95% CI −0.6, 1.4) in the luspatercept vs PBO arms. In Weeks 33–48, mean change in RBC units transfused in the luspatercept arm was −4.9 (95% CI −5.9, −3.9). In Weeks 1–24, mean number of transfusion visits was 5.9 vs 9.5 in the luspatercept vs PBO arms. Risk of recurrent transfusion visits in Weeks 1–24 for luspatercept vs PBO was 0.699 (95% CI 0.597, 0.819; P < 0.0001). Mean number (least squares [LS] mean) of RBC units transfused/48 weeks during Weeks 1–48 was 22.89 (23.28) vs 35.98 (35.20) in luspatercept vs PBO arms (LS mean difference −11.92 [95% CI −15.55, −8.28]; P < 0.0001). The mean number (LS mean) of RBC transfusion events over 48 weeks was 12.95 (13.14) vs 19.54 (19.15) in the luspatercept vs PBO arms (LS mean difference −6.00 [95% CI −8.16, −3.85]; P < 0.0001). LS mean change from baseline in serum ferritin was −2.7 µg/L vs +226.5 µg/L in luspatercept vs PBO (LS mean difference −229.1 µg/L; P = 0.0024) in Weeks 9–24; and −72.0 µg/L vs +247.4 µg/L in Weeks 33–48 (LS mean difference −319.5 µg/L; P = 0.0294). In Weeks 1–24, 38/127 (29.9%) vs 5/65 (7.7%) pts ( P = 0.0005) achieved major HI-E response per IWG 2018 criteria in luspatercept vs PBO arms, respectively. Conclusions: Luspatercept demonstrated clinical efficacy in pts with LR-MDS with RS and was associated with significant reductions in RBC transfusions (≥ 50%) and serum ferritin. Clinical trial information: NCT02631070 .
Activity of decitabine as maintenance therapy in core binding factor acute myeloid leukemia.
Authors: Shoukier Mahran , Kantarjian Hagop M. , Garcia-Manero Guillermo , Patel Keyur P. , Kadia Tapan M. , Ravandi Farhad , Ohanian Maro , Daver Naval Guastad , Issa Ghayas C. , Aldrich Jeffrey , Borthakur Gautam
Published: May 2020

7522

Background: Real-time quantitative (RTPCR) based minimal residual disease (MRD) monitoring provides prognostic information in core binding factor acute myeloid leukemia (CBF-AML). Earlier we reported on the activity of decitabine (DAC) as maintenance therapy in a smaller cohort of patients with CBF AML. Methods: We have summarized the results in patients (pts) with CBF who received DAC maintenance for persistent RTPCR positivity or because of inability to complete all planned consolidation in a fludarabine, GCSF, cytarabine (FLAG) based regimen. The planned number of DAC cycles was 12 but could be adjusted at the discretion of the treating physician based on RTPCR response. Serial RTPCR was obtained approximately every 2-3 months. Results: Thirty-four pts with CBF-AML [t(8;21)=14 and inv(16)=20] received DAC as maintenance. Eighteen pts (53%) completed a full course (7 cycles) of FLAG based regimen before DAC for persistent PCR positivity (group 1). Sixteen pts (47%) were switched to DAC as they did not complete planned consolidation (group 2). In group 2, 9 pts (56%) had negative PCR (group 2A) and 7 pts (46%) had positive PCR (group 2B) prior to starting DAC. Patient characteristics are summarized in table. The median follow up was 59.2 [15.4-107.2] and 32.47 [8.5-86.3] months for group 1 and 2, respectively. In Group 1 and group 2A only 1 patient each had relapse, while 5 pts (72%) from group 2B had relapse. All the patients in group 2B with relapse were at suboptimal RTPCR response (>0.1%). Conclusions: Our study shows DAC is an effective maintenance for CBF-AML pts who have persistent PCR positively after FLAG based induction consolidation and those unable to tolerate a full course, but have negative PCR. However patients with high levels of MRD persistence should be considered for stem cell transplant. [Table: see text]
Comparative study of therapy-related (tALL) and de novo adult acute lymphoblastic leukemia (dnALL): Contemporary Mayo Clinic ALL cohort.
Authors: Abdel Rahman Zaid , Parrondo Ricardo Daniel , Heckman Michael , Spiegel Matthew , Miller Kevin Charles , Sproat Lisa Ostrosky , Jiang Liuyan , Murthy Hemant S. , Alkhateeb Hassan , Litzow Mark Robert , Greipp Patricia T. , Foran James M.
Published: May 2020

