bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes with preemptive donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes: A systematic review and meta-analysis.
Authors: Hussain Syed Ather , khan Atif N , THAMMINENI VENKATA S , Riaz Muhammad Nauman , Shahzad Moazzam , Pulipati Priyanjali , Khalid Fatima , Ahmed Zahoor , Anwar Iqra , Chaudhary Sibgha Gull , Balusu Ramesh , Ahmed Nausheen , Khurana Sharad , Anwer Faiz , Mushtaq Muhammad Umair
Published: June 2021

e19014

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) but relapse and graft versus host disease (GVHD) remain the most common challenges. Donor lymphocyte infusion (DLI) is the infusion in which lymphocytes from the original stem cell donor are infused, after the transplant, to augment an anti-tumor response or to ensure that the donor stem cells remain engrafted. In this systematic review and meta-analysis, we focused at outcomes of preemptive DLI in AML and MDS. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) PubMed, CINAHL, Cochrane, and Clinical trials.gov were searched. We included 8 out of 214 articles, excluding duplicates and non-relevant articles. The quality of the included studies was evaluated using NIH quality assessment tool. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2) to report the efficacy of preemptive DLI. We pooled the experimental arms results of the included trials using the inverse variance method and logit transformation. Between studies, the variance was calculated using Der Simonian-Laird Estimator. Results: We identified 222 patients who received preemptive DLI. Median age, time since transplant and DLI dose were 48 (32-58) years, 82 (7-160) days and 1.4 million cells/kg respectively. CR and PR were 43% (95%CI 0.14-0.78, I293%, n= 127) and 61% (95%CI 0.40-0.78, I262%, n= 81) respectively. After median follow up of 46 months, non-relapsed mortality (NRM) was 52% (95%CI 0.38-0.65, I249%, n = 121). OS was reported 72% (95%CI 0.62-0.80, I20%, n= 100). Acute and chronic GVHD incidence after DLI was 20% (95% CI 0.13-0.29, I24%, n= 105) and 25% (95% CI 0.08-0.56, I2=79%, n=101) respectively (Table). Conclusions: Preemptive DLI significantly improves OS with a low incidence of acute and chronic GVHD. However, NRM was seen in more than half of all the patients and prospective studies are needed to evaluate safety of preemptive DLI. Outcomes with preemptive DLI (n= 222).[Table: see text]
Outcomes with CD34 stem cell boost for poor graft function after allogeneic hematopoietic stem cell transplantation for hematologic malignancies: A systemic review and meta-analysis.
Authors: Shahzad Moazzam , Anwar Iqra , Siddiqui Raheel Sufian , Ahmed Tehniat Faraz , Majeed Mahrukh , Hassan Maha Awaiz , Ahmed Zahoor , Neupane Karun , Ali Tayyaba , Faisal Muhammad Salman , Naseem Masooma , Chaudhary Sibgha Gull , Balusu Ramesh , Ahmed Nausheen , Singh Anurag K , Abhyankar Sunil H. , McGuirk Joseph , Anwer Faiz , Mushtaq Muhammad Umair
Published: June 2021

e19021

Background: Poor graft function (PGF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HCT) characterized by severe multilineage cytopenia in the absence of mixed donor chimerism, relapse, or severe graft-vs-host disease (GVHD). We present a systemic review and meta-analysis aimed to assess the outcomes with stem cell boost (SCB) for PGF in adult allo-HCT patients. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, 752 articles were screened from 4 databases (PubMed, Embase, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for “hematological malignancies”, “hematopoietic stem cell transplantation”, “CD34 antigen(s)” and “treatment outcome(s)” from the date of inception to Jan 2021. After excluding review, duplicate and non-relevant articles, we included 8 studies (1 prospective, 7 retrospective) reporting hematologic complete/overall response rate (CR/ORR), GVHD and overall survival (OS) after SCB for PGF after Allo-HSCT. Quality evaluation was done using the NIH quality assessment tool. Pooled analysis was done using the ‘meta’ package (Schwarzer et al, R programming language) and proportions with 95% confidence intervals (CI) were computed. Inter-study variance was calculated using Der Simonian-Laird Estimator. Results: We identified 217 patients who received SCB for PGF after allo-HCT. Median age, time since transplant and SCB dose were 48 (37-54) years, 133 (113-450) days and 3.43 (1.7-4.9) million CD34 cells/kg respectively. CR and ORR were 71% (95%CI 0.63-0.77, I216%) and 80% (95%CI 0.74-0.85, I20%) respectively. After median follow up of 41.5 (5-77) months, actuarial survival rate (ASR) was 54% (95%CI 0.48-0.61, I20%). OS was reported from 80% (1y) to 40% (9y) Acute and chronic GVHD incidence after SCB was 17% (95% CI 0.12-0.23, I2=0%) and 17% (95% CI 0.08-0.32, I2=72%, n=197) respectively, and 25% (95% CI 0.14-0.39, I2=63%, n=163) deaths were due to relapse (Table). Conclusions: CD34 SCB improves outcomes after PGF after allo-HSCT with acceptable toxicity profile. However, current literature lacks high-quality randomized evidence and there remains an unmet need for prospective studies to address optimal dosing and manipulation of SCB. Outcomes with SCB for PGF after allo-HCT (n=217).[Table: see text]
Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients.
Authors: Lingamaneni Prasanth , Katiyar Vatsala , Kumar Rohit , Elsebaie Maha A.T. , Mann Hashim , Rodriguez Pierre , Zia Maryam
Published: June 2021

