bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of p53/p21 expression in DLBCL treated with CHOP or R-CHOP: A correlative study of E4494
Authors: Aurora V. , Li S. , Horning S. J. , Variakojis D. , Nelson B. P. , Krajewska M. , Habermann T. M. , Fisher R. I. , Gascoyne R. D. , Winter J. N. 
Published: March 2020

8038 Background: P21 is a downstream effector protein of p53 that induces cell cycle arrest by inhibiting cyclin/cyclin dependent kinase (cdK) complexes. In this prospective correlative study, we investigated the prognostic significance of p21, p53, Bcl-6, and Bcl-2 in diffuse large B cell lymphoma (DLBCL) in the context of E4494, a randomized trial comparing conventional CHOP to rituximab(R)-CHOP induction, and maintenance R (MR) to observation for responding patients. Methods: Protein expression was quantified by immunohistochemical (IHC) staining of 198 DLBCL paraffin-embedded biopsy specimens and scored by an expert panel of hematopathologists. Results: No differences in the distribution of patient characteristics were detected between p21+ and p21- cases and between p53+ and p53- cases as well as across treatment arms. Among all study patients, there were no differences in clinical outcomes between p21+ and p21- cases. However, when analyzed by induction arm (removing the effect of MR), R-CHOP patients had marginally better FFS (p=0.06) if p21+; among CHOP-treated patients, p21 status had no effect on outcome. For R-CHOP patients but NOT CHOP patients, p21+ was an independent, favorable prognostic factor after adjusting for Bcl-6, IPI and Bcl-2 in multivariate analysis (FFS relative risk 0.3; p=0.003; OS relative risk 0.4; p=0.02). P21+ patients treated with R-CHOP had higher %FFS at 5 years compared to p21+ patients treated with CHOP (61 ± 7% vs. 24 ± 7%; p=0.007) but p21- R-CHOP and CHOP patients had similar FFS (37 ± 7% vs. 35 ± 7%; p=0.64). P53 staining (+ scored as either >20% or 50%) did not predict for FFS or OS in uni- or multivariate analyses. The p53+/p21- phenotype, a possible surrogate for mutated p53, was not prognostic. Further, no significant correlation was seen between p53 and p21 expression by IHC. Conclusions: These data suggest that p21 expression by IHC predicts for favorable outcome in older DLBCL patients treated with R-CHOP but not in those treated with CHOP. Furthermore, p21+ identifies patients who benefit from the addition of rituximab to CHOP. Complex interactions between p53, p21, and Bcl-6, as well as other unknown pathways, may account for this treatment-related effect and should be further investigated. [Table: see text]
IgG and IgA hypogammaglobulinemia is pervasive in Waldenstrom's macroglobulinemia (WM) and persists regardless of response or type of therapeutic intervention
Authors: Hunter Z. R. , O'Connor K. , Soumerai J. , Branagan A. , Leleu X. , Hatjiharissi E. , Treon S. 
Published: March 2020

8042 Background: IgG and IgA hypogammaglobulinemia (HG) is a commonly observed in patients with WM and has often been attributed to the extensive infiltration of lymphoplasmacytic cells in the bone marrow (BM). Methods: In this retrospective study we analyzed immunoglobulin and BM infiltration levels from 196 previously untreated patients at their first visit to our clinic who met the clinical and pathological criteria for WM. In addition, we also serially evaluated 65 WM patients who received various therapies for changes in IgA and IgG. All lab values and biopsies used were conducted at our clinic at the Dana-Farber Cancer Institute to insure consistency. Pre-therapy, end of therapy, and best Ig response post therapy were evaluated and patients were followed up to the point of their next treatment regimen. Results: Of the 197 previously untreated patients, 117 (59.7%) demonstrated abnormally low levels of IgG (<700 mg/dl), whereas 131 (66.8%) had abnormally low levels of IgA (<70 mg/dl), and 102 (52.0%) had abnormally low levels of both IgG and IgA. Median value for IgM was 2820 mg/dl (Range 179 - 12400), for IgG 623 mg/dl (Range 127–2770), for IgA 48.5 mg.dl (range 7 - 509), and for the 94 patients for whom BM biopsies were available, the median intratrabecular space involvement was 37.5% (range 5 - 95). No correlation was found between BM involvement and any Ig level. Results from each of the trials is summarized in the table below. Median follow up was 455 days. No correlation between degree of response and Ig recovery was observed. No Ig level that started abnormally low was ever restored to normal levels in this study despite the fact that some recovery is noted in the non-rituximab based trials. Conclusions: These studies indicate that there is no relationship between BM involvement HG in WM. Moreover, therapeutic intervention does not restore IgG or IgA levels indicating a possible constitutive Ig dysregulation problem in patients with WM. No significant financial relationships to disclose. [Table: see text]
Prospective comparison of subcutaneous to intravenous administration of bortezomib in patients with multiple myeloma: Pharmacokinetics, efficacy and toxicity
Authors: Moreau P. , Coiteux V. , Hulin C. , Facon T. , van de Velde H. , Acharya M. , Harousseau J. 