7523

Background: tALL is a recently appreciated but poorly defined clinical entity. We define tALL as any prior exposure to cytotoxic chemotherapy and/or radiation for another malignancy, and we report a comparative analysis of characteristics, cytogenetics and outcomes for this subset among a modern unselected ALL cohort from the Mayo Clinic Cancer Center (MCCC). Methods: We performed a systematic search in the 3-site MCCC registry and included all patients (pts) diagnosed and received at least 1 cycle of ALL-directed therapy and/or underwent allogeneic transplantation (AlloHCT) between 2008-2018. Comparisons of characteristics between tALL and dnALL were made using a Wilcoxon rank sum test (continuous variables) and Fisher’s exact test (categorical variables). Time-to-event variables were compared using unadjusted Cox proportional hazards regression models. Results: 431 ALL pts were identified during the study period, including n = 69 (16%) classified as tALL. Median follow-up from diagnosis was 2.3 years (range 0-18 years). The most common prior malignancies among tALL pts were Breast (24.6%), Lymphoma (15.9%), Myeloid (15.9%), GU/GYN (14.5%) and Myeloma (11.6%). In comparison to dnALL, pts with tALL were significantly older (63.2 vs 45.2 years, P < 0.001), more often female (65.2% vs 39.8%, P < 0.001), less frequently Hispanic (3.5% vs 13.1%, P = 0.042); more often of B-lineage (92.8% vs 81.8%, P = 0.022). On review of cytogenetics, tALL pts more often had hypodiploidy/near triploidy (Ho/Tr) (21.7% vs 4.1%, P < 0.001), more often had monosomal (MDS-like) (33.3% vs 12.4%, P = 0.0047) and complex karyotype (38% vs 17.3%, P = 0.0069). Importantly, incidence of BCR/ABL-positive (Ph+) ALL was not significantly different. Latency period between exposure to prior cancer therapy and development of tALL was significantly longer for Ph+ compared to Ph-negative ALL (median 9 vs. 4 years, P = 0.007). Patients with tALL had a 3-year OS after diagnosis of 37% [vs 59.7% for dnALL (HR death 1.86, 95% CI 1.31-2.65, P < 0.001)]. However, the two groups did not differ significantly regarding occurrence of AlloHCT (HR = 0.91, 95% CI 0.63-1.31, P = 0.61) or post-AlloHCT survival (HR = 1.29, 95% CI 0.75-2.23, P = 0.35). Conclusions: Therapy-related ALL represents an important & unique clinical entity with poor prognosis & adverse cytogenetic features. Ph+ tALL has a longer latency and similar frequency in both tALL and dnALL. AlloHCT appears to be an appropriate treatment strategy, possibly abrogating the poor prognosis of tALL.
Effect of early blood counts on overall survival (OS) following glasdegib + LDAC in newly diagnosed AML: BRIGHT AML 1003 post hoc analysis.
Authors: Wang Eunice S. , Heuser Michael , Sekeres Mikkael A. , Papayannidis Cristina , Candoni Anna , Merchant Akil , Brown Andrew , O'Connell Ashleigh , Ma Wendy , Chan Geoffrey , Cortes Jorge E.
Published: May 2020

