bluuebunny/crossref_metadata_2025 huggingface dataset:
Current practice for screening and management of financial distress at NCCN member institutions.
Authors: Khera Nandita , Sugalski Jessica , Krause Diana , Butterfield Richard , Zhang Nan , Smedley Warren , Stewart F. Marc , Griffin Joan M. , Zafar Yousuf , Lee Stephanie
Published: March 2020

11615

Background: Deficiencies and barriers exist to delivering comprehensive and affordable cancer care. Understanding the variation in organizational commitment, existing programs, and expected outcomes for screening and management of financial distress is needed. Methods: Representatives from 17 of 27 NCCN Member Institutions (63%) completed an online survey in November 2018 conducted by the NCCN Best Practices Committee. Centers were classified based on number of unique patients seen per year, as large ( > 10,000) (76%), or small ( < 10,000) (34%). The survey focused on institutions’ screening and management practices for patient financial distress, perceived barriers in implementation, and leadership attitudes. Results: Routine screening for financial distress was reported by 77% of centers, and most used social worker assessments (94%). 56% screened patients throughout the cancer journey. Help with drug costs, meal or gas vouchers and payment plans were offered by 100% of centers. Formal pre-authorization programs and assistance with claims and denials was offered by 81%. Charity care for medical costs was provided by 100% of the large centers compared to only 33% of small centers (p = 0.03). Median number of social workers (24 vs. 3; p = 0.01) and pharmacy representatives (6 vs. 2; p = 0.02) was also different between large and small centers. 76% evaluated the impact of financial advocacy services through number of patients assisted (85%), bad debt and charity write-offs (85%) or patient satisfaction surveys (54%). 6% and 12% reported overall effectiveness of institutional practice for screening and management of financial distress as poor/ very poor respectively. Inadequate staffing and real time resources (69%), limited institutional budget (50%), lack of reimbursement (50%), and clinical time constraints (50%) were reported as potential barriers in provision of these services. 94% agreed about stronger integration of financial advocacy services into oncology practice and 84% felt that success of these services should be a quality metric. 31% of large centers vs. 100% of small centers plan to increase staffing in this area in the next 5 years. Conclusions: Majority of NCCN Member Institutions report screening and management programs for financial distress, though the actual practices and range of services vary widely. Information from this study can help centers benchmark their performance relative to similar cancer programs and identify best practices in this area.
Lung cancer stigma: A ten-year look at patient and oncologist attitudes about lung cancer.
Authors: King Jennifer C. , Rapsomaniki Eleni , Rigney Maureen
Published: March 2020

11619

Background: The presence of lung cancer stigma is well documented and has been shown to impact the care and treatment of lung cancer survivors (Tod et al. 2008; Carter-Harris et al. 2014). In the past decade, there has been considerable research progress in lung cancer but it is unknown if the level of stigma has changed and how that affects patient care. Methods: 205 oncologists who treat lung cancer, 208 patients with lung cancer, and 1001 members of the general public were surveyed with the same survey instrument from a 2008 survey (Weiss et al. 2014) plus 5-15 additional questions at the end. The survey was carried out with identical methodology by phone and online between June 6 and July 26, 2018. Statistical analysis was performed comparing 2008 and 2018 datasets using paired t-tests if normally distributed or Mann-Whitney U tests for continuous data and Chi-squared or Fisher’s exact test for categorical data. Results: In 2018, significantly more oncologists feel they have adequate treatment options for metastatic lung cancer (67% vs 36%, p < 0.001) and the majority of patients report being satisfied with their medical care (87%) and treatment options (71%). Despite these advances, there was a non-significant increase in oncologists indicating both that there is a stigma associated with lung cancer (68% in 2018 vs 60% in 2008) and that patients blame themselves (67% vs 57%). Significantly more patients felt that there was a stigma associated with having lung cancer (70% vs. 54%, p < 0.001). In addition, 57% of oncologists indicated that patients with different cancers are thought about, approached, or handled differently, similar to 2008. Lung cancer patients were most frequently cited as treated differently. In 2018, 40% of patients agreed with the statement “patients with lung cancer are treated differently by doctors and nurses” compared to 26% a decade ago (p = .01). Both groups felt the most common way patients were treated differently was “received less sympathy from medical staff.” Conclusions: After a decade of research progress in lung cancer, stigma surrounding the disease remains a critical problem even in a healthcare setting. Patients are perceiving stigma at higher levels and oncologists are not reporting any improvement. This work underscores the need to address stigma with proactive multilevel approaches including the need for medical providers to practice empathic communication.
Relationship between perceptions of treatment goals and psychological distress in patients with advanced cancer.
Authors: Jankowski Amanda L. , Forst Deborah Anne , Greer Joseph , Nipp Ryan David , Waldman Lauren , Temel Jennifer S. , El-Jawahri Areej
Published: March 2020

11621

Background: Several studies have demonstrated discordance between how patients perceive their goal of treatment versus how they perceive their oncologist’s goal. Studies evaluating the extent and risk factors of this discordance are lacking. Methods: We conducted a cross-sectional study of 559 patients with incurable lung, gastrointestinal, breast, and brain cancers. We used the Perception of Treatment and Prognosis Questionnaire to assess patients’ perceptions of both their treatment goal and their oncologist’s goal and categorized responses: 1) patients who reported that both their goal and their oncologist’s goal was concordant (either to cure or not to cure); and 2) patients who reported discordant perceptions of their goal versus their oncologist’s goal. We assessed patients’ psychological distress using the Hospital-Anxiety-and-Depression-Scale and used linear regression to assess the relationship between patients’ perceptions of their treatment goal and psychological outcomes. Results: 61.7% of patients reported that both their goal and their oncologist’s goal was non-curative; 19.3% reported that both their goal and their oncologist’s goal was to cure their cancer; and 19.0% reported discordance between their goal and their perception of the oncologist’s goal. Older age (OR = 0.98, P = 0.01), non-Hispanic ethnicity (OR = 0.31, P = 0.049), and higher education (OR = 0.62, P = 0.042) were associated with lower likelihood of reporting discordant goals. Patients with discordant perceptions of their goal and their oncologist’s goal reported higher anxiety (B = 1.56, P = 0.003) compared to those who reported that both their goal and their oncologist’s goal was curative. Patients who reported both their goal and the oncologist’s goal was non-curative had higher depression symptoms (B = 1.06, P = 0.013) compared to those who reported that both their goal and the oncologists’ goal was curative. Conclusions: One-fifth of patients with advanced cancer report discrepancies between their perceptions of their own and their oncologists’ treatment goal which is associated with psychological distress. Tools are needed to identify patients at risk of cognitive dissonance about their prognosis.
Evaluating the effects of a structured exercise intervention on physical self-worth in men with prostate cancer: Addressing an unmet need.
Authors: Dunne Richard Francis , Heckler Charles E. , Inglis Julia Ellen , Lin Po-Ju , Fung Chunkit , Peppone Luke Joseph , Lopez Gilberto , Culakova Eva , Kleckner Ian , Janelsins Michelle Christine , Jatoi Aminah , Mohile Supriya Gupta , Mustian Karen Michelle
Published: March 2020

