bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic value of baseline elevated red cell distribution width in DLBCL.
Authors: Diamond Akiva , Boughan Kirsten M , De Lima Marcos J.G. , Caimi Paolo Fabrizio
Published: May 2020

e20031

Background: Elevated red cell distribution width (RDW) has been associated with all-cause mortality, risk of developing cancer and cancer mortality in large retrospective studies. The underlying mechanism may be due to inflammatory and nutritional abnormalities. We hypothesized DLBCL patients with an elevated RDW at the time of diagnosis would have a worse prognosis. Methods: A retrospective single-institution study included 541 DLBCL patients diagnosed between 2001 and 2016. RDW over 14.5% was considered high, as this was the upper limit of normal at our institution. The overall and progression free survival was estimated using Kaplan-Meier methods, and the difference between groups was compared using the log-rank test. Univariate and multivariate analyses were performed with Cox proportional hazards regression. Results: We identified 410 DLBCL pts with available baseline RDW, 229 (56%) had RDW > 14.5. Median follow up from diagnosis was 60 months. The complete response rate was 63.8% in the group with high RDW (n = 152) and 88.4% in the normal RDW group (n = 216, p < 0.0001) . For patients with high RDW, 1-year overall survival (OS) was 65% (95%CI 0.58-0.72) vs 90% (95%CI 0.87-0.94) for pts with normal RDW < / = 14.5; 2-year OS was 57% (95%CI 0.50-0.65) vs 84% (95%CI 0.79-0.89), respectively (p < 0.0001). This difference remained statistically significant when the analysis was restricted to patients treated with anthracycline-containing regimens given with curative intent (2y OS = 66% vs. 87.5%, p < 0.0001). Univariate analysis revealed that R-IPI, high RDW, elevated LDH, albumin < 3.5mg/dl, Hgb < 10g/dl, advanced stage disease, bulky disease, extra nodal disease, and ECOG performance status 3-4 were associated with worse OS. In multivariate analysis, older age (HR 2.07, 95%CI 1.38-3.1), high RDW (HR 1.68, 95%CI 1.15-2.5), albumin < 3.5mg/dl (HR 1.76, 95%CI 1.18-2.6) and ECOG 3-4 (HR 2.47, 95%CI 1.47-4.2) were independent prognostic factors for OS. Conclusions: High RDW is associated with worse response rates and independently associated with worse OS in patients with DLBCL. Based on our study, DLBCL patients with high RDW at diagnosis should be considered at higher risk of mortality and treatment failure. Further research is needed to clarify the underlying mechanism and to evaluate the utility of incorporating RDW into prognostic indices.
Factors affecting 48-hour methotrexate levels following high-dose methotrexate (HDMTX) in lymphoma.
Authors: O'Donoghue Darragh , Truong Huong , Finnes Heidi Diann , McDonald Jennifer , Ansell Stephen M. , Leung Nelson
Published: May 2020

e20033

Background: HDMTX is an important component of lymphoma therapy due to its central nervous system penetration. Although HDMTX can be safely administered to most patients, it can cause significant toxicity with those who have prolonged exposure to high plasma concentrations of MTX due to delayed elimination. Therefore, serum MTX concentration monitoring is still a standard approach for identifying patients at high risk of developing MTX toxicity. A majority of MTX is excreted within the first 48 hours of infusion. Higher MTX plasma concentrations at 48 hrs increase the likelihood of delayed MTX elimination. This study will assess baseline characteristics associated with high 48-hour MTX levels (≥ 1µM) which has been associated with increased risk of complications. Methods: A retrospective review of the electronic medical record was conducted to identify lymphoma patients who received HDMTX from 1/1/2002 to 12/31/18. Baseline demographics including age, gender, comorbidities, body surface area, BMI, weight and baseline chronic kidney disease (CKD) were recorded. Demographics, HDMTX dosing per protocol (3.5g/m2 vs 8g/m2), HDMTX adjusted by renal function (CrCl < 100), and ratio of MTX dose to BSA (MTX/BSA) were compared to 48 hour MTX levels. Analysis was performed in JMP 15. Results: 2553 cycles were of HDMTX were identified. There was a significant association of increasing age, (p = 0.039), male patients (p < 0.001), 8g/m2 dosing (p < 0.001), higher MTX dose (p < 0.001), MTX/BSA (p < 0.001), GFR by CKD-EPI (p < 0.001) and lower number of comorbidities (p < 0.001) with 48-hour MTX levels ≥1. There was no significant association of 48-hour MTX levels ≥1 and GFR by Cockcroft-Gault (p = 0.73), baseline CKD (p = 0.78), and renal adjusted HDMTX (p = 0.52). Multivariate analysis revealed significance for MTX/BSA, gender, BSA, GFR by CKDEPI (p < 0.001), and age (P = 0.0002). Conclusions: Hematologists should be aware that age, gender, GFR by CKD-EPI, and ratio of MTX dose to BSA are associated with elevated 48-hour MTX levels ≥1.
Safety and outcome of allogeneic stem cell transplantation in mycosis fungoides and Sezary syndrome: A seven-year tertiary center analysis.
Authors: Toprak Selami Kocak , Cengiz Seval Guldane , Atilla Erden , Civriz Bozdag Sinem , Kurt Yuksel Meltem , Topcuoglu Pervin , Akay Bengu Nisa , Sanli Hatice , Gurman Gunhan , Ozcan Muhit
Published: May 2020