Published: March 2020

8046 Bortezomib (Bz) is a novel proteasome inhibitor that is registered for treatment of relapsed or refractory MM as an IV bolus injection. Animal toxicology studies have indicated good local tolerability and an acceptable PK profile of SC injection of Bz supporting together with preliminary clinical data the exploration of this route of administration in humans. We conducted a randomized trial to compare pharmacokinetics/pharmacodynamics (PK/PD), toxicity and efficacy of SC and IV injections of Bz, both at standard dose of 1.3 mg/m2 twice weekly for 2 wks (day 1–4-8–11), with 1 wk rest, for up to 8 cycles. From 01/06 to 10/06, 24 pts with relapsed/refractory MM were randomized to receive Bz either IV (arm A, n = 12) or SC (arm B, n = 12); Patients received a median number of 5 cycles in both groups. The local tolerance of SC injections was good. Response rates were similar in both groups (CR+VGPR/PR/MR: 3/2/1 in arm A, vs 3/2/2 patients in arm B. Grade 3 / 4 adverse events occurred in 7 cases in arm A, vs 5 in arm B, leading to study discontinuation in 5 and 3 cases, respectively. PK analysis: average plasma Cmax values were lower for SC as compared to IV (15 ng/mL at day 1, and 23 at day 11, vs 130 and 127, p < .001), but overall systemic availability as measured by plasma AUC values were comparable between SC and IV administration for both day 1 & 11 (145 and 388 ng.h/mL, vs 133 and 386, p =.7 & .98, respectively). Average Tmax values were less than 1 hour for both routes. PD analysis (20S proteasome inhibition): average area under the curve for effect (AUE) values were comparable between SC and IV administration both for day 1 & 11 (761 and 1,324 %.h, vs 1,089 and 1,110, p = .29 & .54, respectively), while average Emax values were lower for SC administration (Emax day 1 & day 11 SC, 58 and 56%, vs 72 and 69% IV, p =.003 & .01 respectively). The overall systemic availability of Bz was comparable between SC and IV administration for both day 1 and 11. Similarly, the average AUE results were comparable between SC and IV, while average Emax was lower for SC administration. Response rates were identical in the 2 groups of patients, with similar toxicity profile. Given the good local tolerance of SC injection, this route of administration could be an alternative option to IV injection. [Table: see text]
Factors predictive of outcome in relapsed, refractory multiple myeloma patients treated with bortezomib, melphalan, prednisone, and thalidomide (VMPT)
Authors: Palumbo A. P. , Ambrosini M. T. , Benevolo G. , Pescosta N. , Callea V. , Cangialosi C. , Caravita T. , Morabito F. , Gay F. , Boccadoro M. 