e19027

Background: Clostridiodes difficile infection (CDI) is reported to occur up to 9-fold higher in allogenic hematopoietic stem cell transplant (HSCT) recipients compared to the general population of hospitalized patients. This is attributed to disruption of gut microbiome by antibiotics, myeloablative regimens, neutropenia, prolonged hospitalization, and immunosuppressive regimens administered to prevent acute graft-versus-host disease (aGVHD). CDI by disruption of the intestinal microbiome may trigger gastrointestinal aGVHD. Previous studies from HSCT centers have reported conflicting data on the relationship between CDI and subsequent development of aGVHD. Methods: The Nationwide Readmissions Database was queried for admissions of adult allogenic HSCT patients between 2016 and 2018. Those with and without CDI during index admission were compared. Multivariable logistic regression was used to evaluate the primary outcome of risk of aGVHD in the index admission or within 100 days post-engraftment. Results: A total of 13518 allogenic HSCT patients were included in the study. Mean age was 52.4 years. 57.2% of patients were female. The most common underlying diagnoses were acute myeloid leukemia (38%), myelodysplastic syndrome (17%) and acute lymphoblastic leukemia (14%). 11.1% of the index admissions were complicated by CDI. Rates of aGVHD during the index admission or 100 days post-engraftment were similar between CDI and non-CDI groups: 13.8% vs. 12.1%, p=0.19 during index admission and 29.2% vs. 26.1%, p=0.09 during 100 days post-engraftment. Nonetheless, patients with CDI had longer length of hospital stay (34.6 vs 29.8 days, p<0.0001), higher hospitalization costs ($608K vs $506K USD) and greater rate of inpatient mortality (7.3% vs 4.6%, p<0.001). In the multivariate regression analysis, CDI during index admission was not associated with risk of development of aGVHD (Adjusted Odds Ratio 1.14, 95% Confidence Interval 0.87-1.48, p=0.34). Age and unrelated donor HSCT were predictive of risk of aGVHD. Conclusions: CDI during index admission was not predictive of aGVHD during the first 100 days post-allogenic HSCT. HSCT patients are frequency colonized with C.difficile. Diarrhea secondary to CDI may resemble gastrointestinal aGVHD. Therefore, overdiagnosis of CDI in this population is a concern. Antimicrobial stewardship and use of clinical decision support tools have been advocated recently to decrease testing of HSCT patients with C.difficile colonization. Multivariable analysis of risk factors of aGVHD.[Table: see text]
Analyzing treatment patterns and time to the next treatment in chronic lymphocytic leukemia real-world data using automated temporal phenotyping.
Authors: Lee Kyeryoung , Liu Zongzhi , Ma Meng , Mai Yun , Gilman Christopher , Li Minghao , Zhang Mingwei , Mullaney Tommy , Pan Qi , Chen Rong , Schadt Eric , Wang Xiaoyan
Published: June 2021

e19512

Background: Targeted therapy is an important treatment for chronic lymphocytic leukemia (CLL). However, optimal strategies for deploying small molecule inhibitors or antibody therapies in the real world are not well understood, largely due to a lack of outcomes data. We implemented a novel temporal phenotyping algorithm pipeline to derive lines of therapy (LOT) and disease progression in CLL patients. Here, the CLL treatment pattern and time to the next treatment (TTNT) were analyzed in real-world data (RWD) using patient electronic health records. Methods: We identified a CLL cohort with LOT from the Mount Sinai Data Warehouse (2003-2020). Each LOT consisted of either a single agent or combinations defined by NCCN CLL guidelines. We developed a natural language processing (NLP)-based temporal phenotyping approach to automatically identify the number of lines and therapeutic regimens. The sequence of treatment and time interval for each patient were derived from the systematic treatment data. Time to event analysis and multivariate (i.e., age, gender, race, other treatment patterns) Cox proportional hazard (CoxPH) models were used to analyze the patterns and predictors of TTNT. Results: Four hundred eleven CLL patients received 1 to 7 LOTs. Ibrutinib was the predominant 1st LOT (40.8% of patients) followed by anti-CD20-based antibody therapies and chemotherapy in 30.6 and 19.2% of patients, respectively, followed by Acalabrutinib, Venetoclax, and Idelalisib in 3.4, 2.7, and 0.7% of patients, respectively (Table 1). The 2nd to 5th LOT showed the same or similar trends. We next analyzed the TTNT in the 1st line of each therapeutic class. Acalabrutinib resulted in a longer median TTNT than Ibrutinib. Both Acalabrutinib and Ibrutinib showed longer TTNT compared to Venetoclax (median TTNTs were 742 and 598 vs. 373 days: HR = 0.23, p=0.015 and HR = 0.48, p=0.03, respectively). In addition, patients with age equal to or older than 65 showed longer TNNT (HR=0.16, p=0.016). Conclusions: Our result shows the potential of RWD usage in clinical decision making as real-world evidence reported here is consistent with results derived from clinical trial data. Linking this study to genetic data and other covariates affecting treatment outcomes may provide additional insights into the optimal sequences of the targeted therapies in CLL. Table 1: Therapeutic class and patient numbers (%) in each line.[Table: see text]
ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) as front-line therapy for Hodgkins lymphoma in Hispanic patients: A single center experience from Texas-Mexico Border.
Authors: Gaur Sumit , Philipovskiy Alexander , Dwivedi Alok Kumar , Eiring Ana , Onyedika Umeanaeto , Orazi Attilio
Published: June 2021

