bluuebunny/crossref_metadata_2025 huggingface dataset:
Erlotinib (E) in non small cell lung cancer (NSCLC) patients (pts) ≥75 years old with comorbidities (cM): Experience at a tertiary referral center.
Authors: Syrigos Konstantinos N. , Sarris Evangelos , Strimpakos Alexios S
Published: March 2020

e19111

Background: Besides chemotherapy, E is another option in NSCLC pts especially in those with EGFR mutations. Elderly pts enrolled in trials are fit without cM, but in clinical practice most suffer from cM. Methods: Medical records of 1221 pts diagnosed with NSCLC between 2008-2012 were screened. We examined pts ≥75 yrs for demographics, clinical data and Tx details. Results: 233/1221 NSCLC pts received E at any line. 53/233 (23%) were ≥75 yrs old. Male:female ratio was 34:19 and median age 79 yrs (range 75-88). NSCLC subtypes included 31 adenoca, 8 squamous cell, 9 NOS and 5 others. 50/53 pts had cM (≥2 in 46 pts, 1 in 4pt). Main cM were cardiovascular disease (n=41), COPD (n=14), other cancer (n=10) and diabetes (n=8). 8 pts were tested for EGFR mutations (5 -ve, 3 +ve). Performance Status was satisfactory (ECOG 0-1) in 8 pts and poor (2-3) in 45pts. 8pts were treated with E 100mg and 45 pts with E 150mg (12 pts needed dose reduction). Complete follow up data were found in 46pts. Mean duration of treatment was 79 days (range 9-662). 35/46 pts experienced side effects (s.e) [rash n=29, diarrhea n=17] which led to treatment discontinuation in 12pts. Pts with abnormal creatinine clearance (n=13) were more likely to stop treatment due to s.e (6/13 versus 6/33). 17/46 pts (37%) achieved disease control (5 PR, 12 SD) and a time to progression (TTP) of 157 days (range 106-662, 95% CI 132.79-270,74) while 22/46 pts had PD as best response (TTP 49d, range 19-88, CI 44,67-64,97). 7pts were not evaluable (stopped Tx due to s.e). All EGFR+ve pts had disease control (2PR, 1SD). Conclusions: E is a valuable option in elderly NSCLC patients with co-morbidities, especially if they harbor EGFR mutations. Impaired renal function might be associated with propensity to side effects and early Tx discontinuation.
Volumetric tumor growth in advanced NSCLC patients (pts) with EGFR mutations during EGFR-TKI therapy: Developing criteria to define slow progression.
Authors: Nishino Mizuki , Dahlberg Suzanne Eleanor , Cardarella Stephanie , Jackman David Michael , Rabin Michael S. , Ramaiya Nikhil H. , Hatabu Hiroto , Janne Pasi Antero , Johnson Bruce E.
Published: March 2020

e19125

Background: EGFR-mutated advanced NSCLC pts treated with EGFR TKI typically progress after an initial tumor response. Most pts continue TKI beyond RECIST progression, and an objective guide for treatment decisions is needed. We analyzed the volumetric tumor growth in these pts as an initial step to develop criteria for slow progression to aid therapeutic decision making. Methods: The study population included 58 advanced NSCLC pts with sensitizing EGFR mutations, treated with first-line single-agent gefitinib or erlotinib between 2002-2011, who had baseline CT showing measurable lung lesion and at least two follow-up CTs while on TKI and experienced volumetric tumor growth. Tumor volume (mm3) of the dominant lung lesion was measured on baseline and all follow-up chest CT scans during therapy, using volume analysis software [Nishino et al. Acad Radiol. 2011]. A total of 405 volume measurements from nadir to the end of TKI therapy or last follow-up, with data closure on 6/1/12, were analyzed in a linear mixed effects model, fitting time as a random effect [Laird and Ware, Biometrics, 1982]. Results: Among 58 pts, 46 (79%) were female, median age was 62 (range: 35-84), 29 (50%) were never-smokers, 53 (91%) were stage IV at diagnosis, and 53 (91%) received erlotinib. The median time on TKI was 15.8 months. The median time to tumor nadir was 6.3 months. A linear mixed effects model was fitted to predict growth of the logarithm of tumor volume (logeV), adjusting for time in months from baseline. The growth rate of logeV, obtained as the regression coefficient for time, was 0.12/month (SE: 0.015; p<0.001; logeV=0.12*months+7.68). The model provided a reference value for the volumetric tumor growth rate in EGFR-mutant NSCLC pts after they have achieved their nadir. Conclusions: Tumor volume analysis defined volumetric tumor growth after the nadir in EGFR-mutant advanced NSCLC pts receiving TKI. This provides a reference value for the tumor growth rate in pts progressing after the nadir on TKI. Based on these data which can be studied in additional cohorts, we are currently developing practical radiographic criteria to help define patients as slow progressors who can safely remain on EGFR TKIs.
A phase II trial of a cremophor-free, polymeric micelle formulation of paclitaxel and gemcitabine in patients with advanced non-small cell lung cancer.
Authors: Ahn Hee Kyung , Hong Junsik , Kang Shin Myung , Sym Sun Jin , Park Jinny , Shin Dong Bok , Lee Jae Hoon , Cho Eun Kyung
Published: March 2020

