bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced detection of EGFR mutations in plasma from non-small cell lung cancer (NSCLC) patients using Scorpion primers
Authors: Holland W. , Davies A. M. , Farneth N. C. , Gautschi O. , Lara P. N. , Gandara D. R. , Mack P. C.
Published: March 2020

7682

Background: Activating epidermal growth factor receptor (EGFR) mutations identified in NSCLC patient tumors are often associated with rapid and profound response to EGFR tyrosine kinase inhibitors (TKIs). Conventional detection methods are cumbersome and may underestimate mutations frequencies due to limited sensitivity. We and others have shown that tumor-specific mutations such as KRAS can be detected in tumor DNA shed into patient plasma (Kimura, Ann N Y Acad Sci, 2004). Here we describe the performance of an allele- specific real-time PCR system utilizing Scorpion primers (kindly provided by DxS, UK) to detect EGFR mutations in plasma. Methods: DNA was extracted from archival tumor blocks, slides and plasma obtained from consenting patients. In order to determine the sensitivity of this technique both in terms of the ratio of mutant-to-wild-type genomic DNA as well as the minimum amount of DNA required for detection, a dilution experiment was conducted. Genomic DNA from cell lines containing either the exon 21 L858R point mutation or the exon 21 E746–750 deletion was diluted with wild-type genomic DNA at ratios ranging from 1:2 to 1:10,000. Clinical specimens including plasma and/or tissue from 35 advanced stage NSCLC patients treated with EGFR-TKIs were examined. Results: Mutant DNA was successfully detected when it comprised as little as 0.1% of the total sample or as low as 25 pg of mutant-positive genomic DNA in a pool of 2.5 μg of total DNA. EGFR mutations were identified by this approach in both plasma and tissue of 2 patients who were complete responders to EGFR-TKI therapy, only one of which was detectable by direct sequencing. For the 7 patients where only tissue was available, two were positive both with the Scorpion primers and direct sequencing while the rest were wild-type. Of 21 patients where only plasma was available, 6 mutations were detected using the Scorpion primers. Conclusions: Allele-specific Scorpion technology is 1) highly specific and sensitive for EGFR mutation analysis, 2) able to detect mutations that were not observable by direct sequencing in plasma and tissue, 3) capable of detecting mutations in shed tumor DNA in plasma of advanced NSCLC patients and 4) may be suitable for monitoring response or detecting recurrence.

No significant financial relationships to disclose.
Patterns of practice in radiation therapy for non-small cell lung cancer among members of American Society of Therapeutic Radiology and Oncology
Authors: Kong F. , West B. , Bonner J. , Choy H. , Gaspar L. E. , Komaki R. , Sun A. , Morris D. , Wang L. , Sandler H. M. , Movsas B.
Published: March 2020

7693

Purpose: To investigate the dominant pattern of current practice in radiation therapy (RT) for lung cancer among members of American Society of Therapeutic Radiology and Oncology (ASTRO). Methods: A 35-item survey was designed by a panel of 8 board certified radiation oncologists regarding RT for lung cancer. Surveys were sent through email to 3,800 radiation oncologist members on September 10, 2006, with the results collected online on December 10, 2006. Here we report results on radiation decisions for non-small cell lung cancer (NSCLC). Results: The response rate was 19% (n = 727). The respondents saw an average of 8 consults (ranged 1–25) monthly during the survey time (summing up to a total of >60,000 new cases yearly). For stage I peripherally located NSCLC, 33%, 10% and 20% of respondents reported conventional fractionated, hypofractioned and stereotactic RT, respectively. Another 25% of respondents would have offered stereotactic RT if this technique were available at their center. For stage I centrally located tumors, 78% of respondents did not agree with, but 10% selected, stereotactic RT. For stage II and III, 76% of respondents selected 60–70 Gy in 1.8–2 Gy with chemotherapy. With regard to the combined modality approach for stage II and III disease, 76–77% of respondents selected concurrent chemoRT followed by adjuvant chemotherapy, and 11–16% sequential followed by concurrent chemoRT for patients with good performance status. For stage IV NSCLC with remarkable local disease, the consideration of RT ranged from 0 Gy, 3 Gyx10, 3 Gyx15, 2.5 Gyx20, to 2 Gyx30 in 27%, 17%, 8%, 13%, and 21% of respondents, respectively. Conclusions: The dominant pattern of practice for stage II/III disease is concurrent chemoRT, consistent with results of phase III trials. The treatment decisions for stage I and IV disease are diverse, partially due to technology advancement and the lack of large phase III trials.

No significant financial relationships to disclose.
A clinical trial design applying Bayesian adaptive randomization for targeted therapy development in lung cancer: A step toward personalized medicine
Authors: Zhou X. , Kim E. S. , Herbst R. S. , Liu S. , Wistuba I. I. , Mao L. , Lewis J. , Lippman S. M. , Hong W. K. , Lee J. J.
Published: March 2020

