bluuebunny/crossref_metadata_2025 huggingface dataset:
The influence of parvovirus B19 (B19V) on the results of chemotherapy in adult patients with lymphoma.
Authors: Zykova Tatiana A. , Kit Oleg I. , Lysenko Irina B. , Guskova Nailya K. , Shevyakova Elena A. , Nikolaeva Nadezhda V. , Shatokhina Olga N. , Kapuza Elena A. , Pushkareva Tatiana F. , Velikorodnaya Lilia A.
Published: March 2020

e19022

Background: The purpose of the study was to reveal the prevalence of B19V in adult patients with lymphomas and the influence of B19V on the on the results of chemotherapy (CT). Methods: The study included 41 patients aged 48.9±2.3 years: 12 with Hodgkin’s lymphoma (HL), 29 with Non-Hodgkin’s lymphoma (NHL) (21 aggressive, 8 indolent). Patients received CT according to the tumor immunophenotype. B19V DNA was determined in plasma and in bone marrow (BM) by qPCR, B19V IgМ and IgG in the serum by ELISA. Results: 78.0% of patients had B19V IgG, mean concentration was 158.1±12.9 U/mL. B19V DNA in plasma was detected in 7.3%, in BM in 48.8%. Viral load in plasma was 68.7±35.8 IU/mL, in BM – 438240.0±281316.8 IU/mL. Seroprevalence and the mean concentration of B19V IgG was higher in NHL than in HL (79.3% vs 75.0% and 161.4±16.3 vs 153.6±20.5, p > 0.05). In NHL, the number of seropositive patients and the mean level of B19V IgG were higher in aggressive than in indolent tumors (81% vs 75% and 177.9±19.3 U/mL vs 114.4±22.8 U/mL, p = 0.052). B19V IgМ were not found. B19V DNA in plasma was found only in NHL patients (10.3%). The frequency of B19V DNA detection in plasma was higher in indolent (12.5%) than in aggressive lymphomas (9.5%), while DNA concentration was higher in aggressive lymphomas (102.5±20.5 IU/mL vs 1.0±0.0 IU/mL, p > 0.05). B19V DNA detection frequency in BM was similar in HL (50.0%) and NHL (48.3%, p > 0.05), but the mean B19V DNA concentration was higher in NHL than in HL: 624496.9±395398.3 IU/mL vs 3640.5±1649.2 IU/mL, p > 0.05. In NHL, B19V DNA in BM was more frequent in indolent than in aggressive lymphomas (50.0% vs 47.6%), and the average concentration was higher in aggressive lymphomas (865689.2±541738.6 IU/mL vs 21516.3±19352.8 IU/mL, p > 0.05). Complete remission was observed in 68.3% of patients, partial remission 17.0%, stabilization 4.8%, progression 9.9%. CT results depended neither on serostatus and B19V IgG concentration nor on B19V DNA presence in BM or plasma (p > 0.05). Conclusions: All parameters of the viral infection (B19V IgG, DNA) were higher in NHL than in HL (p > 0.05). The mean concentration of B19V IgG was higher in aggressive NHLs than in indolent ones (p = 0.052). B19V infection did not influence results of antitumor CT (p > 0.05) in adult patients with lymphoma.
Treatment outcomes of HIV patients with non-Hodgkin’s lymphoma treated with standard dose CHOP compared with dose-modified CHOP chemotherapy at the Uganda Cancer Institute.
Authors: Bakenga Alex
Published: March 2020

e19025

Background: Despite the increased access to effective combination ART, there is still significant mortality associated with malignancies in HIV-positive patients. Because majority of patients present late especially with advanced disease, some of whom may not be able to tolerate standard dose chemotherapy, the Uganda Cancer Institute utilizes both standard dose and dose-modified CHOP chemotherapy for HIV-related NHL. We evaluated HIV patients with NHL treated with standard dose or dose-modified CHOP with the aim of accessing treatment outcomes. Methods: A retrospective cohort study was conducted among patients who received chemotherapy at the UCI between January 2004 to December 2014. 410 eligible patients were reviewed and information on clinical characteristics, chemotherapy regimens, treatment outcomes and vital status at 6-months after completion of chemotherapy. Results: Overall 450 patients were available for screening, 12 did not receive chemotherapy and 37 received other chemotherapy regimens. 410 patients with HIV-related NHL were analyzed with 291 receiving standard dose and 119 patients received dose-modified CHOP chemotherapy. Most patients were male 59.8% and 50.4% in standard dose and dose-modified group respectively. 83.2% in the standard dose and 79.8% in the dose-modified group had advanced disease. A complete response was achieved in 67 of the 291 (23%) patients who received 6 standard dose chemotherapy cycles and 32 of the 119 (27%) patients who received 6 cycles dose-modified chemotherapy. The overall mortality was (18/202) 8.9%; 13/143 (9.1%) in the standard dose group and 5/59 (8.5%) in the dose-modified group. On multivariate analysis, female gender (OR 1.71, 95% CI 1.02-2.85, at least 6 cycles of chemotherapy (OR 0.31, 95% CI 0.11-0.87), chemotherapy received on schedule (OR 0.52, 95% CI 0.30-0.90) and disease progression (OR 3.58, 95% CI 1.01-12.63) were significantly associated with mortality. Conclusions: The complete response rates and mortality were not different; thus, recommendation is to consider dose-modified therapy because of the fewer associated side effects and lesser chemotherapy associated toxicities. Although, this was not statistically significant.
Single-center analysis of post-transplant lymphoproliferative disorder (PTLD) outcomes with Epstein Barr virus (EBV) assessments.
Authors: Moyers Justin , Liu Lawrence , Kim Matthew , Mo Huan , Kamal Muhammad Omair , Villacana Rafael , Chen Chien-Shing , Cao Huynh Le
Published: March 2020