e19129

Background: Non-platinum doublet paclitaxel and gemcitabine has shown efficacy on par with platinum-based doublet regimens as first-line chemotherapy in advanced non-small cell lung cancer patients. Genexol-PM is a Cremorphor EL(CrEL)-free polymeric micelle formulation of paclitaxel. This study was designed to evaluate the efficacy and safety of Genexol-PM and gemcitabine combination in advanced non-small cell lung cancer patients. Methods: This is a single-arm, single-center phase II study. Patients with advanced NSCLC received Genexol-PM at 230mg/m2 on day 1 and gemcitabine 1000mg/m2 on day 1 and day 8 of a 3-week cycle as first-line chemotherapy. Six cycles of chemotherapy were administered unless there is a disease progression. The primary endpoint was response rate. Results: Forty-three patients received the study drugs with median of 4 cycles per patient (range, 1-6). Among 35 patients who received more than one cycle, mean dose intensity of CrEL-free paclitaxel and gemcitabine was 209 mg/m2/3-week and 1,853 mg/m2/3-week respectively. Overall response rate was 46.5%. The median progression free survival was 4.0 months (95% CI 2.0-6.0 months) and median overall survival was 14.8 months (95% CI 9.1-20.5 months). 18 patients (51%) experienced grade 3/4 adverse events, including neutropenia or febrile neutropenia (n=7), pneumonia (n=3), asthenia (n=3), peripheral neuropathy (n=2), diarrhea (n=1), skin rash (n=1), myalgia (n=1), pulmonary thromboembolism (n=1), LV dysfunction (n=1), and dyspnea with sudden death (n=1). Adverse events leading to drug discontinuation were occurred in 9 patients, among which 2 patients were died of adverse events (pneumonia, dyspnea with sudden death). Conclusions: CrEL-free paclitaxel in combination with gemcitabine demonstrated comparable antitumor activity with less emetogenicities in non-small cell lung cancer patients. Clinical trial information: NCT01770795.
Phase II study of danusertib (D) in advanced/metastatic non-small cell lung cancers (NSCLC).
Authors: Gauler Thomas Christoph , Besse Benjamin , Novello Silvia , Smit Egbert F. , Plummer Elizabeth R. , Delord Jean-Pierre , Nicodemo Maurizio , Santoro Armando , Barone Carlo , Marchetti Paolo , Conte Pier Franco , De Jonge Maja J. , Awada Ahmad , Mariani Mariangela , Jannuzzo Maria Gabriella , Petroccione Anna , Ceruti Roberta , Davite Cristina , Eberhardt Wilfried Ernst Erich
Published: March 2020

e19138

Background: D is an ATP competitive pan-aurora kinases inhibitor with activity also against FGFRs, VEGFR, Ret, TrkA, Scr, and Abl. Methods: Eligible pts had NSCLC progressing for advanced/metastatic disease after 1 prior chemotherapy line (CT). Primary endpoint was progression-free survival at 4 months (PFS-4) evaluated in a Simon two-stage design. Number of successes required for not rejecting the alternative hypothesis (40% PFS-4) was ≥4/19 evaluable pts while the number of successes required to reject at the end of stage 2 the null hypothesis (20% PFS-4) was ≥11/36 (α 1-sided = 0.1). D was administered at 500 mg/m² as 24 hr IV infusion q2w. The expression of Aurora A/B, TPX-2, MDR, Scr, Survivin by IHC and the amplification of FGFR1 by FISH on tumor biopsies of consenting pts were evaluated. Results: 3 out of 19 evaluable pts were PFS-4 at the end of the 1st stage, thus precluding passage to the 2nd stage. Interestingly, in pts with squamous (SCC) (n=7), median PFS and OS were 6.4 and 10.6 mos respectively (vs. 2.2 and 7.6 mos, in non-SCC pts), suggesting a possible specific effect in this subtype. Additional pts with SCC were therefore treated under a protocol amendment. At the end of this 2nd stage, 5/31 evaluable SCC pts (80% CI: 0.08-0.28) were PFS-4 indicating that the predefined threshold required to conclude for activity would not have been reached. Overall 56 pts, all histology NSCLC, were treated: median age 62 yrs (39-79), 64% male, 70% SCC, 36% with >1 prior CT. Best response was a PR in 1 pt and SD in 20 pts; median PFS and OS were 2.1 and 8.3 mos respectively. The most frequent drug-related AEs (any Grade, ≥20%) were: uncomplicated and short lasting neutropenia (94%), nausea (39%), fatigue (37%), asthenia (30%), anorexia and diarrhea (29%), alopecia (23%). Histological analyses by IHC and FISH is still ongoing: results will be presented. Conclusions: Limited evidence of activity was observed, insufficient to meet the predefined threshold to call efficacy in NSCLC when D was administered as monotherapy at this dose/schedule. D confirmed to have a manageable safety profile. Clinical trial information: 2006-003772-35.
Time trends in overall survival (OS) gain in advanced non-small-cell lung cancer (NSCLC).
Authors: Saad Everardo D. , Buyse Marc E. , Jassem Jacek
Published: March 2020