7697

Background: Multiple axes of signaling pathways are associated with lung carcinogenesis. These signaling axes are different in pts (pts) and their cancers. Utilization of molecularly targeted agents may inhibit these specific aberrant pathways and lead to clinical efficacy. Biomarkers expressions can be used as indicators for the aberrant signaling to identify effective targeted therapy. Methods: The program, “Biomarker-integrated Approaches of Targeted Therapy of Lung Cancer Elimination (BATTLE),” consists of an umbrella screening trial and 4 parallel phase II targeted therapies trials (with erlotinib, sorafenib, vandetanib, and the combination of erlotinib and bexarotene) in advanced non-small cell lung cancer pts with prior chemotherapy. All pts will have biopsy samples taken for biomarker profile assessment prior to the randomization. A ‘surrogate response‘ to treatment is defined as progression free at 8 weeks after randomization. The Bayesian ordinal probit model is used to characterize the response rate. Pts with certain biomarker profile will be adaptively randomized (AR) to one of the 4 treatment arms with the randomization rate based on the updated response rate based on accumulated data in the trial. For each biomarker profile, better performing arms will have higher randomization rates and vise versa. Early stopping rules are set so that low-performing arms may be suspended for new patient entry. Results: Based on extensive simulation studies, the proposed design with a total of 200 pts has desirable operating characteristics to: (1) identify effective agents with high probability; (2) suspend ineffective agents; and (3) treat more pts with effective agents according to their biomarker profiles. The Bayesian design incorporates prior data and findings from the current pts to form better estimates of the treatment efficacy for pts with different biomarker profiles. The design continues to “learn” and improve the estimates as the trial moves along. Conclusion: The Bayesian AR design is a smart and ethical design and ideally suitable for the development of targeted therapy. It may help in identifying effective agents based on pts’ tumor biomarker profile and thus treat more pts with effective therapies.

No significant financial relationships to disclose.
Safety assessment for the combination of docetaxel, carboplatin, and thoracic radiotherapy in unresectable stage III non-small cell lung cancer (NSCLC): A report of the first 100 patients treated with chemoradiation on D0410
Authors: Rigas J. R. , Rubin M. S. , Waples J. M. , Dragnev K. H. , Zimmerman D. M. , Reimer R. R. , Droder R. , Rathmann J. , Green N. B. , Carey M.
Published: March 2020

7701

Background: Concurrent chemoradiotherapy (chemoRT) is the preferred treatment for patients with unresectable stage III NSCLC. Limited safety information is available on the use of concurrent docetaxel, carboplatin and thoracic RT. We report the safety information on the initial 100 patients (pts) treated with this chemoRT as part of an ongoing US randomized phase III trial (D0410) evaluating the role of erlotinib/placebo following this concurrent chemoRT treatment. The sample size is 400 pts and the primary endpoint is progression-free survival. Methods: Pts with unresectable pathologically confirmed stage III NSCLC are randomized to receive either erlotinib 150 mg or placebo orally daily for 2 years following concurrent chemoRT with docetaxel 20 mg/m2, carboplatin AUC=2 intravenously weekly for 6 wks with thoracic RT of at least 61 Gy in 33 fractions over 6.5 weeks. The planned total lung volume exceeding 20 Gy (V20) was less than 32%. Only the chemoradiation safety information is being reported. This data was reviewed by an independent safety and data monitoring committee. Results: Pt characteristics; 59% males, median age 69 years (range 38 to 86), 21% adenocarcinoma, 48% squamous cell, 94% ECOG PS0–1, 49% stage IIIA, 15% weight loss = 10%. Of 600 planned chemotherapy treatments, 492 were administered (93 wk 1, 85 wk 2, 82 wk 3, 81 wk 4, 77 wk 5, 74 wk 6). There were 25 chemotherapy dose reductions; most commonly for esophagitis (8), neutropenia (5), renal dysfunction (3), hypersensitivity (2). There were no treatment-related deaths. There were 25 grade 3 and 3 grade 4 treatment-related adverse events. The most common grade 3/4 events were esophagitis (6), fatigue (3), odynophagia (2), neutropenia (1), thrombocytopenia (1), dematitis (1). Conclusions: This concurrent chemoradiation regimen appears to be safe. Enrollment to the phase III trial continues. There is a planned interim efficacy evaluation at 150 events (deaths or disease progression). Funded in part by Sanofi- Aventis, Genentech, and OSI Pharmaceuticals.

[Table: see text]
Is symptom improvement in patients with small cell lung cancer (SCLC) associated with clinical response? An analysis using the Patient Symptom Assessment Lung Cancer (PSALC) scale in a randomized trial comparing oral topotecan (OT) with best supportive care (BSC)
Authors: O'Brien M. E. , Duh M. , Chen L. , Antras L. , Neary M. , Dharan B. , Gralla R. J.
Published: March 2020

7725

Background: SCLC is a highly symptomatic disease with poor survival in prior treated patients. To evaluate the role of chemotherapy, a recent multicenter trial randomized 141 patients with prior treatment to receive either OT + BSC or BSC only. This was the first trial to use a BSC control group in SCLC while evaluating survival, response and symptoms. Survival data were reported (O'Brien et al JCO 2006; median survival of 25.9 weeks on OT + BSC vs 13.9 weeks on BSC, p = 0.01). 51% on OT had “disease control” (partial response [PR] + stable disease [SD]); no patient on BSC was reported to have a major response, although response was not an endpoint for this group. Trials have shown that those with progressive disease have the most symptom worsening, as occurred in this trial. The objective of this analysis is to determine if patients with PR report greater symptom relief than those with SD, in that SD can reflect a more indolent course in some patients while PR is due to treatment effect only. Methods: We used the investigators evaluation of response (PR or SD) and analyzed these groups by the patients’ scoring of their symptoms using the PSALC instrument which evaluates 9 SCLC symptoms, in the 71 patients on the OT + BSC arm. Results: Patients with lower ECOG PS at baseline reported more severe symptoms (higher PSALC score). Mean changes in PSALC score from baseline are shown in the Table and demonstrate an association between tumor response and decrease in symptoms. Conclusions: Patients who achieved a major response on OT treatment reported significantly better symptom control than those whose best response was SD. This indicates that in addition to a survival benefit, treatment with this chemotherapy can aid in symptom control. While the small number of patients limits the strength of the conclusions, this trial represents the largest BSC controlled study in SCLC.

No significant financial relationships to disclose.