e19514

Background: Population-based studies in Hodgkin Lymphoma (HL) have shown reduced survival in patients of Hispanic ethnicity as compared with non-Hispanic Whites. ABVD is the most commonly used regimen for HL in the United States. We retrospectively reviewed the charts of Hispanic patients with HL treated at a single institution located along the Texas-Mexico border. Methods: We performed a chart review of Hispanic patients with HL treated at our institution over an 8 year period. Prognostic (Stage, International Prognostic Score) and predictive (results of interim and end of therapy PET scan) factors were recorded. Relative dose intensity (RDI: fraction of drug dose administered to the standard dose) of each chemotherapy drug was calculated.Treatment delays and their causes were recorded. Quantitative variables were described using median, inter-quartile range, minimum and maximum observations. Categorical variables were described using frequency and proportions. Kaplan – Meier curves were used to show relapse-free survival. Results: Base line characteristics are shown in table. A total of 24 patients were treated in the time frame of whom 45% were dependent on charity care. All were treated with ABVD or an ABVD-like regimen. After a median follow-up of 43 months, relapse rate for the entire cohort was 45.8%. ( 33.3% in early stage and 53.3% in advanced stage disease). Of the patients who relapsed 45% were unable to receive a stem cell transplant based salvage therapy. The RDI for each chemotherapy drug in ABVD was as follows: Doxorubicin (98.8%), Bleomycin (82.1%), vinblastine (97.9%) and dacarbazine (100%). The mean and median delay in completing chemotherapy was 9.9 and 5.5 days respectively (range 0-56). Conclusions: HL patients of Hispanic ethnicity have a high relapse rate with ABVD despite optimal delivery of the regimen. As medically underserved minority patients face significant barriers in accessing stem cell rescue based salvage treatments, decreasing the relapse rate with upfront therapy can help in addressing the disparity seen in survival. Non ABVD regimens shown to have a higher upfront remission rate like escalated dose BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) or A-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine) should be studied in these patients.[Table: see text]
Imaging determinants of early progression in relapsed and refractory Hodgkin and diffuse large B cell lymphoma.
Authors: Bajpai Surabhi , Sharma Manish , Narang Shweta , Mankala Ravikanth , Lalchandani Usha , Narang Jayant , Jarecha Rudresh , Bohnsack Oliver
Published: June 2021

e19522

Background: Diffuse Large B-cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma with over 18,000 new cases diagnosed each year in the United States and approximately 7-8 cases per 100.000 people globally. Hodgkin’s Lymphoma (HL) is less common accounting for approximately 9,000 new cases each year. However, their imaging manifestations overlap; with both the diseases demonstrating extensive lymph nodal and extra-nodal involvement along with intense uptake on 18FDG-PET. Novel targeted therapies have been developed to improve survival in patients with DLBCL and HL. The purpose of this study analysis was to determine if there was a correlation between the baseline tumor burden and early tumor progression based on imaging. Methods: This retrospective study involved the analysis of baseline imaging data (CT, MRI and PET) of 469 patients enrolled in multiple phase II/III clinical trials involving a diagnosis of DLBCL and HL. Image analysis was performed utilizing the IWG criteria Lugano 2014 modification. The staging of the baseline disease burden was performed as per the Revised Staging System for Primary Nodal Lymphomas. In addition to the staging, the sum of the product of perpendicular diameters of all target lesions (SPD), and spleen size at baseline were recorded. The time point of disease progression was also captured in this analysis for each patient. These baseline imaging parameters were compared among patients with early progression (≤6 months following onset of therapy). Results: Out of the 469 patients, 61.4% of patients (n = 288/469) demonstrated disease progression during treatment and/or follow up phase of the trial. In this cohort, 64.5% (n = 186/288) of patients showed early progression. Patients with advanced stage disease at baseline (Stage II bulky, III and IV) showed a higher rate of early progression compared to those with limited baseline disease burden (Stage I and II) (47.1% vs 32.9%). The occurrence of early progression was similar in patients with normal spleen size at baseline compared to those with an enlarged spleen at baseline (39.3% vs 41%). There was a trend towards higher baseline SPD in patients with early progression (3204mm2, +12.5%) and late progression (3185mm2, +12%) compared to patients who did not demonstrate progression during the trial phase (2804mm2, p = 0.23-0.45). Conclusions: Baseline disease staging is an important determinant of early progression in patients with DLBCL and HL. Baseline tumor burden is potentially a predictive marker of disease progression. Therefore, precise staging along with accurate recording of baseline tumor burden have important prognostic and subsequent therapeutic strategy implications for prospective decision making in the era of precision medicine. Further prospective studies may be needed to validate our results.
Outcomes in peripheral T-cell lymphomas: An analysis of patients treated at a single academic institution.
Authors: Costa Philippos Apolinario , Ocejo Gallegos Jesus Antonio , Pongas Georgios
Published: June 2021

