bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic utility of bronchoscopy in newly diagnosed acute leukemia patients.
Authors: Curley Thomas , Koenig Kristin Lynn , Mani Shylaja , Lustberg Mark , Behbehani Gregory , Bhatnagar Bhavana , Blachly James Stewart , Haque Tamanna Zohra , Larkin Karilyn T.M. , Long Meixiao , Mims Alice S. , Vasu Sumithira , Wall Sarah Allison , Byrd John C. , Walker Alison R. , Grieselhuber Nicole Renee
Published: May 2020

e19510

Background: Over 40% of newly diagnosed acute leukemia patients receiving induction therapy develop acute respiratory failure. Bronchoscopy is a valuable tool for evaluating airway disease, but its diagnostic yield in this setting has not been fully explored. Methods: We performed a retrospective chart review of 75 newly diagnosed acute leukemia patients who had bronchoscopies. Data recorded prior to bronchoscopy included age, diagnosis, induction treatment regimen, chest imaging, assisted ventilation, duration of neutropenia and antibiotic therapy and microbiological studies. Bronchoalveolar lavage (BAL) cultures were sorted by organism, as well as by other pathologic findings. The primary outcome was antibiotic change supported by culture data. Results: The study population is summarized in the table. Induction regimen backbones included 7+3 (51), 7+4+ATRA (2), decitabine (12), hyperCVAD (2), AYA (3), other (1) and none (4); 18 patients were treated on clinical trial. Average days of neutropenia was 10.92 and average days of antibiotic therapy was 10.57. Thirty-eight patients had chest infiltrates, 11 received NIPPV, and 17 were mechanically ventilated. We identified 24 patients with +BAL studies. Of these, 37.5% (9) had + blood, urine or sputum studies before bronchoscopy, but only 3 had cultures positive for the same organism as the BAL. Of 51 patients with –BAL studies, 33.3% (17) had prior negative cultures. Infections were most commonly bacterial (15, 62.5%), followed by viral (5, 20.8%) and fungal (4, 16.7%). The most common organisms were rhinovirus, vancomycin sensitive Enterococcus (4, 16.7% each) followed by VRE, Candida albicans and MRSA (2, 8.3% each). Five patients (6.7%) had alveolar hemorrhage. Of the 24 patients with +BAL cultures, bronchoscopy findings supported changing antibiotics in 18. In contrast, antibiotics were changed in 16 patients without +BAL cultures. Conclusions: We investigated the utility of bronchoscopy on AL patients during their initial admission. BAL cultures were positive in 32% of newly diagnosed AL patients undergoing bronchoscopy. However, +BAL cultures identified a new organism in 87.5% and guided antibiotic therapy in 75% of these patients. Further studies will be needed to establish predictors of bronchoscopy findings in this patient population. [Table: see text]
Genomic profile at diagnosis by targeted high throughput sequencing, and real-world clinical outcomes in patients diagnosed with acute myeloid leukemia at a tertiary care cancer center.
Authors: Radhakrishnan Vivek Sulekha , Bhaduri Arunima , Arora Neeraj , Nair Reena , Bhattacharya Shreya , Sanyal Somanka , Veldore Vidya , Parihar Mayur , Bhave Saurabh Jayanth , Kumar Jeevan , Ramprasad VL , Mishra Deepak Kumar , Chandy Mammen
Published: May 2020

e19515

Background: Acute Myeloid Leukemia (AML) is a highly heterogeneous disease. High throughput sequencing (HTS) has led to the discovery of a number of recurrently mutated genes in AML & has provided a detailed molecular landscape of the disease. This information is now extensively utilised & interpreted in AML. Methods: Retrospective analysis of 47 patients with newly diagnosed AML for those who had both cytogenetic and targeted HTS information at diagnosis, [median age: 44y (12-80y); 24 females] & treated at Tata Medical Center, India between 2013-2019. HTS was performed using Illumina Trusight myeloid panel and/or Thermo Fisher Scientific Oncomine Myeloid panel, and mutation data from the common 28 genes were used. Patients were stratified by European Leukemia Net (ELN) 2010 and 2017 guidelines. Standard of care clinical outcome data was available for all patients. Results: 45 of 47 patients had mutations. The most frequently mutated gene was FLT3 (n = 13, 28.9%), followed by NPM1 (n = 8, 17.8%), and others [ IDH1, IDH2, TET2, CEBPA, and NRAS; n = 7, 15.6%). ELN-2010 classified 6 patients as Favourable (12.8%), 10 as Intermediate-I (21.3%), 25 as Intermediate-II (53.2%) and 6 as Adverse (12.8%) risk groups. One patient migrated to the adverse group from Intermediate-II when ELN-2017 was applied. ELN 2017 re-classification: Favorable (n = 6, 12.8%), intermediate (n = 34, 72.3%), and adverse risk groups (n = 7, 14.9%). Co-occurrence of driver gene mutations was found in NPM1 and FLT3 (8.2%) frequently. Patients with mutations in epigenetic modifiers ( ASXL1, IDH1, IDH2, DNMT3A) had high Variant Allele Frequency (VAF, 40-50%) while those with signaling pathway gene mutations ( NRAS, KRAS) had low VAF (9-25%). At a median follow up of 3.25 years, median overall survival in the three risk groups (favorable, intermediate, adverse) were 11.25 mons, 7 mons and 8 mons respectively, and relapse rates were 16%, 29% and 42% respectively. Conclusions: Early experience from a middle-income real-world setting suggests feasibility of integration of HTS information in practise, as additional prognostic/ predictive information. The pattern of a high VAF in epigenetic modifier gene mutations, potentially as a result of early acquisition during clonal development, needs further evaluation. This data set has helped us initiate a prospective multimodal omics study at our institution.
Myeloablative fludarabine and busulfan regimen in myelofibrosis: Long term outcomes and analysis of prognostic factors.
Authors: Joseph Jacinth , Milton Denai R. , Chen Julianne , Alatrash Gheath , Alousi Amin Majid , Bashir Qaiser , Ciurea Stefan O. , Daher May , Im Jin Seon , Mehta Rohtesh S. , Oran Betul , Olson Amanda Leigh , Saini Neeraj , Srour Samer Ali , Andersson Borje , Champlin Richard E. , Popat Uday R.
Published: May 2020