[Table: see text]
Phase II study of short course CHOP-rituximab (R) followed by ibritumomab tiuxetan (IT) as first-line treatment for follicular lymphoma (FL)
Authors: Jankowitz R. C. , Foon K. A. , DeMonaco N. A. , Osborn J. , Wu M. , Evans T. , Swerdlow S. H. , Joyce J. , Land S. , Jacobs S. A.
Published: March 2020

8005

Background: Therapy with CHOP-R and radioimmunotherapy (RIT) is a promising treatment for untreated FL. Press reports complete responses (CR) of 69% in FL patients (pts.) with 6 cycles of CHOP followed by I-131 tositumomab. We report efficacy and safety using 3 cycles of CHOP-R followed by IT and extended R. Methods: Eligibility criteria include symptomatic or grade 3 untreated FL. 60 pts. have been accrued and 47 evaluated. The treatment consists of two phases: CHOP-R for 3 cycles followed by IT. One week after IT, pts receive R weekly × 4. Bone marrow (BM) biopsies and fusion PET-CT scans are obtained at baseline, after CHOP-R, and 12 weeks post RIT. The primary endpoint is CR rate. CR requires a neg. PET scan and conventional Working Group criteria. Results: Toxicity data are available for 47 pts of median age 56 (range, 39–78), 44 of whom completed both phases of therapy and are evaluated for response. Characteristics and CR rates after IT are shown: 3 pts. did not receive RIT (1 second malignancy, 1 non-compliance, 1 septic death). Of the 44, CR after CHOP-R is 41%. After IT, CR improved to 89%. Of the 5 pts who did not achieve CR, 3 had neg. PET scans (2 with PR, 1 with SD by CT), and 2 had residual disease by PET with PR by CT. At a mean follow-up of 16 months (range, 6–33 months), there are 4 relapses: 3 who achieved CR by PET-CT, 1 with PR by PET-CT. Toxicity was predominantly myelosuppression. There was 1 episode of febrile neutropenia after RIT. Conclusions: 3 cycles of CHOP-R followed by IT and R achieve a high CR in previously-untreated pts. with FL. Addition of RIT increased CR from 41% to 89%. Data will be presented on the affect of bulky disease, positive BM, grade 2 or 3 histology, and high FLIPI score on CR. Further follow-up is necessary to evaluate response duration and determine whether there is a correlation with early or late CR.

[Table: see text] [Table: see text]
Maintenance rituximab (MR) compared to observation (OBS) after R-CHOP or CHOP in older patients (pts) with diffuse large B-cell lymphoma (DLBCL): An Intergroup E4494/C9793 update
Authors: Morrison V. A. , Weller E. A. , Habermann T. M. , Cassileth P. A. , Cohn J. B. , Gascoyne R. D. , Woda B. , Fisher R. I. , Peterson B. A. , Horning S. J.
Published: March 2020

8011

Background: Maintenance therapy is generally not used in treatment of DLBCL. However, older pts are a unique group in which to study this approach, due to poorer outcome. Methods: As part of intergroup trial E4494/C9793, 415 pts >= 60 years (yr) of age with DLBCL who responded to induction therapy with CHOP or R-CHOP were randomized to MR (rituximab, 375 mg/m2 weekly {wk} X 4 every 6 months for 2 yr) starting 4 wk after the last chemotherapy (n=207) or observation (OBS, n=208) in a prospective 2 × 2 randomized trial design (J Clin Oncol 2006;24:3121). Impact of MR on failure-free survival (FFS) was the primary objective, and impact on time to failure (TTF) and overall survival (OS) were secondary objectives. All p-values are two-sided. Results: Results are presented for 352 centrally reviewed evaluable pts, with a median follow-up after maintenance randomization of 5.5 yr. All results were similar for the intent-to-treat population. Baseline characteristics and response to induction therapy are balanced among the CHOP/R-CHOP pts. At 6 yr, FFS was 46% for those pt who received MR and 36% for the OBS cohort (p=0.005, hazard rate {HR} 0.64); 6-yr OS was 62% for MR and 64% for OBS (p=0.83, HR 0.96). Outcome was also examined in the four treatment subgroups. The 6-yr FFS were: CHOP+MR 44%, CHOP+OBS 35%, R-CHOP+MR 47%, and R- CHOP+OBS 40%. No differences in 6-yr OS were observed according to maintenance randomization following CHOP (57% MR vs 55% OBS) or R-CHOP (67% MR and 72% OBS). Median TTF after maintenance randomization following CHOP+MR was 5.2 yr vs 1.6 yr for CHOP-OBS (p=0.0004), and following R-CHOP+MR was 5.6 yr vs 5.4 yr with R-CHOP-OBS (p=0.50). Proportionately more of the treatment failures occurred within 2 yr after CHOP+OBS (85%) compared to CHOP+MR (61%), p=0.01. In contrast, the proportion of failures within 2 yr was similar for R- CHOP+OBS (47%) and R-CHOP+MR (53%), p=NS. Conclusions: MR after CHOP, but not after R-CHOP, significantly prolongs TTF, but fails to prolong OS, possibly due to a delayed pattern of relapse and/or the efficacy of rituximab in the salvage setting. As 6-yr FFS declined to <50% among R-CHOP responders, with or without MR, there is a need for more effective treatment strategies in older DLBCL pts.