e20038

Background: Allogeneic hematopoietic stem cell transplantation (AHSCT) is a promising strategy for treatment of advanced-stage mycosis fungoides/Sezary syndrome (MF/SS). In this study, we retrospectively analyzed the outcomes of AHSCT for MF/SS and found that MF/SS appears to be susceptible to graft versus leukemia (GVL) effects. Methods: We studied outcomes in a consecutive series of 14 patients with MM/SS who underwent AHSCT between January 2012-November 2019 at our center. Treatment response was evaluated according to the Consensus WHO criteria for MF/SS. Results: The median age of patients 51.5 years (range: 28-68 years). Eight patients had MF and six patients had SS. Nine of those 14 patients had large cell transformation. All patients had advanced disease (stages IIB: n = 1, IIIA: n = 2, IIIB: n = 6, IVA1: n = 2 and IVB = 3). The median interval from disease onset to AHSCT was 3.7 years (range: 10.5 mos-11.3 years). All of the patients received at least three lines of treatments prior to AHSCT. Four patients achieved CR (3 are alive and still in CR) and all the other patients had progressive disease (PD) at the time of AHSCT. Graft source was peripheral blood stem cell in all patients. Six patients underwent transplantation from 9/10 HLA-matched unrelated donors and eight patients from HLA-identical sibling donors. Most of the patients (12/14) received RIC regimen (Flu-Cy-TBI) and ATG-Fresenius also added the protocol in AHSCT from unrelated donors. Five patients had stage 2-4 cutaneous acute GVHD and chronic GVHD developed in four patients (mild: n = 1, moderate: n = 2, severe: n = 1). Six patients who underwent transplantation at PD attained CR after AHSCT however relapse occurred in four patients at a median of four months (range: 3-10 months) after HSCT. At the time of data collection, nine patients have deceased; three were due to early TRM, three were underlying disease, two had aspergillus infection and one had nocardia infection. Two patients were alive with disease being treated by the Brentixumab vedotin, gemcitabine and DLI. With a median follow up period of 8.7 months after AHSCT, the estimated 1-year OS and PFS was 40.4%±5% and 35.4%±3.9%, respectively. Conclusions: AHSCT is an effective treatment option for advanced-stage MF/SS. Further studies are warranted to improve the outcome after AHSCT.
Primary cutaneous diffuse large B-cell lymphoma, leg-type: The Mayo Clinic experience.
Authors: Alhaj Moustafa Muhamad , Parrondo Ricardo Daniel , Gannon Nicole , Hastings Jacquelyn , Seegobin Karan , Hoppe Bradford , Menke David M , Kharfan-Dabaja Mohamed , Ayala Ernesto , Jiang Liuyan , Tun Han W.
Published: May 2020

e20044

Background: Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg-type (PCDLBCL) is a rare lymphoma comprising 4% of all cutaneous lymphomas with an aggressive clinical course. We investigated disease characteristics and outcomes among patients PCDLBCL. Methods: Following IRB approval, we identified patients retrospectively with PCDLBCL treated at the Mayo Clinic Cancer Center 1998-2019. Results: 45 pts were identified with a median age of 71 years (Range- 48-95) and 28 (62%) were female. Disease locations were legs (62%), arms (22%), head (11%), trunk (2%) and multiple sites (2%). At diagnosis, (51%) had a single lesion, (29%) had multiple lesions in 1-2 contiguous regions, (16%) had multiple lesions in non-contiguous regions or > 2 regions and data was not available (4%). Immunohistochemistry showed positive staining for BCL-2 (92%), BCL-6 (76%), c-MYC (62%), MUM1 (95%), CD10 (11%), and cytoplasmic IgM (8/9- 89%). By Han’s criteria, (95%) had activated B cell lymphoma (ABC). Median Ki-67 was 90% (range, 50,100%). 9/12 (75%) were positive for MYD88 L265P mutation. 13/21 (62%) were double expressor and 3/22 (14%) had double hit lymphoma. 37/45 (82%) had ECOG < 2. LDH was elevated in 13/37 (35%). The median number of therapies was 1 (range; 1-11). The initial treatments were chemo-radiation (30%), chemo alone (38%), rituximab alone (11%), radiation (RT) alone (16%), rituximab-RT (2.5%), and surgical (2.5%). The median follow-up time for the whole cohort was 80 months (95% CI; 32, 169). The median progression free survival and overall survival (OS) were 20 months (95% CI; 12, 34) and 80 months (95% CI; 48, 119). 22/45 (49%) are alive. The cause of death was disease-related in 11/23 (48%). The median number of relapses was 1 (range; 0, 11) with (60%) relapsed after first line. 4/45 pts had autologous stem cell transplant after relapse. 7/45 (16%) had a systemic relapse at a median time of 35 months from diagnosis (range; 16, 112). Age above 60 years was associated with worse OS; 70 months (95% CI; 30, 99) vs NR (95% CI; 135, NR), p = 0.025. ECOG performance status < 2 was associated with better OS, NR months (95% CI; 80, NR) vs 48 months (95% CI; 3.3, 88),p = 0.0003. 1 pt received Ibrutinib on 11th relapse and had 3 years of PFS. Conclusions: PCDLBCL is predominantly ABC type, affects elderly pts and is characterized by multiple cutaneous relapses followed in some cases by systemic relapses. Increased age and poor performance status had a negative impact on OS. High incidence of MYD88 L265P mutation is observed in PCDLBCL similar to immune-privileged site lymphomas.
A closer look at Hispanics with follicular lymphoma in a majority-minority community.
Authors: Janania Martinez Michelle , Snedden Tyler William , Garza Juan , Surapaneni Prathibha , Ananth Snegha , Rawlings Jeremy , Gregorio Dave , Kakarla Sushanth , Liu Qianqian , Michalek Joel , Diaz Duque Adolfo Enrique
Published: May 2020