e19520

Background: Scoring systems, such as DIPSS-plus, prognosticate outcomes of myelofibrosis (MF) at diagnosis and at transplant. In this study, we evaluated the impact of individual components of these scoring systems, along with other factors previously reported to significantly prognosticate transplant outcomes in patients with MF. Methods: We identified 65 consecutive patients conditioned uniformly with Fludarabine(40 mg/m2X4days)/Busulfan(AUC-4000X4days) and ATG(MUD), tacroliumus and methotrexate for GVHD prophylaxis for allo-SCT during 2007-2019 at MD Anderson Cancer Center, USA. Associations between factors of interest and overall survival(OS), cumulative-incidence-of-relapse(relapse) and non-relapse mortality(NRM) were evaluated. Results: At transpant, median age was 61(range = 27-73) years; 42% were transfusion-dependent, 31% had secondary MF and 53% patients were intermediate2 and 42% were high-risk by DIPSS-plus. Forty percent of the 35 patients who had 28-gene panel tested had atleast one high-molecular-risk mutation, per MIPSS. Median follow-up for survivors was 35.6 months(range = 0.5-123). One-year and 5-year rates for OS were 78% and 51%, for relapse were 21% and 30%, and for NRM were 16% and 28%, respectively. Our multivariate analysis shows the following significant prognostic factors: HCT-CI > 3[hazard ratio(95% CI):5.63(1.48-21.27)p = 0.011], peripheral-blood blasts≥5%[5.98(1.33-26.89)p = 0.020] and prior splenectomy[6.41(1.83-22.47)p = 0.004] were associated with worse OS. Matched-unrelated donor[4.07 (1.38-12.08)p = 0.011) and mismatched-unrelated donor[7.36 (1.36-39.83)p = 0.021] versus matched-related donor as well as peripheral blasts≥5%[4.10(1.00-16.83)p = 0.05] were associated with worse NRM. Diagnosis to transplant duration > 12months[5.81(1.33-25.420)p = 0.020] was associated with higher relapse. Presence of 2 or more poor-risk mutations [6.39(1.35-30.21)p = 0.019] predicted higher relapse on univariate analysis and was not included in multivariate analysis(as data was available in 35 patients only). Conclusions: Of the IPSS-components used at diagnosis, only peripheral-blood blasts(at threshold ≥5%) was associated with worse outcome(OS and NRM). Unrelated-donor source was associated with higher NRM. Diagnosis to transplant duration > 12months predicted higher relapse. The effect of mutations needs to be validated in a bigger study.
Ruxolitinib (RUX) retreatment in patients (Pts) with myelofibrosis (MF): Real-world evidence on pt characteristics and outcomes.
Authors: Pemmaraju Naveen , Yu Jingbo , Parasuraman Shreekant , Paranagama Dilan , Kish Jonathan , Visaria Jay , Singhal Mukul , Verstovsek Srdan , Gerds Aaron Thomas
Published: May 2020

e19535

Background: RUX is a JAK1/JAK2 inhibitor FDA-approved for treatment (tx) of int/high risk MF. In the COMFORT studies, RUX reduced spleen volume in pts with MF (primary endpoint), with a median time to response of 3 mo. Case reports and clinical studies have shown some pts’ symptoms and/or splenomegaly improve upon RUX reinitiation after interruption. In the era of novel JAK inhibitors (JAKi), dose optimization and identifying indicators for tx changes remain major challenges. This study describes tx patterns and clinical outcomes of pts with MF with RUX interruption and retreatment in community-based clinical practices. Methods: Two independent patient care data sources were queried (not directly compared): (1) Cardinal Health Oncology Provider Extended Network (OPEN), (2) HealthCore Integrated Research Environment (HIRE); retrospective review of medical charts was conducted. Rigorous entry criteria for this analysis included: age ≥18 y; primary MF (PMF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF diagnosis between 1/1/2012–12/31/2016 (OPEN) or 1/2013–11/2017 (HIRE); use of RUX for MF; and documented physician-directed RUX interruption. MF-related symptoms, splenomegaly, and tx dose and patterns were analyzed. Results: 26 pts met entry criteria (Table). Pre-interruption median (IQR) RUX tx duration was 123 (57–391, OPEN) and 110 (37–148, HIRE) days; 50% had tx interruption within 3 mo. Most interruptions were for adverse events (AEs; 50% and 71%, respectively), followed by (in OPEN) alternative tx (17%), disease progression (8%), no response (8%), or loss of response (8%). After restarting RUX, median (IQR) retreatment duration was 196 (54–553) and 166 (108–262) days, respectively. Symptoms improved in 45% and 43% of evaluable pts, respectively, and spleen size improved in 40% and 33%. Conclusions: Consistent with previous reports, MF symptoms and spleen size improved with RUX retreatment in some pts. While RUX was discontinued for various reasons, one reason for clinical improvements upon reinitiation may be that tx was discontinued before deriving full JAKi benefit. Future studies are warranted investigating JAKi tx sequencing and reinitiation. [Table: see text]
Langerhans cell sarcoma: The Mayo Clinic experience with an extremely rare disease.
Authors: Alhaj Moustafa Muhamad , Jiang Liuyan , Tun Han W.
Published: May 2020