e19144

Background: There is an ongoing debate about the adequacy of OS as primary endpoint (PEP) in phase III trials in various tumor types, including NSCLC (Soria Ann Oncol 2010). Moreover, median OS and post-progression survival are increasing in NSCLC (Hotta PLoS One 2011 and Hayashi Ann Oncol 2012). We assessed the frequency and time trends in OS gain in recent trials. Methods: We searched PubMed for phase III trials in advanced NSCLC published between January 1998 and December 2011 in 13 leading journals. The PEP was the endpoint stated explicitly, used for N calculation, or listed first. Gain in OS was ascertained when there were significant differences in any pairwise comparison on OS following the original authors’ definitions. Results: We retrieved 148 trials that enrolled a total of 70,716 patients in 325 trial arms. The median number of patients per arm was larger for the 2005-2011 period than for the 1998-2004 period (207 vs 150; P<0.01). OS was used as PEP alone in 99 trials, and as one of the co-primary endpoints in 3 trials (the PEP could not be ascertained for one trial). There was no trend regarding the use of OS as PEP in the two periods compared, either overall (P=0.44) or in first line (P=0.41). Gain in OS according to trial features is shown in the Table. Conclusions: Significant gains in OS appear to decrease along the years, despite the growth in size of NSCLC trials and the continued use of OS as PEP. [Table: see text]
Phase I/II trial of combination nab-paclitaxel and pemetrexed in advanced solid tumor patients (pts) with emphasis on non-small cell lung cancer (NSCLC).
Authors: Riess Jonathan , Ho Cheryl , Davies Angela M. , Lau Derick , Lara Primo , Chew Helen K. , Beckett Laurel , Sangha Randeep S. , Mack Philip C. , Gandara David R.
Published: March 2020

e19147

Background: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in NSCLC. Preclinical evaluation has demonstrated additive cytotoxicity of pemetrexed and taxanes. We evaluated the safety and efficacy of combining nab-paclitaxel (nP) and pemetrexed (P) in solid tumors with a focus on NSCLC for the phase II expansion. Methods: A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: P 500 mg/m2 day 1 plus nP on day 1 at doses of 180, 220, and 260 mg/m2 every 21 days. Dose limiting toxicity (DLT) in cycle 1 was defined as: grade 4 platelets or grade 3 platelets with bleeding, neutropenia with fever or documented infection, or other grade ≥ 3 non-heme toxicity. Phase II eligibility included advanced NSCLC, ≤ 2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. Results: Planned dose escalation during the Phase I portion was completed without reaching the MTD. The RP2D was P 500 mg/m2 and nP 260 mg/m2. The phase II portion accrued 37 pts before early closure due to increasing use of first-line pemetrexed/platinum doublet therapy in non-squamous NSCLC. Phase II patient characteristics: median 63 (45-77); M:F 23:14; median cycles 3. In 31 assessable patients: 5 PR, 12 SD and 14 PD. Efficacy: RR =14%; disease control rate (DCR) = 46%; median survival time (MST) = 8.7 months. Pts in the DCR group had a MST of 15.4 vs 4 months in the PD group (p=0.02). Conclusions: P 500 mg/m2 day 1 with nP 260 mg/m2 was feasible and well tolerated. The phase II component demonstrated activity in second-line therapy of advanced NSCLC. Practice patterns have evolved; so further trials of this regimen are not planned. Clinical trial information: NCT00470548.
KRAS gene mutation status and sensitivity to pemetrexed: A retrospective analysis.
Authors: Kamdar Manali K. , Parent Teresa , Walker Paul R.
Published: March 2020

e19154

Background: KRAS is the most frequently mutated oncogene (25%) in lung adenocarcinoma. KRAS mutations are a negative prognostic factor for survival. Recent phase II trial with a MEK inhibitor has shown promising efficacy albeit at the cost of higher adverse events. Preclinical work by Moran et al showed that antifolate therapies like pemetrexed decrease KRAS gene expression in KRAS wild type and KRAS mutant but do not do so in KRAS mutant amplified cells. Targeted therapies for EGFR, ALK and ROS1 have increased the survival for lung adenocarcinoma expressing these actionable targets. No therapies are yet approved for KRAS mutant subsets. Hence therapeutic strategies that target this cohort represent an unmet medical need. Methods: We reviewed data from patients (pts) in our thoracic oncology clinic with stage IIIB and stage IV lung adenocarcinoma with KRAS mutation positive tumours who received pemetrexed either during induction or maintenance therapy. Pt characteristics including age, sex, race, smoking history, KRAS mutation subtype and overall survival were analyzed. Results: Between April 2010 and October 2012 we treated 154 pts with stage IIIB and stage IV lung adenocarcinoma. Of these 154 pts we found 34 patients with KRAS mutation positive tumours. 10 pts out of 34 pts with KRAS mutation positive tumours received pemetrexed during induction or maintenance therapy and were analyzed further. Median age 63. 60% females. 90% Caucasians. 90% were smokers. KRAS 12C mutation was found in 2 pts, KRAS 12V in 4, KRAS 12A in 3 and KRAS 13A in 1 pt. 4(40%) patients died. Median overall survival (OS) in the KRAS 12C, 12V, 12A and 13A was 14, 9.5, 10 and 12 months respectively. Conclusions: The median OS in published series is 15.4, 14, 8 and 7 months in the KRAS 12C, 12V, 12A and 13A cohorts respectively (Rosell et al). Our analysis found that pts with KRAS 12C, 12A and 13A mutation had a survival advantage with pemetrexed therapy as compared to pts with KRAS 12V mutation. Thus this retrospective study supports the concept that KRAS mutation status affects sensitivity to antifolate therapy (pemetrexed).
Comorbidity: Usage of, and survival after chemotherapy for advanced lung cancer.
Authors: Mellemgaard Anders , Bredin Philomena , Iachina Maria , Green Anders , Krasnik Mark , Jakobsen Erik , Lüchtenborg Margreet , Møller Henrik
Published: March 2020