e19029

Background: EBV is associated with the majority of cases of PTLD, a serious complication after solid organ and hematopoietic stem cell transplantation. EBV serum viral loads have been used to identify those at risk of this disease in EBV-positive cases. We aimed to characterize the clinical presentation, pathologic diagnosis andprognostic implications of EBV viral load and its response to treatment. Methods: This is a retrospective observational study approved by IRB including all organ transplant patients with histologic diagnosis of PTLD between 2000 and 2018 at Loma Linda University Medical Center. Data was collected by chart review. Kaplan-Meier survival estimates were used to determine primary outcomes of overall survival and progression free survival. Results: 68 patients (41 male, 27 female) were identified who developed PTLD following solid organ transplantation (22 kidney, 37 heart, 6 liver, 3 multi-organ). Median time from transplant to PTLD diagnosis was longest among neonatal transplants 12.0 years versus 3.76 in pediatric and 6.43 in adult transplantations. EBER positive histology was observed in 93% (39/42) of pediatric population versus 52% (12/23) of the adult population. During treatment 16 (23%) experienced acute rejection with 5 (7%) graft losses. The largest subset, monomorphic diffuse large B-cell lymphoma (n = 34), had a median overall survival of 15.1 years. M-DLBCL with high levels of EBV copy load > 10,000 IU/mL had a trend toward worse overall survival of 9.0 versus 15.1 years in < 10,000 IU/mL (HR 2.74, p = 0.14). Treatment resulted in complete serologic EBV copy load response in 15/19 and a trend toward improved overall survival with a median OS not yet reached versus 13.7 years in incomplete responders (HR 0.76, p = 0.76). Conclusions: Our study introduces the hypothesis that initial EBV viral loads and treatment response may have prognostic importance. The characteristics, pathologic diagnosis and treatment response for this cohort of patients will be presented. [Table: see text]
Are double-hit lymphoma patients being adequately evaluated for CNS disease?
Authors: Hancock Christie , Bitran Jacob D. , Almanaseer Imad , Green Angel
Published: March 2020

e19036

Background: Double hit lymphoma (DHL) is a high-grade lymphoma with a propensity to involve the central nervous system (CNS) compared to the typically less aggressive diffuse large B cell lymphoma (DLBCL). Guidelines recommend considering cerebrospinal fluid (CSF) evaluation and prophylaxis per institution guidelines in DHL patients (pts). It is not clear when this evaluation should occur and what prophylaxis should be delivered. Methods: We performed an IRB granted retrospective analysis of pts with de novo DHL based on assessing high-grade lymphoma FISH panels treated within the Advocate Health Care System. The pt’s age, IPI score, CNS-IPI score, systemic treatment, CSF evaluation, CNS prophylaxis or treatment, CNS event (yes/no), progression free survival and overall survival were recorded. Results: Thirty-one pts were evaluated. Seventeen were male. Median age was 72 years (range: 40 to 89). Fifteen were stage IV. Median IPI score was 3 and CNS IPI was 3. Fifteen pts had CSF evaluated within their disease course. Fifteen pts received CNS prophylaxis or treatment including intrathecal (IT) methotrexate (n = 10), IT methotrexate plus hydrocortisone (n = 2), IT cytarabine (n = 1), IT methotrexate and systemic methotrexate (n = 1), or only systemic methotrexate (n = 1). The number of patients with a CNS event during their disease course was 3 with all 3 having leptomeningeal involvement. These 3 pts had CNS IPI scores > 4. Two had CSF involvement at diagnosis. One died at 2 months; the other is alive and disease free at 44 months. The third pt developed CSF disease at relapse and ultimately died at 12 months. This pt had previously received IT methotrexate. For all pts, the median disease free survival (DFS) was 8.1 months; median survival was 11 months and 3-year DFS was 45%. Conclusions: Our small, but extensive review of community oncologists treating DHL patients showed there was a lack of CSF evaluation in these high-risk patients with a rate of less than 50%. For the patients evaluated, there was significant heterogeneity in CNS prophylaxis. The rate of 10% of patients having CNS disease is consistent with other reports of high-risk lymphoma and CNS relapse suggesting all DHL patients should have CNS prophylaxis.
Elevated serum lactate in lymphoma: Not always infection.
Authors: Gandhi Sangeetha , Pophali Priyanka Avinash , Witzig Thomas E.
Published: March 2020