No significant financial relationships to disclose.
Increased incidence of disease transformation and development of MDS/AML in Waldenstrom's macroglobulinemia (WM) patients treated with nucleoside analogues
Authors: Leleu X. P. , Manning R. , Soumerai J. , Hunter Z. R. , Moreau A. , Hatjiharissi E. , Roccaro A. , Adamia S. , Patterson C. J. , Ghobrial I. M. , Treon S. P.
Published: March 2020

8018

Background: WM is an indolent B-cell lymphoma. NA are widely used in the treatment of WM, and are considered as appropriate first line agents for the treatment of WM (Gertz et al, Semin Oncol 2003; Treon et al, Blood 2006). Increased incidences of disease transformation and development of MDS/AML have been observed among patients with indolent B-cell malignancies receiving NA. We therefore sought to delineate the incidence for these events in a large population of WM patients treated at our institution. Methods: 326 previously treated patients with the consensus panel definition of WM, who received treatment with (n=173) or without (n=153) a NA were included in this analysis. Baseline characteristics between NA and non-NA treated patients were not significantly different and were as follows: median age 59 years; male/female ratio 1.4; median B2M 2.9 mg/L; serum IgM 3,000 mg/dL; BM involvement 40%; Hct 34%; WBC 5,100/ul, and PLT count 243,000/ul. For patients receiving NA, treatment consisted of either fludarabine (n=117; 68%), cladribine (n=48; 27%) or both (n=8; 5%). For non-NA treated patients, therapy included chlorambucil, rituximab, CVP, CHOP, thalidomide, and cyclophosphamide alone or in combination with rituximab, and alemtuzumab. Median follow-up of patients was 64 (range 10–270) months. Results: Among NA treated patients, 10 (5.7%) patients had transformation to an aggressive NHL (to DLBCL) (n=7; 4%) or developed MDS/AML (n=3; 1.7%). Disease transformation and development of MDS/AML occurred at a median time of 48 (range 7–114), and 48 (range 38–52) months following NA treatment, respectively. In contrast, among non-NA treated patients, only 1 patient demonstrated disease transformation (to DLBCL) at 10 months and no patients developed AML/MDS (p=0.025). Conclusions: These data demonstrate an increased incidence of disease transformation and development of MDS/AML among WM patients treated with NA.

No significant financial relationships to disclose.
Confirmation of the prognostic value of the EORTC/WHO classification of primary cutaneous B-cell lymphoma in the United States: The Stanford University experience
Authors: Reddy S. A. , Kim Y. H. , Advani R. H. , Hoppe R. T.
Published: March 2020

8028

Background: Primary cutaneous B cell lymphoma (CBCL) represent distinct clinicopathologic entities with superior prognosis compared to their nodal counterparts. In the new WHO/EORTC Classification of Cutaneous Lymphomas (WHOc), CBCL are classified as either Marginal Zone (MZ), Follicle center lymphoma (FC) or diffuse large cell-leg type (DLBCL leg-type). WHOc combined previous FL and DLBCL into the category of FC. Only DLBCL leg-type was considered to be aggressive and thus separately categorized. In order to confirm the utility of the WHOc categories, we reclassified our cases. Methods: Records of 154 CBCL patients (pts) managed at Stanford University were reviewed. A diagnosis of CBCL was made based on H&E evaluation, immunohistochemistry including CD20 staining, along with a negative systemic staging evaluation. All pts were reclassified according to the WHO/EORTC classification of CBCL. Overall Survival (OS), disease specific survival (DSS) and freedom from progression (FFP) were analyzed according to the method of Kaplan and Meier. Prognostic factors were evaluated by multivariate regression model and included initial therapy, histology, LDH, stage, IPI, extent of disease and anatomic location. Results: 154 cases were reclassified as follows: 87 FC, 58 MZ, and 9 DLBCL leg-type. The median follow-up was 46 months. The 5 year OS and DSS were 86 and 95% respectively. For the MZ and FC subtypes the % 10 year OS/DSS was: 93/100, and 86/97 respectively. For DLBCL leg-type the % 5 year OS/DSS was 17/33 respectively. There were 22 deaths, seven of which were disease specific (4 DLBCL-leg type and 3 were FC). FFP was unaffected by the type of therapy given (chemotherapy or skin-directed). Conclusions: Our series is the largest single center experience in CBCL. We confirm the utility of the WHOc in distinguishing categories with differing prognosis. The indolent histologies have an excellent outcome and can be managed with local skin-directed therapy. The outcome of pt with DLBCL leg-type is significantly worse than the FC or MZ types and warrants a more aggressive approach in management.

No significant financial relationships to disclose.
Treatment and biology of lymphomatoid granulomatosis
Authors: Healey Bird B. R. , Grant N. , Dunleavy K. , Janik J. , Cohen J. , Pittaluga S. , Steinberg S. , Jaffe E. , Wilson W.
Published: March 2020