e19157

Background: Comorbidity may influence prognosis in lung cancer, affect performance status (PS) of patients as well as complicate treatment. The present study examines usage and outcome of chemotherapy (CT) for advanced-stage lung cancer, and focuses on the role of comorbidity. Methods: Patients with advanced-stage lung cancer were identified in the Danish Lung Cancer Registry. A total of 22,999 patients with non-resectable, advanced-stage lung cancer were identified. Data on stage, PS, Charlson comorbidity score (ChS), age, histology and type of first treatment (if any) were avaliable. First treatment was categorized as chemotherapy (n=7,346), chemo-radiotherapy (2,636), radiotherapy (n=4,155) or no therapy (n=8,862). Survival was examined separately for 0-1 year and 1-5 years, and further distinction was made between metastatic and non-metastatic lung cancer. Data are presented for the subgroup of patients receiving chemotherapy as first treatment only. All estimates are derived from logistic regression model adjusting for the effect of performance status, pulmonary function and histological type, except for usage where models included same variables plus stage. Results: Use of chemotherapy was less frequent for more comorbid patients (OR 0.86, 0.64, 0.56 for Charlson score 1, 2, 3+ respectively compared to no comorbidity). Older patients and men were less likely to receive CT. For patients receiving CT as first treatment for non-metastatic lung cancer, survival in the first year was slightly worse for those with co-morbidity (HR 0-1year, non metastatic =0.91, 0.92, 0.87 for ChS 1,2,3+ respectively). For 1-5years and for metastatic lung cancer no correlation between comorbidity and survival was noted. In contrast, PS and sex was strongly associated with survival. Conclusions: With increasing co morbidity, chemotherapy was used less often. Comorbidity is not an important prognostic factor in advanced lung cancer treated with chemotherapy. However, sex and especially performance status remain as strong prognostic factors in this patient group.
Clinical predictive model for brain metastasis at presentation in patients with non-small-cell lung cancer (NSCLC).
Authors: Acevedo-Gadea Carlos Rodrigo , Trinkaus Kathryn , Govindan Ramaswamy , Morgensztern Daniel
Published: March 2020

e19158

Background: There is limited data on the prevalence of brain metastases at presentation in NSCLC. Between 1988 and 1997, the Surveillance, Epidemiology, and End Results (SEER) database recorded the use of brain radiation in patients with lung cancer. We developed a predictive clinical model for brain metastases (BM) at presentation based on the use of brain radiation (BRT), which may be used as a surrogate since it is not indicated in NSCLC patients without BM. Methods: Patients with NSCLC diagnosed between 1988-1997, aged 21 or older were subdivided according to radiation data into none or indicated (given, refused or unknown if administrated). Since the database records only initial therapy, patients with indication for radiotherapy were assumed to have had early brain metastases. Frequencies and odds Ratio (OR) were calculated for each demographic factor and the most significant were included in the predictive model. Results: Among the 131,456 patients evaluated, 10,963 (8.4%) had BRT indicated. The most significant predictors in multivariate analysis were age > 60 (HR 0.5; 95% CI 0.46-0.54), non-squamous histology (HR 0.53; 95% CI 0.48-0.59), size > 5 cm (HR 1.27; 95% CI 1.16-1.39), grades III-IV (HR 2.04; 95% CI 1.82-2.27) and N2-3 involvement (HR 2.55; 95% CI 2.34-2.78). The 40,963 patients with known status of all 5 factors were used in the predictive model. The frequency of BM for patients with zero, 1, 2, 3, 4 and 5 factors were 0.7%, 1.8%, 4.7%, 8.9%, 13.7% and 20.2% respectively. Conclusions: Despite the limitations of this study, including indication for BRT as a surrogate for BM, older data and possible bias in the use of brain imaging according to demographic factors, our findings showed that the risk of BM at presentation may be stratified with the use of 5 clinical factors. These results may be used as a baseline for studies on clinical and molecular determinants of BM.
Third-line therapy and beyond for patients with advanced/metastatic non-small cell lung cancer (NSCLC).
Authors: Corral Jaime Jesus , Gonzalez de la Peña Miriam , Alonso Miriam , Sanchez Gastaldo Amparo , Mediano Maria Dolores , Amerigo Marta , Robles Carlos Enrique
Published: March 2020

e19160

Background: Lung cancer is the leading cause of cancer-related deaths globally, with a 15% 5-year survival rate. Platinum-based chemotherapy constitutes the main treatment modality, with a median overall survival (OS) of approximately 10–12 months. The current National Comprehensive Cancer Network (NCCN) guidelines recommend several options for first-line and second-line therapies but endorse only erlotinib/gefitinib as third-line therapy in unselected patients, as well as crizotinib in ALK-positive selected patients.The paucity of approved agents for third-line therapy and beyond for patients with non-small cell lung cancer (NSCLC) constitutes an important unmet medical need. Methods: Retrospective analysis of 22 patients with advanced/metastatic NSCLC in progression after a minimum of 3 lines of therapy. Results: Between January 2009 and October 2012, 22 patients were analysed. Median age at diagnosis was 62 years old. 15% of patients were never smokers and 72.7% had non squamous NSCLC histology. Stage at diagnosis resulted: 6 (27.3%) stage IIIA, 3 (13.6%) stage IIIB and 13 (59.1%) stage IV. 3 (13.6%) patients were EGFR mutation carriers and 1(1%) patient had ALK translocation. Third line therapy options resulted a clinical trial (27.3%), erlotinib (22.7%), paclitaxel/gemcitabine (13.6%), docetaxel (9.1%) and crizotinib (4.5%). Estimated median progression-free survival (PFS) between first and second line therapy was 5.3 months; PFS between second and third line resulted 4.4 months. Median PFS and overall survival (OS) beyond third line treatment has not been reached yet. Conclusions: Currently, erlotinib/gefitinib and crizotinib, which target EGFR and ALK, are the only recommended agents for third-line therapy in patients with advanced/metastatic NSCLC. Real-world clinical practice reveals a variety of chemotherapeutic agents used in this setting. Additional systemic and/or targeted therapeutic under development, with complementary biomarker analysis, should be the key in identifying those patients most likely to benefit from newer agents.
Effect of LIM domain only (LMO2) protein expression on survival in multiple myeloma patients.
Authors: Kelkitli Engin , Atay Memis Hilmi , Yildiz Levent , Turgut Mehmet
Published: March 2020