e19039

Background: In patients with lymphoma, lactate dehydrogenase (LDH) is an important prognostic marker. Serum lactate can also be elevated due to hypermetabolism from aggressive lymphoma. We have observed critically ill lymphoma patients with elevated serum lactate who had a delay in the diagnosis and treatment of their underlying lymphoma because the cause of the elevated lactate was presumed to be infection. This clinical observation led us to perform a study to evaluate the relationship between serum lactate and LDH levels in lymphoma patients. Methods: We used the Mayo Clinic Lymphoma Database to search for patients with lymphoma and elevated lactate during a recent two year time period, January 2014 through December 2015. Fifty patients met these initial criteria and underwent medical chart review. The patients were divided into two groups – those with documented infection (SepsisLA group) and those without infection (all cultures negative) where the elevated lactate was due to lymphoma hypermetabolism (LymLA group). The Wilcoxon/Kruskal-Wallis test was used to compare the SepsisLA and LymLA groups. Kaplan-Meier analysis was used to estimate survival. Results: The mean age of the 66 patients was 65 ± 14.8 years and 60% were male. At the time of presentation, the mean lactate and LDH values were 4.5 ± 2.81mmol/L (UNL < 2 mmol/L) and 835.1 ± 1741.4 U/L (UNL < 222 U/L), respectively. 64% (32/50) of patients had elevated LDH values. After review, 32 (64%) patients were in the SepsisLA group; 18 (36%) were in the LymLA group. DLBCL was the most common disease type in both the SepsisLA (50%; 16/32) and LymLA (88%; 16/18). The sepsisLA and LymLA groups were not significantly different in terms of age, sex, lactate levels, or maxSUV on PET scan (N = 13). However, patients in the LymLA group did have higher LDH values (p = 0.02) compared to those with SepsisLA. Patients with LymLA had a reduced overall survival (OS) (1.45 median months) compared to those with SepsisLA (7.83 median months) p = 0.02. Conclusions: This study demonstrates that the level of lactate elevation is not helpful indiscriminating SepsisLA vs LymLA; however an elevated LDH with elevated lactate is more likely LymLA. Lymphoma pts with LymLA had an inferior survival compared to SepsisLA. We are unable to define the true incidence and prognostic value of elevated serum lactate in lymphoma; this will require a prospective study with fresh samples. In summary, lymphoma activity can masquerade as infection with elevated lactate. Once sepsis is ruled out, treatment for the lymphoma should not be delayed as this presentation portends poor prognosis.
An objective based model of published treatment options for relapsed or refractory (R/R) peripheral t-cell lymphoma (PTCL): An evidence-based decision-making approach.
Authors: Marchi Enrica , Tobinai Kensei , Maruyama Dai , Nagai Hirokazu , O'Connor Owen A.
Published: March 2020

e19048

Background: PTCL are rare diseases with a poor prognosis. Front line therapy achieves CR in 30% to 60% and OS of 25%. Patients with R/R disease have an even worse prognosis. There is no consensus on the management of R/R disease because evidence supporting most treatment approaches is modest. Many approaches are often not supported by literature, and categorizations regarding efficacy and toxicity without attention to details are ignored. Treatments that have achieved regulatory approval with stringent independent assessment of pathology and response are viewed as less established, or equivalent to smaller published experiences. In the effort to take a critical and comprehensive evidence-based approach to available standards in R/R PTCL we developed an objective scoring system for all types of studies published in the literature (eg randomized phase 3, case match control, phase 2, phase 1, case reports and small series) to aid decision-making based on an assessment of all the available data. Methods: An extensive review on PubMed of clinical trials published in literature for R/R PTCL was performed. A rigorous scoring system based on a survey from 100 authorities in the field to quantitate scientific impact of each study based was developed. These include: type of study (randomized phase 3, case match control analysis, phase 2 weighted based on number of PTCL patients [ > 100 vs < 100 patients], phase 1 with > 5 or < 5 PTCL patients enrolled, and retrospective); weighting for use of central pathology or response review; weighting for detailed study metrics (ORR, CR, DoR, PFS). The scoring system included a penalty for omission detail. The proposed scoring system was evaluated by a panel of experts. The scoring system was modified based on recommendations made by 2 or more panel members. Results: We identified 58 publications between 2004 and 2018. The scoring system spanned from 0 to 9. Only 12 of the 58 studies had a score above 5; 15 of 58 had a score between 1 - 5; remaining publications scored 0 - 1. Conclusions: Our analysis suggests practice patterns are based on studies with low priority scores, and underweight robust clinical experiences. This analysis aims to produce an evidenced based approach for R/R PTCL.
Real-world treatment patterns among patients (pts) diagnosed with primary mediastinal large B-cell lymphoma (PMBCL) in the United States (US).
Authors: Yang Xiaoqin , Laliberté François , Germain Guillaume , Raut Monika Kumar , Duh Mei Sheng , Sen Shuvayu , Lejeune Dominique , Desai Kaushal , Armand Phillippe
Published: March 2020

e19050

Background: PMBCL is a rare mature B-cell neoplasm (2-4% of non-Hodgkin lymphomas) for which there is only limited data on treatment patterns in clinical practice. In October 2015, PMBCL was differentiated from diffuse large B-cell lymphoma (DLBCL) with the advent of ICD-10-CM PMBCL-specific codes. This study aims to describe real-world treatment patterns among pts diagnosed with PMBCL in the US. Methods: A retrospective database analysis was conducted using the Optum Clinformatics DataMart database (01/2013-03/2018). Pts with a first PMBCL ICD-10-CM diagnosis (with or without an antecedent ICD-10-CM diagnosis of DLBCL/other lymphoma, which may have been assigned before PMBCL confirmation) after October 1st, 2015 (index date) and no ICD-9-CM diagnosis code for unspecified PMBCL/DLBCL, were identified as incident pts. Those with PMBCL ICD-10-CM and unspecified ICD-9-CM diagnosis for PMBCL/DLBCL before October 2015 (index date) were identified as prevalent pts. PMBCL diagnoses on ≥2 medical visits and ≥12 months of continuous enrollment pre-index date were required. An adapted algorithm developed from previously published studies was used to identify lines of therapy (LOT). Duration of therapy spanned from LOT initiation up to discontinuation of all agents in the LOT, a switch to another LOT, or the addition of a new agent. Results: Among 148 PMBCL pts (118 incident; 30 prevalent), median (interquartile range) age was 66 (42-77) years. In incident pts, 48.3% were treated with ≥1 LOT (mean ± standard deviation [SD] duration of therapy: 86.0 ± 69.8 days) and 14.4% were treated with ≥2 LOT. The most frequently used first-line (1L) therapy (54.4% of pts) was R-CHOP (rituximab, cyclophosphamide, doxorubicin and vincristine). In prevalent pts, 63.3% were treated with ≥1 LOT (mean ± SD duration of therapy: 88.3 ± 44.6 days) and 20.0% were treated with ≥2 LOT. The most frequently used 1L therapy was R-CHOP (68.4%). Conclusions: This study demonstrated that a large portion of pts require additional therapy after 1L treatment to manage PMBCL, underscoring the significant unmet need in this population.
Bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies: Results of phase I-II trial.
Authors: Bachanova Veronika , Cao Qing , Weisdorf Daniel Jordan , Curtsinger Julie M , Cooley Sarah A. , Miller Jeffrey , Vallera Daniel
Published: March 2020

