bluuebunny/crossref_metadata_2025 huggingface dataset:
Timed sequential therapy with high-dose cytarabine and mitoxantrone as an induction regimen for acute myeloid leukemia: An update on adverse events.
Authors: Richardson Kristin J. , Kollipara Revathi , Katz Deborah Ann , Hoyt Maura , Gallas Kirstin , Venugopal Parameswaran , Larson Melissa L.
Published: March 2020

e18524

Background: Traditionally, patients eligible for induction chemotherapy for AML are treated with the “7+3” regimen, standard doses of infusional cytarabine and an anthracycline, with historical CR rates of 50-60%. We present a retrospective analysis of an alternate induction regimen. Based on timed sequential therapy, it consists of a 2-day treatment with high dose cytarabine, which improves remission rates when used in induction, and dose intensified anthracycline therapy, which improves outcomes while maintaining an acceptable safety profile. Methods: 200 patients were treated from 2010-2015. Patients received 2 doses of cytarabine 2 gm/m2 (1.5 gm/m2 age > 70 years) IVPB over 3 hours, 12 hours apart followed by 1 dose of mitoxantrone 30 mg/m2 IVPB over 1 hour on days 1 and 5. Cytogenetics and adverse events data were collected. IWG remission criteria were used to determine remission status. Results: Median age 57.6 years (range 23-79); 105 (53%) age > 60. 119 male; 81 female. Risk stratification: 12 favorable; 108 intermediate; 80 unfavorable . Overall CR rate (CRR: CR+CRi+CRp) for all patients was 68.5%. CR rates based on risk karyotypes: favorable 100%, intermediate 76.8%, unfavorable 52.5%. Most common G3-4 adverse events: anemia (60% G3, 40% G4), neutropenia (1% G3, 99% G4), thrombocytopenia (0.5% G1, 99.5% G4). 196 patients (98%) had neutropenic fever; 134 (67%) documented infections (100 with G3/4), 62 (31%) neutropenic fever with no source. 52 (26%) experienced bleeding (15 G1, 31 G2, 4 G3, 1 G4, 1 G5). G3/4 renal or hepatic toxicity was rare. No cerebellar toxicity occurred during induction. 30 day mortality 0.5%; 60 day mortality 3%. 62 (31%) patients are still alive; 122 died, 16 lost to follow-up. Conclusions: This two-day induction regimen is an effective treatment for AML with an acceptable safety profile including patients age >60. There is a high response rate, particularly for favorable and intermediate risk karyotypes, with a low rate of early mortality. The high response rates and tolerability with this regimen provides a platform for further clinical trials to enhance outcome by combining with novel targeted therapies for AML.
Mortality of acute promyelocytic leukemia in a rural tertiary care center.
Authors: Vadakara Joseph , Kharel Prakash , Bhattacharya Prianka , Vanenkevort Erin , Manikowski Jesse
Published: March 2020

e18529

Background: Acute promyelocytic leukemia (APL) has a very good prognosis when diagnosed and treated promptly. Despite the excellent prognosis, early mortality remains high, ranging 17-40%. Geisinger Health System (GHS) has provided treatment for a significant number of APL patients, but mortality of APL at GHS has not been studied. We conducted a study to assess early mortality related to APL in GHS. Methods: Retrospective analysis was performed of patients diagnosed with APL from January 1988 to February 2019, determining the number of patients diagnosed and treated for APL in GHS, overall 30-day mortality rate, stratified by risk group (low, intermediate, high based on presenting white blood cell and platelet counts) and age above or below 55. Results: A total of 61 patients with APL were identified. Average age at diagnosis was 44.77 years (SD = 19.12). The death rates in patients in whom risk data was available was 7%, 9.3% and 11.6% respectively in the low, intermediate and high risk groups respectively. There was no statistically significant difference in the frequency distribution between risk categories for survival, χ2 = 1.03, p = .60. Between age groups, 8.3% of patients under age 55 died, whereas 18.3% of those 55 or older died. Survival between the two age groups was statistically significant, χ2 = 10.92, p = .001. Estimated 30-day overall mortality in the studied population was 16.39%; and 7.69%, 5.56% and 38.46% for the low, intermediate, high-risk patients respectively. Conclusions: Among patients diagnosed with APL in the GHS over the past 30 years, the early mortality rate has been comparable to reported mortality rates in centers around the world. Our study showed a statistically significant higher mortality rate in patients 55 years or older. Further study is planned to assess factors contributing to mortality and outcomes.
Effect of secure clinical messaging on chemotherapy adherence.
Authors: McLarty Sarah , Friend Kayla E , Chadha Neha , Verma Santosh K , Sawicki Christine , Johnson Kjel Andrew
Published: March 2020