e19500

Background: Better understanding of the biology of myeloma paved the way for new treatments that target myeloma cells which are playing a critical role in the pathogenesis of the disease and microenvironments of the bone marrow. LMO2 (LIM domain only 2) is located on 11p13 and belongs to a family of 4 genes encoding LIM only proteins, that are transcription regulators that control cell fate in normal hematopoiesis. LMO2 has been identified as a novel oncogene associated with carcinogenesis and better prognosis in several malignant tumors such as pancreatic, prostate cancer. We examined if LMO2 protein expression can predict the outcome in MM patients. Methods: Forty-one patients were enrolled with MM admitted to our hospital. Immunohistochemistry on bone marrow biopsy material for LMO2 protein was performed in our hospital pathology laboratory, and staining in greater than 30% of plasma cells was assigned positive score. Results: Of the 41 patients , 21 were male and 20 were female. The mean age was 62±11. The demographic characteristics of patients are shown in the table. Thirty patients had LMO2 protein expression in bone marrow samples whereas in eleven patients LMO2 protein expression was not detected. LMO2 negativity were more frequent in patients with type of lambdaM protein (P=0.04). The risk of death was increased in the patients with LMO2 protein expression compared with patients who had no LMO2 protein expression. While overall survival was %100 in the patients with no LMO2 protein expression, it was %76.7 in the patients with LMO2 protein expression (according to Kaplan Meier test, long rank p=0.04). Conclusions: We report that the no LMO2 protein expression is correlated with improved overall survival in the MM patients. This method is simple, inexpensive, and effective. We suggest that the expression of LMO2 should be tested in a larger series of MM patients. [Table: see text]
Rituximab and dose-adjusted EPOCH (R-EPOCH) for treatment of aggressive B-cell non-Hodgkin lymphomas: A developing country perspective.
Authors: Jain Hasmukh , Shet Tanuja , Sridhar Epari , Menon Hari , Dangi Uma Bhaskar , Bagal Bhausaheb Pandurang , Gujral Sumeet , Laskar Siddharth , Rangarajan Venkatesh , Sengar Manju
Published: March 2020

e19503

Background: Biological heterogeneity of diffuse large B-cell lymphomas (DLBL) is reflected in variable outcomes with R-CHOP. Clinicopathological features like high IPI, underlying acquired immunodeficiency, non-germinal center phenotype, primary mediastinal B-cell histology and Bcl-2 positivity correlate with adverse biology. Effect of adverse biological attributes is also reflected in outcomes B-cell lymphoma intermediate between diffuse large cell B-cell and Burkitt’s lymphomas (BCLU) and Burkitt’s lymphoma in elderly and HIV-positive individuals with low CD4 counts. Given the promising efficacy of R- EPOCH in poor-risk DLBL we used it in therapy of aggressive B-cell NHL. Methods: From May 2010 to December 2012 patients with de-novo aggressive B-cell lymphomas with adverse clinicopathological features (DLBL with multiple extranodal sites, high IPI, primary mediastinal B-cell lymphoma, BCLU, Burkitt’s lymphoma in elderly or in HIV-positive individuals) were treated with R-EPOCH. Demography,stage, bulk of disease, IPI, CD4 counts, grade 3/4 toxicities and death were recorded. Responses were evaluated at mid and end of therapy. Overall and progression-free survivals were calculated. Immunohistochemistry was used to classify the germinal center and non-germinal center phenotype. Results: 33 patients (males-21, female-12) were treated with median of 6 cycles (range 3-6) of R-EPOCH. Histologicalsubtypes distribution was- DLBL-16, BL-8, BCLU-5, and PMBL-4. Sixty percent of DLBL were non-germinal center type and bcl-2 positive. Median age was 33 years (range 15-73 years). More than 2/3 of patients had stage 3/4 bulky disease with high IPI. Twelve patients were HIV positive with median CD4 count of 173/µL (range 43-359/µL). Complete responses were seen in 66.7% at interim evaluation and in 90% at the end of therapy. At a median follow up of 8 months, 1- year overall survival and progression- free survival were 72.5% and 90% respectively. Two patients died due to therapyand grade 3/4 toxicities were seen in 10% patients. Conclusions: R-EPOCH regimen is efficacious in patients with poor-risk aggressive B-cell NHL however longer follow-up is needed.
Biologic variations of plasma cells in the bone marrow of smoldering multiple myeloma (SMM) and multiple myeloma (MM) patients: Multiple biopsies in the same patient.
Authors: Manasanch Elisabet E. , Korde Neha , Yuan Constance , Kwok Mary , Tageja Nishant , Bhutani Manisha , Flanders Aaron W. , Zingone Adriana , Costello Rene , Tembhare Prashant , Mulquin Marcia , Zuchlinski Diamond , Maric Irina , Calvo Katherine R. , Steinberg Seth M. , Roschewski Mark J. , Landgren Ola , Braylan Raul , Stetler-Stevenson Maryalice
Published: March 2020