e19066

Background: The novel bispecific toxin DT2219 consists of a fusion between the catalytic domain of diphtheria toxin (DT) and single-chain variable fragments (scFV) of antibodies targeting human CD19 and CD22. Methods: The primary objective of Phase I Dose was to determine DT2219 dose which is well tolerated on an 8 dose schedule (days 1, 3, 5, 8 and day 15, 17, 19 and 22). Phase II Extension aimed to establish a preliminary estimate of overall response at day 29 in patients stratified to Arm A (relapsed/refractory B-cell lymphoma) and Arm B (B-cell leukemia). Baseline serum level of neutralizing antibody (NA) against diphteria toxin below 50% was required for eligibility. Results: Eighteen patients (NHL n = 12; ALL n = 6) at median age 65 years (range 50-83 yrs) with relapse/refractory disease and confirmed expression of CD19 and/or CD22 were enrolled. Treatment was well tolerated at 60 mcg/kg x 8 doses and the most common adverse events included capillary leak sy, elevated AST/ALT, low albumin, weight gain and leukopenia. All were Gr 1-2 and resolved after 3-5 days allowing day 15 DT2219 administration. There were no neutropenic fever or immune mediated adverse events. Four patients experienced dose limiting toxicity at dose 80 μg/kg/day: Gr 4 capillary leak syndrome (n = 1), Gr 3 LFTs abnormalities (n = 2) and Gr 4 thrombocytopenia > 7 days duration (n = 1). Thirteen patients were evaluable for response and 3 experienced objective clinical benefit. One patient with primary refractory pre-B acute lymphoblastic leukemia achieved complete remission after 1st cycle. Two patients with transformed lymphoma demonstrated transient tumor shrinkage, however, DT2219 therapy was discontinued due to DLT and increased NA titer after 1st cycle (pre C1 28%, pre C2 108%). Correlative studies showed a low incidence of neutralizing antibody in NHL patients recently exposed to Rituximab. Conclusions: We have established the biologically active dose of DT2219 at 60 μg/kg/day ×8 doses. Further development of DT2219 includes combination with rituximab (to reduce NA formation) and synergistic combinations against B-cell malignancies. Clinical trial information: NCT02370160.
A mixed method analysis of toxicities of anti-CD19-CAR T cell therapy in hematological malignancies.
Authors: Jindal Vishal , Akella Padmastuti , Piranavan Paramarajan , Siddiqui Ahmad Daniyal
Published: March 2020

e19068

Background: CAR (Chimeric Antigen Receptor) T cell therapy is a promising therapy with significant benefits. But cytokine release syndrome (CRS) and neurological toxicities (NT) are major obstacles in its success. In this study we did mixed method analysis of literature to explore side effect profile of Anti CD19-CAR T cell therapy in hematological malignancies. Methods: A review of literature was done to find appropriate studies on Medline database. Total 11 studies were selected on the basis of 1) Anti CD19-CAR T cell therapy 2) Lymphodepletion 3) Sample size equal to or more than 15, 4) Hematological Malignancies 5) Detailed toxicities mentioned. Data was extremely heterogenous for metanalysis therefore results were descriptively formatted using summary texts and tables. Results: Total patient count was 452, out of them 59% had ALL, 35.61% had NHL and 5.30% had CLL. Majority of studies used second generation CAR T cells (n = 10, 90.1). CAR T cell dosage protocol was variable among studies and it range from 1 X 105 to 1 X 107 cells. CRS occurred in 82.7%, with grade 1-2 CRS in 58.4% and grade 3-4 CRS in 24.3%. CRS presented early (range of median = 2.5 – 4 days) and recovers completely generally with in 1st week (range of median = 4.8 - 8 days). NT are seen in 45.6%, with grade 1-2 NT in 20.6% and grade 3-4 NT in 25.0%. NT have variable presentations, encephalopathy was seen in 22.65% of patients and 3.22% had seizures. For management of side effects 28.6% patients required ICU level of care and 21.86% required pressor support. Tocilizumab was used in 30.7%. Total 10 patients (2.2%) died due to side effects and out of them 6 (1.32%) due to CRS and 4 (0.88%) due to NT. Clinically significant associations were shown between tumor grade and CRS (n = 6, 54.5%), IL-6 and CRS (n = 8, 72.7%), CRP (C reactive Protein) and CRS (n =6, 54.5%), and CRS and NT (n = 7, 63.6%) (Table). Conclusions: This study concludes that CRS and NT are most common side effects of CAR T cell therapy. Most of the time they are completely reversible and manageable with tocilizumab and steroid therapy. Levels of IL6, Interferon gamma, CRP and ferritin are elevated in CRS patients. Therefore, can be used as biomarkers. NT and CRS are also associated with each other and likely share the pathological pathway. [Table: see text]
Tumor-collagen digital proximity signature to indicate prognosis in diffuse large B-cell lymphoma.
Authors: Qaiser Talha , Pugh Matthew , Margielewska Sandra , Hollows Robert , Murray Paul , Rajpoot Nasir
Published: March 2020