8029

Background: LYG is a rare angiocentric-destructive process with EBV+ B-cells and reactive T-cells. LYG is graded with grades I-II showing rare-moderate large EBV+ B-cells (usually polyclonal or oligoclonal) and grade III showing numerous large EBV+ B-cells (usually monoclonal), likely reflecting progressive transformation. Historically, steroids and/or chemotherapy have a 14 mos median survival. Methods: We are investigating Interferon-a (I-a) for grade I/II and dose-adjusted EPOCH ±Rituximab (R) for grade III LYG. Results: Characteristics of 53 pts are: male sex 68%; median age (range) 46 (17–67) and median ECOG P.S. 1 (0–3). Disease sites include lung 98%, CNS 38%, kidney 15%, skin 17%, liver 19% and nodes 4%. On study LYG grades are I-30%, II-26% and III-44%. Prior treatment was none-28%, chemotherapy± R-34%, and steroids alone-40% of pts. For grades I/II, I-a is begun at 7.5 million IUs TIW and escalated as tolerated until disease regression and continued 1 yr after CR. Of 31 patients treated with I-a, PFS is 62% at the median f/u of 5.3 yrs. Of 25 evaluable pts (3 NE; 3 TE), 60% had sustained CR for a median of 60 mos (4–175). In 9 pts who progressed on I-a, grade III was found in 5. Thus, in 20 pts with only grade I/II, 75% had sustained CR with I-a. In 11 evaluable pts with CNS disease, 81% achieved remission with I-a alone. The median time to remission is 9 mos (3–40) and median I-a dose is 20 MIU (7–40). Among 24 pts receiving DA-EPOCH±R, PFS is 40% at the median f/u of 28 mos. Of 21 evaluable pts (2 NE, 1 TE), 66% achieved CR. OS of all 53 pts is 68% at the median f/u of 4 yrs. Median EBV viral loads in 29 pts at study entry were 18 copies/10e6 genome equivalents (0–22727) (normal<200). Lymphocyte subsets in 30 pts showed a median CD4–428 (24–2322) and CD8–165 cells/mm3 (42–1316). In 12 pts in CR and with serial values, the mean CD8 cells (131 ± 44) (p2= 0.013) but not CD4 cells (65 ± 75) increased with treatment. Conclusions: High dose I-a produces sustained remissions in grade I/II LYG and is effective in CNS LYG. DA-EPOCH±R can produce durable CRs in grade III LYG. We hypothesize LYG emerges in a compromised immune milieu and undergoes progressive transformation if not effectively treated. Historical results suggest steroids may allow transformation by compromising immune function.

No significant financial relationships to disclose.
Effect of addition of rituximab to CHOP on survival of patients in both the GCB and non-GCB subgroups of diffuse large B-cell lymphoma
Authors: Fu K. , Perry K. D. , Smith L. M. , Hans C. P. , Greiner T. C. , Chan W. C. , Weisenburger D. D. , Bierman P. J. , Bociek R. G. , Armitage J. O. , Vose J. M.
Published: March 2020

8040

Background: Diffuse large B-cell lymphoma (DLBCL) includes at least two prognostically important subgroups, i.e. germinal center B-cell (GCB) and activated B-cell (ABC) DLBCL, which were initially characterized by gene expression profiling and subsequently validated by immunostaining. Bcl-2 has also been identified as a prognostic indicator in the ABC subgroup. However, with the addition of rituximab (R) to standard chemotherapy, the prognostic significance of this subclassification of DLBCL is unclear. Methods: We studied 119 cases of de novo DLBCL including 70 cases treated with R-CHOP and 49 cases treated with CHOP. The cases were assigned to either the GCB or non-GCB subgroups using the methodology described by Hans et al (Blood 2004; 103:275). Characteristics of the patients were compared using the Chi-square test. Overall survival (OS) and event-free survival (EFS) were estimated using the Kaplan Meier method and compared with the log-rank test. Results: The median age of the 119 patients was 67 years, ranging from 20 to 90 years, and there were 62 males and 57 females. The clinical characteristics of patients treated with CHOP versus R-CHOP, including the IPI, were comparable. R-CHOP was more effective than CHOP with improved 5-year EFS (63% vs 41%, p=0.013) and OS (78% vs 47%, p<0.001). In both patient groups treated with R-CHOP or CHOP, the GCB subgroup had a significantly better 5-year EFS and OS compared to the non-GCB subgroup (OS: 91% vs 64% for R-CHOP, p=0.0073; 67% vs 31% for CHOP, p=0.034, respectively). Additionally, both the GCB and non-GCB subgroups treated with R-CHOP had a significantly improved OS compared to their respective subgroups receiving CHOP alone (GCB, p=0.015; non-GCB, p=0.019). Bcl-2 expression was not a significant predictor in either the GCB or non-GCB subgroups treated with R-CHOP (OS, GCB: p=0.32; non-GCB: p=0.43). Conclusions: In this retrospective study, we demonstrate that subclassification based on the cell of origin continues to have prognostic significance in patients with DLBCL treated with R-CHOP. Addition of rituximab to CHOP improves the overall survival of patients with DLBCL in both the GCB and non-GCB subgroups.

No significant financial relationships to disclose.
High-dose melphalan (MEL) based autotransplants (AT) for multiple myeloma (MM): The Arkansas experience since 1989 in more than 2,800 patients
Authors: Pineda-Roman M. , Haessler J. , Hollmig K. , Anaissie E. , van Rhee F. , Zangari M. , Tricot G. , Mohiuddin A. , Crowley J. , Barlogie B.
Published: March 2020

8043

Background: The dose-response effect for MEL has been safely exploited through the use of AT. Long-term follow-up studies from large centers are critical to understand who benefits most and who should be considered for alternative treatment approaches. Methods: 2,836 patients receiving at least one MEL AT were considered. Kaplan-Meier analysis was used to estimate median event-free survival (EFS) and overall survival (OS). Cox regression was used to evaluate independent prognostic factors of EFS and OS from AT. Results: Of the 2,836 patients, 979 were enrolled into front-line Total Therapy protocols 1/2/3 (TT); 1,064 were entered on protocols for previously treated patients (non-TT); and 793 were treated off protocol (non-P). Overall median EFS and OS from 1st AT are 31mo and 53 mo; 10-yr EFS and OS were 19% and 24%; 15% survived >15 yr. The 5 strongest favorable OS features included TT (HR 0.46, p<0.001), absence of cytogenetic abnormalities (no CA) (HR 0.48, p<0.001), B2M <3 mg/L (HR 0.46, p<0.001), albumin >=3g/dL (HR 0.45, p<0.001) and platelet count >=100.000/microL (HR 0.41, p<.001), so that 10-yr OS rates were 58% with 5, 24% with 4, 16% with 3, 4% with 2 and 0% with =<1 favorable parameter (p<0.0001). The corresponding median durations of EFS were 80 mo, 37 mo, 27 mo, 18 mo and 7 mo (p<0.0001). Conclusion: This large single institution experience demonstrates that > 10 yr OS can be accomplished in over one-half of the 16% of all patients presenting without CA, with low levels of B2M and albumin, high platelet count and receiving TT. The worst constellation affected 3% of all patients presenting with at most 1 good-risk feature whose 5-yr survival was only 7%. These data should serve as guidepost for MM investigators and patients alike, against which newer treatments should be measured.