e19506

Background: The European Myeloma Network has reported that plasma cell (PC) enumeration by flow cytometry (FC) varies depending on quality of aspirate pull and field biopsied. We conducted a prospective study to evaluate PC site variation content in the core biopsy (CB), PC viability (V) and proportion of monoclonal PCs based on immunophenotypic characteristics, anticoagulant use, and aspirate (A) pull sequence in SMM and MM treatment-naïve patients. Methods: Untreated SMM (n=5) and MM (n=5) patients underwent bilateral bone marrow (BM) A and CB. Bilateral first-pull A were anticoagulated with ethylenediaminetetraacetic acid (EDTA). The second-pull A were anticoagulated with heparin. CB were performed after obtaining all A. The first pull A was sent for morphology and FC evaluation, and the second-pull for FC. CB infiltration by PC was assessed by CD138 immunohistochemistry (IHC). Analysis of PC by FC used CD markers: 19, 45, 20, 38, 138, 27, 28, 19, 81, 126, 200 and 117. V was measured by FC using 7-amino-actinomycin D exclusion. We used the two-tailed Wilcoxon signed rank test to determine the significance of the difference between paired values. Results: The mean difference in estimated percentage of PC infiltration between the right and left CB was 0.033 +/- 0.017 (p=0.25). Phenotypic analysis of PCs by FC showed similar expression of CD markers. PC V was significantly lower in samples anticoagulated with EDTA when compared to heparin (p<0.005), suggesting that the latter is superior for PC analysis. Of importance, the fraction of abnormal PCs determined by FC did not differ significantly between the two sides, use of EDTA/heparin or order of A pull (p>0.05). Conclusions: Based on IHC and FC, our results suggest that in untreated patients with SMM or MM there are no major differences in the estimated number or immunophenotypic characteristics and distribution of PC in marrow samples obtained from two distant bone sites. These observations have implications for current diagnostic and treatment of MM and its precursor disease. More advanced molecular profiling may find biological variation in bone marrow tumor PC extracted from different locations.
Results of upfront therapy for marginal zone lymphoma (MZL).
Authors: Cabanillas Fernando , Ortega Jose Luis , Rivera-Rodriguez Noridza , Rodriguez Blanca , Pardo Wandaly Ibis , Pavia Orestes Antonio , Bruno Margarita , Santiago Karen J.
Published: March 2020

e19510

Background: MZL is an indolent NHL composed of 3 subtypes: extranodal (MALT), splenic marginal zone (SMZL) and nodal marginal zone (NML). While MALT usually presents with early stage, the others frequently present with advanced disease. Early stage MALT is usually treated with XRT or antibiotics with ~85-90% failure free survival (FFS) and overall survival (OS), while for SMZL watch and wait or splenectomy (Spl) have been the mainstay of therapy. Spl leads to improvement but rarely to CR. 5 yr FFS and OS with Spl have been 45% and 80%. At 10 yrs FFS and OS are 22% and 62%. NML is usually managed with watch and wait. The 5 yr FFS and OS for NML have been 30% and 60%. Watch and wait and Spl are used in part because advanced MZL is considered incurable. Rituximab (R) as well fludarabine (F) are active in this disorder but traditionally are given after relapse. Methods: Instead of watch and wait or Spl, we have used upfront chemo with curative intent for SMZL and NML as well as for advanced MALT. For early stage MALT we used either XRT alone or antibiotics. We hereby report on 44 pts with MZL of which 31 were MALT, 9 SMZL, 4 NMZL. For the purpose of analysis we divided the pts in 2 groups. Group 1 consists of 22 early stage MALT who were all treated with either XRT (N=17) or antibiotics +/- surgery (N=5). Group 2 consists of 22 cases who were treated with chemo alone. This group is made up of 9 MALT (4 advanced stage, 3 early stage but with transformation, 2 early stage but in whom XRT was contraindicated), 9 advanced stage SMZL, 4 NML. Chemo for group 2 consisted of F, mitoxantrone, dexamethasone, rituximab (FND-R) (N=14) or R-CHOP (N=8). Maintenance R was used in 70% of group 2. Results: Of the whole group, 100% were CR and only 2 relapsed at 70 and 75 months; both relapses were stage I MALT and had received XRT only. Both were salvaged with FND-R and remain NED 27 and 39 months from relapse. At 10 yrs, FFS was 80% and OS=100%. None of the 22 in group 2 have relapsed. The long-term toxicity has been acceptable. Conclusions: The excellent FFS and OS using upfront chemotherapy in group 2, suggests that this disorder is curable and our results should be confirmed in a prospective trial. For those with early stage MALT, XRT alone +/- antibiotics and when necessary salvage with FND-R, should be tested.
Post-transplant lymphoproliferative disorder (PTLD) after liver transplantation: Report of 16 cases from a single center.
Authors: Ulusakarya Ayhan , Delmas Marsalet Beatrice , Misra Srimanta , Cucherousset Nahla , Ichai Philippe , Haydar Mazen , Almohamad Watek , Gumus Yusuf , Bessaoud Hamid , Innominato Pasquale , Goldschmidt Emma , Samuel Didier , Guettier Catherine , Machover David , Turhan Ali , Morere Jean-Francois
Published: March 2020