e20047

Background: Follicular Lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. It is most commonly diagnosed in non-Hispanics (NH) and is well characterized in this population. Hispanics (HI) on the other hand have been historically underrepresented in clinical trials and observational studies. Some studies suggest that there are differences in age, clinical presentation, treatment patterns and outcomes in HI. The aim of our study was to determine demographics and clinical characteristics of FL patients and compare outcomes between HI and NH. To our knowledge, this is the largest cohort of FL patients from a single academic institution that serves predominantly HI. Methods: We retrospectively analyzed 123 patients with FL; all received care between 2008-2018. Key variables included age, gender, race/ ethnicity, comorbidities, insurance status, stage, treatment received, outcome at 3 and 5 years and vitality status in 2018. Continuously distributed outcomes were summarized with mean/standard deviation and categorical outcomes with frequencies/percentages. Significance of associations between categorical outcomes was assessed with Pearson’s Chi Square or Fisher’s Exact test. All statistical testing was two-sided with a significance level of 5%. Results: We identified 123 patients with diagnosis of FL, 71 HI (58%), 49 NH (40%), 3 unspecified (2%); 88% Caucasian, 5% African American, 4% Asian, 3% other; 56% females and 44% males. Median age at diagnosis was 56.31 (SD 11.97). Funding source was commercial insurance N = 55 (45%), Medicare N = 40(33%), hospital payment plan N = 20 (16%), unfunded N = 5 (4%) and Medicaid N = 3 (2%). Most prevalent co-morbidities were HTN 40% and diabetes mellitus 20%; 40% had no co-morbidities. At diagnosis ECOG of 0-1 was seen in 116 (94%); 21 were Stage I (17%), 19 Stage II (15%), 40 Stage III (33%), and 43 Stage IV (35%). FLIPI score was 0-1 in 43 patients (35%), 2 in 32 (26%), 3 in 23 (19%), not documented in 25 (20%). Median PFS was 1287.10 days (SD 879.18). At 3 year follow up there was: complete/ partial response in 76% HI vs 84% NH; disease progression in 18% vs 3%; death in 6% vs 3%, respectively (p-value = 0.739). At 5 year follow up: complete/partial response in 76% HI vs 86% NH; disease progression in 14% vs 10%; death 10% vs 3%, respectively (p-value = 0.62). At the end of 2018, 88% HI were alive compared to 95% NH, [p-value = 0.457]. Conclusions: Contrary to existing data, our study found that HI with FL have no difference in outcome when compared to NH. This could be explained by our prevalently HI population, but further studies are needed.
Hypomagnesemia is associated with an increased risk of early clinical failure in patients with Burkitt lymphoma.
Authors: Gile Jennifer , Ruan Gordon , Abeykoon Jithma P. , McMahon Molly , Witzig Thomas E.
Published: May 2020

e20048

Background: No literature exists regarding whether hypomagnesemia at the time of diagnosis in Burkitt Lymphoma (BL) is associated with inferior survival. Methods: Patients with new diagnosis of BL who were seen at Mayo Clinic, MN from 2000-2019 with a serum magnesium level available prior to chemotherapy were included. Patients were allocated to two groups; Abnormal Magnesium Group (AMG), defined as a magnesium level < 1.7 mg/dL and Normal Magnesium Group (NMG), defined as ≥ 1.7 – 2.3mg/dL. Two-sided Wilcoxon rank sum test and Chi square/Fischer’s exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier and log-rank tests were used to perform all time to event analysis which were done from time of treatment. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Results: Of 90 patients with a diagnosis of BL, 42 patients had a magnesium level at or before time of diagnosis. The Table lists the baseline characteristics and significant findings of the AMG/NMG groups. The median follow-up was 30 months. Hypomagnesemia was predictive for inferior EFS at 30 months - 34.3% (95% CI: 8.7–74.0) for AMG and 79.3% (95% CI: 60.8-90.4) for NMG (p = 0.038). OS at 30 months for AMG was 42.9% (95% CI: 14.4-77.0) and for NMG was 93.7% (95% CI: 78.1-98.4%) (p = 0.002). Other parameters significant on univariate analysis included the Charlson Comorbidity Index (p = 0.034), creatinine (p = 0.009), and number of treatments (p = 0.048). In the multivariate analysis, creatinine (p = 0.005) and number of treatments (p = 0.004) were significant. Likelihood ratio testing of predictors associated with inferior OS were significant for hypomagnesemia (likelihood ratio 3.99, p = 0.046). Conclusions: Patients with hypomagnesemia at the time of BL diagnosis have inferior outcomes compared to BL patients with a normal magnesium level. Prospective studies are needed to confirm this finding and test Mg replacement strategies to mitigate the effects of hypomagnesemia. [Table: see text]
Survival from time of transformation in patients with transformed lymphoma at time of diagnosis.
Authors: Kelly Alaina , Boughan Kirsten M , Rojas Patricio , Ahmad Nausheen , Diamond Akiva , De Lima Marcos J.G. , Caimi Paolo Fabrizio
Published: May 2020