e19543

Background: Langerhans cell sarcoma (LCS) is a very rare cancer with the reported incidence of 2 per 100,000,000. It originates from antigen presenting cells belonging to the dendritic cell/macrophage family. Methods: Following IRB approval, we identified LCS patients treated at the Mayo Clinic Cancer Center. Medical charts were reviewed to extract clinical data. Results: Our cohort consists of 5 patients with confirmed diagnosis of LCS. The median age at diagnosis was 34 years (range, 11-75) with 60% (3/5) females. One female was an African American and the rest were Caucasians. ECOG performance status at the time of diagnosis was 0 in 4 patients and 3 in 1 patient. Four patients had disseminated disease at diagnosis. 3/5 patients had moderate splenomegaly at diagnosis. 2/5 patients presented with a bulky mediastinal tumor and 1/5 patients presented with bulky intraabdominal disease. Predominant sites of disease are summarized in the table. BRAF mutation was negative in all 3 tested patients. The median follow up for the whole cohort was 25 months (range; 5, 41). Three patients relapsed after the initial treatment. Patient # 4 received allogeneic stem cell transplantation after the 4th relapse and is in CR 14 months later. Patient # 5 had PD-L1 expression > 95% and was started on pembrolizumab with sustained response for 1 year. Conclusions: LCS is extremely rare and is associated with unfavorable outcomes after currently available therapeutic interventions. More studies on the genetic and molecular basis of LCS are necessary to develop targeted therapies. [Table: see text]
Voruciclib plus venetoclax show high efficacy for CLL b cells on human stromal cells.
Authors: Lesnick Connie , Wood Jamie , Parikh Sameer Ashok , Kay Neil E.
Published: May 2020

e20009

Background: Although treating B-Chronic Lymphocytic Leukemia (CLL) with small molecule inhibitors has shown promise, a lasting cure for this disease has yet to be found. Further treatments directed at key molecular targets in the CLL B cell need development for patients with adverse prognostic factors, and relapsed/refractory patients. We evaluated the impact of two novel drugs with non-overlapping mechanisms of action on CLL B cells: Voruciclib, a cyclin dependent kinase (CDK) inhibitor targeting CDKs 9, 6, 4, 1 and Venetoclax a BCL-2 inhibitor. To mimic the protective effect of the CLL micro-environment these experiments were done with CLL cells cocultured in the presence of bone marrow mesenchymal stromal cells (BMSC). Methods: Voruciclib, (MEI Pharma) and Venetoclax were tested for killing activity alone and in combination against CLL cells cocultured with healthy human bone marrow MSC. CLL B cells were from untreated patients stratified on risk of disease progression. Low risk had mutated and high risk patients had unmutated IVGH genetic status. CLL cells were cultured on BMSC’s with a series of escalating doses of individual drugs and drug combinations at fixed molar ratios then Annexin/PI stained for viability testing by flow cytometry. Killing curves generated for each drug/combination were analyzed by the combination index (C.I.) approach of Chou and Talalay with Calcusyn, characterizing interactions as synergistic, additive or inhibitory. C.I. value hierarchy classes synergy as moderate (0.7-0.9), synergistic (0.3-0.7), strong (0.1-0.3) and very strong (below 0.1). Results: CLL cells with unmutated IGVH status were more sensitive to Voruciclib than mutated IGVH both with and without BMSC’s. The combination Voruciclib +Venetoclax showed synergism for all patients regardless of risk; half strongly to very strongly (Table). Similar synergistic effects were seen with relapsed/refractory patients. Conclusions: Based on these preclinical data, Voruciclib + Venetoclax is a very promising combination to improve treatment of CLL patients. We speculate that CDK9 inhibition, which regulates transcription of Mcl-1, with Bcl-2 inhibition results in potent apoptosis induction in CLL B cells. [Table: see text]
Early data from a phase II trial investigating the combination of pembrolizumab (PEM) and entinostat (ENT) in relapsed and refractory (R/R) Hodgkin lymphoma (HL).
Authors: Sermer David J. , Vardhana Santosha Adipudi , Ames Ashley , Biggar Erin , Moskowitz Alison J. , Batlevi Connie Lee , Caron Philip , Hamilton Audrey M. , Moskowitz Craig H. , Matasar Matthew J. , Zelenetz Andrew David , Horwitz Steven M. , Von Keudell Gottfried , Yahalom Joachim , Rademaker Jurgen , Dogan Ahmet , Seshan Venkatraman E. , Younes Anas
Published: May 2020

e20018

Background: Histone deacetylase (HDAC) inhibitors have single agent activity in various types of lymphoma. They have been shown to restore antigen-specific immune recognition in cancer cells and to downregulate PD-1 expression in circulating T lymphocytes. In preclinical studies, the combination of HDAC inhibitors and anti-PD-1 antibodies acts synergistically against various tumor models in mice. Accordingly, we investigated the safety and efficacy of the novel combination of the HDAC inhibitor ENT and the PD-1-blocking antibody PEM in patients with R/R HL. Methods: Patients with R/R HL received ENT 5-7 mg orally once weekly and PEM 200 mg intravenously once every three weeks. The primary objective is overall response rate (ORR) and 12-month progression-free survival (PFS). Multiplexed serum cytokine analysis of 20 pro-inflammatory cytokines and chemokines was performed on sera from peripheral blood samples collected at baseline and at 21 days on treatment. Results: At data cutoff on 2/5/20, 14 patients with HL have been enrolled. Out of 13 evaluable patients, 12 responded (92% ORR), including 3 who progressed on prior anti-PD-1 therapy. With a median duration of follow-up of 176 days (21-632), 9 patients are currently receiving treatment on study, 2 discontinued due to toxicity, 1 for progression, and 2 for consolidation with transplant or radiation. After 21 days on treatment, there was a decrease in median serum levels of eotaxin (-39%, p = 0.002), eotaxin-3 (-56%, p = 0.04), MDC (-78%, p = 0.025), MIP1a (-60%, p = 0.025), and TARC (-98%, p < 0.001) and a 3-fold increase in median levels of IFNγ (p = 0.032). There was an association between extent of tumor reduction and greater decrease in the cytokines eotaxin-3 (-62%, p = 0.064), MDC (-90%, p = 0.064), and MIP1a (-85%, p = 0.064), which trended towards statistical significance. Out of 22 total patients enrolled in this study (including 8 patients with follicular lymphoma), 62% had grade ≥3 adverse events (AE), which were predominantly hematologic, including neutropenia (48%), thrombocytopenia (19%), and anemia (10%). Immune-related AEs included 3 cases of hypothyroidism, 2 cases of hepatitis and 1 case of pneumonitis. Four patients who experienced serious AEs due to pericarditis (n = 2), hemophagocytic lymphohistiocytosis, and bullous dermatitis were taken off study. Conclusions: Early results from this ongoing phase II clinical trial suggest that the combination of PEM and ENT is safe with encouraging responses in HL. Clinical trial information: NCT03179930 .
Clinical anti-lymphoma effect of T cells expressing an anti-CD19 chimeric antigen receptor in synthetic biology optimizing system.
Authors: Dai Hong-jiu , Li Yanyun , Shi Lan , Dai Hui , Li Yan , Xu Hui , Zhu Jingjing , Zhang Pei-xian
Published: May 2020