e19513

Background: PTLD is a rare complication of organ transplantation, but it can jeopardize the transplantation outcome. Methods: Paul Brousse University Hospital is the largest liver transplantation center in France. We retrospectively analyzed data from all of the patients who experienced PTLD and treated in our hematology/oncology department in the last 10 years. Results: 16 cases of PTLD occurred after various intervals following the liver transplant without correlation with the type of underlying liver disease or immunosuppressive treatment. Overall, the patients had poor general health (ECOG 3-4: 69%), renal and/or hepatic failure (75%), and cytopenia (63%). PTLD were often of high grade (81%), B phenotype (94%), stage IV (75%), with high LDH (88%). The most frequent disease sites were liver (63%), subdiaphragmatic lymphadenopathy (69%), and extranodal (69%). After a reduction in the immunosuppressive treatment, the patients received their initial chemotherapy mostly with a combination of prednisolone, cyclophosphamide, vincristine, and rituximab. As soon as their general condition improved, R-CHOP was given as the standard regimen. All patients experienced severe and frequent complications during chemotherapy. Two patients had liver transplant rejection, lethal in one case. Six patients died: 4 of progression or relapse of PTLD, one after 4th liver transplantation, one of leukoencephalitis. Complete remission was obtained in 81% of patients. Ten patients (63%) are alive in complete remission after a median follow up of 6.5 years. Conclusions: Despite the clinical complexity of these patients, PTLD can be treated utilizing common lymphoma chemotherapy with treatment accommodations to poor ECOG, liver and renal dysfunctions.
Impact of bone marrow fibrosis (BMF) at diagnosis in patients with multiple myeloma (MM).
Authors: Preet Mohan , Liu Jinli , Axiotis Constantine A , Braverman Albert S , Sidhu Gurinder Singh
Published: March 2020

e19522

Background: BMF is known to occur in a minority of myeloma patients, but its incidence in American patients of African origin is not known. The impact of BMT on presenting clinical and laboratory findings, and its relationship to genetic variants has not been defined. Methods: Kings County Hospital is located in the East Flatbush section of Brooklyn, New York, where the population is mainly of African-Caribbean origin. Records and bone marrow specimens of myeloma patients who presented from 2000 through 2010 were reviewed. Degree of fibrosis was graded according to World Health Organization criteria: mild, moderate and severe. Results: Records of 113 patients were reviewed, 110 (97%) 97 of whom were African American or Caribbean; 62 (55%) were female and 51 (45%) male. Their ages ranged from 38 to 89 (median 65). Of the 27 patients with BMF (24%), 17 (63%) were female. Mild, moderate and severe BMF were present in 14 (52%), 7 (26%) and 6 (22%) patients respectively. Presentation calcium and creatinine levels were normal in all patients. Hemoglobin levels were similar (median 9.6 G/dl) in patients without BMF and in those with mild and moderate grades, the median level was 7.5 G/dl in those with severe BMF. Immunoglobulin G, A and D levels (67, 20 and 1) were similar in patients with and without BMF, but lambda light chain expression was greater in the BMF patients: 41 vs 24%. Cytogenetic data (CGD) was available in 46 patients; and abnormal in 10 (22%). All patients with abnormalities of chromosomal number were hyperdiploid. Of the 27 BMF patients CG data was available in 17, and was abnormal in 2 (12%). FISH results were normal in 23 of 25 patients, and in all of those with BMF. The fraction of the BMF and non BMF patients surviving after median follow up periods of 828 and 885 days were similar. Conclusions: BMF in this population was 24%, and severe in 5%. Female preponderance is a characteristic of MM patients of African origin, and was more marked in those with BMF. The BMF patients were characterized by more severe anemia and greater lambda light chain expression.
Is rituximab-based chemotherapy a standard practice in the treatment of B-NHLs in the developing world.
Authors: Kota Rajesh , Linga Vijay Gandhi , Gullipalli Muralidhar , Kalpathi Krishnamani , Goteke Vamshi Krishna Reddy , Maddi Rahul Narayan , Ganta Ranga Raman , Arigela Ravi Sankar , Nasaka Srividya , Gundeti Sadashivudu , Digumarti Raghunadharao
Published: March 2020

e19533

Background: B Non Hodgkin Lymphoma (B-NHL) constitutes 90% of all NHLs. Surface CD20 is expressed in most of them. Standard of care worldwide for B NHLs currently is rituximab-based chemotherapy. In the present era, still rituximab-based chemotherapy is seldom used in India. We tried to analyze the proportion of eligible patients who received rituximab during their first line treatment and their outcome. Methods: We retrospectively analyzed all the cases of NHL patients registered at our center from 2001 to 2010. We defined “Refusal to treatment” as rejection of any therapeutic intervention, “abandonment” if treatment was initiated but not completed, “lost to follow up” as patients who have completed treatment, but missed the subsequent appointments. Results: A total of 1,351 cases of NHLs were registered during 2001-2010. B-NHLs constituted 90.6%. DLBCL accounted for 78.2% of all B-NHLs followed by follicular lymphoma (14.6%). Out of the 1,216 B-NHL patients registered, less than a third (377/1216 i.e 31%) were started on treatment, rest (69%) refused treatment. Four-fifths (79.3%) of the patients could complete at least 4 cycles of the intended chemotherapy, whereas 20.7% of them abandoned treatment in between. Rituximab-based chemotherapy could be initiated in only a quarter (94/377, 24.9%) of the eligible patients, out of which 68% (65/94) completed at least 4 cycles. Chemotherapy without rituximab was initiated in the remaining 75.1% of the patients, of which 78%(221/283) could complete at least 4 cycles. Among the 65 patients who completed at least 4 cycles of rituximab-based chemotherapy, 52% (34/65) were still alive without any evidence of disease as compared to 19% (42/221) of the patients who received chemotherapy without Rituximab at a median follow up of 17 months (range 1-125 months) p<0.05. The proportion of patients who were lost to follow up with evidence of disease at their last visit in the clinic was 4%(3/65) vs. 39%(86/221), in the rituximab vs. non-rituximab-containing chemotherapy groups respectively. Conclusions: Only 7.7% (94/1216) of the eligible B-NHL patients were able to receive rituximab-based chemotherapy. A distinct survival advantage is noted in patients who received rituximab.
Multiplexed IHC analysis to enable Hodgkin lymphoma differential diagnosis on a single slide.
Authors: Weiss Lawrence , Bordwell Alexander , Corwin Alex , Henderson Dave , Hollman- Hewgley Denise , Kenny Kevin , Lazare Michael , McCulloch Colin , Seppo Antti
Published: March 2020