e20054

Background: Histologic transformation (HT) to aggressive lymphoma can occur in indolent lymphoma and is considered to convey poor prognosis. Most data come from follicular lymphoma (FL). We conducted a retrospective analysis to compare outcomes of transformed marginal zone lymphoma and lymphoplasmacytic lymphoma (tMZL/LPL) with those of transformed FL (tFL). Methods: We collected data from patients diagnosed with HT between 2000 and 2018. Transformed CLL was excluded. Survival estimates were done with the Kaplan Meier method; comparisons were done with log-rank test. The effect of covariates on OS was evaluated with Cox proportional hazards method. Results: We identified 87 pts (58 tFL, 29 tMZL/LPL). There were no differences in baseline characteristics, except for COO subtype by Hans criteria and circulating IgM. There were no differences in OS or EFS based on the underlying lymphoma subtype (OS: tFL = 60.1m vs. tMZL/LPL = 64.8m, p = 0.53; EFS: tFL = 25.2m vs. tMZL/LPL = 27.6m). Univariate and multivariate analyses identified age at HT (HR for age > 60 = 3.5, 95% CI: 1.7-7.6), poor performance status (HR for ECOG ≥3 = 23, 95% CI: 7.3-70) and having a previous diagnosis of indolent lymphoma (HR for previous diagnosis = 3.7, 95% CI: 1.87-7.4) as adverse risk factors for OS after HT. Pts with previous diagnosis of indolent lymphoma with subsequent HT had inferior OS than pts presenting first with HT (median OS 25m vs. not reached, p < 0.0001); EFS (median EFS for treated pts = 11m vs. 49m). Conclusions: Underlying lymphoma does not affect OS after HT and long term survival can be achieved in pts who receive treatment. tMZL/LPL is more frequently of non-GCB origin has monoclonal IgM. Pts who present with HT as their first lymphoma-related event have better OS. These findings will lead to further exploration of the genetic changes that occur at the time of transformation of indolent lymphomas. [Table: see text]
Presenting international prognostic scoring system affects time to treatment: A retrospective single center review.
Authors: Sutcliffe Sierra , Woldie Indryas , Hamm Caroline M.
Published: May 2020

e20058

Background: Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin’s lymphoma, which requires prompt initiation of chemotherapy to cure, as any delays can result in worse outcomes. A recent study in Japan found that patients with an IPI score ≥3 had a worse prognosis if their diagnosis was delayed, whereas with an IPI score < 3, there was no effect. Methods: This study investigated how long Windsor patients wait to receive chemotherapy after diagnosis, and how this affects relapse status. A retrospective chart review was conducted, looking at all patients diagnosed with DLBCL who underwent treatment at the Windsor Regional Cancer Center from 2007 to 2018 (N = 317). Each chart was reviewed for variables relating to treatment and outcomes. Results: Overall survival within the studied time period was 71% with the median survival time of 11.99 years. The overall relapse rate was 19.24% with a mean relapse-free interval of 4.87 years. A longer time to initial treatment resulted in a decreased risk of relapse (p = 0.038); however, these patients tended to have a lower stage (p = 0.002), no family history of cancer (p < 0.001), and lower IPI scores (p = 0.004). When broken down by IPI score, the mean times to treatment after diagnosis were: IPI 0 = 40 days; IPI 1 = 35 days; IPI 2 = 38 days; IPI 3 = 29 days; IPI 4 = 22 days; IPI 5 = 29 days. Conclusions: These results show that while DLBCL patients with worse prognostic measures are prioritized to receive treatment quicker, there is a large discrepancy in time to treatment between IPI scores. There was an 11-day delay between early and late IPI scores, likely driven by patient symptoms, rather than evidence of safety. The natural history of DLBCL is known to be aggressive, but more granular information is necessary to determine appropriate wait times for presenting IPI score. Further research should focus on identifying delays in the process, and if it can be streamlined to improve wait times for all patients, regardless of IPI score.
Efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor in the primary and secondary prevention of chemotherapy-induced neutropenia in patients with lymphoma.
Authors: Tu Meifeng , Zhu Jun , Song Yuqin
Published: May 2020

e20061

Background: To evaluate the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF, brand name: Jinyouli) in the primary and secondary prevention of chemotherapy-induced neutropenia in patients with lymphoma. Methods: This single-center, one-arm and open-label clinical study enrolled 119 patients with lymphoma in Peking University Cancer Hospital & Institute from May 2016 to December 2018. Patients ≥45 kg received a single dose of PEG-rhG-CSF for 6mg, < 45kg for 3mg, subcutaneous injection once in 24-48 h after chemotherapy. Results: 119 lymphoma patients, including 60 primary and 59 secondary prevention patients, underwent a total of 427 cycles of chemotherapy. The overall incidence of febrile neutropenia (FN) was 6.32% (27/427), with rates of 5.39% and 7.17% in the primary and secondary prevention groups, respectively. There was no significant difference between two groups ( P> 0.05).The incidence of FN was significantly lower in the second cycle than in the first cycle in both the primary and secondary prevention groups ( In the primary group: cycle 1 vs. cycle 2: 15.00% vs. 2.22%, respectively, P= 0.027; In the secondary group: cycle 1 vs. cycle 2: 16.95% vs. 5.08%, respectively, P= 0.040). The overall incidence of grade Ⅳ neutropenia was 13.58% (58/427), with rates of 8.82% and 17.94% in the primary and secondary prevention groups, respectively. There was a significant difference between two groups ( P= 0.006). The incidence of grade Ⅳ neutropenia was significantly lower in the second cycle than in the first cycle (In the primary group: cycle 1 vs. cycle 2: 25.00% vs. 4.44%, respectively, P= 0.005; In the secondary group: cycle 1 vs. cycle 2: 47.46% vs. 11.86%, respectively, P< 0.001). The main treatment-related adverse event was bone pain, with an incidence of 2.52% (3/119). Conclusions: PEG-rhG-CSF can effectively reduce the incidence of FN and neutropenia with good safety in patients with lymphoma after chemotherapy. Primary prevention can significantly reduce the risk of grade IV neutropenia in all chemotherapy cycles compared with the secondary prevention. Clinical trial information: NCT02905916 .
Clinicopathological features and outcome of diffuse large B-cell lymphoma patients treated in a resource-limited setting.
Authors: Nair Sukesh C , Gogia Ajay , Kumar Lalit , Sharma Atul , Biswas Ahitagni , Mallick Saumyaranjan
Published: May 2020