e19073

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous tumor that originates from normal B-cells. Despite the use of combination chemotherapy, around 40% of DLBCL patients die (de Jonge, et al. European Journal of Cancer, 2016). Limited studies have investigated the role of collagen in the acellular tumor microenvironment. In this study, we present a novel digital signature of the proximity of tumor cells and collagen-VI (COL6) that can predict overall survival (OS) in DLBCL patients. To the best of our knowledge, this is the first study of its kind to employ automated image analysis. Methods: The proposed digital proximity signature (DPS) aggregates summary-level statistics from the entire whole slide image (WSI) and serves as a marker of regions, categorizing weak, moderate, significant, and strong tumor-collagen proximity and can be described as a surrogate for signaling. To accomplish this, we developed a novel artificial intelligence (AI) based multi-task model for simultaneous detection and classification of tumor cells and another bespoke method for automatically identifying COL6 fiber. The tumor-collagen proximity analysis was then performed by aggregating tumor cell statistics within the vicinity of COL6 fibres. Finally, the prognostic significance of DPS for OS in DLBCL was investigated with Kaplan-Meier analysis, stratifying patients into two groups based on the median of the DPS values. Results: We took WSIs of DLBCL tissue slides for 32 cases immunohistochemically stained with COL6 and Hematoxylin counterstain. The AI model for tumor cell identification achieved a high F1-score of 0.84, outperforming recent single-task learning models. Our results show that strong proximity of COL6 and tumor cells is linked to better OS in DLBCL patients ( p = 0.03). Conclusions: Our novel digitally computed COL6-tumor proximity signature shows prognostic significance for overall survival on a pilot dataset of 32 DLBCL patients. We are further validating the utility of this novel signature as a prognostic biomarker in larger cohorts of DLBCL patients.
Once-weekly (70 mg/m2) versus twice-weekly (56 mg/m2) dosing of carfilzomib (CFZ) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM).
Authors: Moreau Philippe , Stewart A. Keith , Dimopoulos Meletios A. , Siegel David Samuel DiCapua , Facon Thierry , Berenson James R. , Raje Noopur S. , Berdeja Jesus G. , Orlowski Robert Z. , Yang Hui , Ma Haijun , Klippel Zandra Karina , Zahlten-Kumeli Anita , Mezzi Khalid , Iskander Karim , Mateos Maria-Victoria
Published: March 2020

e19505

Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m2 (Kd70 QW) or twice-weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.
Early mortality following diagnosis of multiple myeloma from 2011 to 2016 in Alberta, Canada: Initial results from the population-based Identifying Outcomes in Real-World Multiple Myeloma (INFORMM) study.
Authors: Tay Jason , Chen Guanmin , Cowling Tara , Shaw Eileen , Farris Megan , Liu Fei Fei , Jimenez-Zepeda Victor H.
Published: March 2020

e19509

Background: The clinical outcomes of patients with newly diagnosed multiple myeloma (NDMM) have improved. However, early mortality (EM) post-diagnosis remains a concern, with incidence ranging from 13% at 2 months to 29% at 1 year after diagnosis. EM can be influenced by patient age, comorbidities, performance status, therapy, and disease biology. Our aim is to examine EM incidence in patients with NDMM and to describe variables that may influence EM in the era of novel chemotherapeutic agents using the INFORMM Study, an ongoing, province-wide real-world evidence study in Alberta, Canada. Methods: Using administrative health data in Alberta (population 4.32 million in 2018), we identified our study population from a validated algorithm of International Classification of Diseases-9 and -10 diagnostic codes. Additionally, the NDMM cohort was confirmed using bone marrow biopsy records, and patients who received therapy for myeloma were derived from the province-wide Pharmaceutical Information Network database. EM was defined as death by any cause within 90 days of diagnosis. Further analyses will be performed to explore potential risk factors associated with EM using regression modeling. Results: We identified 1,729 patients diagnosed with NDMM between 2011 and 2016. EM occurred in 185 patients (10.7%). Of the 185 patients who experienced EM, 156 (84.3%) were aged ≥ 65 years, 174 (94.1%) had a Charlson Comorbidity Index score ≥ 3, and 48 (25.9%) had infectious complications within 90 days of diagnosis. In addition, 99 (53.5%) patients received ≥ 1 anti-myeloma therapy regimen (lenalidomide-based = 5, bortezomib-based = 22, other = 72), whereas 86 (46.5%) did not receive any anti-myeloma therapy. Conclusions: Despite advances in chemotherapeutics and supportive care, patients with NDMM still have a high risk of EM. The higher EM incidence observed in older patients could be attributable to treatment toxicity, comorbidities, or issues surrounding delivery of suitable treatments. Clinicians should consider potential factors associated with EM in their care plan, including in serious illness conversations.
The impact of newly approved drugs on clinical and operational strategies for multiple myeloma clinical trials.
Authors: Krishnan Bhavani , Collins Bernadette , Cho Michael Jeffrey , Partridge Tanya , Vighnay Durga , Given Marie , Enschede Sari Heitner , Bochenska Katarzyna , Hodge Jeff Paul
Published: March 2020