No significant financial relationships to disclose.
Predictors of initial treatment in older adults with follicular non-Hodgkin lymphoma
Authors: Elkin E. B. , Portlock C. , Yahalom J.
Published: March 2020

8054

Background: Multiple treatment options are available for patients with follicular lymphoma (FL), including expectant management (EM), radiation therapy (RT), various chemotherapy (CTX) regimens, and immunotherapy (IM). Older age is a well established adverse prognostic factor in FL. Our objective was to identify factors associated with initial treatment in a population-based cohort of older adults with FL. Methods: Using SEER cancer registry data linked with Medicare claims, we identified cases of FL diagnosed in adults age 66 and older from 1995–2002. Initial treatment was defined as EM, CTX alone, RT alone, or combined CTX and RT based on Medicare claims within six months of diagnosis. IM with rituximab was grouped with CTX. We assessed the effects of demographic and clinical characteristics on the odds of receiving each treatment. In patients who initially received EM, we estimated the time until first treatment. Results: In 3,241 FL patients, the most common initial treatment strategy was CTX alone (n=1,351, 42%), followed by EM (n=1,242, 38%), RT alone (n=434, 13%) and combined CTX+RT (n=214, 7%). Treatment varied widely by age ( Table ). In multivariable analysis, predictors of EM included older age at diagnosis (p<0.0001), greater comorbidity (p<0.001) and earlier stage of disease (p<0.01). Use of CTX and RT, each alone or in combination, decreased with increasing age (p<0.0001 for any CTX, p<0.05 for any RT). Later disease stage was positively associated with CTX (p<0.0001) and negatively associated with RT (p<0.0001). Over time, use of CTX increased (p<0.05) and use of RT decreased (p<0.05). About 70% of EM patients remained treatment-free at two years, and the median time until first treatment for this group was 50 months. Conclusions: A substantial fraction of FL patients over age 65 do not receive any cancer-specific treatment at diagnosis, and most of those patients will remain untreated for more than four years. The potential benefits of earlier or more aggressive treatment of these patients remain to be demonstrated.

[Table: see text] [Table: see text]
MicroRNA regulation in mantle cell lymphoma
Authors: Chen R. , Patel S. , Bemis L. , Robinson W. , Myint H.
Published: March 2020

8056

Mantle Cell Lymphoma (MCL) represents only 5–10% of all non-Hodgkins lymphomas, making it an uncommon but difficult form of lymphoma to treat. It has the worst prognosis among the B cell lymphomas with median survival of three years. The genetic hallmark of MCL is a t(11;14) q32 translocation which results in ectopic and dysregulated expression of cyclin D1. Recent comparative genomic hybridization studies have identied Syk as another gene important in the pathogenesis of MCL. Previous studies have suggested that post transcriptional regulation of Cyclin D1 and Syk may be important the pathogenesis of in MCL. MicroRNAs are a new class of abundant small RNAs that play important regulatory roles at the post transcriptional level by binding to the 3’ untranslated region (UTR) of mRNAs blocking either their translation or initiating their degradation. There have been numerous reports of misregulation of microRNAs and their targets in human cancers. We hypothesized that altered microRNA regulation of cyclin D1 and/or Syk may be present in MCL. Based on bioinformatics, we identified 8 microRNAs and their putative docking sites in either Cyclin D1 and Syk. We then examined their integrity in MCL cell lines, and identified a mutation in the 3’UTR of Syk at the docking site of 1 mir-452* and a SNP in mir-458. Using a GFP reporter construct with the mutated Syk 3’UTR we demonstrated that this mutation resulted in altered microRNA function. We also show that mimics of the microRNA leads to down regulation of Syk protein. This data suggests that microRNA regulation of important genes in MCL may be compromised and play a role in the development and progression of this disease.

No significant financial relationships to disclose.
The inclusion of high-dose therapy and autologous stem cell transplantation (ASCT) in the treatment of follicular lymphoma (FL) is associated with prolonged overall survival (OS) from diagnosis
Authors: Sweetenham J. W. , Rybicki L. , Pohlman B. , Sobecks R. , Kalaycio M. , Dean R. , Andresen S. , Brown S. , Bolwell B.
Published: March 2020

8061

Background: Recent studies have suggested that OS for patients (pts) with FL is improving compared with older reports in which median OS was typically 8 to 10 years. We analyzed outcomes for pts with FL undergoing ASCT at any time in the course of the disease to determine whether this contributes to improved OS. Unlike previously reported transplant series, we calculated OS from the date of diagnosis to determine the potential effect of ASCT on the overall course of the disease. Methods: Between 1/79 and 10/05, 188 pts with FL underwent ASCT at our center. Male/female = 103/85. Median age = 47yrs (20–73). Other pt characteristics are summarized in the table . The International Prognostic Index (IPI) was used since data for the FLIPI were only available for a minority of pts. All pts received chemotherapy-only conditioning regimens, most commonly with busulfan, cyclophosphamide and etoposide (82%). OS was calculated from the date of diagnosis, and survival comparisons were made using the logrank test. Results: 120 pts (64%) are alive at a median follow-up of 8.2 years (0.8–23.7 years). Median follow-up from date of transplant is 5.2 years (0.1–15.3 years). The median OS from the date of diagnosis is 15.2 years. IPI at diagnosis was predictive of OS (low-risk median not reached, low-intermediate = 18.3 yrs, high-intermediate = 4.9yrs) (p = <0.001). Status at transplant (CR/PR1 vs CR/PR2 vs CR/PR3 vs relapsed/refractory) had no effect on OS (p = 0.36). Conclusions: The use of ASCT as part of the overall treatment strategy for pts with FL is associated with prolonged OS and may in part be responsible for the reported improvement in survival for FL reported in recent years. Further prospective evaluation of the role of ASCT in the context of treatment regimens which include monoclonal antibodies is required.