e20062

Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma worldwide. Clinicopathological features and outcome of DLBCL patients and the prognostic significance of cell of origin (COO) on outcome are scarce from developing countries. Methods: We carried out an ambispective analysis of newly diagnosed DLBCL patients (n = 417) over a period of 5 years (2014-2018).Clinicopathologic features and outcome data were collected from prospectively maintained clinical case records. Prognostic factors were identified using Cox-regression analyses. Results: Median age of our population was 50 years (18-86) with male to female ratio of 2:1. B symptoms was seen in 42% patients and bulky disease in 36%. Sixty percent of patients were having ECOG performance status (ECOG PS) of 0 or 1 and advanced disease was present in 60%. Extra nodal involvement was documented in 53% cases, most common sites being bone (17.5%) followed by gastrointestinal tract (16.5%).RCHOP was used in 62.8% of cases .COO data (based on Hans algorithm) was available in 80% patients with germinal center B cell like (GCB) and non GCB forming 50% each. Bone marrow involvement was present in 7.2% patients. Low risk International Prognostic Index (IPI) was seen in 44% and 15% were having high IPI. The overall response rate was 76% with a complete response (CR) rate of 65.5%. After a median follow up of 26 months the 3 year event free survival (EFS) and overall survival (OS) were 62% and 81% respectively. Low albumin, bulky disease, central nervous system (CNS) involvement, non GCB histologic subtype, high IPI and use of non R-CHOP regimens were associated with inferior EFS. Age > 60 years, poor ECOG PS, raised LDH, involvement of extranodal sites (stomach, kidney, adrenals and central nervous system) were associated with poor overall survival on multivariate analysis. Conclusions: This is one of the largest studies from India. Non GCB subtype was found to be associated with inferior EFS. Non R-CHOP regimen and high IPI were associated with inferior survival.
Correlation of PI3K upregulation with NOTCH2 mutations in ibrutinib-resistant mantle cell lymphoma.
Authors: Nomie Krystle , Jain Preetesh , Kotlov Nikita , Segodin Vitaly , Cai Qingsong , Liu Yang , Navsaria Lucy , Svekolkin Viktor , Bagaev Alexander , Frenkel Felix , Ataullakhanov Ravshan , Fowler Nathan Hale , Wang Michael
Published: May 2020

e20065

Background: PI3K dysregulation has been linked to ibrutinib resistance in mantle cell lymphoma (MCL); however, the investigation of PI3K signaling as an important ibrutinib resistance mechanism has been rarely assessed in clinical samples. Therefore, we sought to more fully characterize PI3K dysregulation in ibrutinib-sensitive and -resistant MCL clinical samples at the genomic and transcriptomic levels. Methods: Whole exome sequencing (WES; n = 41) and RNA-seq (n = 93) were performed on fresh peripheral blood, apheresis, or biopsy patient primary samples. All analysis was performed using the BostonGene automated pipeline. Results: To evaluate ibrutinib resistance in MCL, we compared the activity of 11 cellular pathways calculated by PROGENy between ibrutinib-sensitive and -resistant MCL. The PI3K pathway was the most differentially expressed between the two groups (q < 0.005; > 1 median absolute deviation in ibrutinib-resistant MCL). Increased PI3K pathway expression in the ibrutinib-resistant MCL tumors strongly correlated with hyperproliferation (r = 0.49; p = 6e-07). Both hyperproliferation and enriched PI3K expression associated with more frequent NOTCH2 somatic mutations (~22% ibrutinib-resistant MCL with high PI3K expression (p = 0.004) and hyperproliferation (p = 0.003)) that generate a premature stop codon in the PEST domain, likely resulting in hyperactive NOTCH2. Frequent TP53 mutations were identified in ibrutinib-resistant MCL tumors (58%; 3-fold greater vs ibrutinib-sensitive tumors; p = 0.02) based on our cohort and the Agarwal et al., 2019, Nature Medicine cohort. PI3K signaling is a known p53 activator, which may lead to a compensatory tumor suppressive mechanism, indicating that PI3K activation may induce mutational pressure on TP53 to promote MCL survival. VH gene usage variability of the B-cell receptor (BCR), the inducer of PI3K signaling, was not different between ibrutinib-sensitive and -resistant MCL, suggesting that diverse BCR expression does not underlie enriched ibrutinib-resistant MCL PI3K expression. Conclusions: PI3K inhibitors have resulted in underwhelming MCL clinical outcomes; yet, the advent of next-generation PI3K inhibitors such as copanlisib with potentially greater efficacy and less toxicity warrants the continued investigation of PI3K signaling in ibrutinib-resistant MCL. We identified a strong correlation between gain-of-function NOTCH2 mutations and enriched PI3K signaling, suggesting that dual inhibition of NOTCH and PI3K may overcome ibrutinib resistance in MCL.
REPOCH compared with RCHOP for the treatment of diffuse large B-cell lymphoma of activated B-cell type.
Authors: Martinez-Knouse Phillip , Nabrinsky Edward , Chandran Anjana , Lestingi Timothy M. , Bitran Jacob D.
Published: May 2020