e19511

Background: The global burden of multiple myeloma (MM) has increased steadily in last 3 decades. The IARC reports there were ~160,000 new cases worldwide in 2018. There has been an increase in the development and approval of more effective targeted therapy options (new immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies); this, coupled with high adoption of these therapies presents a major challenge in enrollment of current ongoing clinical trials. We assessed the impact of near-term regulatory approvals on clinical trial enrollment. Methods: Public domain clinical trial enrollment data from MM studies (Phase I, I/II, II) closed/completed between 2011-2018 were used to determine enrollment trends pre and post 2014. We leveraged real-world medical claims data to project/model adoption of recently approved drugs in the U.S.; additionally, drug sales volume data was used to evaluate ex-US national adoption trends. The utilization rates of 5 recently approved drugs by regimen and line of treatment was determined. Results: In the U.S., there is a 13% increase in median enrollment duration with a corresponding 25% decrease in median p/s/m enrollment in MM studies, irrespective of phase, where enrollment was completed between 2015 -2018 compared to 2011-2014. We hypothesize that one of the factors for this increase in enrollment timeline is the approval and adoption of newly approved therapies post 2014. Two of the five recently approved drugs show a steady increase in the number of patients treated over 2016, 2017 and 2018, while one of the drugs plateaus over the same period. Outside of the U.S., our analysis confirms the existence of gaps in time to approval /adoption of recently approved drugs; for example, we observe a two-year delay in approval/adoption for one of the drugs in France compared to the other countries in Western Europe. Conclusions: There are over 10 investigational MM drugs currently in development which are anticipated to be granted approval between 2019-2021. Factoring the real-world adoption of near-term drug approval into global clinical and operational strategies offers insights into mitigating potential future enrollment challenges.
Treatment sequencing patterns for relapsed refractory multiple myeloma (RRMM) in the era of new therapies in a single center institution.
Authors: Tungesvik Alexandre , Sudalagunta Praneeth Reddy , Huang Jessica , Dimaggio Elizabeth , De Avila Gabe , Tandon Ankita , Nelson Rebecca , Olson Laura , Tobon Katherine , Shain Kenneth H. , Brayer Jason B.
Published: March 2020

e19513

Background: Although there is much to be optimistic about in the multiple myeloma community as the approval of new therapies and regimen-combinations for relapsed refractory disease continues to grow, determining the best option for a patient can be complicated. Both carfilzomib- (C) and daratumumab- (D) based regimens have demonstrated superior efficacy in this setting, but there is a paucity of data supporting which should be selected first, and if regimen sequence influences outcomes. The aim of this study is to describe sequencing patterns in the era of these newer agents and to determine if there is a difference in outcomes for patients with RRMM who received one of the following treatment sequences: C-regimen with a D-regimen given immediately prior (DC); C-regimen without any prior D (C only); D-regimen with a C-regimen given immediately prior (CD); or D-regimen without any prior C (D only). Methods: This is a retrospective analysis of patients with RRMM consecutively treated at Moffitt Cancer Center between 1/1/2015 and 6/25/18. Response to therapy was assessed using the International Myeloma Working Group (IMWG) criteria. Progression-free survival (PFS) was measured in days from the start of therapy to progression. Time to response (TTR) was measured in days from the start of therapy to first response. Results: 132 patients with RRMM who received 1-3 prior lines of therapy with at least one line of therapy containing either C or D were identified. Overall, the majority of patients were treated with C only (n = 101), 10 received DC, 31 received D only, and 35 received CD. In patients that received C only, partial response (PR) was achieved in 38%, very good partial response (VGPR) was 20%, and stringent complete response (sCR) was 2%. In patients that received DC, PR was 20% and VGPR was 10%; no patient achieved a sCR. Of the patients that received D only, PR was 29%, VGPR was 10%, and sCR was 3%. In patients that received CD, PR was 31% and VGPR was 26%; no patient achieved sCR. Median PFS in patients who received C only, DC, D only, and CD was 117 days, 126 days, 104 days, and 190 days, respectively. TTR in patients who received C only, DC, D only, and CD was 82 days, 39 days, 98 days, and 88 days, respectively. Conclusions: The data suggests that RRMM patients who receive either CD or DC appear to have a PFS advantage over those patients who did not. Notably, an early TTR was found in patients that received DC. Further analysis is ongoing.
Incidence of serious adverse events in bortezomib, lenalidomide and bortezomib plus lenalidomide maintenance for multiple myeloma: Interim analysis of MMRF-CoMMpass study.
Authors: Vosuri Venkata , Fiala Mark A , Ballard Wenners , Wildes Tanya Marya , Schroeder Mark A. , Vij Ravi , Stockerl-Goldstein Keith
Published: March 2020