11625

Background: Improving body image and self-esteem are top ASCO priorities in the survivorship care of men with prostate cancer (PCa). Body image and global self-esteem, influenced by physical self-worth, are negatively affected by PCa treatment. We investigate whether exercise can improve physical self-worth in men treated for PCa and if improving self-worth is associated with changes in quality of life (QoL) and mental health. Methods: We performed a secondary analysis of a phase II randomized controlled trial comparing the effects of Exercise for Cancer Patients(EXCAP), a structured, 6-week, home-based exercise intervention, to usual care (UC) in men with non-metastatic PCa receiving radiation or Androgen Deprivation Therapy (ADT). The Physical Self-Perception Profile (PSPP), a valid 30-item questionnaire where higher scores indicate greater physical self-worth, was assessed at pre- and post-intervention. Changes between arms were compared using ANCOVA. Spearman correlations were calculated for pre/post-intervention change scores for PSPP and QoL, depression, and anxiety as measured by the Functional Assessment of Cancer Therapy (FACT), Center of Epidemiologic Studies Depression (CES-D) scale, and State-Trait Anxiety Inventory (STAI), respectively. Results: Fifty-eight men were randomized; average age was 67.1 years. Physical self-worth at baseline moderated the effect of the intervention. Compared to UC, EXCAP improved physical self-worth in those with baseline PSPP scores above the median (p < 0.04). Exercisers with baseline PSPP scores in the top quartile demonstrated a more significant improvement over UC (p < 0.01). Improvements in physical self-worth were associated with improved QoL (r = 0.29, p = 0.04), depression (r = -0.28, p = 0.04) and anxiety (r = -0.30, p = 0.03). Conclusions: Exercise significantly improves physical self-worth in men with PCa on radiation or ADT, and greater physical self-worth is associated with improved QoL, depression and anxiety. Those with higher baseline physical self-worth derived the most benefit from exercise. Exercise should be prescribed to boost self-esteem and body image in men receiving radiation or ADT for PCa. Clinical trial information: NCT00815672.
Primary results of the phase 4 BYOND study of bosutinib (BOS) for pretreated chronic phase (CP) chronic myeloid leukemia (CML).
Authors: Gambacorti-Passerini Carlo , Abboud Camille N. , Gjertsen Bjorn T. , Brümmendorf Tim H. , Smith B. Douglas , Giraldo-Castellano Pilar , Olsson-Strömberg Ulla , Saussele Susanne , Bardy-Bouxin Nathalie , Viqueira Andrea , Leip Eric , Leone Jocelyn M , Rosti Gianantonio , Watts Justin M. , Giles Frank , Hochhaus Andreas ,   BYOND Study Investigators
Published: March 2020

7012

Background: The tyrosine kinase inhibitor (TKI) BOS is approved for patients (pts) with Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed pts in CP. Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior TKIs. Primary endpoint (not powered) in Ph+ CP CML cohorts is cumulative confirmed major cytogenetic response (MCyR) by 1 y. Results: Of 163 pts who received BOS, 156 had Ph+ CP CML (46, 61 and 49 after 1, 2 and 3 prior TKIs, respectively). Across Ph+ CP CML cohorts, 51.9% of pts were male; median age was 61 y. As of 1 y after last enrolled pt (median follow-up 30.4 mo), 56.4% remained on BOS. Median BOS duration was 23.7 mo and median dose intensity after adjustment due to adverse events (AEs) 313 mg/d. Of 144 evaluable pts with a valid baseline assessment, cumulative confirmed MCyR by 1 y was 71.5% (95% confidence interval [CI] 63.4–78.7). Cumulative complete cytogenetic response rate anytime on treatment was 81.3% (95% CI 73.9–87.3). Cumulative molecular response (MR) rates were high across lines of therapy (Table). 10 deaths occurred (5 on treatment); 1-y overall survival rate was 98.0%. No pt progressed to accelerated/blast phase on treatment. 25.0% discontinued BOS due to AEs and 5.1% due to insufficient response. Most common treatment-emergent AEs (TEAEs) were diarrhea (87.8%) and nausea (41.0%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.7%) and increased alanine aminotransferase (ALT; 14.7%). The only TEAE leading to discontinuation in > 5% of pts was increased ALT (5.1%). Conclusions: Most pretreated pts with Ph+ CP CML had MCyR by 1 y with BOS; a substantial proportion achieved or preserved major MR (MMR) and deep MR in all therapy lines. Results further support BOS use for Ph+ CP CML resistant/intolerant to prior TKIs. Clinical trial information: NCT02228382. [Table: see text]
Clinical features, molecular aberrations, treatments, and outcomes in histiocytic sarcoma.
Authors: Ruan Gordon , Goyal Gaurav , Bennani Nabila Nora , Shah Mithun Vinod , Rech Karen , Go Ronald S. ,   Mayo Clinic Histiocytosis Working Group
Published: March 2020