e18542

Background: Oncologists offer essential clinical information to patients face-to-face or by phone. Today, patients commonly prefer digital communication. To test the effectiveness of this in patients, we deployed proprietary secure messaging (SM) to communicate clinical messages to patients regarding prescribed oral chemotherapy in an effort to improve adherence. Methods: Chronic myelogenous leukemia (CML) patients receiving a tyrosine kinase inhibitor (TKI) were evaluated as two groups: a test group of patients starting therapy between Jan - Jun 2018 who received SM within 45 days therapy start who received SM refill reminders, adherence, condition management, laboratory testing reminders every 30 days, and information regarding side effects, versus a control group that included propensity matched patients initiating therapy between Jan - June 2017 and who received only non-clinical text message refill reminders within 45 days of therapy start. Adherence was compared 6 months after the initial prescription. Primary outcomes were medication possession ratio (MPR) (total day supply/ [(last fill date+last fill day supply)-first fill date]), number of prescriptions filled, % of patients optimally adherent (MPR ≥ 85%), and rate of discontinuation after first fill. The secondary outcome was days of therapy. A t-test evaluated MPR and length of therapy; logistic regression compared discontinuation after first fill and % optimally adherent. Results: 478 CML patients opted into SM and 478 where in the control group. MPR improved 1.6% absolute points (93.20 control v 94.80 test, p = 0.04); no change was seen in number of prescriptions filled (5.04 control v 5.17 test, p = 0.19). More patients receiving SM were optimally adherent (83.05 control v 88.31 test, p = 0.03); discontinuation after first fill was unchanged (6.90 control v 6.49 test, p = 0.79), as were days of therapy (156.51 control v 159.22 test), p = 0.35). Conclusions: Patients initiated on TKI therapy with receiving clinical SM had significantly higher adherence than the control group and were more likely to be optimally adherent, despite the high adherence rates of CML patients at baseline. Further analysis is needed to understand the durability of this adherence improvement.
Outcome of CML patients with de novo bleeding complications: Do they behave differently?
Authors: Sandal Rajeev , Jandial Aditya , Mishra Kundan , Prakash Gaurav , Khadwal Alka , Lad Deepesh , Varma Neelam , Malhotra Pankaj
Published: March 2020

e18546

Background: Chronic myeloid leukemia (CML) is a clonal hematopoietic neoplasm. A subset of CML patients present may present with unusual bleeding manifestations. There is limited data on the incidence and outcome of such patients on treatment with imatinib. Methods: We analysed the CML patients treated at PGIMER Chandigarh from January 2003 to December 2018. Baseline spleen and liver size, hematological parameters, Sokal and Hasford score, site and severity of bleeding (as per WHO classification) were recorded. The treatment response, occurrence of cytopenias and need for second line TKI were analyzed. Results: Sixty-six patients (2.8%) out of 2350 adult CML patients had bleeding at diagnosis. The median age was 35 years (range 15 – 66 years); 56.1% were males. The median duration of follow up was 79 months (range 6 – 123 months). Splenomegaly and hepatomegaly was found in 89.3% and 65.1% patients, respectively. Baseline median hemoglobin was 9.5 g/dL; TLC was 151600/mm3 and platelet count was 301000/mm3. Based on Sokal score, 15/66, 26/66 and 25/66 patients belonged to low, intermediate and high risk categories, respectively. According to Hasford score, 22/66, 36/66 and 8/66 patients belonged to low, intermediate and high risk categories, respectively. Based on WHO grading, 33/66, 30/66 and 3/66 patients had grade 1, 2 and 3 bleed, respectively. 48 patients had mucocutaneous bleeding [cutaneous 17, gum bleed 16, epistaxis 15], 4 had psoas haematoma, 7 had vaginal bleeding, 3 had ocular bleeding, 6 had GI bleed [upper GI 3, lower GI 3], 3 had hematuria. 74.2% achieved CHR at 6 weeks and 83.3% achieved MMR at 12 months with Imatinib. 18 developed cytopenias which required Imatinib interruption or dose reduction. 18 required Imatinib dose escalation for suboptimal response, 5 patients received second line TKI. Six patients progressed to advanced phase CML (AP/BC) after a median duration of 32 months (range 21 – 49 months). Bleeding manifestations resolved in all patients and there was no recurrence of bleeding on follow up. Conclusions: Bleeding is an uncommon presentation of CML. It might be a harbinger of an increased risk of cytopenias, suboptimal treatment response and disease progression on Imatinib.
Clinical validation of NGS workflow in myeloid neoplasms.
Authors: Bourgne Céline , Berger Marc , Kurze Alexander
Published: March 2020

e18557

Background: The advent of NGS technologies revolutionized patient management. Compiling a comprehensive list of genomic alterations and summarizing the clinical implications is complex and time-consuming. One main difficulty lies in detecting relevant genomic alterations with actionable, diagnostic and prognostic value. The development of bioinformatic tools is essential to interpret genomic data. Here we describe the validation of an end-to-end genomic NGS workflow to diagnose myeloid disorders. Methods: Performed on 81 patients previously diagnosed using non-NGS diagnostic tests, this study aims at finding out if an NGS diagnostic approach can accelerate the diagnosis process. DNA was extracted from purified mononuclear cells (n = 54), polymorphonuclear cells (n = 50) and/or total leucocytes (n = 58) from peripheral blood and bone marrow (n = 9). Genomic analysis was performed using a capture-based solution (MYS by SOPHiA GENETICS) covering 30 relevant genes associated with MDS, MPN and Leukemia. Sequencing was performed on Illumina MiSeq and results were analyzed using the SOPHiA platform. Results: We performed 2 validation runs with high raw reads quality (Phred-score > 35). Over 90% of reads were on-target and coverage was larger > 1000x with a mean of 10 regions falling below this threshold for each sample. Repeatability and reproducibility were evaluated with 6 samples and showed a good correlation between intra (R = 0.993) and inter run (R = 0.97) replicates. Average number of driver mutation was 1.3 for patients with MPN (n = 38), 3 for patients with CMML (n = 9), 2.3 for patients with MDS (n = 10), 2.5 for patients with AML (n = 13) and 1.2 for other neoplasms (n = 11). Obtained NGS results supported previous diagnoses. However for patients where peripheral blood and bone marrow samples were used to perform the analysis, one patient with mastocytosis has a discrepancy of variants found in each sample type. We detected 4 variants in peripheral blood and one additional variant in DNA extracted from bone marrow. The mutation occurred in the RUNX1 gene and was associated to an unfavourable prognosis with higher risk of relapse. Conclusions: We described here the successful validation of a single NGS panel to diagnose multiple myeloid neoplasms. The workflow shows excellent reliability in terms of reproducibility and repeatability which is essential for clinical implementation. Each method has its own benefits and limitations and interpretation of results should be made taking into account the type of the sample used.
The value of low, fixed, single dose rasburicase in the prevention and treatment of tumor lysis syndrome.
Authors: Ponnada Bharadwaj , Raghuram Saadvik , Kotne Sanketh , Keechilat Pavithran
Published: March 2020