e19516

Background: Autologous stem cell transplantation (ASCT) followed by maintenance therapy is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma. Maintenance typically consists of lenalidomide (LEN), however, bortezomib (BOR) and bortezomib-lenalidomide combination are other options. The respective toxicity of these regimens has not been well studied. We performed secondary data analysis to compare incidence of serious adverse events associated with each maintenance therapy group during post-ASCT maintenance treatment period. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis from the CoMMpass study. We extracted data of first-time autologous stem cell transplant patients who completed maintenance therapy post-ASCT. We categorized patients into three sub groups bortezomib, lenalidomide or combination (bortezomib and lenalidomide) maintenance therapy. Incidence rate for serious adverse events (grade 3 or higher) was calculated by number of events per 100 person-months for each maintenance therapy. Results: 231 patients were eligible for our analysis. 169 patients received lenalidomide, 27 bortezomib and 35 combination. The most common adverse event was neutropenia and second most common is pneumonia. Neutropenia incidence was 1.1,0.7 and 0.9 per 100 person-months in lenalidomide, bortezomib and combination regimens respectively. Incidence of deep vein thrombosis, GI intolerance and peripheral neuropathy 0.1 per 100 person-months respectively was observed in lenalidomide group only. Combination maintenance had the highest total adverse event incidence rate of 5.4 per 100 person-months. Incidence of 1.7 and 3.8 per 100 person-months is observed in bortezomib and lenalidomide cohorts respectively. Conclusions: Lenalidomide and bortezomib maintenance had similar incidence of serious adverse events. A higher incidence of serious adverse events was noted in the combination lenalidomide/bortezomib regimens. Interestingly, we observed lower incidence of adverse events in all groups in CoMMpass study compared to respective clinical trials involving maintenance regimens. This may be due to under reporting of adverse events in CoMMpass study. The incidence of adverse events mentioned above should be interpreted in the context of drugs and other factors involved in the disease.
Factors associated with over and underuse of response evaluation in elderly myeloma patients.
Authors: Leng Siyang , Lentzsch Suzanne , Chen Yizhen , Bhutani Divaya , Wright Jason Dennis , Accordino Melissa Kate , Hershman Dawn L. , Neugut Alfred I.
Published: March 2020

e19518

Background: Most patients with multiple myeloma (MM) have detectable monoclonal protein. While guidelines do not specify the frequency of lab testing for response evaluation, most MM clinical trials perform monthly assessment. We examined the use of 4 serologic tests – protein electrophoresis (SPEP), immunofixation (IFE), quantitative immunoglobulins (QIG), and free light chain (FLC) in newly-diagnosed MM patients. Methods: We identified patients age ≥65 with MM (ICD-O 34000) in the Surveillance, Epidemiology and End Results (SEER)-Medicare database from 2000-2013. Patients were required to have bone marrow biopsy within 6 months of diagnosis, and taken chemotherapy approved for MM. Use of a test was defined as having ≥1 instance of its CPT code within 12 months of diagnosis. Patients with > 12 instances were defined as overusers. Multiple instances of a test on the same date were counted once. Multivariable logistic regression models using covariates including: age and year at MM diagnosis, race, marital status, Charlson comorbidity, chemotherapy use, number of hospitalizations and oncology office visits within 12 months of diagnosis, were developed to examine associations with overuse. Results: Among 6,214 identified patients, users were: SPEP 5,532 (89%), IFE 4,745 (76%), QIG 5,524 (89%), and FLC 3,864 (62%). The median (interquartile range) times each test was used in the first year following diagnosis were: SPEP 6 (3-10), IFE 3 (2-7), QIG 6 (3-10), FLC 5 (2-9). The numbers of overusers were: SPEP 721 (13%), IFE 265 (6%), QIG 498 (9%), FLC 350 (9%). 231 (4%) patients were overusers of 2 tests. Factors associated with overuse common to all 4 tests were: younger age at diagnosis (eg, SPEP: odds ratio (OR) 2.0 for aged 65-74 vs ≥85; P < .001), more oncology office visits (eg, QIG: OR 2.2 for > 15 vs 0-6; P < .001), and use of combination chemotherapy (eg, SPEP: OR 2.2 for proteasome inhibitor + immunomodulatory drug (IMID) vs those on IMID ; P < .001). Conclusions: In our Medicare population, patients on average underwent response evaluation much less often than monthly, but we also found overuse. Further investigation of the use of these tests is warranted given their central importance to MM care and their cumulative financial cost.
3-weekly daratumumab-IMiD-dexamethasone is highly efficacious and cost-effective in relapsed/refractory multiple myeloma.
Authors: Chim James , Wong Vincent , AU Elaine , Kwong Yok-Lam
Published: March 2020