Published: March 2020

8048 Background: In relapsed/refractory multiple myeloma (MM) patients, the addition of thalidomide and bortezomib to the standard oral melphalan/prednisone (VMPT) significantly increased response rate and progression-free survival (PFS) (Blood. 2006 Dec 5; [Epub ahead of print]). Baseline parameters which may predict outcome after VMPT have been investigated to identify which patient subgroups most benefit from this drug combination. Methods: Thirty patients with relapsed or refractory MM after 1 or 2 lines of treatment, were treated with six 35-days courses of bortezomib (3 dose levels: 1.0,1.3 and 1.6 mg/m2) on days 1,4,15,22, plus melphalan (6 mg/m2) and prednisone (60 mg/m2) on days 1–5 and thalidomide (50 mg) on days 1–35. Several parameters such as age, β2-microglobulin, C-reactive protein, chromosome 13 abnormalities, albumin, haemoglobin, stage, creatinine, bone marrow plasmacytosis, line of therapy and dosage of bortezomib were analyzed in association with response rate and PFS, using χ2 and Cox model. Results: At least a very good partial response was achieved in 43% of patients and at least a partial response in 67%. The 1-year PFS was 61%, and the 1- year overall survival was 84%. Subgroup analyses did not show any statistical difference between responses and either age, β2 microglobulin, C-reactive protein, chromosome 13 abnormalities, line of treatment or dosage of bortezomib. Serum albumin <3.5 mg/dL was loosely associated with a lower response rate (p=0.09). Factors predictive of shorter PFS were C-reactive protein = 6 mg/L (p=0.02) and 3rd line of therapy (p=0.009). Factors loosely associated with shorter PFS were β2-microglobulin = 3.5 mg/L (p=0.06) and creatinine = 2 mg/dL (p=0.09). No difference in PFS was observed between patients with or without chromosome 13 abnormalities. Conclusions: VMPT induced a high proportion of responses and appeared to overcome the poor prognosis of patients with chromosome 13q deletion. [Table: see text]
Prognostic significance of maximal tumor size (MTS) in young patients with good-prognosis diffuse large B-cell lymphoma (DLBCL) treated with CHOP-like chemotherapy with and without rituximab: Analysis of the MabThera International Trial Group (MInT) study
Authors: Pfreundschuh M. G. , Hensel M. , Cavallin-Stahl E. , Vasova I. , Kvaloey S. , Gill D. , Walewski J. , Zinzani P. , Pettengell R. , Kuhnt E. 
Published: March 2020

8053 Purpose: To determine the impact of MTS in young (18 to 60 years) patients with DLBCL and aaIPI=0,1. Patients and Methods: Outcome of patients treated with CHOP-like chemotherapy with (R-CHEMO) or without rituximab (CHEMO) was analyzed according to MTS. Results: A Martingale residual analysis revealed a linear negative prognostic impact of MTS on event-free (EFS) and overall (OS) survival. The hazard ratios for MTS per centimeter increase were significant for EFS (1.07; 95%-CI: 1.04–1.11; p<0.001) and OS (1.11; 95%-CI: 1.06–1.16; p<0.001). CHEMO 3-year EFS rates ranged between 78% for MTS <5cm and 41% for MTS >10cm. R-CHEMO 3-year EFS ranged from 83% (MTS <5cm) to 73% (MTS >=10cm). CHEMO 3-year OS rates decreased from 93% (MTS <5cm) to 74% (MTS >=10cm). R-CHEMO 3-year OS decreased from 98% (MTS <5cm) to 85% (MTS >=10cm). With CHEMO, any cut-off point between 5 and 10 cm separated a thus defined “non-bulky” from a “bulky” population with a 3-year EFS difference >20% (p<0.0001) and OS difference >12% (p<0.003), while with R-CHEMO only cut-off points >=10cm separated two populations with a significant EFS difference (9.1%; p=0.047), and cut-off points >=6cm discriminated two populations with a significant OS difference (7.6%-11.3%; p=0.037–0.0009). Conclusion: Due to the linear prognostic impact of MTS on outcome, cut-off points for “bulky” disease can be set rather arbitrarily between 5 and 10cm depending on clinical considerations. Rituximab reduces, but does not eliminate the negative prognostic impact of MTS in young patients with good-prognosis DLBCL. [Table: see text]
A two-arm prospective trial evaluating the ability of EBV PCR to diagnose and monitor posttransplant lymphoproliferative disorder
Authors: Tsai D. E. , Douglas L. , Andreadis C. , Arnoldi S. , Blood R. , Olthoff K. , Brozena S. , Stadtmauer E. A. , Kotloff R. , Ahya V. 