7020

Background: Histiocytic sarcoma (HS) is a rare and aggressive malignancy of the monocyte/macrophage lineage. There is a paucity of data on treatments and outcomes in HS. Methods: This is a retrospective study of patients with histologically confirmed diagnosis of HS from 2000-2018. Kaplan-Meier and log-rank tests were used to perform overall survival (OS) analyses. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Results: There were 27 patients in the study (median age 59; range 3-83) and 63% were males. Nine had unifocal involvement and 18 had multifocal disease. Common sites involved were lymph node (50%), soft tissue (40%), bone (36%), and bone marrow (22%). Two of 8 patients had the BRAF-V600E mutation. Next-generation sequencing was performed on 8 patients and showed ≥1 oncogenic alterations (DNMT3A, FLT4, KRAS, NRAS, NUP98, PTCH1, PTPN11, TP53, TSC1, PDGFR, or BRAF genes) as well as a CLIP2-BRAF fusion. The median OS for the cohort was 12 months. Factors associated with worse OS included multifocal disease (OS 10 vs. 125 months, p = 0.03; HR 5.0, CI 1.1-21.8) and marrow involvement (OS 3 vs. 43 months, p = 0.003; HR 8.9, CI 1.7-45.0). Twelve (44%) had surgery with median OS of 42 months (range 1-125). Fifteen had chemotherapy with median OS of 12 months (range 2-67; Table). Conclusions: HS is an aggressive neoplasm, with multifocal disease and bone marrow involvement portending worse outcomes. Most patients have somatic oncogenic alterations involving the MAPK-ERK pathway and other genes. Chemotherapeutic regimens have variable response rates but are not durable. More studies on targeted kinase inhibitors in HS are needed to improve outcomes. [Table: see text]
Evaluation of etiologic genetic polymorphisms by whole exome sequencing (WES) in the Mayo Clinic AML epidemiology cohort (MCAEC).
Authors: Abdel Rahman Zaid , Cherukuri Yesesri , Heckman Michael , Finn Laura Elizabeth , Cerhan James Robert , Asmann Yan W. , Foran James M.
Published: March 2020

7021

Background: Case-control studies (CCS) have identified germline variants (GVs) & genes associated with AML risk and/or outcome. However, whether these genes also harbor somatic mutations (SMs) in AML and whether these SMs are associated with clinical phenotypes and outcome is unknown. We systemically interrogated PubMed (terms "AML genetic polymorphisms"), yielding 612 reports (1981-2018), from which we identified unique variants/single nucleotide polymorphisms (SNPs) in 100 genes associated with AML risk and/or outcome in CCS. To determine the prevalence and relevance of SMs in these genes in an unselected AML population, we performed an analysis using WES of cases in the highly-annotated MCAEC (Finn, Ca Epidemiol 2015). Methods: We performed WES using remnant cytogenetic pellets from AML diagnosis in 98 MCAEC patients with available samples, sequenced at a depth of ~100 million paired-end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Sequencing reads were aligned to human reference genome, and SMs including non-synonymous (NS) and truncating single nucleotide variants (SNVs) and small INDELs were identified and filtered using Exome Sequencing Project, 1000 genome, HapMap, & Mayo Clinic (MC) internal Biobank GV database. Copy number aberrations (CNAs) were identified & filtered using public CN polymorphism databases. For this analysis we evaluated the prevalence of somatic SNVs, INDELs, & CNAs in the 100 nominated genetic risk genes in collaboration with MC Cancer Center to determine their association with clinical phenotype and outcome. Results: Of the 100 unique genes, there were 40 with SM in our dataset, with 126 total mutations. Most were mutated in a very small number of patients, allowing insufficient statistical power to perform association analyses. However, an NS mutation in CYP2B6 (c.785A > G, p.Lys262Arg) had a minor allele frequency of 12.0%; this variant has been reported in association with breast cancer risk, but not with AML. Conclusions: We studied SM’s in AML genetic risk genes using WES of tumor samples. While representing a smaller sample size, this suggests their contribution to AML development may be limited in a broader clinical population. These results & prevalence of the novel CYP2B6 rs2279343 variant in AML must be confirmed in larger cohorts.
Results from the first-in-human study of mivebresib (ABBV-075), a pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory acute myeloid leukemia.
Authors: Odenike Olatoyosi , Wolff Johannes E. , Borthakur Gautam , Aldoss Ibrahim Taha , Rizzieri David , Prebet Thomas , Hu Beibei , Dinh Minh , Chen Xiaotian , Modi Dimple , Freise Kevin J , Jonas Brian Andrew
Published: March 2020

7030

Background: Bromodomain and extra-terminal (BET) proteins bind to acetyllysines and upregulate oncogenic target genes. Mivebresib (ABBV-075) is a pan-BET inhibitor with antitumor activity in vitro and xenograft models of AML. This 2-part phase 1 study evaluates the safety and pharmacokinetics of mivebresib at monotherapy or combination dosing schedules in patients with solid tumors (part 1) and acute myeloid leukemia (AML; part 2) (NCT02391480). Here, we report preliminary data from part 2 in patients with relapsed/refractory (RR) AML. Methods: Mivebresib monotherapy (MIV-mono), or combined with venetoclax (MIV-VEN), were administered daily to adult patients with AML. The dose-limiting toxicity (DLT) period was 28 d. Results: As of Dec 2018, 41 patients (median age: 69 y [range, 29–84]; 19 patients had > 2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-combo) and 22 who began treatment in MIV-VEN cohorts. 23 patients had high cytogenetic risk. Median time on treatment was 28 d (range, 8–562). There were no DLTs. All patients experienced a treatment-emergent adverse event (AE), most commonly (≥40% patient incidence), fatigue (56%), dysgeusia (46%), decreased appetite (44%), diarrhoea (42%), nausea (42%), vomiting (42%). 40 patients had grade ≥3 AEs (febrile neutropenia (37%), anemia (34%) and thrombocytopenia (32%). 33 patients had serious AEs, most commonly febrile neutropenia (19%). 25 deaths were reported; 15 patients died of causes unrelated to mivebresib and 10 patients due to AML progression. The median best % bone marrow blast change for 26 evaluable patients was -20% (range, -98% to +300%). Gene expression analysis in pre- and post-treatment peripheral blood samples showed that HEXIM1, DCXR and CD93 genes were reliable PD biomarkers of ABBV-075 which were consistently modulated in a dose-dependent manner. At the cutoff date, median overall survival for all patients was 2.6 m. Conclusions: Mivebresib was well tolerated and showed antileukemic effects in patients with RR AML. Clinical trial information: NCT02391480.
Activity of venetoclax-based therapy in TP53-mutated acute myeloid leukemia.
Authors: Shoukier Mahran , Konopleva Marina , Dinardo Courtney Denton , Ravandi Farhad , Andreeff Michael , Garcia-Manero Guillermo , Jabbour Elias , Daver Naval Guastad , Borthakur Gautam , Pemmaraju Naveen , Montalban-Bravo Guillermo , Benton Christopher Brent , Short Nicholas James , Bhalla Kapil N. , Cortes Jorge E. , Kantarjian Hagop M. , Kadia Tapan M.
Published: March 2020