e19521

Background: Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) is highly effective in relapsed multiple myeloma (MM). The recommended schedule of dara is weekly for 8 doses, followed by 2-weekly for 8 doses, and then every 4-weekly thereafter. Given the high cost and the long half-life as an antibody, a 3-weekly dosing of dara was used together with IMiD/dexamethasone. Methods: Dara at 16mg/kg was used every 3-weekly with lenalidomide or pomalidomide. Patient achieving best response received single agent IMiD maintenance until disease progression. Results: Fourteen relapsed MM patients were enrolled. One had received weekly dara from a private oncologist, hence was excluded from analysis. Thirteen patients at a median age of 63 years (range: 50-84 years) were studied. The median number of previous therapies was 2 (range: 1-5), with nine patients (69.2%) having undergone autologous stem cell transplantation. Three patients (23.1%) were refractory to bortezomib, seven patients (53.8%) to lenalidomide, and eight patients (61.5%) to last treatment. At relapse, two (15.4%) had high LDH, eight (61.5%) impaired renal function, and three (23.1%) extramedullary disease. Treatment was dara-lenalidomide-dex in six (46.2%), and dara-pomalidomide-dex in seven (53.8%). Responses after four cycles included CR in 5 patients (38.5%), VGPR in five patients (38.5%), and PR in three patients (23.1%). After a median of four dara infusions (range: 3-10), the best responses included CR in seven patients (53.8%), nCR in two patients (15.4%), VGPR in two patients (15.4%), and PR in two patients (15.4%). Median time to VGPR was one month. At 10 months, the OS was 90%, and PFS 54.7%. Three patients progressed, one of whom died of ruptured hepatic plasmacytoma. The most frequent toxicity was haematological especially neutropenia (all grades: 92.3%, Grade ¾: 76.9%), infusion reaction (38.5%, all grade ½), neuropathy (38.5%, all grade ½), gastrointestinal (all grades: 38.5%, grade ¾: 7.7%), and sepsis (all grades: 30.8%; grade ¾: 23.1%). Neutropenia was effectively prevented with prophylactic G-CSF. Conclusions: In conclusion , a 3-weekly dara-IMiD-dex regimen is highly efficacious, inducing deep and rapid responses, hence cost-effective for less affluent countries. In view of prevalent grade 3/4 neutropenia despite less frequent dara, 3-weekly dara might be more suitable for Asian patients.
Safety and efficacy of four drug regimens in newly diagnosed multiple myeloma: Systematic review.
Authors: Grewal Udhayvir Singh , Chakraborty Rajshekhar , Raziq Fazal I , Ashraf Afia , Majeed Ammara , Kapoor Vikas , Hubben Anne , Parikh Rujul , Lakhani Midhat , Latif Azka , Russ Atlantis Dawn , Anwer Faiz
Published: March 2020

e19537

Background: To improve outcomes, multiple agents with varied mechanisms of action targeting different multiple myeloma (MM) clones are needed. Methods: Systematic review of ongoing phase I-III clinical trials in newly diagnosed multiple myeloma (NDMM) was performed, (PRISMA guidelines) using 5 databases. Results: 8 trials n = 1,990 patients included (Table 1). We evaluated the efficacy of following four drug combinations Isatuximab (Isa), bortezomib (V), lenalidomide (R)dexamethasone (d) (Isa-VRd) Daratumumab (Dara) plus V, Melphalan (M) and Prednisone (P) (Dara-VMP) vs VMP Dara-VRd vs VRd Carfilzomib (K), Cyclophosphamide (C), R, Dexamethasone (KCRD) vs an immunomodulatory agent containing triplet (CTD/CRD) Dara with Ixazomib (I), R,d (Dara- IRd) Dara, Cyclophosphamide (Cy), V,d (Dara-CyBord) Elotuzumab (Elo) VRd Dara with K,R,d (Dara- KRd) For transplant-eligible patients, Dara-VRd demonstrated the best treatment response (VGPR = 100%, CR rate = 63% and 15 months PFS = 94%). Dara-VMP (ORR = 90.9%,VGPR+ = 72.9%, mPFS at 27. 8 m = NR) and Isa+VRd (ORR = 93%, VGPR = 71.43%, 7.5 m PFS = 100%) were associated with improvement in OR in transplant ineligible patients. Dara-KRd showed excellent efficacy (ORR = 100%, ≥VGPR = 86%) with 100% 6 m PFS. Conclusions: Four-drug regimens have improved efficacy (higher ORR, deeper response, higher proportion of MRD negativity and higher ≥VGPR responses) compared to three-drug regimens in NDMM, with a comparable incidence of toxicities. Longer follow-up is needed. [Table: see text]
The frequency of chromosomal abnormalities in AL amyloidosis and their impact on treatment response.
Authors: Yameen Hassan , Sarosiek Shayna , Sanchorawala Vaishali
Published: March 2020

e19539

Background: Chromosomal abnormalities (CA) found in AL amyloidosis (AL) are similar to those found in multiple myeloma (MM.) However, t(11;14) has been reported more frequently in AL, anywhere from 30% - 50% in studies. It has been reported that the presence of t(11;14) confers a lower hematologic response rate with bortezomib-based therapy (BBT) and a better hematologic response rate with high dose melphalan and autologous stem cell transplantation (HDM/SCT). Methods: We performed a retrospective review of 307 newly diagnosed patients seen at our center between January 2013 and December 2017, for whom interphase fluorescent in-situ hybridization (iFISH) data, performed on bone marrow aspirate using standard MM FISH probes on enriched plasma cells after magnetic separation, were available. Patients who already had iFISH performed prior to their visit with us were also included. We collected data on the incidence of CA, first line treatment, and hematologic response to this treatment. Results: Of the 307 patients, CA were not detected in 37%. 21% had t(11;14), 25% had 13q deletion, 21% had IgH rearrangements with an undetermined partner chromosome, and 11% had 1q21 gain. In those for whom initial treatment and hematologic response data were available, in patients with t(11;14), hematologic complete response (CR) was achieved by 18% following HDM/SCT and 27% following BBT. For those with 1q21 gain, CR was achieved by 33% following HDM/SCT and 19% following BBT. In contrast, hematologic CR was achieved by 47% following HDM/SCT and 40% following BBT for those who had no detectable CA with iFISH. Conclusions: Our study shows a lower incidence of t(11;14) in AL compared to other studies. This may be partly explained by the high number of patients with IgH rearrangements with undetermined partner chromosomes, some of whom may indeed harbor t(11;14). Our study also did not show a better hematologic response rate with HDM/SCT in t(11;14) patients compared with BBT. Hematologic response rates were much better both with HDM/SCT and BBT for those with no detected CA compared to patients who had t(11;14) or 1q21 gain.