e18558

Background: Rasburicase is a recombinant urate oxidase drug approved by the US FDA for the management of hyperuricemia in Tumor Lysis Syndrome (TLS). Recommended dose of 0.2 mg/kg/day for 5 days is expensive and the benefit of extended schedule compared to a single fixed dose of 1.5 mg is not known. Methods: This is a retrospective cohort study done at a tertiary medical center including 165 (144 adult and 21 pediatrics) patients admitted between January 2013 and December 2018. We analyzed the efficacy of single low dose rasburicase 1.5 mg irrespective of bodyweight in adults and in children a dose of 0.15 mg/kg (maximum 1.5 mg) intravenously over 30 min for prevention and treatment of TLS and subsequent doses were given based on clinical and biochemical response. Plasma samples for uric acid were collected at baseline, 6–24 hrs, 48 hrs post-rasburicase, and daily during treatment. The primary outcome was achieving a uric acid level less than 7.0 mg/dl after a single dose of rasburicase in the groups. Secondary outcomes included need for repeat rasburicase doses, and a cost analysis. Results: Children accounted for 12.1% (n = 20) and adults 87.9% (n = 145). The median ages in pediatric and adult groups were 7.9 years and 54 years respectively. Rasburicase was used prophylactically in 35 (21.2%), for laboratory TLS in 105 (63.6%) and for clinical TLS in 25 (15.2%) patients. SDR prevented laboratory/clinical TLS in 89% of the prophylactic group and prevented clinical TLS in 72% of the laboratory TLS group. However, 92%(n=23) of the patients with clinical TLS required more than one dose rasburicase. The average total monthly cost of rasburicase was reduced by 96% ($2850 to $114) after adoption of the above protocol. Conclusions: Single low dose rasburicase is a highly economical and clinically effective way of managing patients with TLS and could serve as an alternative to the 5-day treatment. This dose, therefore, balances cost and efficacy of treatment.
Chronic lymphocytic leukemia: An Indian experience.
Authors: Gogia Ajay , Gupta Ritu , Sharma Atul , Kumar Lalit , Raina Vinod , Rani Lata
Published: March 2020

e19007

Background: Chronic lymphocytic leukemia (CLL) is the most common lymphoproliferative disorder in the West accounting for about 30% of leukemias, whereas in Indian subcontinent it accounts for 3-5% of all leukemias. We aimed to evaluate biological and molecular prognostic parameters as well as therapeutic considerations in CLL patients in India. Methods: We retrospectively analyzed 510 patients with CLL, who presented at our institute over a period of 18 years. Results: The median age of CLL patients at presentation was 60 years (range: 28 - 92 years) with male: female ratio = 3:1. The median total leukocyte count was 45X109/L . As per clinical Rai stage distribution 55 (10.08%) patients were in Stage 0, 92 (18%) in stage I, 174 (34%) in stage II, 92 (18%) in stage III and 97 (19%) were in stage IV. ZAP-70 was positive ( > 20%) in 206 (57% , n = 361) , CD 38( > 30%) in 107 (29% , n = 363), and CD49d was positive ( > 30%) in 63 (50.3%, n = 127) cases. Beta-2 microglobulin (B2M) was elevated (≥3.5 mg/L) in 243 patients (70%, n = 347). One hundred and fifty six cases (57%, n = 273) were IGHV mutated and Del (17p) by FISH was observed in 18 cases (12%, n = 150). A total of 331 (64.9 %) patients required treatment wherein 155 patients (46.8%) received Chlorambucil-based, 110 ( 33.2%) received BR, 42 (12.6%) received Fludarabine based ( FC-7,FCR-35) and 41 patients received others regimen. Overall response rate seen with Chlorambucil, BR and Fludarabine based regimen was 67% ( CR-3.2%), 90% ( CR-45%) & 88% ( CR-44%) respectively. Median event free survival (EFS) and overall survival (OS) and was 3.5 years and 5.5 years respectively, with median follow up period of 3.9 years. Clinical stage (Rai III/IV), elevated B2 M, IGHV-unmutated had statistically significant adverse impact on OS and EFS. Fludarabine based chemotherapy appeared toxic as half of patients developed febrile neutropenia and various infections whereas in BR , cutaneous side effects were more common(p = 0.001) . In early stage CLL, median time to first treatment was 22 months and; IGHV-unmutated, elevated B2M and CD38 positivity were significantly associated with shorter treatment free survival. Conclusions: This is the largest series of CLL reported from Asia. Clinical Rai Stage III/IV, unmutated IGHV and elevated B2M have statistically significant adverse impact on survival of patients with CLL. BR was better tolerated than fludarabine based regimen with similar responses and events.
Substitution of single dose intravenous methylprednisolone (MP) for oral prednisone (Pred) in RCHOP in intermediate grade non-Hodgkin’s lymphoma (NHL).
Authors: Quan Walter , Gutierrez Leah I , Quan Francine Marie
Published: March 2020