e19524

Background: T-cell lymphomas are a heterogeneous group of lymphomas, including the cutaneous T cell lymphoma (CTCL) and the peripheral T cell lymphomas (PTCL). Regarding the PTCL, it’s a heterogeneous group including approximately 23 different diseases with the peripheral T-cell lymphoma not otherwise specified (PTCL NOS), angioimmunoblastic lymphoma (AITL), and anaplastic large cell lymphoma (ALCL) being the most frequent subtypes. In contrast with the B cell lymphomas, most of the PTCL have a worse prognosis. We aim in our study to quantify the prognosis in each of the most frequent subtypes of PTCL. Methods: We analyzed patients with either PTCL NOS, AITL, or ALCL treated at Sylvester Comprehensive Cancer Center between 2010 and 2020. We calculated overall survival (OS) using the Kaplan-Meier method with Log-Rank Test to estimate the 95% confidence interval. Results: 98 patients belonged to 1 of the 3 major T-cell lymphoma subtypes: 43 to PTCL NOS, 33 to AITL, and 20 to ALCL, being 7 ALK-positive and 13 ALK-negative. Mean age in PTCL NOS, AITL and ALCL was 56 years (ranging from 8-88), 62 (8-89), and 52 (1-79), respectively. In PTCL NOS, AITL and ALCL respectively, 21 (46%), 15 (45%) and 7 (35%) of patients were female. The three-year and five-year overall survival was 62% (95% CI 42-82) and 30% (95% CI 6-54%) in PTCL NOS, 64% (95% CI 44-84) and 42% (95% CI 4-78%) in AITL, 75 (95% CI 51-99) and 67% (95% CI 33-100) in ALK-negative ALCL. There were no reported deaths in ALK-positive ALCL. The mean survival was lowest in PTCL NOS (p = 0.02), being 3,6 years, while AITL it is 5.2 and in ALCL it is 8.4. Conclusions: Amongst the three major subtypes of PTCL, PTCL NOS have the worse prognosis. Future research is needed to develop a risk stratification tool in each subtype.
Prognostic value of early imaging following CAR T-cell therapy in DLBCL.
Authors: Bajwa Amneet , Huang Ying , Li Rui , Denlinger Nathan , Brammer Jonathan Edward , Saad Ayman A. , Jaglowski Samantha , Kittai Adam
Published: June 2021

e19559

Background: Chimeric antigen receptor T-cell (CART) therapies lead to durable disease control in patients (pts) with relapsed/refractory (R/R) Diffuse Large B-cell Lymphoma (DLBCL). We assessed the prognostic value of response on first staging scan, and whether pts with progression of disease (PD) convert to a response on second scan. Methods: We conducted a retrospective analysis of pts with R/R DLBCL treated with CART at our institute. Baseline characteristics were assessed at apheresis. We included staging scans (CT, PET-CT and MRI) that occurred up to 6 months (mos) after CART infusion. Responses were determined via the Lugano 2014 criteria. Overall survival (OS) was calculated from first scan to last follow-up. Kaplan Meier method and Cox model were used to correlate first scan result with OS. Results: Of the 118 pts who received CART, 111 pts had evaluable staging scans (7 passed prior to first scan). Of the 111 pts, median age was 61 years (range, 23-84), and median number of prior therapies was 3 (range, 1-7). 61 pts received tisagenlecleucel, and 50 pts received axicabtagene ciloleucel. 22% of pts had MYC rearrangement by FISH. The majority of pts were stage 3/4 (91%), with an IPI score ≥2 (82%). 32%, 66% and 2% of pts had a CT, PET-CT or MRI as their first scan respectively. After a median follow-up of 16.2 mos, median OS from first scan was not reached (NR) (95% CI, 17-NR). 37%, 5%, 32%, 25% of pts had PD, SD, PR, and CR on first scan respectively. Median time to first scan was 59 days (range, 13-115). Median OS for pts who had PD was 3 mos (95% CI 2-8), and the median OS for those who attained SD, PR or CR was NR (95% CI NR-NR). Accounting for statistically important factors on multivariate analysis, PD on first scan was an independent predictor of OS (p<.001, HR 10.1 (95% CI 4.7-22)). We observed no evidence that pts with PD on first scan convert to a response on second scan without intervention. 26 of 41 pts who had PD did not start new treatment, 17 passed without follow-up scan, 1 is in follow-up, and 8 continued to show PD on subsequent scans. Conclusions: PD on first staging scan is a strong prognostic marker for survival for pts with R/R DLBCL who receive CART. There is no evidence to suggest conversion to a response will occur for patients who have PD. Performing staging scans at an earlier time-point has value, allowing for earlier treatment changes and goals of care conversations in this pt population.[Table: see text]
Hypercalcemia as a predictor of adverse treatment outcomes in DLBCL during chemotherapy: A national inpatient database study.
Authors: Kumi Dennis Danso , Shrivastava Trilok , Elsebaie Maha A.T. , laswi hisham , Ahuja Kriti , Batra Kunnal
Published: June 2021