7034

Background: Mutations in TP53 are associated with low response rates to standard therapy and poor outcomes in patients (pts) with acute myeloid leukemia (AML). Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an effective treatment option for pts with AML. Methods: We reviewed pts with TP53-mutated AML treated with VEN-based therapy between 2014-2018. Mutation testing was performed using a whole-exome next-generation sequencing panel. We analyzed the characteristics of these pts, responses to therapy, and outcomes. Results: Sixty nine pts with TP53-mutated AML treated with VEN were identified, 36 (52%) in frontline & 33 (48%) in the salvage (R/R) setting (Table). The median follow up was 4.5 [0.5 - 48.5] and 8 [1 - 46.5] months for frontline & R/R pts, respectively. Karyotype was complex in 32 (88%) and 29 (88%) pts in the frontline & R/R cohorts, respectively. In the R/R cohort, the number of median prior treatments was 2 [0 – 8]. VEN was given in combination with: 1) Hypomethylating agents (HMA) (87%), 2) FLAG-Ida (3%), 3) Low dose Ara-C (4%), or 4) CPX-351 (6%). The overall response rate (ORR) was 47% & 24% in frontline and R/R pts, respectively. All 6 pts with negative minimal residual disease (MRD) achieved complete cytogenetic response after taking VEN % remain in complete remission (CR) with a median of 3.4 [1.7-4.7] months. Two pts (both R/R) underwent allogeneic stem cell transplantation. Conclusions: VEN based therapy was associated with similar ORR, but higher CR rates in TP53 mutated AML compared with HMAs alone. Larger studies with longer follow up are needed to determine the role of VEN-based therapy in this difficult subset. Patient characteristics and outcome. [Table: see text]
Interim results from a phase Ib/II clinical study of the glutaminase inhibitor telaglenastat (CB-839) in combination with azacitidine in patients with advanced myelodysplastic syndrome (MDS).
Authors: Guerra Veronica , Dinardo Courtney Denton , Konopleva Marina , Burger Jan Andreas , Borthakur Gautam , Jabbour Elias , Pemmaraju Naveen , Sheppard Kimberley , Garcia-Manero Guillermo , Kantarjian Hagop M.
Published: March 2020

7037

Background: Glutaminase (GLS) is an enzyme that catalyzes conversion of glutamine to glutamate, providing key metabolic fuel for tumor cells. GLS is highly expressed in AML and high-risk MDS, particularly in the setting of complex cytogenetics. Preclinical studies of primary AML cells demonstrate dependence on glutamine; glutaminase inhibition led to reduced cell growth and induced apoptosis. This study was designed to evaluate the safety and efficacy of the oral glutaminase inhibitor CB-839 in combination with azacitidine for MDS. Methods: This is a single arm Phase Ib/II trial of CB-839, evaluating the dose of 600 mg BID orally daily in combination with azacitidine (AZA) for intermediate and high-risk MDS in 28-day cycles. The primary outcome for the Phase 1 portion was to confirm the safety and recommended Phase 2 dose of CB-839 in combination with AZA. Secondary endpoints evaluate efficacy and clinical activity using IWG response criteria for MDS including hematological improvement (HI), complete response (CR), marrow CR (mCR), stable disease (SD) and no response (NR). Results: A total of 10 pts with MDS were enrolled; the Phase I portion is now complete, confirming CB-839 600 mg BID with standard AZA. Median age was 71 [47-76], 90% were men. 7 pts were treatment naïve, 3 pts had prior HMA exposure. 6 pts were intermediate-2, and 4 pts intermediate-1 by IPSS with high-risk mutations. 3 pts had complex cytogenetics. The most frequent mutations were ASXL1 (n = 5), TET2 (n = 4) and TP53 (n = 4). Median number of cycles was 3 [1-9]. The most common non-hematological AEs were grade 1-3 nausea (60%) and constipation (50%). No DLTs were identified; one pt experienced grade 3 transaminitis requiring dose reduction of CB-839 (to 400 mg BID) with resolution. Seven pts (70%) achieved mCR/CR with HI, 2 pts had SD, and 1 pt had NR. The median time to mCR was 3 months [1-3]. 4 pts proceed to hematologic stem cell transplant (HSCT) after 2-4 cycles. 1 pt progressed to AML after 3 cycles of therapy, and 3 pts remain on study. Conclusions: 600 mg BID CB-839 is safe and well tolerated in combination with azacitidine in pts with MDS. The Phase II portion is ongoing. Clinical trial information: NCT03047993.
Identifying Mcl-1 protein dependencies using dimerization-specific antibody biomarker for predicting response to targeted apoptosis inducing therapies.
Authors: Cardone Michael H. , Jean Sae Rin , Karakas Bahriye , Kumar Sonia , Narovlyansky Max , Lim Bora
Published: March 2020