7525

Background: Addition of glasdegib (GLAS) to LDAC approximately doubled OS without significant worsening of myelosuppression-related complications, ostensibly by targeting leukemic stem cells dependent on the hedgehog pathway, which is not involved in normal adult hematopoiesis. We assessed potential association of early blood counts and OS. Methods: In BRIGHT AML 1003, patients (pts) with newly diagnosed AML were randomized to GLAS + LDAC (n = 78) or LDAC alone (n = 38). GLAS was given once daily continuously and LDAC on days 1–10 of a 28-day cycle. We evaluated peripheral blood counts measured early in the study (cycle 2 day 1 [C2D1]), approximately 1 month before the first bone marrow assessments. OS was compared for GLAS+LDAC vs LDAC alone subgroups meeting thresholds of absolute neutrophil count (ANC; ≥1000 or 500/µL), hemoglobin (Hb; ≥10 or 9 g/dL) or platelets (≥100,000 or 50,000/µL). Data cut-off was Apr 2019. Results: Among all pts regardless of baseline values, achievement of ANC, Hb and platelet thresholds at C2D1 was associated with improved OS with GLAS+LDAC (table, left side). Notably, in pts who did not meet ANC, Hb or platelet thresholds (table, right side), OS benefit with GLAS+LDAC was also observed (table, all p≤0.05). Among pts below threshold at baseline, C2D1 recovery of platelets ≥50,000 or 100,000 and Hb ≥9 or 10 was associated with improved OS (not shown). Clinical trial information: NCT01546038 . Conclusions: In pts with newly diagnosed AML, improved OS was associated with various blood count thresholds after 1 cycle of GLAS+LDAC vs LDAC alone. In pts with baseline measurements below threshold, recovery of specific thresholds was associated with improved OS. These exploratory results are consistent with the hematopoiesis-sparing mechanism of GLAS, and merit further evaluation. [Table: see text]
Health-related quality of life (HRQoL) in patients with untreated higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML) receiving glasdegib + azacitidine (AZA).
Authors: Wang Eunice S. , Bell Timothy , Zeidan Amer Methqal , Bhattacharyya Helen , Kudla Art , Chan Geoffrey , Sekeres Mikkael A.
Published: May 2020

7527

Background: Glasdegib + AZA showed promising remission rates and overall survival in an analysis of BRIGHT MDS & AML 1012 in patients (pts) with MDS, AML and CMML. Here we assess the impact of glasdegib + AZA on HRQoL in this ongoing Phase Ib study. Methods: Untreated pts with MDS, AML and CMML ineligible for intensive chemotherapy received glasdegib (100 mg QD) + AZA (75 mg/m2/D on D1–7 q28D). Pt-reported outcomes (PRO) that characterize HRQoL were measured using the MD Anderson Symptom Inventory (MDASI)-AML/MDS, Pt Global Impression of Severity (PGI-S), and Pt Global Impression of Change (PGIC) tools. PRO were assessed at baseline (BL; except the PGIC), D7 and D15 of cycle (Cyc) 1, D1 of each subsequent Cyc and at end of treatment. Data cutoff: Sept 11, 2019. Results: For the MDS (n=30, including 3 with CMML) and AML (n=30) cohorts, median (range) number of Cyc started was 5 (1–14) and 5 (1–15), respectively. HRQoL over time, as determined by MDASI-AML/MDS, is shown in the Table, with mean scores indicating low symptom burden over time. For the PGI-S, both cohorts showed similar trends in pt’s impression of current leukemia symptoms remaining constant over time (i.e. absent to mild). For the PGIC, pt’s impression of change of leukemia symptoms since starting study medication remained constant over time (i.e. no to minimal change) for the MDS cohort and showed improvement in the AML cohort (i.e. minimal change to much improved). Conclusions: Glasdegib + AZA is a promising first-line treatment option that does not negatively impact the HRQoL of pts with MDS, AML and CMML ineligible for intensive chemotherapy. Clinical trial information: NCT02367456 . [Table: see text]
Pre-transplant molecular minimal residual disease (MMRD) is associated with inferior outcomes in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation.
Authors: Husnain Muhammad , Komanduri Krishna , Ramdial Jeremy , Lekakis Lazaros J. , Wang Trent Peng , Goodman Mark , Pereira Denise L. , Beitinjaneh Amer , Carollo Douglas , Ali Robert , Mohammed Yaqub Nadeem , Arshad Junaid , Byrnes Diana , Saul Eduardo Edelman , Aguirre Luis E. , Jimenez Antonio Martin
Published: May 2020