Published: March 2020

8057 Background: EBV PCR is known to be useful in the management of patients with PTLD. However, the optimal DNA target, relative importance of peripheral blood intracellular versus free plasma EBV, and baseline profile of these EBV PCR variations in a transplant population remains unclear. This study explored these issues as well as assessed the utility of a 6 assay EBV PCR panel in the management of patients with suspected PTLD. Methods: A prospective 2-arm study was performed. Arm A consisted of 31 patients who underwent lung transplantation. Arm B consisted of 35 patients evaluated for possible PTLD. All patients underwent an initial evaluation with EBV PCR and EBV VCA antibody titer. Arm B patients were evaluated for PTLD with CT scans and biopsies of lesions. All patients in Arm A and those in Arm B with documented PTLD were then followed. For the EBV PCR panel, peripheral blood was separated into plasma and whole blood cells and then DNA was purified. Real time EBV PCR was then performed on both samples using primer sets against LMP, EBER and EBNA. Results: No patients on control Arm A developed PTLD. Seventeen (49%) patients on Arm B were found to have PTLD. Thirteen of 17 (76%) had EBV(+) PTLD. Eighteen Arm B patients were given non-PTLD diagnoses. Of 62 patients evaluable for EBV antibody titers, 60 (97%) had IgG for EBV VCA. In Arm A, only 1/31 (3%) patients developed a transient positive low level plasma EBV load. Fourteen of 31 (42%) had detectable low-level intracellular EBV. In patients with EBV(+) PTLD, 11/13 had EBV in plasma and intracellular samples, 1 had intracellular EBV only and 1 patient with isolated CNS PTLD had a negative EBV panel. The EBV PCR panel had high sensitivity (92%) and specificity (67%) for diagnosing EBV(+) PTLD. Comparing the individual PCR assays, whole blood EBER had the best sensitivity (92%) and plasma EBNA & EBER had the best specificity (100%). The EBV PCR panel tracked patient's clinical course well (p=0.06) as they proceeded through treatment. EBV plasma (p=<0.01) and whole blood (p=0.04) copy numbers by EBNA PCR inversely correlated with EBV VCA IgG titers. Conclusion: Peripheral blood EBV PCR is useful in the diagnosis and monitoring of patients with EBV(+) PTLD. No significant financial relationships to disclose.
Is rituximab (R) the optimal therapeutic intervention (TI) for post-transplant lymphoproliferative disorder (PTLD) following solid organ transplant (SOT)?
Authors: Tsao R. E. , Jin T. , Richendollar B. , Hsi E. , Pohlman B. 
Published: March 2020

8074 Background: PTLD is a rare, often fatal, complication of SOT. Most are derived from CD20+ B-cells. Historically, patients (pts) received a variety of TIs ranging from decreased immunosuppression to chemotherapy (CT). Based on promising initial study results, most pts now receive rituximab (R) without CT as part of 1st TI. Methods: We searched the Cleveland Clinic pathology archives for SOT pts, who were diagnosed with PTLD between 1987 and 2006; reviewed the medical records; extracted clinical information and outcomes; and analyzed the data by Cox proportional univariate and multivariate analyses. Results: We identified 55 SOT pts (heart, 18; lung, 16; kidney 14; liver, 6; pancreas, 1), who were diagnosed with PTLD at median age 47 years (range 7–66). The median time from SOT to PTLD was 1.7 years (range .2–20.9). 1st TI (usually >1) included “complete” resection (4), decreased immunosuppresion (53), acyclovir or ganciclovir (28), interferon (4), radiation therapy (6), CT (12), and/or R (17). Response to 1st TI was CR (30) or PR (10). The median follow-up among surviving pts is 5.0 years (range .1–11.4). 29 (including 5 CT and 5 R) pts have died; only 2 CT but all 5 R pts died from PTLD. On univariate analysis, younger age+, <2 prior rejection episodes+*, PS <2+*, normal LDH+*, <2 extranodal sites+, lower IPI+*, >1 1st TI+, and 1st TI with CT* were associated with an improved overall survival (OS)+ and/or PTLD-specific survival (PSS)*. On multivariate analysis, only PS <2 (HR 0.04 [CI 0.01–0.14], p<0.001) and >1 1st TI (HR 0.43 [CI 0.19–0.97], p=0.041) were associated with improved OS while PS <2 (HR 0.04 [0.01- 0.16], p<0.001) and 1st TI with CT (HR 0.19 [CI 0.04–0.84], p<0.028) were associated with improved PSS. Conclusions: A significant minority of SOT pts that receive R without CT as part of 1st TI still die from PTLD. PS is the most important predictor of outcome. In conjunction with the improved survival observed in de novo B-cell NHL pts treated with R+CT (compared to CT alone), this retrospective analysis suggests that some SOT PTLD pts should receive R+CT as part of 1st TI. No significant financial relationships to disclose.