7038

Background: The anti-apoptotic Bcl-2 family proteins facilitate pro-survival and resistance to anti-cancer therapies. Measuring the function of these proteins has shown utility in predicting response to therapy. A method that expands the principle of BH3 profiling to solid tumors is presented. Measuring the occurrence of heterodimers of Myeloid Leukemia Cell Differentiation Protein (Mcl-1), and pro-apoptotic binding protein Bim is an indicator of cancer cell apoptotic priming state. The readout of Mcl-1 containing complex-specific biomarkers can identify survival dependencies in cancer cells potentially providing clinical utility in guiding cancer treatments. Methods: Engineered immunogens that recapitulate conformation-specific epitopes induced during binding of the Mcl-1/Bim protein complex were used to generate. monoclonal antibodies. One Heterodimer Specific Mcl-1 Bim (HsMcB) was chosen. The selective binding was confirmed using ELISA, fluorescence polarization, immunofluorescence microscopy and flow cytometry in Bim or Mcl-1 knockdown cells, and by immunohistochemistry in formalin-fixed paraffin-embedded patient tissue. Correlation of HsMcB measurements to BH3 profiling readouts from the Mcl-1 restricted Noxa peptide was explored. Results: HsMcB signal depends on both Mcl-1 and Bim protein levels. The ratio of the HsMcB to unbound protein (Mcl-1) signal ([HsMcB]/[Mcl-1]) was measured. Disruption of the complexes by BH3 mimetics targeted to Mcl-1 and depletion of Mcl-1 level using CDK9 inhibitors diminished the [HsMcB]/[Mcl-1] readout. We see correlations between these readouts and BH3 mimetic peptides readouts from the Mcl-1 specific Noxa and MS1 BH3 mimetic peptides in AML patient samples that have been treated with Mcl-1 inhibitors. Conclusions: Mcl-1 dependence is a predictive biomarker for venetoclax resistance and for response to Mcl-1 targeted therapies. Flow cytometric and IHC based measurements of a heterodimer complex offer a direct and simpler approach that harbors potential for use in clinical settings. Additional antibodies targeting Mcl-1/Bak and Mcl-1 Noxa complexes are being tested.
Outcomes with CPX-351 versus 7+3 by baseline bone marrow (BM) blast percentage in older adults with newly diagnosed high-risk/secondary acute myeloid leukemia (sAML).
Authors: Ritchie Ellen K. , Lin Tara L. , Newell Laura F. , Stuart Robert K. , Solomon Scott R. , Stone Richard M. , Schiller Gary J. , Wieduwilt Matthew Joseph , Ryan Daniel H. , Ryan Robert J , Chiarella Michael , Cortes Jorge E.
Published: March 2020

7042

Background: CPX-351, a liposomal encapsulation of cytarabine (C) and daunorubicin (D) at a synergistic ratio, is approved as Vyxeos in the US and EU for adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study, CPX-351 significantly improved OS and remission rates vs 7+3 in patients (pts) aged 60-75 y with newly diagnosed high-risk/sAML. Some studies suggest a high baseline blast percentage may portend a worse prognosis in AML. This post hoc analysis of phase 3 data assessed outcomes by baseline BM blast percentage. Methods: Pts diagnosed with AML per 2008 WHO criteria (≥20% blasts in peripheral blood or BM) were randomized 1:1 to receive ≤2 inductions of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + D 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Pts achieving complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive ≤2 consolidations. Results: CPX-351 had longer median OS and higher remission rates vs 7+3 irrespective of baseline BM blast percentage; median OS was worse in higher blast groups for both treatments (Table). The incidence of grade ≥3 TEAEs was >80% for both arms; febrile neutropenia was the most common. Conclusions: Improved outcomes were observed with CPX-351 vs 7+3 irrespective of baseline BM blast percentage in older adults with newly diagnosed high-risk/sAML. Clinical trial information: NCT01696084. [Table: see text]
Cardiac, vascular, and hypertension safety of bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia in the BFORE trial.
Authors: Cortes Jorge E. , Brümmendorf Tim H. , Gambacorti-Passerini Carlo , Clark Richard E , Leip Eric , Viqueira Andrea , Kota Vamsi , Deininger Michael W.N.
Published: March 2020

7051

Background: Tyrosine kinase inhibitor therapy has been linked to cardiac and vascular events. Cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) with bosutinib or imatinib for newly diagnosed chronic phase chronic myeloid leukemia were analyzed. Methods: Patients (pts) who received ≥1 dose of bosutinib (n = 268) or imatinib (n = 265) 400 mg/d in the phase 3 BFORE trial were included. Prespecified MedDRA terms comprised the clusters of investigator assessed TEAEs. Exposure-adjusted TEAE rate was defined as the number of pts with TEAEs / total pt-yr (pt-yr = sum of total time to first TEAE for pts with TEAEs and treatment duration for pts without TEAEs). Results: After ≥36 mo follow-up, 65% vs 62% of pts in the bosutinib vs imatinib arm were still on treatment. Rates of TEAEs, treatment withdrawals and drug-related TEAEs in the clusters of interest were low in both arms (Table). The most common cardiac, vascular and hypertension TEAEs, respectively, were sinus bradycardia (2%), angina pectoris (3%) and hypertension (7%) vs prolonged QT (3%), peripheral coldness (1%) and hypertension (9%) with bosutinib vs imatinib; corresponding grade 3/4/5 TEAE rates in the respective clusters were 3%, 3% and 4% vs 1%, 0.4% and 4%. Hypertension was the only grade 3/4 TEAE occurring in ≥1% of pts in either arm (4% each); 1 grade 5 TEAE each was noted for bosutinib (cardiac failure) and imatinib (cerebrovascular accident). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs, respectively, were 0.04, 0.03 and 0.04 vs 0.03, 0.01 and 0.04 (grade 3/4/5 only: 0.01, 0.01 and 0.02 vs 0.01, 0.002 and 0.02) for bosutinib vs imatinib. Conclusions: Cardiac, vascular and hypertension TEAE rates were low with bosutinib and imatinib. A majority of TEAEs were low grade and few led to treatment withdrawal. Clinical trial information: NCT02130557. [Table: see text]
Patterns of leukemic transformation in patients with TP53-mutant myelodysplastic syndromes.
Authors: Chien Kelly Sharon , Benton Christopher Brent , Class Caleb A. , Kadia Tapan M. , Dinardo Courtney Denton , Konopleva Marina , Andreeff Michael , Sasaki Koji , Naqvi Kiran , Ganan Gomez Irene , Wei Yue , Yang Hui , Pierce Sherry A. , Patel Keyur P. , Kanagal-Shamanna Rashmi , Kantarjian Hagop M. , Garcia-Manero Guillermo , Montalban-Bravo Guillermo
Published: March 2020