7547

Background: Allogeneic Stem Cell Transplant (alloSCT) continues to be the optimal consolidation strategy for many patients with AML; cytogenetic and molecular abnormalities are known predictors of post-transplant outcomes. There is increasing evidence that Molecular Minimal Residual Disease (MMRD) following induction has important prognostic implications and its value in the prediction of post-transplant relapse continues to be elucidated. We aim to evaluate the impact of genetics and pre-transplant MMRD on clinical outcomes following alloSCT. Methods: We retrospectively evaluated eighty-nine patients, ≥18 years with a diagnosis of AML in complete morphologic remission (i.e. < 5% BM blasts by morphologic assessment) who received alloSCT between 01/2012-05/2018 at the University of Miami and for whom cytogenetic and comprehensive molecular data was available prior to transplantation. Patients were stratified into favorable, intermediate and poor-risk categories based on 2017 ELN criteria. MMRD was defined as persistent leukemia-specific mutations prior to transplantation (i.e. NPM1, FLT3, CEBPA, IDH1-2, RUNX1 and TP53). Persistence of DTA mutations (DNMT3A, TET2 and ASXL1) was not considered MMRD, patients with unavailable cytogenetic/molecular data at diagnosis were excluded. Results: Seventy-four (83%) patients were transplanted in CR1, myeloablative conditioning was used in 72% of patients. Two-year OS and LFS were 69.4% and 78.2%, respectively. Stratification by ELN criteria resulted in prognostic separation for patients transplanted in CR1: 2-year OS for favorable (87%), intermediate (68%) and adverse risk (51%) patients (p = 0.0417). The presence of MMRD was the strongest predictor of post-transplant outcomes for the whole cohort with 2-year OS and LFS of 29.4% and 37.1% (HR 5.45 [95%CI 2.43-12.3] p = 0.0001; HR 12.4 [95%CI: 3.76 to 39.8] p = 0.0001); respectively. Subgroup analysis confirmed that MMRD was associated with significantly inferior LFS for IM/favorable and adverse risk patients (HR: 6.76 [95% CI 1.12 to 40.9], p = 0.038). Conclusions: Pre-transplant MMRD was the most important prognostic factor for relapse and survival in our cohort of AML patients undergoing alloSCT. Correlation of MMRD with other transplant variables such as conditioning intensity, MRD status by MFC and the impact of pre-emptive/therapeutic strategies in high-risk patients continues to be explored.
Disparities in receipt of complete diagnostic evaluation to confirm myelodysplastic syndromes.
Authors: Mukherjee Sudipto , Dong Weichuan , Statler Abby , Koroukian Siran M.
Published: May 2020