e19571

Background: Hypercalcemia occurs in up to 7% of NHL and up to 18% in diffuse large B-cell lymphoma (DLBCL) representing about 60% of cases. Thus far, there are only a few studies that have established the poor prognosis between hypercalcemia and outcomes in DLBCL. We sought to outline specific acute complications that can during admission for chemotherapy in patients with hypercalcemia. Methods: This is a retrospective analysis of hospital admission using the National Inpatient Sample database (2018), including 15,636 adult patients with DLBCL admitted for chemotherapy. We obtained descriptive data, conducted chi-square test, and stratified logistic regression to look for possible chemotherapy related acute medical complications & predictors of mortality in DLBCL with & without hypercalcemia. Study limitations included lack of long term follow up, variations in chemotherapy and possible under-reporting of test subjects. Results: The mean age among DLBCL patients with & without hypercalcemia were 65.41 and 58.52 years respectively and the mean length of stay were 6.56 and 4.98 days respectively. Patient’s race, type of insurance and Charlson’s comorbidity index were found to be significant predictors of mortality in patients with DLBCL admitted for chemotherapy. Among race, Hispanics & Asian or Pacific islanders were found to be at higher risk for mortality, while patients who had private insurance were found to be associated with higher mortality risk (p<0.01). Similarly, Native Americans (aOR 8.72, 1.93-39.34, p<0.01) and patients with Charlson comorbidity index of 4 or more were at higher risk of mortality (aOR 4.34, 2.30-8.18, p<0.01). In regard to acute medical complications, DLBCL patients with hypercalcemia were at higher risk for tumor lysis syndrome (TLS) (aOR 3.86, p<0.01), acute kidney injury (AKI) (aOR 4.28, p<0.01) and hyperuricemia (aOR 9.74, p<0.01). There was no significant association of hypercalcemia in DLBCL with hyperkalemia, fluid overload, ICU admission, mortality, total cost, or length of stay. Conclusions: Hypercalcemia is associated with higher adverse outcomes during chemotherapy treatment in patients with DLBCL including TLS, hyperuricemia, and AKI during chemotherapy admission. This confirms to the overall accession of poor outcomes as published by other studies.[Table: see text]
Testing Mayo Clinic’s new 20/20/20 risk stratification model in another cohort of smoldering myeloma patients: A retrospective study.
Authors: Tessier Camille , Allard Thomas , Boudreault Jean-Samuel , Kaedbey Rayan , Fortin Flechere , Ethier Vincent , Pavic Michel
Published: June 2021

e20005

Background: Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder associated with a high risk of transformation to symptomatic multiple myeloma (MM). SMM risk of progression to MM is highly heterogeneous and several models have been suggested to predict this risk, but none have yet been adopted internationally. Lakshman et al. recently proposed a risk stratification model based on three markers: bone marrow plasma cell (BMPC) percentage > 20%, free light chain ratio (FLCr) > 20 and serum M protein > 20 g/L. In this “20/20/20” model, patients with 0, 1 or ≥ 2 risk factors are respectively considered at low, intermediate and high-risk of progression. The goal of our study was to test this risk model in our population and to determine if similar results could be obtained in another cohort of SMM patients. Methods: We conducted a retrospective, single center study with 89 patients diagnosed with SMM between January 2008 and December 2019. Patients were identified by query of the electronic medical records and the 2014 International Myeloma Working Group (IMWG) diagnostic criteria for SMM were used to determine eligibility. The main endpoint was progression to symptomatic multiple myeloma or amyloidosis. Results: All three markers proposed by Lakshman et al. were associated with an increased risk of progression: BMPC percentage ≥ 20% (hazard ratio [HR]: 4.28 [95% C.I., 1.90 – 9.61]; p < 0.001), serum M protein ≥ 20g/L (HR: 4.20 [95% C.I., 1.90 – 15.53]; p = 0.032) and FLCr ≥ 20 (HR: 3.25 [95% C.I., 1.09 – 9.71]; p = 0.035). Immunoparesis (HR: 2.61 [95% C.I., 1.07 – 6.41]; p = 0.036) was also an independent risk factor in our population. The estimated median time to progression (TTP) was not reached for the low and intermediate risk groups and was 29.1 months (95% C.I., 3.9 – 54.4) in the high-risk group (p = 0.006). The estimated mean TTP for the low-risk group, the intermediate-risk group and the high-risk group were respectively 78.4 months (95% C.I., 68.3 – 88.5), 48.3 months (95% C.I., 31.9 – 64.8) and 35.2 months (95% C.I., 19.1 – 51.2). Sex, IgA isotype, positive Bence-Jones, abnormal β2-microglobulin and MGUS prior to SMM did not result in an increased risk of progression. The estimated proportion of progression-free patients at 1, 2 and 5 years were 96.8%, 93.4% and 77.5% for the low-risk group, 80.0%, 80.0% and 62.2% for the intermediate risk group and 70.0%, 58.3% and 29.2% for the high-risk group. Conclusions: When Mayo Clinic’s new 20/20/20 risk model was applied to our population, it adequately predicted the risk of progression to symptomatic disease at 2 years. As it relies on readily available biological parameters, this model is easy to use and can be applied in most clinical settings. We believe this model could be used to further study therapeutic approaches in higher risk SMM.
Correlation of Agent Orange exposure, cytogenetics, and clinical outcomes in multiple myeloma and MGUS.
Authors: Kulkarni Pruthali , Copeland Laurel , Hall James Andy , Dodlapati Jyothi
Published: June 2021

e20008

Background: Multiple myeloma (MM) accounts for 1-2% of cancers worldwide. MM and monoclonal gammopathy of unknown significance (MGUS) are associated with Agent Orange exposure (AO) in Vietnam war veterans. Studies show poor outcomes in AO-exposed patients developing MM. No study has evaluated AO exposure and adverse cytogenetics in patients with MM. Methods: We reviewed patients with MGUS and/or MM in the Central Texas Veterans Health Administration system in 2010-2015 to evaluate AO exposure, adverse cytogenetics, transformation from MM to MGUS, and overall survival (OS). Inclusion criteria were active-duty military when AO was used (1961-1971). Presence of 17p13, t(4;14), t(14;16), t(14;20), or Gain 1q by FISH defined high-risk cytogenetics. Poor prognosis per serum free kappa/lambda ratio was defined as < .03 or > 32 K/L (high-risk). Regulatory review approval was obtained. Cox survival models generated hazard rate ratios and their 95% confidence intervals (HR) for AO status (AO, non-AO, undetermined), age, race/ethnicity, transformation, and FISH data. Results: Among 129 veterans, 30% were Black and 12% Hispanic (mean age 74.0 years, SD 6.9, range 59-97). MGUS was diagnosed in 44%, MM 74%, and transformation 19%. FISH abnormalities were rare thus AO association cannot be definitively stated; see table. A subsample with known AO and K/L (n = 81) showed no association: 69% high-risk had AO vs 76% moderate-risk; chi2 = 0.54; p = .46. In the adjusted model, Hispanic patients (HR = 3.3; 1.2-9.1) and those with high-risk cytogenetics (HR = 6.0; 1.1-34.1) had higher mortality; AO was unrelated. Conclusions: Although preliminary analyses find no associations of AO and transformation with OS, ethnicity and FISH abnormality associations are intriguing. Chart review is 50% complete. The paucity of cytogenetics data begs further examination, and continued study is merited to fully recognize what predisposes MM development following AO exposure.[Table: see text]
Frailty in relapsed/ refractory multiple myeloma registration trials.
Authors: Murugappan Meena N. , King-Kallimanis Bellinda , Kanapuru Bindu , Chen Ting-Yu , Bhatnagar Vishal , Kluetz Paul Gustav
Published: June 2021