e19019

Background: The regimen CHOP (cyclophosphamide, Hydroxydaunorubicin [doxorubicin], Oncovin [vincristine] and Pred) has been the basis of therapy given with curative intent for intermediate grade NHL for over 40 years. Rituximab added to CHOP (RCHOP) has been the standard for more than a decade. For patients (pts) with prior medical problems such as brittle diabetes, gastrointestinal bleeding, or psychiatric disorders, oral Pred given daily for 5 days is problematic. Methods: In this retrospective study between January, 2007 and September 2018, twenty pts, Diffuse Large B-cell (18) or grade III Follicular NHL (2), for whom standard oral Pred (100 mg daily for 5 days) was not felt to be medically well-suited or who refused or were not compliant with such therapy following an initial cycle, were treated with curative intent with the substitution of MP 125 mg IV (one received 60 mg IV) on day 1 (in place of oral Pred for 5 days) in combination with standard doses of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 2 mg (total dose) all given intravenously on day 1 with peg-filgastrim 6 mg subcutaneously on day 2 every 21 days. Results: Pt characteristics: 14 males/6 females, median age-56 (range: 24-76), stages: II (8), III (2), IV (10), B symptoms (12), subtypes: activated B-cell (11), germinal center (6), diffuse B-cell NOS (1), follicular grade III (2). Two were treated with 5 cycles. Fifteen received 6 cycles while three were treated with 8 cycles. Sixteen had complete responses (evaluated by PET/CT) following RCHOP. One pt with activated B-cell subtype had a short-lived partial response before experiencing disease progression. The three remaining pts had partial responses, all 3 of which were converted to complete responses following involved site radiation therapy. One with activated B-cell subtype relapsed at 68.2 months. Eighteen remain progression-free with the longest at 120.3+ months. Median progression-free survival has not been reached at 23+ months. Conclusions: RCHOP with the substitution of a single dose of MP in place of oral Pred has activity in intermediate grade NHL. Long-term disease-free survival may be seen.
Sandoz rituximab (GP2013; SDZ-RTX) for the treatment of diffuse large B-cell lymphoma (DLBCL): Interim safety results of the non-interventional, observational, multicenter, open-label REFLECT study.
Authors: Welslau Manfred , Marschner Norbert , Wolff Thomas , Otremba Burkhard Joerg , Topaly Julian , Bittencourt da Silva Larissa
Published: March 2020

e19020

Background: SDZ-RTX is approved in Europe for the same indications as reference rituximab, based on the totality of evidence for biosimilarity. REFLECT, a real-world study of SDZ-RTX as curative therapy for treatment-naïve CD20+ DLBCL, represents the first biosimilar rituximab post-approval study in DLBCL. Methods: The study includes patients (pts) aged ≥18 years, eligible for rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP). R-CHOP is administered according to product label. The primary endpoint is complete response rate at the end of treatment. Secondary endpoints include overall response rate, progression-free survival at 12 months, and adverse events (AE). Data are collected at baseline and every study visit for 12 months (efficacy) and ≥30 days after last SDZ-RTX dose (safety). No imputation for missing data is planned; endpoints are summarized descriptively. Results: In an interim analysis (cut off: Sep 6, 2018; recruitment approx. 50% complete), the full analysis set comprised 80 pts: 38 males (47.5%) and 42 females (52.5%), with median (min, max) age 68.5 years (23, 91); 70% of pts were aged ≥60 years. In total, 6 pts have discontinued. Most pts had little or no restriction in daily activities; >80% had ECOG score of 0 (34%) or 1 (50%). B-symptoms were reported in 15 pts (19%). Extranodal infiltration was observed in 40 pts (50%) and bulky disease was observed in 9 pts (11.3%). Most pts had early stage (I–IIB: 63.8%), low to intermediate risk disease (IPI Score 0–2: 61.3%). A summary of safety is reported in the Table. AEs were reported in 53 (66%) pts and 19 (24%) pts had serious AEs. Treatment-related AEs were reported in 13 pts (16%). The most frequent AEs were polyneuropathy (n=10, 12.5%), anemia (n=8, 10%), and fatigue (n=8, 10%). Conclusions: Interim baseline data are as expected for treatment-naïve pts with CD20+ DLBCL; safety results are as expected for rituximab-based treatment. The study is ongoing. [Table: see text]
Retrospective analysis of elderly patients with DLBCL: Single center experience with FIL.
Authors: Khan Yasir , Del Rosario Michael , Rezk Sherif , Taylor Thomas H. , Brem Elizabeth
Published: March 2020