e20021

Background: Anti-CD19 chimeric antigen receptor (CAR) T cells for relapse/refractory B-cell malignancies has been remarkably effective in previous clinical trials. However, most of subjects has severe adverse effect even though the infusion of CAR T cells is at the low dose. Herein, we investigated the safety of administering CAR T cells which express the anti-CD19 chimeric antigen receptor in synthetic biology optimizing system. Methods: We designed an anti-CD19 CAR with FMC63 Scfv (KD-019). This CAR has a CD8 hinge and transmembrane domains and a 4-1BB costimulatory domain; T cells expresses CAR in synthetic biology optimizing system. A phase I dose-escalation trial was conducted to investigate the safety of KD-019 CAR T cells and to assess efficacy for patients with previously treated B-cell lymphoma. The patient at the 76 years old received Flu/Cy chemotherapy to enhance CAR T cells activity. Two days after the completion of chemotherapy, about 3 million KD-019 CAR T cells were infused. Results: The patient who has chemotherapy-refractory lymphoma has received KD-019 CAR T cells infusion. Post infusion KD-019 CAR T cells expansion were observed; peak CAR T cells level occurred between Day 3 and 10, and CAR T cells were still detected on Day 243. In addition, we found that CD3+CD8+ T cells level peaked on Day 15. Moreover, after infusion of CAR-T cells, the right peripheral pulmonary lymphaden and visible nodules were respectively shrunk by 53% and 85% on Day 28; and some peripheral pulmonary nodules were obviously reduced and nearly disappeared. We also found that pelvic effusion was significantly reduced, and pain symptoms of the left hip and leg were reduced by 50%. Exhilaratingly, our KD-019 CAR therapy has no obvious cytokine release syndrome (CRS) and central nervous system toxicity. Conclusions: KD-019 CAR T cells express an anti-CD19 chimeric antigen receptor in synthetic biology optimizing system. this innovative KD-019 product can offer significant clinical benefit for NHL patients at the low dose without fever and neurotoxicity. Clinical trial information: NCT03854994. Clinical trial information: NCT03854994 .
Post-transplant lymphoproliferative disorder (PTLD) after solid organ transplant (SOT): A multicenter real world analysis (RWA) of 877 patients (pts) treated in the modern era.
Authors: Jagadeesh Deepa , Tsai Donald Edward , Wei Wei , Alvarez Bustamante Jean , Wagner-Johnston Nina D. , Berg Stephanie , Kim Seo-Hyun , Reddy Nishitha M. , Sriram Deepika , Portell Craig , Ghione Paola , Voorhees Timothy , Kamdar Manali K. , Koff Jean Louise , Dharnidharka Vikas , Evens Andrew M.
Published: May 2020

e20026

Background: Historically, SOT PTLD have modest outcomes in part due to heterogeneous treatment approaches. Additionally, there remains an absence of a large data repository in PTLD to help delineate contemporary pt outcomes & prognostic factors. We conducted a large, multicenter RWA to study outcomes & prognostication of SOT PTLD in the modern era. Methods: Retrospective data on 877 untreated SOT PTLD pts ages ≥18 years (yrs) (2000-2018) were analyzed from 15 academic centers. Prognostic factors for relapse free survival (RFS) & overall survival (OS) were assessed by Cox model. Results: The median age at diagnosis was 54 yrs (range 18-84). The majority of pts were white (78%) & male (67%). Median time from SOT to PTLD diagnosis was 57 months (range 0.23-470). SOT types: kidney (41%) liver (19%), lung (16%), and heart (11%); 11% multi-organ. Tumor was EBV+ in 52%. Graft involvement (18%) and rejection (21%) were seen in a proportion of pts. Most pts had reduction in immunosuppression (79%) and rituximab (R)-containing regimen (61%) as part of 1st line therapy (Tx). Most common Tx: R monotherapy (34%), R+chemotherapy (29%) & chemotherapy without R (8%). Maintenance R use was infrequent (6%). Overall response rate was 63% [51% complete response (CR) and 12% partial response (PR)] and 19% of pts had primary refractory disease. With 44-month median follow-up (0.1-304), 62% of pts were alive. Median OS & RFS for all pts were 12 & 9 yrs, respectively, while differential survival rates were identified for several pt subsets (Table). On univariate analysis, lung SOT was associated with borderline RFS (HR 0.68 [95% CI 0.44-1.03], P= 0.07) and inferior OS (HR 0.67 [95% CI 0.49-0.91], P= 0.012), while EBV negative PTLD was associated with poorer RFS (HR 1.51 [95% CI 1.12-2.04, P= 0.006). In addition, achievement of PR to 1st line Tx vs CR was strongly prognostic for inferior RFS (HR 2.58 [95% CI 1.88-3.54], P< .0001) and OS (HR 2.30 [95% CI 1.60-3.29], P< .0001). Conclusions: In this large, multicenter PTLD RWA, type of SOT was strongly associated with long-term RFS and OS and EBV status predicted RFS. Furthermore, depth of response to 1st line Tx was a critical determinant for long-term pt survival. [Table: see text]
Hepatosplenic T-cell lymphoma: The Mayo Clinic experience.
Authors: Bojanini Molina Leyla , Alhaj Moustafa Muhamad , Parrondo Ricardo Daniel , Seegobin Karan , Hastings Jacquelyn , Gannon Nicole , Hoppe Bradford , Menke David M , Kharfan-Dabaja Mohamed , Ayala Ernesto , Jiang Liuyan , Tun Han W.
Published: May 2020