No significant financial relationships to disclose.

[Table: see text]
Alemtuzumab plus CHOP as front-line chemotherapy for patients with peripheral T-cell lymphomas
Authors: Moon J. , Kim J. , Sohn S. , Yang D. , Lee J. , Kim H. , Shin H. , Chung J. , Lee W. , Joo Y. , Oh S.
Published: March 2020

8069

Background: The present study was conducted to evaluate the safety and efficacy of alemtuzumab plus CHOP chemotherapy for patients with peripheral T-cell lymphomas (PTCLs). Methods: Twenty patients with newly diagnosed PTCLs were enrolled. The treatment consisted of classical CHOP plus alemtuzumab (10 mg/m2 i.v on day 1 and 20 mg/m2 i.v on day 2 in the first cycle, then 30 mg/m2 i.v on day 1 in the subsequent cycles) based on 3-week intervals. Results: Thirteen complete responses (65.0%) and 3 partial responses (15.0%) were confirmed, giving an overall response rate of 80.0 %. The estimated event-free survival at 1 year was 43.3%. The most severe hematologic adverse event was neutropenia, which occurred with a grade 4 intensity in 18 patients (90.0%). Plus, febrile neutropenia was observed in 11 patients (55.0%). Five patients (25%) experienced CMV (cytomegalovirus) reactivation, while 3 patients developed CMV diseases, such as pneumonitis or retinitis. There were 2 treatment-related deaths. Conclusions: The alemtuzumab plus CHOP chemotherapy seemed to produce active antitumor activity in terms of the complete response rates in patients with PTCLs. However, since high infectious and hematologic toxicities were observed, careful monitoring and early treatment to prevent treatment-related mortality are needed.

No significant financial relationships to disclose.
Association of CD20 positivity (+) with event free survival (EFS) in children with post-transplant lymphoproliferative disease (PTLD) following solid organ transplantation (SOT)
Authors: Orjuela M. , Alobeid B. , Kott E. R. , Addonizio L. J. , Lobritto S. J. , Siebert A. L. , Morris E. , Garvin J. H. , Cairo M. S.
Published: March 2020

8070

Background: The roles of CD20 and EBV as prognostic features for development and survival of pediatric PTLD after SOT are poorly understood. We previously demonstrated the safety and efficacy of cyclophosphamide, prednisone and rituximab (CPR) in CD20+ PTLD (Orjuela/Cairo, CCR 2005) Methods: All patients (pts), =25 yrs with PTLD in the past 15 yrs were analyzed and classified according to presence of detectable EBV or CD20 by IHC or ISH. Overall survival (OS) and EFS were estimated using Kaplan-Meier, significance was assessed by t-test comparison and Mantel-Cox. Results: 41 SOT pts (28 heart, 8 liver, 4 kidney) had PTLD (53.6% female) at a median of 38.8 months (mo) post SOT (4–43); Age 14–263 mo. Of 35 evaluable tumors, 29 (82.9%) had detectable EBV, while 22 (62.9%) expressed CD20 antigen. All pts had immunosuppression reduced, followed by chemo- and immunotherapy as needed. In pts with =9 mo follow-up after PTLD (n = 38) (median 49 mo, 10–184) OS is 73.2% and PTLD related EFS is 63%. Pts with EBV+ tumors had a shorter time to onset than those with EBV- tumors (median 18 vs 44 mo, p = 0.002). Pts with CD20+ PTLD were diagnosed earlier than those with CD20- PTLD (median 19 vs 62 mo, p= 0.006). PTLD-related 5 yr EFS showed significantly increased survival for CD20+ over CD20- pts (90 ± 6.5% vs 25 ± 11.2%, respectively [95% CI], p = 0.001). EBV status did not have a significant effect on OS (p=0.7) or EFS (p=0.7). Conclusions: CD20 and EBV are important predictors of time to PTLD development and presence of CD20 predicts for significantly improved EFS for SOT PTLD. CD20- PTLD pts appear to have lower EFS suggesting a need for alternative treatment strategies.

No significant financial relationships to disclose.
VEBEP regimen and highly active antiretroviral terapy (HAART) in patients (pts) with HD and HIV infection (HD-HIV)
Authors: Spina M. , Rossi G. , Antinori A. , Allione B. , Fasan M. , Rizzardini G. , Tirelli U.
Published: March 2020