e19024

Background: Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of Non-Hodgkin’s Lymphoma (NHL). According to the SEER database, median age of diagnosis is 67 with 30% of cases diagnosed in patients greater than 75. 1/3 of patients older than 80 do not receive therapy for this potentially curable disease. The Lymphoma Italian Foundation (FIL) tool has been shown to help objectively identify elderly DLBCL patients most likely to benefit from therapy with curative intent. The tool identifies patients as “Fit,” “Unfit,” or “Frail” based on age, comorbidities, and ability to perform activities of daily living. We retrospectively applied the FIL tool to patients treated at our center to evaluate its efficacy in identifying elderly patients most likely to benefit from curative chemoimmunotherapy. Methods: Research protocol was approved by University of California, Irvine IRB. We identified patients with a diagnosis of systemic DLBCL and age ≥70 between January 1, 2010 and November 8, 2018. Medical charts were used to retrospectively apply the FILtool. Results: A total of 86 patients were identified. Mean age was 77. Ratio of germinal center (GC) DLBCL to non-GC was approximately 1:1. 23 patients were categorized as Fit, 8 as Unfit, and 55 as Frail. 96% of Fit, 100% of Unfit, and 91% of Frail patients were evaluated. Rates of complete responses (CR) to initial therapy with curative intent were 77% (17/22) in Fit, 88% (7/8) in Unfit, and 44% (22/50) in Frail patients. CR rate was not different between Fit and Unfit (p>0.05), but the CR rate in Frail patients was significantly reduced compared to the other groups combined (p<0.01). Among Fit and Unfit patients, only one death was treatment-related, but in the Frail group, 6 deaths were related to treatment. Conclusions: Our data suggest that the FILTool is useful in identifying Frail patients that perhaps should be treated with reduced dose-intensity. Additionally, our findings support that Fit and Unfit patients benefit from treatment with curative intent. Future studies will apply the FIL tool prospectively to further validate these findings. [Table: see text]
Survival outcomes of patients with peripheral T-cell lymphomas (PTCL) treated with chemotherapy and/or novel agents: The Columbia University experience.
Authors: Ma Helen , Cheng Bin , O'Connor Owen A.
Published: March 2020

e19049

Background: CHOP-based regimens have been considered the standard of care for PTCL despite disappointing results. Several lines of evidence, including the regulatory approval of novel drugs since 2009, raise the question as to whether these drugs are changing the natural history of relapsed PTCL. Recent molecular insights into the pathogenesis of PTCL, especially in angioimmunoblastic T-cell lymphoma (AITL), have revealed a number of genetic lesions that might portend a unique vulnerability to select agents, such as histone deacetylase inhibitors (HDACi). Methods: This is a retrospective study of patients with PTCL who were seen and treated between 1994 and 2018. Kaplan-Meier curves for overall survival were generated and compared based on the log-rank test. Cox proportional hazard models were used to investigate the association by adjusting for age, gender, subtype, prognostic score and type of treatment. The analysis was done in SAS version 9.4. A p-value < 0.05 was considered statistically significant. Results: At Columbia University Medical Center, a total of 186 patients with PTCL were identified. Excluding patients with incomplete data, 168 patients were analyzed. The median overall survival was 7.5 months (95% CI 5.6-8.9) for the whole study group. Cox modeling adjusted for the aforementioned variables found little impact from the novel agents on the natural history of the disease. In particular, among patients with AITL, no survival benefit was associated with any HDACi. In addition, these data demonstrated that patients with adult T-cell leukemia lymphoma (ATLL) had a better overall survival compared to other subgroups, p = 0.0097. Conclusions: These data are concordant with other large experiences noting the poor prognosis of patients with PTCL, and in particular, those with relapsed disease. The lack of impact of HDACi on the natural history of AITL raises issues about the role of these drugs in this disease. We will present a variety of subanalyses to identify prognostic factors in PTCL. [Table: see text]
TRANSCEND NHL 001: Health-related quality of life (HRQL) and symptom (Sx) impact in patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) receiving lisocabtagene maraleucel (Liso-cel; JCAR017).
Authors: Patrick Donald L. , Chung Karen C. , Kim Yeonhee , Garcia Jacob , Dehner Christine , Maloney David G.
Published: March 2020

e19052

Background: R/R DLBCL is associated with decreased HRQL. Liso-cel is an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells. In the ongoing TRANSCEND study, pts with R/R DLBCL achieved high best overall response rates with liso-cel, with low rates of severe cytokine release syndrome and neurological events (Abramson et al, ASCO 2018). We examined the impact of Sx and HRQL in pts with R/R DLBCL. Methods: Eligible pts with R/R DLBCL (≥18 yr, ≥2 prior therapy lines) received lymphodepletion followed by a single liso-cel infusion. The EORTC QLQ-C30 was administered at baseline (BL), day 29 (mo 1), and mo 2 and 3. Sx and functional scales and gIobal health status were analyzed. Increases from BL ≥10 points in functional and QL scores or decreases from BL ≥10 points in Sx scores were considered clinically meaningful improvement. Scores range from 0-100. Results: At data cutoff, 87/127 pts (mean [SD] age 62 [11] yr) were evaluable (BL+≥1 post-BL assessment). Sx scores generally improved postinfusion (Table). Mean global health status and emotional and cognitive function scores improved vs BL from mo 1-3 postinfusion, while physical, role, and social function scores declined at mo 1, followed by improvements vs BL in mo 2-3. The proportion of surviving pts achieving clinically meaningful improvement in key domains 3 mo postinfusion were: fatigue, 50%; pain, 51%; physical function, 22%; and global health status, 41%. Conclusions: In TRANSCEND, symptoms and HRQL improved in surviving pts, with clinically meaningful improvements in key domains, 2-3 mo after liso-cel infusion. Clinical trial information: NCT02631044. [Table: see text]
High risk patients with diffuse large B cell lymphoma are not enrolled on clinical trials.
Authors: Alshaibani Alfadel , Lee Christina , Rutherford Sarah Camp , Loh Kah Poh , Baran Andrea M , Casulo Carla , Barr Paul M. , Friedberg Jonathan W. , Reagan Patrick Michael
Published: March 2020