e20036

Background: Hepatosplenic T cell lymphoma (HSTL) is a rare subtype of mature T cell lymphomas accounting for less than 1 percent of non-Hodgkin lymphomas. it has been associated with poor prognosis. It typically involves sinusoids in the spleen, liver, and bone marrow. Methods: Following IRB approval, we retrospectively evaluated patients with HSTL treated at the Mayo Clinic Cancer Center 1996-2019. Kaplan-Meier survival analysis and univariate analysis to identify prognostic factors were performed. We investigated clinical characteristics and outcomes among patients with HSTL. Results: 22 patients (15 males) with median age of 45.5 years (range- 15.5-80.6) were identified. The majority of patients had B symptoms (12/22), cyotpenias (20/22), massive splenomegaly (16/22), liver involvement (13/22), and/or bone marrow involvement (14/22). Additionally, 42% tested positive for peripheral blood involvement and 8/22 (36%) were on chronic immunosuppression related to solid organ transplant (2), inflammatory bowel disease (2), and rheumatologic disorders (4). Phenotypically, the majority of patients were positive for gamma/delta (18/22), isochromosome 7q (8/13), and 4/9 (44%) tested positive for trisomy 8. Initial therapies included CHOP/CHOEP (14), ICE (2), EPOCH (1), pentostatin (1), and radiation (1). The median follow-up was 33 months (range 2,137). Progression free survival and overall survival (OS) were 9.5 months (95% CI; 1.8, 16.3) and 12 months (95% CI; 4.9, 18.5) respectively. 10/22 (45%) underwent splenectomy with one patient receiving splenectomy alone as treatment. 8/22 (36%) had stem cell transplant (SCT- 5 allogeneic and 3 autologous). Out of the 22 patients 4 (18%) were long-term survivors with 55, 74, 95, and 137 months; 3/4 had splenectomy at diagnosis and 2/4 had allogeneic SCT. The longest survivor had splenectomy only. Liver involvement was associated with worse OS; 10 months (95% CI; 1.6, 18) vs 35 months (95% CI; 4, NR), p = 0.036. Immune suppression at diagnosis was associated with worse OS; 5 months (95% CI; 1.3, 18) vs 18 months (95% CI; 9, 74), p = 0.036. A trend for better OS was seen with splenectomy and SCT. Conclusions: HSTL is a rare lymphoma with poor prognosis. Long-term survival was seen in 18% only. Liver involvement and immune suppression had a negative impact on OS. A larger cohort is needed to better evaluate the impact of different treatment options.
Phase Ib study of brentuximab vedotin (BV) with low-dose total skin electron beam (LD-TSEB) for treatment of mycosis fungoides (MF) and Sezary syndrome (SS).
Authors: Song Shiyu , Holkova Beata , Mukhopadhyay Nitai , Williamson Daeryl , Dickinson Molly
Published: May 2020

e20037

Background: MF is generally not curable, causing severe symptoms and eventually leading to patient (pt) death. LD-TSEB is currently used for diffuse skin lesions but with short duration of response. BV is effective and approved for MF but also limited by short duration of response. In this study we proposed to evaluate the feasibility of combining these 2 treatments by assessing the safety and response rate/duration in these pts. Methods: Pts with stage IB - IVA CD30+ MF or SS who were candidates for TSEB were recruited for a 2-cohort open-label phase 1b trial. Cohort A included pts with earlier stage disease; cohort B included pts with more advanced disease. BV was given at 1.8 mg/kg 3 wks before initiation of TSEB and then every 3 wks. Pts in Cohort A received 3 doses of BV; pts in Cohort B continued BV until disease progression or unacceptable toxicity, up to 2 years. Standard 12 Gy TSEB was administered in 6 fractions (2/wk) beginning 3 wks after the first dose of BV. The Modified Severity Weighted Assessment Tool (mSWAT) was used to determine skin involvement at baseline and during and after treatment. Skindex-16 was used to assess pt-reported symptoms and toxicities. Pts were seen weekly during TSEB, monthly after TSEB, and every 3 months after the last dose of BV for response evaluation and time to progression (TTP). Results: Five pts were enrolled and treated in this study. Two were enrolled to Cohort A, and 3 were enrolled to Cohort B. One pt in Cohort B expired before completing study treatment due to comorbidity unrelated to MF. The other pt data is listed in the table. None of the pts developed grade 4 or 5 toxicities; pt 1 developed recurrent neuropathy and stopped BV after 5 cycles. Conclusions: As BV became approved for the indication, accrual slowed, and the trial was stopped with very few pts. These pt cohorts are heavily treated before trial entry, making conclusions regarding response hard to generalize. However, the combination of BV and TSEB is well tolerated with no significant increase in skin toxicity. Response rate seems comparable to current standard of care, though with no improvement in duration of response over BV alone. Clinical trial information: NCT02822586 . [Table: see text]
Prognostic value of event-free survival at 24 months for adolescent and adult T-cell lymphoblastic lymphoma.
Authors: Chen Haizhu , Shi Yuankai
Published: May 2020