7054

Background: TP53 is the most frequently mutated gene in human cancers, including 7-13% of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Although it is associated with transformation to AML in patients with MDS, the additional genomic events leading to transformation are poorly understood. Methods: We retrospectively evaluated 312 patients with TP53-mutated AML or MDS diagnosed between 2013-2016. Patient characteristics and bone marrow data, including cytogenetic and next generation sequencing information, were assessed at the time of diagnosis and progression to AML. Results: There were 151 TP53-mutated MDS patients and 161 TP53-mutated de novo AML patients with a median follow-up time of 34.1 months. Forty-one patients with TP53-mutated MDS transformed to AML. Sequencing data at transformation was available in 17 patients (41%). At diagnosis, median age was 67 with 2 patients with intermediate-risk, 7 patients with high-risk, and 32 patients with very high-risk MDS by IPSS-R. Complex karyotype was seen in 40 patients, and 12 patients had 1, 25 patients had 2, and 4 patients had 3 TP53 abnormalities. Predictors of transformation to AML include TP53 loss of heterozygosity (p = 0.008), 3 TP53 abnormalities (p = 0.049), complex cytogenetics (p = 0.023), and female gender (p = 0.002). Median time to transformation was 10.4 months. At transformation, an increase in TP53 variant allelic frequency was observed in 7 patients (41%), and new mutations, particularly NRAS, IDH1, TP53, MLL, KDM6A, TET2, and NOTCH1, were acquired by 10 patients (59%). Cytogenetic evaluation revealed identical clones in 5 patients, linear acquisition of cytogenetic abnormalities in 12 patients, and new clones in 8 patients. Patients with TP53-mutated AML from MDS also had worse median overall survival than patients with TP53-mutated de novo AML at 2.5 months vs. 5.7 months respectively (p < 0.001). Conclusions: TP53 mutations confer a worse prognosis, especially in the setting of AML transformed from MDS. This may be due to the acquisition of new mutations and cytogenetic abnormalities. Further exploration of the biological mechanisms leading to transformation in TP53-mutant MDS is warranted.
Fedratinib (FEDR) in myelofibrosis (MF) patients previously treated with ruxolitinib (RUX): A reanalysis of the JAKARTA-2 study.
Authors: Harrison Claire N. , Schaap Nicolaas , Vannucchi Alessandro M , Kiladjian Jean-Jacques , Jourdan Eric , Silver Richard T. , Schouten Harry C. , Passamonti Francesco , Zweegman Sonja , Talpaz Moshe , Verstovsek Srdan , Gerike Torsten , Rose Shelonitda , Li Mingyu , Brownstein Carrie , Mesa Ruben A.
Published: March 2020

7057

Background: MF is a life-threatening MPN for which RUX is the only approved treatment (Tx) option. Patients (pts) who are relapsed/refractory (R/R) or intolerant to RUX have a particularly high unmet medical need. FEDR is an oral selective JAK2 inhibitor active against wt and mut JAK2. The JAKARTA-2 study demonstrated ≥35% spleen volume responses (SVR) in pts resistant or intolerant to RUX per investigator assessment. This JAKARTA-2 reanalysis employs a more stringent definition of RUX failure than used in the previous analysis. Methods: Adult pts previously treated with RUX with intermediate or high-risk primary, post-PV, or post-ET MF, palpable splenomegaly, ECOG PS ≤2, and platelet counts ≥50 × 109/L received FEDR 400 mg QD in continuous 28-day cycles. The primary endpoint was spleen volume response rate (SVRR): ≥35% SVR from baseline (BL) at cycle 6 end per blinded central review of MRI/CT scans. A key secondary endpoint was symptom RR (≥50% decrease in total symptom score from BL). Results: 79/97 enrolled pts (81%) met the more stringent criteria for RUX R/R (n=65, 82%) or intolerance (n=14, 18%). Median BL spleen volume was 2946 mL (~14× normal). Median prior RUX Tx duration was 11.5 mo (range 1.0–62.4). Median number of FEDR Tx cycles was 7 (1–20). SVRR with FEDR was 30% (95% CI 21, 42). KM estimated median spleen response duration was not estimable (95% CI 7.2 mo, NE). Symptom RR was 27%. Safety was consistent with prior reports. Conclusions: FEDR provided clinically meaningful reductions in splenomegaly and symptom burden in pts with MF who met more stringent criteria for R/R or intolerance to RUX. Clinical trial information: NCT01523171. [Table: see text]
Outcomes with rituximab plus bendamustine (R-Benda), dexamethasone, rituximab, cyclophosphamide (DRC), and bortezomib, dexamethasone, rituximab (BDR) as primary therapy in patients with Waldenstrom macroglobulinemia (WM).
Authors: Abeykoon Jithma P. , Zanwar Saurabh , Ansell Stephen M. , Kumar Shaji , Thompson Carrie A. , Habermann Thomas Matthew , Witzig Thomas E. , Buadi Francis , Go Ronald S. , Gonsalves Wilson I. , Leung Nelson , Dispenzieri Angela , Kourelis Taxiarchis , Lacy Martha , Warsame Rahma M. , Inwards David James , Rajkumar S. Vincent , Kyle Robert A. , Gertz Morie A. , Kapoor Prashant
Published: March 2020