8083

Background: The outcome of pts with HD-HIV is still poor, mainly because the duration of complete remission (CR) is short. To improve the prognosis of HD-HIV, a feasibility study with the third generation VEBEP regimen (developed at the NCI, Milan) and radiotherapy and concomitant HAART was started in previously untreated HD-HIV pts within the GICAT (Italian Cooperative Group on AIDS and Tumors). Methods: CT included epirubicin 30 mg/m2/day (days 1–3), cyclophosphamide 1,000 mg/m2 (day 1), vinorelbine 25 mg/m2 (day 1), bleomycin 10 mg/m2 (day 3) and prednisone 100 mg/m2/day (days 1–3), every 3 weeks. Results: Between September 2001 and June 2006, 43 pts have been enrolled. The median age was 39 yrs. The median CD4+ cell count at entry was 269/mm3 (range 44–887) and 24 pts had a detectable HIV viral load (median 12780 copies/mm3, range 89->500,000). Stage III and IV disease was present in 30/43 (70%) pts. Histologic subtypes were: MC 72%, NS 16%, LD 5%, LP 2%, and unknown 5%. One toxic death, due to hepatic failure in a HCV positive pt was observed. An absolute neutrophil count <500 was noted in 21/43 pts (49%). Grade 3–4 anemia was observed in 12/43 pts (28%) and severe thrombocytopenia in 6/43 pts (12%). Thirteen pts (30%) had febrile neutropenia with 10 documented infections in 8 pts (2 bacterial pneumonia, 2 bacterial sepsis, 2 varicella, one PCP, one cerebral toxoplasmosis, one salmonellosis, one prostatitis). A grade 2–3 mucositis was observed in 9/43 pts (21%). CR was obtained in 33/43 pts (76%) and PR in 5/43 pts (12%). With a median follow up of 30 months, only 3 pts have relapsed (9%). OS and TTF at 30 months are 80% and 66%, respectively. Conclusions: Our preliminary data demonstrate that VEBEP regimen in combination with HAART is less toxic and as active as Stanford V regimen in pts with HD-HIV. This study was supported by ISS grants.

No significant financial relationships to disclose.
Utility of PET imaging in predicting the aggressiveness and histopathology of lymphoma
Authors: Chandana S. R. , Movva S. , Arora M. , Singh T.
Published: March 2020

8085

Background: F (18)-fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used in the staging and restaging of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). Few studies have investigated whether the intensity of tumor FDG uptake, measured by standard uptake value (SUV), a semiquantitative measure, could differentiate between indolent and aggressive disease. The clinical utility of SUV in determining the aggressiveness of NHL and HD and in differentiating histopathological subtypes was investigated in the present study. Methods: FDG-PET studies and histopathology of patients with NHL and HD were evaluated retrospectively. Inclusion criteria include PET before any therapy or on relapse of the disease, no diagnosis of diabetes mellitus or other types of cancer and time interval of < 90 days between PET and biopsy. After reviewing the PET scans, the SUV of biopsy site were measured by drawing regions of interest. Mean ± SD of SUV was calculated for HD and various histopathological subgroups of NHL. Results: Fifty-five patients (mean age 58.1 ± 17.2 years, 30 males, 25 females, 13 patients with HD, 42 with NHL, among which 24 with aggressive and 18 with indolent NHL) were included. The mean SUV was 9.9 ± 7.8 for aggressive NHL, 4.1 ± 2.6 for indolent NHL and 11.5 ± 7.3 for HD. Mean SUV was statistically different between aggressive and indolent NHL (p < 0.001) and HD and indolent NHL (p < 0.001), but not between aggressive NHL and HD (p = 0.4). The SUV for the aggressive NHL can be subdivided further as follows: anaplastic (n =3, 15.1 ± 1.7), diffuse large cell (n=19, 9.6 ± 5.3) and follicular grade III (n=2, 8.1 ± 2.2). Indolent NHL included: mantle cell (n=1, 4.3), marginal zone (n=1, 6.3), small cleaved (n=12, 4.2 ± 3.5), low grade follicular (n=4, 3.2 ± 1.4) and small lymphocytic NHL (n=1, 2.3). Conclusions: Our study suggests that FDG- PET can distinguish aggressive from indolent lymphomas. There was a considerable overlap between HD and aggressive NHL.A SUV of seven or less indicates indolent lymphoma. PET could potentially differentiate between different histopathological subgroups of lymphomas. Future studies with greater sample size are warranted.

No significant financial relationships to disclose.
Meta-analyses of the association between Chlamydia psittaci and ocular adnexal lymphoma and the response of ocular adnexal lymphoma to antibiotics
Authors: Husain A. , Roberts D. , Pro B. , McLaughlin P. , Esmaeli B.
Published: March 2020

8090

Background: There are conflicting reports regarding the association between Chlamydia psittaci (Cps) and ocular adnexal lymphoma (OAL) and the efficacy of antibiotics for OAL. We sought to clarify the association between Cps and OAL and the efficacy of antibiotics for OAL. Methods: We conducted 2 meta-analyses. One focused on Cps association with OAL across geographic regions and among different studies. The other was a meta-analysis of responses to antibiotic treatment. Results: We identified 10 studies of Cps prevalence which included 430 cases of OAL from 10 different countries. We found 4 studies on the efficacy of oral antibiotics to treat OAL. Ninety-six (22%) of the 430 OAL specimens and 78 (26%) of the 305 MALT lymphoma specimens were positive for Cps. Ninety-four (98%) of the 96 Cps-positive OAL specimens came from 3 of the 10 studies. There was wide variation between geographic regions and even between studies from the same geographic region in the rate of Cps positivity. The 4 studies on the efficacy of antibiotics for OAL were from Italy, Austria, Taiwan, and the United States and included 24 patients. Eleven patients (46%) had some response (complete response in 4, partial response in 3, minimal response in 4). Twelve patients had stable disease, and 1 patient progressed during antibiotic therapy. Objective documentation of response (radiographs or clinical slit-lamp photographs) was available for only 2 out of 24 patients. Conclusions: Our findings suggest a striking variability in the association of Cps and OAL across geographic regions and even between studies from the same geographic regions. The overall rate of Cps positivity in our meta- analysis (22%) was much lower than that reported in the original report by Ferrari et al. Our findings also suggest that antibiotics have low efficacy against OAL. Future prospective trials with standard objective response criteria and a longer follow-up time would be necessary to further evaluate the role of antibiotics in the treatment of OAL.

No significant financial relationships to disclose.