e20081

Background: Patients with diffuse large B-cell lymphoma of activated B-cell type (DLBCL-ABC) have a worse prognosis than patients with DLBCL of germinal center origin. Recently, a phase III randomized trial of patients with DLBCL showed no improvement in response rates or progression free survival (PFS) with REPOCH compared to RCHOP. However, the PFS reported in this study was significantly better than expected, indicating that high-risk patients, such as those with DLBCL-ABC, may have been underrepresented. The optimal treatment for patients with DLBCL-ABC remains unknown. Methods: We undertook a retrospective analysis of patients with DLBCL treated in our practice from January 1, 2015 to May 31, 2019. We then examined treatment approaches and outcomes of patients treated for DLBCL-ABC. Results: We treated 136 patients with DLBCL and identified 18 of 136 patients with DLBCL-ABC. There were 9 men and 9 women with a median age of 74 years (range 26-92 years) and a median performance status of Eastern Cooperative Oncology Group 1, (0-2). The median international prognostic index score was 3. Nine of 18 patients were treated with REPOCH, 8 with RCHOP, and one with bendamustine and rituximab (BR). The stage distribution was stage I in 2 patients, stage III in 4 patients, and stage IV in 12 patients. Of 9 patients treated with REPOCH, 9 (100%) achieved a complete remission with no relapses to date. Of 8 patients treated with RCHOP, 6 (75%) achieved a complete remission and 2 had no response and died. The one patient treated with BR failed to respond and died. The median PFS for the 8 patients treated with RCHOP was 19.5 months; whereas, the PFS in the REPOCH group had not been reached at a median follow up of 2 years. Grade 3 and 4 toxicities were more common in the RCHOP group and included cardiomyopathy in 1 patient and two episodes of neutropenic fever (one resulting in septic shock and death). There were no grade 3 or 4 toxicities in the REPOCH group. Conclusions: In this retrospective analysis, our patients with DLBCL-ABC treated with REPOCH had better overall outcomes. A prospective trial in this subset of DLBCL patients is warranted.
Changes in erythron peripheral component during chemotherapy in patients with malignant lymphomas and parvovirus B19 infection.
Authors: Guskova Nailya K. , Zykova Tatiana A. , Lysenko Irina B. , Guskova Ekaterina A. , Nozdricheva Anastasia S. , Abakumova Svetlana V. , Selyutina Olesya N. , Shevyakova Elena A. , Velikorodnaya Lilia A. , Belgova Svetlana V. , Tselishcheva Irina V. , Zakharchenko Viktoria R. , Kit Oleg I.
Published: May 2020

e20086

Background: The purpose of the study was to analyze changes in the erythron peripheral component during chemotherapy for malignant lymphomas in patients infected with parvovirus B19 (B19V). Methods: The study included 34 patients with lymphomas (48.7±4.3 years). B19V infection was determined by the presence of IgM/IgG antibodies to B19V in blood serum and DNA in blood plasma and bone marrow before chemotherapy (CT). Parameters of the erythron peripheral component - RBC, HGB, MCW, MCH, MCHC, RDW, PLT, RET (#), IRF, LFR, MFR, HFR (%), and myelogram were evaluated before and after CT (Sysmex XE 2100, Japan). Results: 82.5% of patients had IgG to B19V, including IgM in 11.8%. B19V DNA was detected in 23.4% of patients: in the bone marrow and blood in 11.7%, only in the bone marrow in 11.7%. The range of viral load in the bone marrow was 1435-79573 IU/ml, in the blood 2-349 IU/ml. RBC in all patients before CT was within the reference range, with a tendency to decrease in the group with B19V: 4.01±0.06×1012/L with B19V and 4.57±0.08×1012/L without B19V. Levels of HGB before CT were respectively 112±1.26 g/L and 116±1.26 g/L, decreasing after CT by 1.5 and 1.3 times (p < 0.05) depending on the viral load. MCV, MCH and MCHC varied: 78.6 – 84.8 fl, 24.9 – 28.0 pg and 314–330 g/L in the group with B19V, and 89.7–91.3 fl, 29.5–29.8 pg and 324–337 g/L, respectively, in the group without B19V, which indicates the development of hypochromic microcytic anemia. RET levels before CT in the group with B19V were 38.3±3.44×109/L, after CT – 10.6±2.7×109/L, being lower than in the group without B19V by 1.8 and 3.8 times (p < 0.001), respectively. IRF, MFR and HFR in patients with B19V before CT were 10.6±2.23%, 9.5±1.54% and 1.1±0.022%, being lower than in non-infected patients by 1.6, 1.3 and 3.6 times, respectively. After CT, the downward trend in the proportion of young fractions continued. The noted changes in the erythron peripheral unit indicated inhibition of erythropoiesis, more pronounced in patients with B19V, and were consistent with the myelogram data. Conclusions: The development of anemia without the expected increase in RET, and in particular immature forms - IRF, MFR, HFR - in patients with lymphomas and B19V infection indicates inhibition of erythropoiesis. Early manifestation of these changes allows for timely treatment correction.
Efficacy of daratumumab + SOC versus SOC in myeloma induction regimens, by risk-stratification: Meta-analysis of phase III randomized control trials.
Authors: Joseph Nisha , Hofmeister Craig C. , Dhodapkar Madhav V. , Boise Lawrence , Lonial Sagar , Behera Madhusmita , Kaufman Jonathan L. , Nooka Ajay K.
Published: May 2020

e20512

Background: Addition of daratumumab, a CD38 monoclonal antibody, to standard of care (SOC) myeloma induction regimens resulted in deeper responses. Phase 3 trials comparing daratumumab + SOC vs SOC consistently favored the daratumumab combinations. The objective of this analysis is to test the hypothesis that high-risk patients benefit from the addition of daratumumab to SOC induction regimens. Methods: We identified four phase 3 clinical trials (RCT) that randomized newly diagnosed myeloma patients to receive daratumumab +SOC vs. SOC. The GRIFFIN trial did not have PFS events and was excluded. A meta-analysis of 3 RCTs with updated data from ASH 2019 (ALCYONE, MAIA, CASSIOPEIA) was performed using the fixed (Mantel-Haenszel) model to calculate the impact of daratumumab + SOC versus SOC. The consistency of results (effect sizes) among studies was investigated by means of two heterogeneity tests, the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P value of the Cochran's Q test was < 0.1 and I2 statistic was > 50%. Results: The pooled hazard ratios (HR) for standard risk patients for PFS was HR 0.589 (95% CI 0.502-0.691; P < 0.001) in favor of daratumumab. Q-statistic for PFS ( P= 3.462; df= 2; I2 = 42.23) suggests homogeneity across studies. The pooled hazard ratios (HR) for high risk patients for PFS was HR 0.799 (95% CI 0.609-1.047; P= 0.104) in favor of daratumumab. Q-statistic for PFS ( P= 1.306; df= 2; I2 = 0.00) suggests homogeneity across studies. Conclusions: Our meta-analysis demonstrates that addition of daratumumab to SOC myeloma induction regimens prevented progression in both standard and high-risk patients, though the impact was more pronounced in the standard-risk patients. This benefit seems to improve with longer follow up, as seen both in ALCYONE (Mateos et al ASH 2019) and MAIA trial (Bahlis et al ASH 2019). Focused accrual of high-risk patients in larger daratumumab induction trials and longer follow up of the existing trials are further needed.
Outcomes of sepsis in patients with multiple myeloma.
Authors: Moturi Krishna Rekha , Lingamaneni Prasanth , Vohra Ishaan , Baral Binav , Farooq Muhammad Zain , Batra Kunnal
Published: May 2020