e20017

Background: Multiple Myeloma (MM) is predominantly a disease of older adults with a median age of onset at 70 years. There is growing interest in using criterion other than chronological age, like frailty, to determine fitness for treatment and ultimately improve clinical outcomes in MM. Frailty is the accumulation of aging-associated diseases and disabilities, making patients more vulnerable to adverse outcomes when exposed to stressors like anti-cancer treatment. MM frailty measures have primarily been developed and tested in newly diagnosed patients. MM patients typically relapse, but there is limited knowledge regarding the prevalence of frailty in the relapsed/refractory (RRMM) setting. The aim of this research was to determine the prevalence of frailty in RRMM commercial clinical trials, at the time of trial enrollment, using the International Myeloma Working Group (IMWG) Frailty Index. Methods: We pooled baseline data from 6 RRMM clinical trials submitted for FDA regulatory review between 2010 and 2020. The IMWG Frailty Index was calculated for each patient based on 4 variables: age (≤75, 75–80, >80 years, score 0, 1, 2, respectively), Charlson Comorbidity Index (CCI; ≤1 or ≥2, score 0 or 1), and (Instrumental) Activities Daily Living (ADL >4 or ≤4, score 0 or 1; IADL >5 or ≤5, score 0 or 1). As ADLs and IADLs are not routinely collected in clinical trials, we substituted this information with corresponding EQ-5D items on self-care and usual activities. Fit, Intermediate-fit, and Frail patients received IMWG scores of 0, 1, and ≥2 respectively. Descriptive statistics for frailty were summarized by age. Results: 2766 RRMM patients were aggregated from six clinical trials. 1502 (54%) patients were Fit, 780 (28%) were Intermediate-fit, and 484 (18%) were Frail. The median age of patients across trials was 65 [range 30-91]. The median CCI was 0 [range 0-7] out of 37. IMWG frailty scores have been presented by age category in Table. Prevalence of frailty at baseline by age in RRMM registration trials. Conclusions: Most patients in RRMM registration trials were classified as Fit at baseline, using the IMWG Frailty Index. This was expected due to stringent trial enrollment criteria which exclude patients with severe comorbidities, as reflected in the low average CCI. The IMWG index heavily weights patient age. As such, there were no Fit patients in the 75 – 80 year old cohort and only Frail patients in the 80+ year old cohort. This is despite the fact that these older patients met stringent trial enrollment criteria and had CCI scores < 7. Chronologic age alone should not be used as an absolute exclusion for treatment, whether in the trial or real-world setting. Future research into frailty indices that do not heavily weight age is warranted.[Table: see text]
Role of adjunct plasma exchange or high cut-off hemodialysis in the management of myeloma cast nephropathy: A systematic review.
Authors: Hanif Nazma , Sana Muhammad Khawar , Abdelazeem Basel , Rafae Abdul , Mushtaq Muhammad Umair , Anwer Faiz
Published: June 2021

e20032

Background: Renal impairment by cast nephropathy is a common complication in multiple myeloma. Tubulointerstitial injury results from precipitation of filtered free light chains (FLC) with Uromodulin in the distal convoluted tubules. Rapid reduction in serum FLC levels has shown to improve renal function in modeling studies. Extracorporeal light chain removal techniques such as plasma exchange (PEX) and high cut-off hemodialysis (HCO-HD) have been explored as potential adjunct treatment options for cast nephropathy in various clinical trials. Methods: PubMed, Cochrane library, and Clinicaltrials.gov were searched systematically for the use of plasma exchange and/or hemodialysis with chemotherapy in the treatment of myeloma cast nephropathy using their MeSH words and keywords. PRISMA guidelines were followed for screening and 5 out of 866 studies were finalized (N = 342). Results: Zucchelli et al. 1988 (n = 29) reported a dramatic reduction in Bence Jones protein (BJP) levels of 0.81 ± 0.46 g/day (P value < 0.01) and 1-year survival rate of 66% in the PEX group and decrease in BJP of 3.25 +/- 0.21 g/day (P-value < 0.05) with a survival rate of 28% in the control group. Clark et al. 2005 (n = 104) reported a primary composite response (patient alive at 6 months + dialysis independence + serum creatinine improvement of 50% at 6 months) in 57.9% of patients in the PEX group and 69.2% in the control group [95% CI, -8.3% to 29.1%]; P = 0.36. Johnson et al. 1990 (n = 21) reported a mean change of 880 μmol /L ± 260(SD) in serum creatinine in the PEX group and 570 μmol /L +/-240 in the control group. HD independence at 3 months was reported as 41.3% (n = 19) in the HCO-HD group and 33.3% (n = 16) in the conventional HD group (95% CI -12%–27.9%; P = 0.42) in the MYRE trial 2017 (n = 98). The EuLITE trial 2019 (n = 90) compared the efficacy of the high cut-off vs high flux hemodialysis (HF-HD) technique and concluded that there was no clinical benefit of one over the other. Independence from HD was achieved in 56% (n = 24) in the HCO-HD cohort vs 51% (n = 24) in HF-HD cohort (relative risk [RR] 1.09, 95% CI 0.74–1.61; P = 0.81). Conclusions: The use of high cut-off hemodialysis and plasma exchange as adjunct therapy did not show any significant survival benefit or improvement in clinical outcome. The role of routine use of PEX/HCO-HD in the management of cast nephropathy is still unclear and the decision to use these modalities should be made on an individual basis.
Continuous genomic monitoring of multiple myeloma patients to identify patients of high risk for poor prognosis.
Authors: Liu Yu , Yu Haocheng , Lagana Alessandro , Parekh Samir , Schadt Eric , Wang Li , Zhu Jun
Published: June 2021