7509

Background: Waldenstrom macroglobulinemia (WM) is a rare lymphoma for which scant comparative data exist to guide frontline therapy. Herein, we compare 3 commonly used regimens in WM: R-Benda, DRC, and BDR in frontline setting. Methods: Patients (Pts) with active WM seen at Mayo Clinic between 2000 & 2018 who received R-Benda, DRC or BDR as primary therapy were included in this retrospective study. Response rates were assessed by Consensus Criteria. All time to event analyses were performed from the frontline therapy, using Kaplan-Meier method. Results: The study included 172 pts with active WM (R-Benda, n=67, DRC, n=75, BDR, n=30).The median follow-up for the entire cohort was 3.7 years (y) (95% CI 3.7-3.0). Baseline characteristics, including IPSS, and time to frontline therapy from WM diagnosis were similar across the 3 cohorts. Clinically relevant endpoints are shown in the Table. Hematologic and non-hematologic toxicities were similar across the 3 groups. Grade 3 neuropathy requiring treatment discontinuation was encountered in 13% pts treated with BDR. 56 pts received subsequent salvage therapy [(10% in R-Benda arm, 44% in DRC arm, & 53% in BDR arm]; 29% pts in the R-Benda arm and 30% pts in DRC arm received a PI-based regimen while 69% pts in the BDR arm received alkylator-rituximab based therapy. Conclusions: Outcomes (MRR, TTNT and EFS) with frontline R-Benda are superior in comparison to frontline DRC or BDR in patients with WM. Clinically relevant endpoints are not significantly different with DRC vs. BDR. The toxicity profile across the 3 groups was comparable. [Table: see text]
MAGNIFY: Phase IIIb interim analysis of induction R2 followed by maintenance in relapsed/refractory indolent non-Hodgkin lymphoma.
Authors: Andorsky David Jacob , Coleman Morton , Yacoub Abdulraheem , Melear Jason M. , Fanning Suzanne R. , Kolibaba Kathryn , Lansigan Frederick , Reynolds Chris , Foon Kenneth A. , Li Jiahui , Llorente Mary , Rummel Mathias J. , Sharman Jeff Porter
Published: March 2020

7513

Background: Standard treatment is lacking for patients with relapsed indolent NHL (iNHL). PI3K inhibitors reported a median PFS of < 1 y in R/R iNHL. The immunomodulatory agent lenalidomide shows enhanced activity with rituximab (ie, R2), which recently reported a 39.4-mo median PFS in R/R iNHL patients (AUGMENT; Leonard. ASH 2018:445). Methods: MAGNIFY is a multicenter, non-registrational phase IIIb trial in patients with R/R FL grade 1-3a and MZL designed to determine the optimal duration of lenalidomide. Lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2/wk c1 and q8wk c3+ (R2) are given for 12c followed by 1:1 randomization in patients with stable disease or better to continued R2 vs rituximab maintenance. These analyses evaluate the primary endpoint of ORR by 1999 IWG criteria for induction R2 in efficacy-evaluable patients receiving ≥ 1 treatment with baseline/post-baseline assessments. Results: At a median 16.7 mo follow-up, 370 patients (80% FL grade 1-3a; 20% MZL) were enrolled with a median age of 66 y, 83% stage III/IV disease, and a median of 2 prior therapies (95% prior rituximab-containing). Efficacy-evaluable patients showed a 73% ORR and 45% CR (Table). Median TTR was 2.7 mo, median DOR was 36.8 mo, and median PFS was 36.0 mo. 142 of 370 patients have been randomized and entered maintenance. The most common all-grade AEs were 48% fatigue, 40% neutropenia, 35% diarrhea, 30% nausea, and 29% constipation. Grade 3/4 AE neutropenia was 34%; all other grade 3/4 AEs were < 6%. Conclusions: R2 therapy is active with a tolerable safety profile in patients with R/R FL and MZL, and in patients refractory to rituximab. Clinical trial information: NCT01996865. [Table: see text]
Efficacy and time to next treatment following lenalidomide/rituximab (R2) or rituximab/placebo in patients with R/R indolent NHL (AUGMENT).
Authors: Gribben John G. , Izutsu Koji , Fowler Nathan Hale , Hong Xiaonan , Zhang Huilai , Offner Fritz , Scheliga Adriana A. S. , Nowakowski Grzegorz S. , Pinto Antonio , Re Francesca , Fogliatto Laura Maria , Scheinberg Phillip , Flinn Ian , Moreira Cláudia , Kalambakas Stacey Anastasia , Fustier Pierre , Wu Chengqing (Alan) , Leonard John Paul
Published: March 2020

7514

Background: Relapse is expected in treated indolent lymphoma patients, and an unmet need exists to prolong remission with effective therapies. Lenalidomide + rituximab (R2) may improve the efficacy of next treatment by their unique mechanisms. Methods: The AUGMENT phase III study evaluated patients with R/R FL gr 1-3a (82%) and MZL (18%) after ≥ 1 prior systemic therapy (not rituximab refractory). Randomization was 1:1 to R2 (lenalidomide PO 20 mg/d, d1-21/28 X12 cycles [c] + rituximab [R] IV 375 mg/m2/wk, c1, d1, 8, 15, 22 and c2-5, d1) and R/placebo (same dosing schedule). The primary endpoint was PFS by 2007 IWG; secondary/exploratory analyses were time to next antilymphoma/chemotherapy treatment (TTNLT/TTNCT) and response to next treatment. Per regulatory guidance, PFS2 was defined as time from randomization to first PD or death from any cause after next antilymphoma treatment, or initiation of a third antilymphoma treatment. Results: Median PFS was superior for R2 over R/placebo (39.4 vs 14.1 mo; HR = 0.46; P < 0.0001). As of 22June2018, median TTNLT, TTNCT, and PFS2 were not reached for R2, and were significantly longer than R/placebo (HR = 0.54, 0.50, and 0.52, respectively). For 49/178 (28%) R2 and 80/180 (44%) R/placebo patients receiving next antilymphoma therapy, response was generally higher with R2 (57% ORR; 31% CR) than R/placebo (36% ORR; 16% CR; Table). Conclusions: These analyses suggest that R2 (vs R/placebo) prolonged time to subsequent treatment and is associated with longer PFS2, enabling greater response to next therapy. Although patient numbers were modest, it is hypothesized that patients who received R2 were generally more sensitive to subsequent therapy than those treated with R/placebo. Clinical trial information: NCT01938001. [Table: see text]
Outcomes in large B-cell lymphoma progressing after axicabtagene ciloleucel (Axi-cel): Results from the U.S. Lymphoma CAR-T Consortium.
Authors: Spiegel Jay Y. , Dahiya Saurabh , Jain Michael D. , Nastoupil Loretta J. , Ghobadi Armin , Lin Yi , Lunning Matthew Alexander , Reagan Patrick Michael , McGuirk Joseph , Deol Abhinav , Munoz Javier , Locke Frederick Lundry , Neelapu Sattva Swarup , Tamaresis John S , Rapoport Aaron , Miklos David Bernard , Hill Brian Thomas
Published: March 2020