e20513

Background: Patients with Multiple Myeloma (MM) are at risk for developing sepsis due to defective humoral immunity, underlying disease factors like renal failure, iron overload, and treatment with immunosuppressive agents. Sepsis is a significant cause of morbidity and mortality in patients with MM. In this study, we aimed to study trends of inpatient outcomes and health care burden of patients with sepsis in MM. Methods: Adult patients with MM admitted to the hospital from 2012 to 2017 were identified from the Nationwide Inpatient Sample database and were stratified into two groups based on the diagnosis of sepsis. Multivariate regression analysis was used to adjust for confounders when calculating for mortality. Statistical tests for trends of mortality, length of stay and hospital charges were performed. Results: A total of 513,615 patients with MM met the inclusion criteria. Sepsis was found to be the most common cause of admission amongst these patients (12.2%) and of the patients with MM who died in the hospital, 38.1% carried the primary diagnosis of sepsis. Mean age of the patients was 70.1 years and they were predominantly Caucasian (62.1%) with male preponderance (57.7%). MM patients admitted with sepsis were found to have higher mortality (15.7 and 3.5% P < 0.0001),higher hospital costs (22,082$ vs 15,206; P < 0.0001) and longer hospital stays (8.1 days vs 6.0 P < 0.0001) when compared to those admitted for other reasons. Temporal trends have been noted to improve over the years, with mortality decreasing from 18% to 13.1%, (p trend < 0.001). Length of stay (in days) decreased from 8.3 to 7.7 days (p trend = 0.009) and hospital charges (in dollars) decreased from 22,407 to 21,209 (p trend < 0.001). Conclusions: Although the improving trends are promising, sepsis still continues to be significantly contributing to morality and morbidity in patients with MM. Measures to identify the changing spectrum of infectious diseases, their predisposing risk factors along with strategies to recognize and prevent early stages of sepsis could have a significant impact on lowering mortality and health care burden. [Table: see text]
Assessing the utility of monitoring IgA multiple myeloma patients with quantitative serum IgA levels.
Authors: Visram Alissa , Al Saleh Abdullah S. , Parmar Harsh V , Murray David L , Dingli David , Lacy Martha , Dispenzieri Angela , Gertz Morie A. , Buadi Francis , Kapoor Prashant , Hayman Suzanne R. , Warsame Rahma M. , Kourelis Taxiarchis , Siddiqui Mustaqeem Ahmad , Gonsalves Wilson I. , Muchtar Eli , Lust John Anthony , Rajkumar S. Vincent , Kumar Shaji
Published: May 2020

e20515

Background: IgA monoclonal proteins (MCPs), unlike IgG MCPs, often migrate in the beta region on serum protein electrophoresis (SPEP) which can lead to underestimation of their size due to the co-migration with physiologic proteins. In IgA multiple myeloma (MM), the utility of quantitative IgA levels in assessing disease response in comparison to SPEP is not well studied. Methods: We retrospectively analyzed 304 IgA MM patients, diagnosed between 2004 and 2018, with available serial MCP and quantitative IgA levels. Kaplan Meier analysis was used to estimate the median progression free survival (mPFS) using the IMWG criteria and our study definition of IgA progression (2 consecutive IgA values that are > 25% above the nadir IgA value and above upper limit of normal (ULN) of 356 mg/dL, and a detectable IgA MCP on serum immunofixation). The mPFS was defined as the time from treatment initiation until disease progression or death. Results: IgA MCP migrated in the beta region in 134 (44%) patients, and in the gamma region in 150 (56%) patients. At diagnosis the median MCP was 3 (IQR 1.9-4) g/dL and the median IgA was 3240 (IQR 2008-4420) mg/dL. The median time from treatment initiation to MCP nadir was 80 (IQR 42-144) days and median time to IgA nadir was 154 (IQR 90-238) days. At MCP nadir 40% of patients had an IgA above the ULN. All complete responders (n = 104) had normal IgA levels, with a median IgA of 54 (IQR 27-88) g/dL. A ≥90% decrease in IgA between treatment initiation and IgA nadir, compared to a < 90% decrease, was associated with a longer mPFS (34 vs. 20 months, p = 0.006) and overall survival (97 vs. 33 months, p = 0.003). Patients with serial MCP and IgA levels available prior to progression (n = 195) were used to compare the mPFS using the IMWG and IgA progression criteria. The mPFS using the IgA criteria was 32 (95% CI 29-39) months, versus 39 (95% CI 33-45) months using IMWG criteria. Overall, 92 (47%) patients progressed by both IMWG and IgA criteria. At the time of progression using the IgA criteria compared to at IMWG progression, the median hemoglobin was higher (13.3 vs. 11.6 g/dL, respectively, p < 0.001) and fewer patients had new symptomatic bone lesions (2% vs. 33%, respectively, p < 0.001). Conclusions: In IgA MM patients, monitoring quantitative IgA levels predicts disease response and allows for earlier detection of disease progression, prior to the development of end organ damage.
Real-world outcomes of venetoclax refractory multiple myeloma patients.
Authors: Maples Kathryn T. , Kaufman Jonathan L. , Gupta Vikas Anand , Joseph Nisha , Heffner Leonard T. , Hofmeister Craig C. , Dhodapkar Madhav V. , Matulis Shannon M. , Boise Lawrence , Lonial Sagar , Nooka Ajay K.
Published: May 2020