e20035

Background: Multiple myeloma (MM) is heterogeneous from symptoms, mechanisms of tumorigenesis and progression, to the treatment outcome. Besides age and tumor stage, prognostic models based on the genomic or transcriptomic profiles were developed to stratify patients into risk groups at diagnosis. Even though mutation burden at diagnosis is not associated with overall survival (OS), its change during the course of treatment, which might reflect the emergence of treatment resistant subclones, could provide insights about the MM evolution and hence associate with patient outcome. Methods: In this study, we developed a new parameter referred to as “tumor evolution rate” and investigated its association withclinical outcomes. The tumor evolution rate was measured as the rate of acquiring new somatic mutations among the sequential samples from the same patients. We utilized genomic data generated on 140 MM patients with two sequential samples from the MMRF CoMMpass database. The prognostic power of evolution rate was compared with other clinical parameters as well as gene expression-based markers. Results: There was significant heterogeneity in the evolution rate among MM patients (median, 0.114; 0.011 – 2.34 new mutations per day). The evolution rate was significantly associated with OS in a univariate Cox regression model (Wald test p = 5.0×10-7). When stratified into high, intermediate and low-rate groups, they had a median OS of 316, 743 and 998 days after the collection date of 2nd samples, respectively (logrank test p = 1.0×10-6). With age and ISS stage as covariates in the multivariate Cox regression model, the evolution rate remained significantly associated with OS (p = 6.3×10-6). The mutation burden itself at either sampling time was not associated with OS. For patients with two sequential samples collected less than 2 years apart (N =82), the evolution rate was significantly associated with OS (Wald test p = 2.0×10-6). However, for patients with two sequential samples collected more than 2 years apart, the evolution rate was not significantly associated with OS anymore, likely due to the inaccurate evolution rate estimates over long intervals. In addition, the patient stratified by the evolution rate shared some similarity with those stratified via a gene expression-based prognostic model (previously developed by us). The majority of patients in the low or intermediate risk group based on gene expression were in the low or intermediate evolution rate group. For patients with a high-risk prognosis (n = 21), 57% (12 out of 21) had tumors with a high evolution rate during treatment, suggesting alternative treatment options may be needed for this group of patients. Conclusions: Our study demonstrated that the tumor evolution rate as derived from continuous monitoring of tumor genomic changes provided extra prognostic information for identifying MM patients of poor prognosis after drug treatment.
Clinical presentation and outcome of patients with AL amyloidosis requiring salvage therapy.
Authors: Wang Chen , Zhang Yumeng , Duncanson Lauren , Brayer Jason B. , Hansen Doris K. , Alsina Melissa , Nishihori Taiga , Liu Hien , Ochoa-Bayona Jose L. , Shain Kenneth H. , Reu Frederic J. , Baz Rachid C. , Blue Brandon Jamaal
Published: June 2021

e20043

Background: The diagnosis and upfront management of immunoglobulin light chain (AL) amyloidosis have greatly improved in recent years. However, little is known about the presentation, treatment, and outcome of these patients at first relapse/progression (R/P). Methods: All patients with AL amyloidosis who received salvage therapy for first R/P disease at Moffitt Cancer Center between 2008 and 2020 were included in this retrospective review. Definitions of hematologic and organ R/P were based on 2012 consensus. Overall survival was measured from the time of salvage to last follow up/death. Survival was assessed by Kaplan-Meier with log-rank comparison. Results: Sixty-nine patients were included. The median age at diagnosis was 62 years and 61% were male. Upfront therapy included high dose melphalan with autologous transplant in 36% and bortezomib in 52%. At salvage, 19% had disease refractory to upfront therapy and 40% had not achieved an organ response. The median time from upfront to salvage therapy was 22 months. Salvage regimens included proteasome inhibitors, daratumumab and immunomodulatory drugs in 55%, 13% and 22%, respectively. At least a very good partial response and organ response were achieved in 35% (22/62) and 39% (21/54) with measurable disease. The median overall survival was 60 months. Based on salvage indication, patients were classified into hematologic (n = 29) and organ R/P (n = 40), and the latter showed more frequent lambda-light chain disease (59% vs. 83%, p = 0.028) and low difference of involved-uninvolved free light chain at diagnosis (< 50 mg/L, 8% vs. 44%, p = 0.002). Negative prognostic markers for survival included bone marrow plasma cells ≥20% at diagnosis (median 17 months vs. not reached; p < 0.001) and organ, particularly cardiac R/P (median, 31 months vs. not reached; p = 0.003). Salvage ( p = 0.48) or prior regimens ( p = 0.11) did not impact post-salvage survival. Conclusions: Our study highlights the unmet need of salvage in R/P AL amyloidosis in a real-world setting, given the low rate of deep responses regardless of current salvage options. Patients with bone marrow plasma cells ≥20% at diagnosis and organ R/P at salvage had inferior survival, supporting use of intensive upfront regimens for the former and adjustment of therapy if deep response is not achieved.[Table: see text]
Deep learning survival model on transcriptomes level in patients with non-small cell lung cancer.
Authors: Yu Hao , Yang Li , Lam Ka-On , Jin Jian-Yue , Hu Chen , Kong Feng-Ming Spring
Published: June 2021