e19058

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. In this study, we explore reasons for non-enrollment in clinical trials for DLBCL and implications on trial design and interpretation. Methods: This is a retrospective analysis of patients (pts) with a pathological diagnosis of DLBCL or high grade B-cell lymphoma (HGBL) at University of Rochester (4/14-6/16) and New York-Presbyterian Hospital/Weill Cornell Medicine (NYP/WCM) (4/14-4/17).Ten clinical trials were opened during this time. Participants were divided into 3 groups: those treated in trial, those not enrolled in trial because of need for urgent treatment, and those not enrolled in trial for any other reason. We used a center-stratified Cox proportional hazards model to estimate association of trial enrollment with progression-free survival (PFS; time from start of treatment until progression/death or the last date the pt was known to be progression free) and overall survival (OS). Results: We identified 263 pts; 17% (n = 45) enrolled in a trial. Reasons for non-enrollment included not meeting eligibility criteria (n = 98), physician choice (n = 50), and pt choice (n = 38). For 32 pts, reasons were unclear. Of the 50 pts who were not enrolled because of physician choice, the primary reason for non-enrollment was the need for urgent treatment (n = 46). Pts who needed urgent treatment had higher risk clinical features compared with pts in trial (Table). Compared with those treated in trial and those not enrolled in trial for any other reason, those not enrolled in trial due to need for urgent treatment had an inferior PFS (HR 2.61, 95% CI 1.23–5.16) and OS (HR 2.27, 95% CI 1.21–4.06). Conclusions: At 2 academic institutions, 52% of patients with DLBCL or HGBL required urgent chemotherapy and failed to enroll on trials. Exclusion of such patients limits the applicability and generalizability of clinical trials in DLBCL. This barrier must be overcome so clinical trials may better reflect true DLBCL demographics. [Table: see text]
Checkpoint inhibitor therapy, with and without radiation, in diffuse large B cell lymphoma: A single-center analysis.
Authors: Yoon Stephanie , Zahid Mohammad , Phull Pooja , Senchak Jordan , Fisher Richard I. , Dulaimi Essel , Ross Eric A. , Yu Jian Qin , Doss Mohan , Khan Nadia
Published: March 2020

e19059

Background: Single agent checkpoint inhibitors (CPI) in NHLs have resulted in modest successes. Exceptions include RT, PCNS and testicular lymphomas, where higher activity is seen. As a single agent, CPI response rates range from 10-40% in relapsed refractory (RR) DLBCL, with few CRs and short response durations. In a cohort of RR DLBCL patients at our institution, we sought to identify clinical features that defined responders and non-responders. Methods: Between 9/2016 and 7/2018, 13 pts with DLBCL/RT, treated with a CPI, either on trial or as off-label therapy, with at minimum 1 infusion/cycle were included. Pathology specimens confirming DLBCL/RT were reviewed at FCCC. All pts had measurable disease by CT or PET/CT prior to CPI and had an evaluable response. Cell of origin was determined by Hans IHC. Results: Almost half (6/13) of pts achieved a response to CPI. Notably all responders had either concurrent or pre-treatment XRT. All 3 RT patients responded to CPI and continued to allo transplant. P3 and P6 both developed GVHD post allo, resulting in a demise in P3. No GC subtype pts responded nor had prior/ concurrent XRT with CPI. In 2 pts responses are ongoing, > 1 yr, and 1 RT pt remains in CR. Conclusions: XRT, prior or concurrent with CPI , was associated with durable responses in RR DLBCL. Patients with bulky ( > 7cm), rapidly progressive disease (8/13 cases) may require a 'debulking' strategy for CPI efficacy. An abscopal effect achieved with XRT/CPI combinations, may be impactful RR NHL. Analysis of PDL1/2 and MHC I/II, with other biomarkers, are underway. These clinical results warrant validation in a larger cohort, therefore a prospectively designed study is planned for 2019 in RR DLBCL/RT. [Table: see text]
Phase II multi-center study of ruxolitinib phosphate for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL).
Authors: Kallam Avyakta , Witzig Thomas E. , Roschewski Mark J. , Lyden Elizabeth , Lunning Matthew Alexander , Bierman Philip Jay , Bociek Gregory , Armitage James O. , Vose Julie
Published: March 2020