e20524

Background: The BELLINI trial investigated the efficacy and safety of venetoclax (ven)/bortezomib (bort)/dexamethasone (dex) vs placebo/bort/dex in patients with bort-sensitive, early relapsed myeloma. The median PFS favored the ven arm (22.4 vs 11.5 months); however, a higher death rate in the ven arm led to study discontinuation. A subgroup of patients with t(11;14) not only had improved PFS but a positive trend in OS with ven, suggesting biomarker-driven patient selection may mitigate the safety concern. BELLIINI results raised concern regarding the natural history of myeloma progressing on ven. We aimed to investigate the clinical outcomes of ven refractory myeloma patients. Methods: We identified 70 refractory myeloma patients at our institution prescribed ven alone or in combination between 03/2014 -11/2019. Our group has published the functional profiling of BCL2 family members to predict responses to ven (Matulis, S et al. Leukemia), and most patients had functional profiling available prior to starting ven. Demographic and outcomes data were obtained from our IRB approved myeloma database and responses were evaluated per IMWG criteria. Results: Patients received a median of 3 (1-13) lines of therapy (LOT), with 37% receiving ≥4prior LOT and 86% had t(11;14) by FISH/CTG. Most patients received ASCT (86%) and were refractory to len and bort (97%), dara (41.4%), car (43%), or pom (53%). The most common combinations with ven were dex (83%), PI and dex (8.5%), or dara and dex (8.5%). At a median follow up of 16.8 months, 38 patients progressed on ven. Median duration of therapy was 9.5 (1-63) months. Median PFS for the entire cohort was 13 (7.9-18.2) months. Use of ven as an early LOT provided PFS benefit ( < 3 vs > 3 LOT: 23.2 vs 10.4 months). Notably, patients who received > 6 LOT also had a PFS benefit of 7.23 (0-15.6) months, and ‘penta-refractory’ patients had a PFS of 7.2 (0-17.2) months. Among the 38 patients that progressed on ven, dara-based combinations (30%) and clinical trials (24%) were the most common subsequent LOT. At a median follow up of 15.4 months, the median OS for the cohort from the time of ven refractoriness was 31.4 months. Patients who received > 6 LOT had an OS of 15.1 (0-14.2) months and ‘penta-refractory’ patients at ven refractoriness had an OS of 13.7 (0-30.6) months. Conclusions: Patients with ven refractory myeloma can still experience good long term outcomes, and our experience does not support the hypothesis that ven resistance leads to a more refractory myeloma phenotype. These data support the early use of ven or ven combinations in the t(11;14) cohort of patients.
DREAMM-1 Patient perspectives from the first-in-human study of single-agent belantamab mafodotin for relapsed and refractory multiple myeloma (RRMM).
Authors: Eliason Laurie , Opalinska Joanna , Martin Mona L. , Correll Julia , Gutierrez Benjamin , Popat Rakesh
Published: May 2020

e20531

Background: Patient-reported outcomes in RRMM remain poor, particularly for those refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies, and there is an increased risk of cumulative toxicities in these patients. Single-agent belantamab mafodotin (GSK2857916), a first-in-class, B-cell maturation antigen–binding immunoconjugate, has demonstrated deep and durable responses with a manageable safety profile in heavily pretreated patients with RRMM (DREAMM-1, NCT02064387). Here, we present patient-reported clinical benefit/tolerability of belantamab mafodotin evaluated by trial-embedded end-of-treatment (EOT) and follow-up interviews. Methods: DREAMM-1 study design and results have been reported ( Blood Cancer J 2019). Patients in the Part 2 expansion phase were administered single-agent belantamab mafodotin 3.4 mg/kg IV once every 3 weeks for 16 cycles and invited to participate in interviews at EOT and 6-month follow-up. Patients discussed symptoms, treatment-related adverse events (AEs), treatment burden, and overall treatment satisfaction, rated 0–10 (0 = not severe to 10 = most severe/0 = not at all satisfied to 10 = extremely satisfied). Results: A total of 17/35 patients (9 female [53%]) were interviewed; 4/17 patients completed both interviews. Most patients (94%; 16/17) achieved a partial response or better. At EOT, patients reported an improvement from the worst point in symptoms of bone pain (mean change in score from 6.4 to 4.0) and fatigue (8.0 to 5.5). The most commonly reported treatment-related AE was blurred vision (76%; 13/17). Among those reporting this AE, 62% (8/13) reported resolution or steady improvement in vision after EOT; with a reduction in severity rating from 7.3 at worst to 5.3 at EOT for this event. Most patients (93%; 13/14) never considered stopping treatment owing to AEs, including ocular events. Overall treatment satisfaction was high (mean score 7.9; median 9.0). Conclusions: Despite small sample sizes, trial-embedded interviews provide valuable insight into patient experience with belantamab mafodotin. Patients treated with single-agent belantamab mafodotin reported high treatment satisfaction and improvements in symptoms. Visual symptoms were frequent but manageable, and improved or resolved after treatment. Funding: GlaxoSmithKline (117159). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT02064387.