7555

Background: A complete diagnostic evaluation (CDE), including bone marrow (BM) biopsy, cytogenic testing, FISH panel, and/or flow cytometry, is widely accepted as a prerequisite for histopathologic confirmation of MDS. Earlier reports have raised concerns regarding accuracy of MDS diagnosis in population registries that do not require confirmatory tests for disease reporting. We queried Medicare files to analyze the extent of use of, and factors associated with CDE for diagnosing MDS. Methods: The study population included Medicare patients with at least one inpatient or two outpatient claims for MDS within a 12-month period during the years 2012 and 2013. Variables included age, sex, race, morphologic MDS categories, cytopenias (isolated or any combination), transfusion burden, comorbididities, as well as county-level characteristics (income, educational attainment, rurality, and availability of internal medicine subspecialists). Classification and regression tree (CART) and multivariable logistic regression analysis were used to identify combinations of factors associated with receipt of CDE. Results: Our study population included 45,067 MDS patients, of whom only 68.6% received CDE that included BM biopsy and/or chromosomal studies. The percent of patients undergoing CDE was significantly lower among those 85 years of age or older (56.1%); women (63.7%); Blacks (64.2%); patients with isolated anemia (60.3%); and those who were transfusion independent (p < 0.001 for all comparisons). On the other hand, CDE was significantly higher among patients with the category of MDS with excess blasts (89.4%); those presenting with pancytopenia (92.2%); and those with high transfusion burden (80%). There was little variation by comorbidity burden, county level characteristics, or availability of subspecialists. In CART analysis, 80% of patients presenting with any two or more cytopenias received CDE. In multivariable analysis, advanced age, female sex, Black race, higher comorbidity burden and availability of subspecialists were associated with a lower likelihood to receive CDE, while patients with MDS with excess blasts, and with any > 2 cytopenias were more likely to receive CDE ( P< .0001). Conclusions: Nearly one third (31%) of MDS patients in the Medicare database lack CDE especially BM biopsy. Disparities in CDE can be corrected through proper physician education and stringent registry reporting to avoid such high diagnostic inaccuracies, leading to potential missed treatment opportunities.
Comparative analysis of characteristics, survival trends, and associated malignancies of B-cell and T-cell prolymphocytic leukemia: A surveillance, epidemiology, and end results (SEER) based study1998 to 2016.
Authors: Attia Doaa , Attia Sara Aly
Published: May 2020

7558

Background: Prolymphocytic leukemia (PLL) compromises two subsets; B-cell and T-cell, accounting for less than 2% of mature lymphocytic leukemia. Both of them are rare lymphoid neoplasms with a very aggressive clinical course and poor prognosis. Methods: We used SEER program dataset between 1998 and 2016. We divided the patients into 2 groups: B-PLL and T-PLL and identified them using ‘ICD-O-3 histology recode: 9833/3 and 9834/3 respectively. We used SPSS software (version 26, IBM, NY, USA) to calculate overall survival using Kaplan-Meier methods and compare the survival between the two subtypes using the log-rank test. We also used multivariable covariate-adjust cox models to determine the impact of age, sex, race, cause of death, and associated primary malignancies on survival in both types. Results: A retrospective cohort study of 783 patients (295 B-PLL and 488 T-PLL) with overall survival rate of 22.5% (30.2% B-PLL and 18% T-PLL). The overall median survival for PLL was 16 months (95 CI, 13.745-18.255). The median survival of B-PLL (25 months, 95%CI, 15.733-34.267) was much better than T-PLL (14 months, 95%CI, 11.922-16.078). The mean age was 68.7±15.3. Patient age was an independent factor in determining the survival and inversely associated with survival time in both types (p < 0.0001). The survival rate was worst ) among age groups older than 79, between 70-79 years (8.9%, 18.9%) respectively. Although white male patients were more affected in both types, neither sex nor race significantly affected survival (P 0.554, 0.062 respectively). 64.7% of PLL patients died due to cancer. Patients with cancer-related death had significantly shorter survival time in both T-PLL group (HR = 0.351, 95% CI 0.241-0.512) and B-PLL group (HR = 0.682, 95% CI 0.491-0.945). We also found that 24.4% of B-PLL and 19% of T-PLL patients have another associated primary malignancy. Among hematological malignancies, non-hodgkin lymphoma was the commonest. Although associated solid tumors were less common, Prostate cancer and breast cancer were the commonest for both types and lung/bronchus malignancies were more associated with T-PLL. Conclusions: T-PLL subtype has worse prognosis. Age is the most important independent predictor of survival in both types. Although most of affected patients were white males, race and gender have no impact on survival. Non-hodgkin lymphoma is the commonest primary associated malignancy followed by breast and prostate cancer in both types.