e20042

Background: T-cell lymphoblastic lymphoma(L-LBL) has an aggressive clinical behavior. To date, powerful and consistent prognostic factors have not been established for adolescent and adult T-cell lymphoblastic lymphoma. In this study, we firstly evaluated the prognostic value of event-free survival (EFS) at 24 months (EFS24) for adolescent and adult T-LBL. Methods: Between January 2006 and December 2017, 91 adolescent and adult patients (aged≥12 years) with newly diagnosed T-LBL and treated with chemotherapy were retrospectively analyzed. EFS was defined as the time from initial diagnosis to relapse or progression, retreatment, death from any cause, or to the last follow up. Subsequent OS was defined as time from achieving EFS24 or time from progression in patients who did not achieve EFS24 to death from any cause or last follow-up. Results: In total, 91 patients with previously untreated T-LBL who had a median age of 24 years were enrolled. At a median follow-up of 40.4months (range, 1.4 to 163.3 months), the 5-year OS and EFS was 47.9% and 45.5%, respectively. Of all patients, 45(49.5%) achieved EFS24 and 46(50.5%) did not. EFS24 was associated with a markedly superior outcome, compared with no achievement of EFS24(5-year OS, 90.5% vs 3%). In addition, the median subsequent OS for patients achieving EFS24 was not reached (5-year subsequent OS, 84.9%), whereas median subsequent OS for patients without achieving EFS24 was only 5.5months (5-year subsequent OS, 2.7%). Multivariate analysis demonstrated that only response to treatment (CR vs no CR) was significantly associated with EFS (HR =0.219,95% CI 0.118-0.404, P < 0.001), and EFS24 achievement was an independent prognostic indicator for OS (HR = 0.044, 95% CI 0.016-0.120, P < 0.001). Conclusions: We confirm that EFS24 is an independent prognostic factor for OS, which can aid clinicians in discussions of risk stratification and in selection of subsequent treatments. Further validation in the context of directed prospective clinical trials is warranted.
Incidence of second primary malignancy (SPM) in patients with mucosa-associated lymphoid tissue lymphoma (MALToma).
Authors: Budhathoki Nibash , Timilsina Sunita , Thomas Charles , Damato Aaron , Magid Diefenbach Catherine S. , Braunstein Marc Justin
Published: May 2020

e20043

Background: MALTomas are extranodal marginal zone lymphomas that arise from B cells in various mucosal lymphoid tissue and are typically indolent. Patients with MALTomas may be at risk for additional cancers due to their long-term survival following treatment, however the incidence of SPM in MALTomas in the U.S. has not been previously described. Methods: Adults with MALT lymphoma were identified using the 2000-2016 SEER-18 database. SPM was defined as tumors diagnosed ≥6 months and up to x months from lymphoma diagnosis. SEER*stat was used to calculate SPM by multiple primary standardized incidence ratio based on observed (O) and expected (E) cases. The expected cases of new cancers of specific types were estimated by assuming that incidence rates for new primary tumors corresponded to sex, age, and calendar time–specific SEER rates for similar invasive primary cancers and applying those rates to the accumulated person-years (PYR) of observation. Excess absolute risk (EAR) of malignancy per 10,000 PYR at risk was calculated as ([O − E]/PYR) × 10,000. Results: As summarized in the table, 12,500 patients were diagnosed with MALT lymphoma of which 1466 (11.8%) developed 1626 SPMs (O/E rate 1.5, 95%CI 1.4-1.5, P < 0.001, EAR 70.4). Median latency period was 54 months (range 6 - 201). Non-Hodgkin lymphomas at separate tissue sites were the most common SPM, with 299 documented cases (O/E rate 6.2, 95%CI -5.4-6.8, P < 0.001, EAR 33.4). Between 6-24 months from MALToma diagnosis, head and neck, renal cell, liver, and anal cancers were increased, while after 24 months, gastric and small bowel cancers, CLL, ALL, and myeloma were increased compared to the general population of the same age group. Conclusions: There is distinct pattern of SPM among patients with MALT lymphoma in within and after 2 years from diagnosis, with an increased incidence compared to the general population. Consider the median latency, SPM may be due in part to the long-term survival and relatively older age of this population. [Table: see text]
Updated results of the ASPEN trial from a cohort of patients with MYD88 wild-type (MYD88WT) Waldenström macroglobulinemia (WM).
Authors: Garcia-Sanz Ramón , Dimopoulos Meletios A. , Lee Hui-Peng , Trneny Marek , Varettoni Marzia , Owen Roger G. , Castillo Jorge J. , Siddiqi Tanya , Tedeschi Alessandra , Buske Christian , Leblond Veronique , Chan Wai Y. , Schneider Jingjing , Ro Sunhee K. , Cohen Aileen , Huang Jane , Tam Constantine Si Lun
Published: May 2020