e19063

Background: Constitutive activation of the JAK-STAT pathway has been reported in lymphomas, suggesting that targeting this pathway could show clinical benefit. Ruxolitinib phosphate, an oral JAK inhibitor represents a potential therapeutic agent for high grade lymphomas. This study is designed to investigate benefits of ruxolitinib in patients with relapsed or refractory PTCL and DLBCL Methods: Patients with relapsed/refractory DLBCL and aggressive T cell lymphomas who were ineligible for, or relapsed after, stem cell transplantation were eligible. Patients received ruxolitinib, at a dose of 10mg or 5mg BID, with gradual escalation to 25mg BID. Weekly hematological assessments were done during the first cycle, CT scans were done after every two cycles. Descriptive statistics for response to therapy were collected. Progression free survival (PFS), Overall survival (OS) curves were plotted using Kaplan-Meier method, comparisons between groups were made using the log rank test. Primary outcome of the study was to assess the overall response rate (ORR). Secondary objectives were to determine PFS, OS, duration of response and safety. Relationship between responses to oral ruxolitnib and gene expression profiling was explored. Results: Of the 60 patients enrolled, 25 patients had PTCL, 32 DLBCL, 3 pending path review. Median age was 62 yrs., 56.6% had stage IV disease. Median number of cycles received was 2 (min 1, max 60). At the time of evaluation, 76% patients had progressed on therapy. The median follow-up of patients was 3.7 months (min 0.9; max 61.4). Data for 41 patients was available for evaluation of response. Complete response (CR) was noted in 1 patient with PTCL. Partial response (PR) was noted in 1, stable disease (SD) in 4 patients. Among the responders, a PTCL patient with SD had a sustained response for 60 months, a patient with PR had a response duration of 31 months. The median OS and PFS were 5.9 and 1.8 months. PFS was 2.2 months in patients with PTCL and 1.8 months in DLBCL. Median OS was 5 months in patients with DLBCL, 6.9 months in PTCL. The estimated 6 month PFS and OS were 17% (95%CI: 9%, 28%) , 49% (95%CI: 35%, 62%). There was no difference in PFS or OS between PTCL and DLBCL (p = 0.42, p = 0.94). Grade 3 or higher adverse events were seen in 62%. Anemia was seen in 20%, thrombocytopenia in 8%, infections in 6%. Conclusions: Ruxolitinib can produce responses in some patients with relapsed/refractory NHL, particularly in patients with PTCL. It may play a role in combination therapies in future. Clinical trial information: NCT01431209.
T-cell large granular lymphocytic leukemia evolution post-transplant: The Cleveland Clinic experience.
Authors: Awada Hassan , Durrani Jibran , Covut Fahrettin , Thapa Bicky , Mahfouz Reda Z. , Kerr Cassandra M. , Nagata Yasunobu , Adema Vera , Hamilton Betty Ky , Visconte Valeria , Majhail Navneet S. , Sekeres Mikkael A. , Sobecks Ronald M. , Maciejewski Jaroslaw P.
Published: March 2020

e19072

Background: T-cell large granular lymphocytic leukemia (LGLL) has been reported after solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT); yet its underlying pathophysiological evolution has been poorly explained. Methods: We retrospectively screened a cohort of 243 LGLL patients at Cleveland Clinic for disease development post-transplantation and postulated several possible responsible pathophysiological mechanisms. Results: Five percent (n = 12) of the patients had a history of transplant. Of these, 67% (n = 8) had SOT (kidney, liver or heart) while 33% (n = 4) had HSCT. Twenty-five percent were females while 75% were males. The median age was 56 years (range: 15-65). The median time from transplant to diagnosis was 7 years. Conventional cytogenetic showed normal karyotype in 89% of the patients. TCR gene re-arrangement by PCR was detected in all tested individuals. Targeted deep sequencing identified somatic STAT3 mutations in 17% (n = 2) of the cases. Fifty percent (n = 6) had EBV DNA, IgM and/or IgG post-transplant. Forty-two percent (n = 5) had CMV DNA, IgM and/or IgG; of which 80% (n = 4) were post-transplant and 20% (n = 1) pre-transplant. The median survival from disease diagnosis was 64.3 months (8.37-232.9). Indeed, T-LGL clonal expansion resulted from long-term stimulation by viral antigens including EBV and CMV causing continuous cytotoxic T cell immune response or by “oncomodulation” as explained in 83% of patients. The latter theory suggests that CMV infects tumor cells and modulates their malignant properties, without direct transformation. Immunosuppression in setting of pre-transplant exposure to CMV, caused reactivation of the latent oncogenic viral genome as seen in 8% of patients. In 17% of cases that were seronegative for viral genome, graft allo-antigenic stimulation has triggered long-term recipient LGLL expansion from antigenic mismatch. Somatic STAT3 mutations, which are highly expressed in leukemic LGL, has led to aberrant signaling and transformation (17%). Conclusions: Our study highlights the complex nature of LGLL evolution post SOT and HSCT and points out confounding mechanisms. Certainly, investigating pre- vs. post-transplantation baseline, clinical and molecular characteristics is warranted to deeply understand this phenomenon.
Venous thromboembolism risk with contemporary lenalidomide-based regimes for multiple myeloma: A systematic review and meta-analysis.
Authors: Chakraborty Rajshekhar , Riaz Irbaz Bin , Malik Saad , Marneni Naimisha , Garcia Alex Mejia , Anwer Faiz , Khorana Alok A. , Rajkumar S. Vincent , Kumar Shaji , Murad M. Hassan , Wang Zhen , Khan Safi U. , Majhail Navneet S.
Published: March 2020

e19503

Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]
Treatment patterns in patients with multiple myeloma (MM): A retrospective study using Medicare data.
Authors: Lin Peggy L. , Latremouille-Viau Dominick , Sasane Medha , Gagnon-Sanschagrin Patrick , Divan Hozefa A. , Drea Edward Joseph , Guerin Annie , Hari Parameswaran
Published: March 2020