e20518

Background: Non-small cell lung cancer (NSCLC) is associated with poor prognosis. Global gene expression profiling with overall survival (OS) may help improving individualize survival. In this study, we identify biological important gene clusters and studied their prognostic abilities for OS by deep learning method. Methods: Using GEO genomics data repository, we identified 196 NSCLC patients (trainset: GSE37745) and 181 NSCLC patients (testset: GSE50081) with clinical information and long-term follow-up. In both cohorts, expression profiling was performed on RNA from tumor tissues using Affymetrix microarrays HG-U133-Plus2; and normalized using the Robust Multiarray Averaging (RMA). We established deep learning survival models through neural network extension of the Cox regression model for predicting OS, which were developed by 5-folds cross-validation in GSE37745 and independently validated in GSE50081. Significant RNA-seq and clinical variables were multiple inputs. Concordance index (CI) was evaluated and compared with multivariable Cox regression. Then we conducted Uniform Manifold Approximation and Projection (UMAP) using weights in hidden layer of the model for clustering the important RNA-seq and then performed enrichment analysis though GO/KEGG for revealing biological progresses. Results: Total 1039 RNA-seq levels were found significant with OS ( P < 0.05) by Cox proportional hazard model adjusted by clinical variables (age, gender, cancer stage, histology) in trainset. The deep learning survival model with 20 most significant RNA-seq and clinical variables had best average performances as CI = 0.74±0.04 in trainset (GSE37745) and CI = 0.68±0.06 in testset (GSE50081) in 10 iterations, better than multivariable Cox regression ( P < 0.05). The deep learning survival model with all significant RNA-seq were also established and the weights in the hidden layer were clustered by UMAP into 5 positive and 5 negative clusters. The clusters were enriched, such as in positive clusters, negative regulation of RNA metabolic process, negative regulation of RNA biosynthetic process and positive regulation of protein modification process were top three significant biological processes for shorten survival; while in negative clusters, DNA metabolic process, positive regulation of phosphate metabolic process and positive regulation of RNA metabolic process were the top three for prolonged survival. Conclusions: In this study, the deep learning survival algorithm was established for survival prediction based on a transcriptome level in patients with NSCLC. Given the models’ robustness and better performances, our study would be useful at predicting and applying more biological information for survival.
Surgery versus radiation therapy outcomes in patients with clinical stage 0 non-small cell lung cancer.
Authors: Narayana Swapna , Kovacs Attila J. , Borgert Andrew J. , McGee Matthew , Frankki Susan M. , Marinier David E.
Published: June 2021

e20537

Background: There are currently no clear national guidelines for management of in-situ (stage 0) non-small cell lung cancer (NSCLC). With no prospective clinical trial data, treatment strategies include both surgical resection and definitive radiation therapy (RT). We aimed to investigate survival outcomes in patients with stage 0 NSCLC who underwent surgery or RT. We also aimed to identify any differences in the treatments that the two groups received with respect to rural versus urban setting and racial variation. Methods: The 2016 National Cancer Data Base was reviewed from 2006-2015 for patients registered with a pathological diagnosis of Stage 0 NSCLC, based on the AJCC 7th edition classification for lung cancer. Patients with a prior history of malignancy, secondary malignancy other than lung, and contraindications to surgery were excluded. Univariate comparison and multivariate logistic regression modeling were utilized to identify factors associated with receipt of surgery. Patients were stratified into two groups, surgical resection and RT. Kaplan-Meier estimators and Cox proportional-hazards regression were used to compare overall survival(OS). Propensity score matching was performed using relevant demographic and clinical factors associated with receipt of surgery. All analysis was completed in SAS version 9.4 and p-values less than 0.05 were considered significant. Results: A total of 156 patients were identified with Stage 0 NSCLC who received surgery (n = 104) or RT (n = 52). Surgery was defined as lobectomy or less. Histologic subtypes were squamous cell carcinoma (54%), adenocarcinoma (45%), and bronchioloalveolar carcinoma (1%). Median age was 65 years for the surgical resection cohort and 70 years for the RT cohort. From diagnosis, median time to surgery was 21 days for the surgical resection cohort and 47 days to start of radiation for RT cohort. We did not identify any major differences with respect to rural versus urban setting or racial differences within the surgery and RT cohorts. Patients who underwent surgical resection had a superior 5 year overall survival 65% (CI, 43.49-80.56) when compared to patients who underwent RT 37% (CI, 10.63-65.05), hazard rate 0.403, p = 0.0009, 95% CI. 0.236 – 0.689). Conclusions: Our findings show a significant improved survival with surgical resection compared to RT in patients diagnosed with Stage 0 NSCLC.