e20056

Background: Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with WM harboring a mutation in the MYD88 gene. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations ( N Engl J Med. 2015;372:1430). The ASPEN trial evaluated zanubrutinib (ZANU), a potent and selective BTK inhibitor, in WM patients. Methods: In the ASPEN trial, bone marrow MYD88 mutations were assessed at study entry by a central laboratory (NeoGenomics). Based on the results of the MYD88 mutation assay, patients were assigned to cohort 1 ( MYD88 mutation) or cohort 2 ( MYD88WT or mutation unknown). All cohort 2 patients received ZANU 160 mg twice daily until disease progression. The objective was to assess the safety and efficacy of ZANU in patients with MYD88WT WM. Results: In total, 28 patients with 26 MYD88WT WM were enrolled into cohort 2. The median age was 72 years; 5 patients were treatment-naïve (TN) and 23 patients were relapsed/refractory (R/R; ≥1 prior therapy). Most patients had intermediate- (39.3%) or high-risk (42.9%) disease by International Prognostic Scoring System for WM. With the median follow-up of 17.9 months, 2 patients discontinued ZANU due to adverse events, and 6 patients experienced disease progression; there were no cases of disease transformation. The overall response rate was 80.8%, with a major response rate of 50.0%, including a very good partial response (VGPR) rate of 26.9% (Table). Progression-free survival event-free rate at 12 months was 72.4%. The most frequently reported adverse events (AEs) were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection. Major hemorrhage was reported in 2 patients, and atrial fibrillation was reported in 1 patient. There were no fatal AEs. Conclusions: ZANU showed clinically meaningful antitumor activity, including achieving major responses and durability of responses, and was considered well-tolerated with a low discontinuation rate due to AEs, in patients with MYD88WT WM. ZANU demonstrated efficacy regardless of MYD88 mutational status in WM. Clinical trial information: NCT03053440 . [Table: see text]
Health-related quality of life (HRQOL) burden in patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL) and non-Hodgkin’s lymphoma (RR-NHL).
Authors: Lin Vincent , Oak Bhagyashree , Snider Julia , Epstein Josh
Published: May 2020

e20070

Background: CAR T therapy is being investigated as 2nd line therapy in RR-DLBCL. To evaluate its impact on patients’ HRQOL, it is essential to understand the HRQOL of patients receiving current standard of care (SOC) therapy for DLBCL and NHL patients. Methods: A systematic literature review (SLR) of studies reporting HRQOL in RR-DLBCL patients was conducted in March 2019 (updated to include RR-NHL in May 2019) using EMBASE, MEDLINE, Cochrane (all from 2007), Northern Light and International Society for Quality of Life Research abstracts (both from 2017). A targeted literature review (TLR) for untreated or 1st line patients was conducted in July 2019 using PubMed. Search terms included diseases, lines of therapy and patient-reported outcome (PRO) measures. Abstracts and publications were screened for eligibility and data were extracted. Results: Of the 977 publications screened for the SLR, 26 met the inclusion criteria. Another 18 studies were included from the TLR. The most commonly used PRO measures were the SF-36 (10 studies), EORTC QLQ-C30 and FACT-Lym (8 studies each). The EORTC QLQ-C30 showed statistically significant or clinically meaningful changes in a greater number of domains (86%) than the FACT-Lym (75%) and SF-36 (62%). Additional results in table. Conclusions: While research is limited, RR-DLBCL patients receiving current SOC therapy report decreases in HRQOL and health utility. Further research is needed on how existing and future therapies may affect HRQOL among RR-DLBCL patients. [Table: see text]
Clinicopathologic features and outcome of extra-nodal diffuse large B-cell lymphoma: An institutional experience from North India.
Authors: Nair Sukesh C , Gogia Ajay , Kumar Lalit , Sharma Atul , Biswas Ahitagni , Mallick Saumyaranjan
Published: May 2020

e20079

Background: Primary extranodal diffuse large B cell lymphoma (DLBCL) forms upto 40-50% of all cases of DLBCL . Clinicopathological features and outcome of extranodal DLBCL patients especially in the rituximab era are scarce from developing countries. Methods: We carried out an ambispective analysis of newly diagnosed DLBCL patients (n = 417) over a period of 5 years (2014-2018).Of this total cohort 224 (53.7%) were found to have primary or predominant extranodal involvement. Prognostic factors were identified using Cox-regression analyses. Results: Median age was 50 years (18-86) with male female ratio of 2:1. B symptoms were seen in 48% patients and bulky disease in 39%. ECOG performance status of 0 or 1 was present in 50% and 63% presented with advanced disease. Bone was the most common site of extranodal involvement (32%) in our study followed by gastrointestinal tract ( 30%).Cell of origin (based on Hans algorithm) was available in 80% patients with Germinal center subtype (GCB) forming 44% and non-GCB forming 36% of all patients. Bone marrow involvement was present in 13 % patients. Low risk International Prognostic Index (IPI) was seen in 32 % and 41% were having intermediate risk IPI, the remaining being high risk. CHOP based treatment was used in 80 % of cases and rituximab was used in 76% of all cases. The overall response rate was 76% with a complete response rate (CR) of 65.5%. Presence of B-symptoms, central nervous system (CNS) involvement, non R-CHOP regimen and non-radiotherapy treatment protocols were associated with inferior CR rate. After a median follow up of 26 months, the 3-year event free survival and overall survival were 65 % and 82.7 % respectively. Involvement of specific extranodal sites (kidney, adrenals and CNS), high IPI score and use of non R-CHOP regimens were associated with poor EFS and OS on multivariate analysis Conclusions: This is one of the largest studies from India on extranodal DLBCL in the rituximab era. Involvement of specific extranodal sites, high IPI score and use of non R-CHOP regimens were associated with inferior survival.
Impact of immunoparesis on clinical outcomes following bone marrow transplantation.
Authors: Torgerson Nicholas , Odetola Oluwatobi , Hagen Patrick , Hossain Nasheed , Tsai Stephanie , Smith Scott E. , Stiff Patrick J.
Published: May 2020