First-line treatment with single agent rituximab, followed by maintenance rituximab plus anti-idiotype Id-KLH active immunotherapy vaccine (FavId) in patients (pts) with low-grade non-Hodgkin lymphoma (NHL): Preliminary results of a phase II trial
Authors: Raefsky E. , Greco F. A. , Spigel D. R. , Litchy S. , Gian V. , Bender J. , Hainsworth J. D. 
Published: March 2020

8080 Background: Single agent rituximab produces a high response rate when used as first-line treatment, and maintenance rituximab prolongs remission duration. Active immunotherapy is a promising treatment approach, when administered following remission induction by initial therapy. In this phase II trial, we evaluate the feasibility, toxicity, and efficacy of administering concurrent maintenance rituximab plus Id-KLH vaccine in pts with low-grade NHL. Methods: Pts with previously untreated low-grade NHL (grade 1/2 follicular or SLL) who were judged to be candidates for single agent rituximab therapy were eligible. All pts had initial biopsy for production of the Id-KLH vaccine. All pts received rituximab 375mg/m2 IV, weekly × 4. Pts with CR/CRu, PR, or stable disease at 8 weeks proceeded with maintenance rituximab (standard 4 week courses at 6 month intervals for 3 courses) and Id-KLH vaccination (Id-KLH 1cc day 1; GMCSF 250μg SQ days 1–4) monthly × 8, beginning month 3, then every 2 months during the second year. Pts were monitored for response rate, progression- free survival, and toxicity. Results: To date, 36 of a planned 56 pts have been enrolled. Idiotype vaccine was successfully manufactured in 27 of 32 pts (84%), with 4 in production. Of the 27 pts for whom Id-KLH was successfully manufactured, 2 progressed during rituximab. 19 of 25 pts (14FL;5SLL) have had response determined after rituximab: 8 PR (42%), 11 stable (58%; 4 of 5 SLL). Pts have now received rituximab maintenance therapy plus Id-KLH for durations of 6 - 34 months. 6 of 19 pts (3 SLL) progressed at months 5, 6, 9, 9, 10, and 12, respectively. Treatment has been well tolerated, with no unusual toxicities observed. Rituximab-related hypotension and atrial fibrillation occurred in 1 pt. The most common Id-KLH related adverse event has been injection site reaction. Conclusions: Concurrent maintenance therapy with rituximab plus Id-KLH is safe and well tolerated. At present, 6 of 25 pts (24%) have progressed (including 3 of the 5 SLL pts) with a median followup of 19 months. This trial is continuing. No significant financial relationships to disclose.
Use of absolute lymphocyte counts to predict response to chemotherapy and survival in diffuse large B-cell lymphoma
Authors: Kim D. , Chae Y. , Baek J. , Kim J. , Kim Y. , Park Y. , Do Y. , Chung J. , Kim M. , Song H. 