e19506

Background: MM is characterized by repeated relapses and refractoriness and is managed by successive lines of therapies (LT) each typically resulting in shorter response duration over prior LT. This study describes current MM treatment (tx) landscape in US clinical practice. Methods: Adult MM patients (pts) with continuous Medicare Part A, B, and D coverage initiated on 1st LT (1L), without stem cell transplant, were identified in the Medicare Research Identifiable Files (2012-2016). Claims for any MM tx within 60 days of the 1st tx constituted the tx regimen of an LT. End of LT was defined as a claim for a new MM tx > 60 days post LT initiation (tx augmentation or switch), discontinuation of all tx in a regimen for > 90 consecutive days, end of Medicare coverage/data or death. From 1L to 3L, overall survival (OS), LT duration (DoT), tx regimens and sequences were assessed. Results: 8374 MM pts with 1L (median [med] age = 76 years at 1L; 55% female) were analyzed. Over a med follow-up of 20 months (mos) from 1L (med 1L DoT = 5.6 mos), 2849 pts received a 2L (med 2L DoT = 5.6 mos) and 978 received a 3L (med 3L DoT = 4.7 mos). The most prominent tx regimens were bortezomib/corticosteroids (CS; VD) in 1L, and lenalidomide/CS (RD) in 2L and 3L. The most prevalent tx sequence was 1L VD, 2L RD and 3L VD. The 1- and 2-year OS rates were 81% [95% confidence interval: 81-82] and 68% [67-69] from 1L initiation, 80% [78-82] and 64% [61-66] from 2L, and 73% [69-76] and 55% [51-60] from 3L initiation, respectively. Conclusions: MM Medicare pts mainly cycle through bortezomib- or lenalidomide-based regimens in front LT; newer agents gain more usage in later LT. A better understanding of tx options and sequencing is warranted to prolong survival. [Table: see text]
Association between immunoglobulin isotypes and cytogenetic risk groups in multiple myeloma.
Authors: Muddasani Ramya , Ramdhanny Angela , Lutz Gabriel , Akerman Meredith , Ho Albert , Suarez Jaime Andres , Braunstein Marc Justin
Published: March 2020

e19510

Background: Cytogenetic abnormalities (CA) carry prognostic significance in MM. Immunoglobulin isotypes also predict disease behavior, with non-IgG subtypes historically being associated with poorer outcomes. We hypothesized that MM non-IgG isotype and higher risk CA are associated with greater degree of marrow infiltration (BM%) and presence of end organ damage at presentation. Methods: 552 MM patients were retrospectively analyzed using a multi-institution repository of BM%, isotype, and CA risk groups stratified by mSMART criteria. A subset of 110 patients were used to assess clinical comparisons and associations between CA, isotype, and end organ damage using the chi-square or Fisher’s exact test for categorical variables and the Mann-Whitney test to compare between groups for continuous variables. Results: There was a higher BM% seen in the intermediate risk group compared to standard risk group (50% vs 20%, p < 0.04). A lower BM% was seen in the IgG subtype compared to other isotypes (27% vs 45%, p < 0.02). CA including del(13q), del(16q), dup(1p), dup(1q), t(4;14), t(11;14), and trisomy 11 were associated with a higher BM%. When comparing isotypes to CA risk groups, IgA isotype was associated with greater risk, including del(13q) and del(16q). IgG isotype was associated with trisomy 11, while light chain MM correlated with higher risk CA including del(17p), and dup(1q). Lytic lesions on presentation were more frequent in patients with trisomy 11 and less frequently in IgA MM. Anemia presented more in IgA MM, and renal failure in patients with t(14;16). Conclusions: Lower BM% was found in IgG isotype MM, which correlated with standard risk CA, whereas light chain MM was associated with higher risk CA; this risk group being more likely to present with renal failure. Unexpectedly, lytic lesions on presentation correlated with non-IgA isotype and better risk CA. Further studies are needed to confirm these findings prospectively to determine if they can predict end organ damage in patients with specific isotypes or CA groups.
Inching towards precision medicine for multiple myeloma with causal network models.
Authors: Zhu Jun , Liu Yu , Wang Li , Yu Haocheng , Yoo Seungyeul , Lee Eunjee , Schadt Eric E.
Published: March 2020

e19526

Background: Multiple myeloma (MM) is the 2nd most prevalent blood cancer. For each molecular subtype of MM defined by molecular profiles, mechanisms underlying prognosis and drug response are largely unknown. Elucidating the mechanisms underlying differences in prognosis and drug response will enable a more personalized, precision medicine (PM) approach to treating patients. Methods: Big multiomics data are now widely available and contain the ingredients necessary to build causal models to uncover mechanisms of prognosis and drug response. However, data from resources like the MM Research Consortium (MMRC) dataset may contain errors (eg, sample mislabeling) that diminish modeling accuracy. We developed a probabilistic data matching method ( proMODMatcher) to correct such errors and applied it to the MMRC data. We identified labeling errors in 10 patients, including swaps in RNA and CNV profiles. Given the corrected MMRC data, we characterized recurrent genomic aberrations in MM. We found > 8000 genes significantly associated (FDR < 0.01) with CNVs spanning the gene locations. To distinguish expression correlations driven by causal biological relationships from those driven by coincident CNV influence, we constructed a causal MM network based on the MMRC dataset. Results: Overlaps among multiomic prognostic or drug response biomarkers are sparse. To identify common mechanisms of different biomarkers, we projected them onto our MM network to define the causal context in which they occur. Prognostic biomarkers were enriched in subnetworks associated with mitotic regulation and lipid metabolism, and predicted by our network to be regulated by ZWINT, BUB1B, DTL, TPX2 and NOP16. Proteasome inhibitor and immunomodulating drug responses were mediated by amino acid biosynthesis and cell surface protein complex subnetworks, respectively, with MTHFD2 and TMC8 inferred as the master regulators of these subnetworks, respectively. Regulators include genes (eg, BUB1B and MTHFD2) known to associate with tumor growth and drug response and novel therapeutic control points. Conclusions: Causal models can elucidate the molecular mechanisms underlying prognosis and drug response, enabling the design of more personalized MM treatments.