e20505

Background: Immunoparesis (hypogammaglobinemia) has been shown to impact outcomes in patients with newly diagnosed multiple myeloma (MM). Its impact in the post-transplant setting and potential risk of both infections and immune dysregulation impacting relapse is less clear. We sought to assess the role of immunoparesis both pre and post autologous stem cell transplant (ASCT) in newly diagnosed MM patients. Our primary outcome was the impact of immunoparesis on progression free survival (PFS) post-ASCT controlling for maintenance therapy. Methods: We evaluated all MM patients between 2008 and 2017 at Loyola University who underwent ASCT. Inclusion criteria included first ASCT and age > 18 years. We evaluated both the presence of and number of impacted immunoglobulin (Ig) classes pre-transplant and day 100, 6-months, and 12 months post-ASCT. Results: The most common MM isotype was IgG Kappa (41.01%). Immunoparesis pre-ASCT and post-ASCT at day 100, 6 months, and 12 months was seen in 75%, 89.5%, 80%, and 58.5% respectively. Median time from diagnosis to transplant was 7.75 months (5.98 – 13.73). When adjusting for pre-transplant response, conditioning regimen, and post-transplant maintenance, neither the absolute presence of or number of Ig-classes impacting was predictive of hazard of disease progression or death (OS) while ISS-stage, best response post ASCT, and time from diagnosis to transplant were (table). Conclusions: Contrary to studies in the pre-transplant setting, our analysis indicates that immunoparesis is not predictive of relapse or survival in the post-transplant setting, suggesting modification of disease process with treatment and ASCT. When controlled for maintenance therapy, immunoparesis does not increase risk of progression or decrease overall survival alleviating the concern for increased morbidity/mortality secondary to infections in the face of immunoparesis in the era of maintenance therapy. [Table: see text]
The effect that β-lactam antibiotics have on progression free and overall survival in multiple myeloma patients undergoing autologous stem cell transplantation.
Authors: McKenna Marshall , Feinman Rena , Ahn Jaeil , Wang Shuqi , Vesole David H. , Goldberg Stuart L. , Suero-Abreu Giselle Alexandra , Gonzalez Velez Miguel , Wang Jun Chih , Rehman Abdul , McKiernan Phyllis , Donato Michele , Paleoudis Elli Gourna , Siegel David Samuel DiCapua , Biran Noa
Published: May 2020

e20518

Background: Gut microbiome dysbiosis is correlated with graft-versus-host disease (GVHD) in allogeneic stem cell transplant (allo-SCT) patients. In the allo-SCT population, antibiotics have been associated with increased risk for GVHD mortality and relapse due to loss of gut obligate anaerobes . It has been shown that antibiotics may negatively impact the efficacy of checkpoint inhibitors for patients with solid tumors. Based on these studies, we performed a retrospective analysis to determine if antibiotic treatment affects outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: This is a single institution retrospective study at Hackensack University Medical Center. A list of consecutive MM patients treated from 1/2012 to 12/2015 was obtained and an electronic medical record review of the first 217 who received ASCT was performed. Baseline characteristics, treatment history, transplant course and antibiotic treatment (including β-lactams, fluoroquinolones, macrolides, metronidazole, and vancomycin) were reviewed. Prophylactic antibiotics were excluded. Response was defined using the IMWG criteria. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Log rank tests were used to compare the difference in survival between stratified groups. The LASSO cox regression analysis method was used for multivariate analyses of PFS and OS. Results: Of the 217 patients, 205 patients were available for analysis. Median age at ASCT was 61. β-lactams were associated with decreased median PFS (1.95 vs 4.77 years (yrs), p < 0.01) and decreased median OS (7.51 vs 13.45 yrs, p = 0.01). Multivariate analysis adjusting for lasso-selected age, gender, complete remission (CR) after ASCT, and ISS demonstrated independent progression risk associated with β-lactam use (HR = 2.00, 95% CI, 1.28–3.12, p < 0.01). β-lactams were associated with worse OS in multivariate analysis adjusting for lasso-selected age, gender, CR after ASCT and high risk cytogenetics (HR = 1.89, 95% CI, 1.07–3.40, p = 0.03). Conclusions: In this preliminary study, β-lactams predicted for decreased PFS and OS compared to patients who did not receive β-lactams in MM patients undergoing ASCT. The study was limited by its retrospective nature but demonstrates one of the first evaluations of antibiotic effect on the ASCT population in MM. Prospective studies evaluating the impact of antimicrobials on patient outcomes and the gut microbiome are ongoing.
Triplet versus doublet therapy in multiple myeloma patients over 75 years.
Authors: Alam Zuhair , Grewal Ravleen , Girnius Saulius Kazmiems
Published: May 2020

e20519

Background: Clinical trials in multiple myeloma (MM) typically enroll patients that are younger and less frail while 33% patients are over the age of 75. Advanced age/frailty is associated with worse prognosis, partly due to poor tolerability of therapy. Compared to doublets, triplets improve progression-free and overall survival (PFS and OS), but these outcomes are not well studied in older patients. Here, we compare doublet and triplet therapy in newly diagnosed MM patients over 75. Methods: The MMRF’s CoMMpass trial is an international, longitudinal, observational study capturing disease progression and response to treatment. Using the MMRF database, we compared doublet versus triplet therapy in patients over 75. Primary outcome was PFS while secondary outcomes included OS, quality of life (QoL) and fatigue. QoL was assessed using EORTC QLQ-C30 questionnaire and fatigue was captured by the MM eCRF survey. Results: 146 patients were eligible for analysis. Median age was 80 years. 27 (18%) were ISS 1, 38 (26%) were ISS 2, and 59 (40%) were ISS 3. Amongst doublets (n = 62), 48% received Bortezomib/Dexamethasone while 48% received Lenalidomide/Dexamethasone. Amongst triplets (n = 71), 35% received both proteasome inhibitors (PI) and immunomodulatory drugs (IMIDs), whereas 58% received PI-based therapy with no IMID. Mean PFS for doublets was 467 days and for triplets was 608 days, with difference of 141 days (p = 0.0663). Mean OS for doublets was 757 days and for triplets was 920 days. Difference of 163 days was not statistically significant (p = 0.1784). In doublets, QoL remained at a median of 50% from baseline to 5 years. In triplets, QoL improved from a median 58% to 83% from baseline to 5 years. With respect to fatigue, levels remained unchanged from baseline to 5 years in doublets (43 to 44%) and dropped from 37% to 29% in triplets. Conclusions: There is a trend towards improved PFS, as well as an improvement in QoL and fatigue in MM patients over 75 that are treated with triplets as compared to those treated with doublets. Limitations include lack of randomization and selection bias.