Published: March 2020

8082 Background: Absolute lymphocyte counts (ALCs) at diagnosis has been shown to be an independent prognostic factor in patients with follicular lymphoma (FL) although the precise mechanism was not fully elucidated. The current study evaluated the impact of Absolute lymphocyte counts (ALCs) at diagnosis in patients with diffuse large B-cell lymphoma (DLBCL) on the response to chemotherapy and survival. Methods: The treatment outcomes of the patients receiving CHOP (n=101) or R-CHOP chemotherapy (n=122) were compared according to ALCs at diagnosis (<1.0 vs. = 1.0×109/L). Results: Forty-two patients (19%) had a lower ALC count at diagnosis (CHOP, 23 [23%]; R-CHOP, 19 [16%]). The lower ALCs showed a good correlation with IPI (p<0.001), performance (p<0.001), LDH (p<0.001), stage (p=0.004), extranodal involvement (p=0.011), but not with age or sex. A significant difference of response rate was noted according to ALCs in favor of a higher ALCs (CR: 80% vs. 60%, p=0.005; ORR: 93% vs. 78%, p=0.003). In addition, event-free survival (EFS) was worse in a lower ALC group than higher ALC group: median duration of EFS, 1,773 days vs. 326 days (p<0.001). The OS was also in favor of a higher ALC group: median duration of OS, 3,000 days vs. 695 days (p<0.001). In multivariate analysis, ALC at diagnosis was an independent predictive factor for CR (HR 2.717, p=0.009) and prognostic factor for EFS (HR 2.148, p=0.004) or OS (HR 2.863, p=0.002). Conclusion: The ALCs at diagnosis appears to predict the survival of DLBCL patients. Our findings suggested that the ALCs at diagnosis may reflect host's immune status against DLBCL, implying that immune system of host will play a critical role on survival of DLBCL patients. No significant financial relationships to disclose.
Use of C-terminal deletion mutation of CD20 molecule to predict CD20 expression and time to progression after rituximab in non- Hodgkin lymphoma
Authors: Terui Y. , Mishima Y. , Yokoyama M. , Mishima Y. , Takeuchi K. , Ito Y. , Takahashi S. , Hatake K. 
Published: March 2020

8088 Background: Rituximab was the first chimeric antibody that is most frequently used for CD20-posistive B-cell lymphomas and gives better response and prognosis. However, resistance to rituximab is one of the important issues to be clarified in the increasing number of monoclonal antibody therapy, and we experienced the case whose lymphoma cells never expressed CD20 at the relapsed phase during rithuximab therapy. We investigated whether CD20 mutation is related to expression level of CD20, relapse or resistance to rituximab therapy, and prognosis. Methods: We analyzed 50 patients with fresh or relapsed/resistant B- cell lymphomas and DNA sequencing analysis of CD20 products from genomic PCR and RT-PCR was performed. CD20 mutants were subcloned by TA cloning, and tested CD20 expression after transfection to K562 cells. Results: Four types of CD20 mutations were found in 11 of 50 NHL patients (22.0%), which include C- terminal deletion (8.0%) extracellular domain (2.0%) transmembrane domain (2.0%) and early termination (10.0%). The group of C-terminal deletion mutations significantly showed lower CD20 expression (3.26, 95%CI = 0.09 to 6.89) than non-mutation (30.8, 95%CI = 22.4 to 39.2) (p 0.05). Although there was no significant difference between the groups with non-mutation and C-terminal deletion mutation in CR rate (49% versus 25%, Fisher's exact test; p = 0.6137), time to progression after rituximab therapy in C-terminal deletion mutation (7 months, 95%CI = 0 to 18 months) was significantly shorter than that in non-mutation (31 months, 95% CI = 18 to 44 months) by log-rank test (p = 0.0481). Non-mutation and early termination groups did not show any significant differences in TTP and CD20 expression. Conclusion: The important mutations of CD20 gene related to shorter duration to progression disease after rituximab therapy were discovered. Especially, point mutations bearing during rituximab therapy should be examined at progression disease after partial remission. No significant financial relationships to disclose.