7517

Background: Axi-cel, an anti-CD19 CART cell therapy, achieved 83% ORR, 58% CR rate, with 39% PFS at 2 years in patients (pts) with relapsed refractory large B-cell lymphoma (LBCL) on the ZUMA-1 study (Locke, Lancet Oncology 2018). Data from a 17-center consortium showed response rates were similar in 274 pts treated with commercial axi-cel (Nastoupil, ASH 2018). Here, we performed retrospective analysis of outcomes in pts with progressive disease (PD) after axi-cel. Methods: Response status was determined by Cheson 2014 and reported as date of radiologic relapse. 274 pts were infused by December 26, 2018 with maximum follow-up of 14 months; 116 pts had PD as of Feb 1, 2019. Twelve sites provided additional data, detailing 85% of PD pts (n=99) with a median time to relapse of 54 days (IQR 16-120). Results: Pre axi-cel pt characteristics: median lines of therapy were 4 (range 2-11), 86% were Stage III/IV and 22% were ECOG >1. Following relapse, 60% (n=61) were biopsied and 70% (43/61) had CD19 expression measured. Thirty percent (13/43) were CD19 negative by: IHC (3/13), flow (2/13) or both (8/13). Seventy percent (n=71) received salvage therapy for PD. Median lines of salvage therapy was 1 (range 0-4). The most common therapies were Lenalidomide-based (30%), checkpoint inhibitors (30%), chemotherapy (20%) and radiation (10%). First salvage therapy ORR by regimen: checkpoint inhibitors = 24%, lenalidomide regimens = 20% and chemotherapy = 11%. One patient received allogeneic transplant. Twelve pts enrolled on clinical trial, with one receiving 2nd CAR-T. Median OS following relapse was 108 days (95% LCL 71). Nineteen pts relapsed <3 months after axi-cel and did not receive therapy with median OS 17 days (95% CI 7-49); 33 pts relapsed <3 months and received therapy with 114 day median OS (95% LCL 82). In contrast, 30 pts who relapsed >3 months post axi-cel and received therapy had estimated median OS >220 days (95% LCL 81). Conclusions: Patients with LBCL relapsing less than 3 months following axi-cel have extremely poor outcomes supporting the development of novel therapies. Therapy for relapse >3 months appears promising. JYS and SD contributed equally; APR, DBM and BTH contributed equally.
Atrial fibrillation (AF) in patients with CLL treated with ibrutinib: Assessing prediction models and clinical outcomes.
Authors: Archibald William , Rabe Kari G. , Kabat Brian , Call Timothy , Ding Wei , Kay Neil E. , Kenderian Saad , Muchtar Eli , Leis Jose Francisco , Schwager Susan M. , Koehler Amber , Fonder Amie L. , Slager Susan L. , Shanafelt Tait D. , Parikh Sameer Ashok
Published: March 2020

7522

Background: Ibrutinib therapy is associated with an increased risk (~15%) of AF. An accurate risk assessment model for the development of AF in pts starting ibrutinib is not established, and outcomes after AF are not well described. Methods: An IRB approved retrospective review of CLL pts treated with ibrutinib at Mayo Clinic between Oct 2012 and Nov 2018 was conducted. Results: 299 pts were identified with a total of 565 years of ibrutinib exposure (Table). After a median follow-up of 24 months (range 0–70 months), 51 pts developed treatment-emergent AF (13 [25%] CTCAE 3 or higher). Our study assessed 3 clinical prediction models, the Framingham (Schanbel:Lancet 2009), Italian (Visentin:Blood 2018;132:3118), and Shanafelt (Shanafelt:Leuk Lymp; 2017) risk scores. Based on a lower Akaike information criteria, the Italian score was best able to predict risk of treatment emergent AF (2-year risk of AF with score 0 6%; 1-2 8%; 3-4 26%; 5+ 47%). Thirty (61%) pts were treated with medical therapy for AF (27 rate control; 2 rhythm control; 1 both). 16 (31%) pts underwent interventional therapy (3 AV node ablation; 11 cardioversion; and 2 pacemaker). Twelve (23%) pts temporarily held ibrutinib and resumed their original dose, 22 (43%) pts continued reduced dose ibrutinib and 11 (22%) continued their initial ibrutinib dose. Six (12%) pts permanently discontinued ibrutinib. Of 51 pts with treatment-emergent AF, 41 (80%) had a CHA2DS2-VASc score of ≥2 (41% received anticoagulation alone; 12% received antiplatelet therapy alone; 10% received both). No pt developed a thrombotic stroke after treatment-emergent AF. Two major bleeds, (1 GI and 1 intracranial) occurred, one in a pt on concomitant antiplatelet and anticoagulation therapy, and one in a pt receiving neither. The development of AF was associated with shorter event-free survival (HR 2.5, 95%CI 1.5-4.2, p<.001) and shorter overall survival (HR 3.5, 95%CI 2.0-6.3, p<.001). Conclusions: The Italian score was the best predictor of AF development in this cohort of ibrutinib treated pts. Although the vast majority of pts who develop AF after ibrutinib are able to continue therapy, the occurrence of AF appears to be associated with shorter EFS and OS. [Table: see text]