e19536

Background: Routine diagnosis of classical Hodgkin lymphoma is performed with a panel of immunohistochemistry markers to evaluate the biomarker expression profile of the relatively rare Hodgkin cells. One of the key challenges of this technique is that serial immunostains are used and hence it can be difficult or impossible to locate the same Hodgkin cell on adjacent slides. Given the rarity of the Hodgkin cells coupled with the number of markers that are needed for a definitive diagnosis, we developed a new technique in which a single patient slide is multiplexed with nine different antibodies . Methods: One FFPE tissue section from 11 cases was probed for the following nine biomarkers: CD30, CD15, CD45, Pax5, CD20, CD79a, OCT2, Bob1, and CD3. An initial 10x whole slide fluorescent image of CD30 was acquired and presented to the pathologist who based on this staining selected regions of interest for higher magnification (40x) imaging of the CD30 and the other antibodies. The fluorescent images acquired were processed for interpretation using an in-house developed viewing tool. The pathologist was able to view each biomarker as a standard grayscale, monochromatic image, an overlay of two or more biomarkers, or as a virtually created molecular DAB image. Results: A correct diagnosis of classical Hodgkin lymphoma vs. other was able to be made using the MultiOmyx platform in all cases. Subjectively, the pathologist noted that the novel methodology allowed for a significantly more confident assessment of marker expression on the Hodgkin cells in the seven cases of classical Hodgkin lymphoma, eliminating many issues of staining ambiguity and allowing recognition of subtle nuances of staining intensity in the Hodgkin cells. The CD30+ cells in the four other cases, three cases of B-cell lymphoma and one case of lymphocyte predominance Hodgkin lymphoma, showed a B-cell profile that was distinguishable from the classical Hodgkin cell phenotype. Conclusions: This new method of fluorescent multiplexing on a single tissue section allows more accurate interpretation of the biomarker expression profile on the same Hodgkin cell. It is likely that this paradigm can be expanded to a greater range of challenging cases in hematopathology.
Prognostic factors for overall survival in non-Hodgkin lymphomas: Nonlinear effect of continuous covariates.
Authors: Flores Claudio J. , Casanova Luis Augusto
Published: March 2020

e19538

Background: To evaluate prognostic factors in patients with primary non-Hodgkin lymphomas (NHL). Methods: We retrospectively analyzed prognostic factors (PFs) for overall survival (OS) in 2160 patients (pts) with NHL treated at INEN between 1990-2002. PFs were determinate according to Cox model with P-splines. Results: The median age was 54 years (range 14 - 96) and 51% were male. The majority of the pts had good performance status (73%, WHO 0-1). The Ann Arbor stage was I-II in 51%, III-IV in 49% and B symptoms were present in 38% of the pts. The hemoglobin (Hb) was low in 48%. Leukocytes (WBC), lymphocytes and LDH were elevated in 17.7%, 7.7% and 60% of pts, respectively. Of all patients, 709 (32.8 %) pts had died. The median follow-up was 12.6 months, with a median survival of 61.8 months and the survival rate at 5 and 10 years of 51.2 % and 41.7 % respectively. PFs identified were: age, sex, zubrod, clinical stage, Hb, leukocytes, lymphocytes and LDH. The following table shows the p-value and hazard ratio (HR). The effect of continuous covariates in the log(HR) is non-linear. The cutoff points of highest (HR >1) match the clinically defined ones, which are: age >60yrs, Hb<12g/dl and LDH >240UI/L. Both leukocytes and lymphocytes have two higher risk breakpoints: leukocytes >3x103 and >10x103, lymphocytes <20% and >60%. Conclusions: PFs for OS in our group of pts were similar to other reports in NHL. Age, Hb, leukocytes, and lymphocytes are relevant to OS, which showed a nonlinear effect in the log (HR). [Table: see text]
Identification of ephrinB2 positive vessels in non-Hodgkin lymphoma subtypes.
Authors: Cohen Kenneth Stuart , Jamali Mina , Hyjek Elizabeth
Published: March 2020

e19542

Background: Current anti-angiogenic therapies for tumors target signaling pathways such as VEGF. However, the role of alternative vascular pathways in tumor biology in general, and lymphoma biology specifically, are less well understood. Recently, the Eph receptor tyrosine kinase signaling pathway has emerged as a novel target for therapeutic inhibition. The EphB family member EphB4, and its reverse signaling ligand ephrinB2, are indispensible for developmental angiogenesis. Inhibition of ephrinB2 signaling results in impaired tumor growth in pre-clinical models. We therefore sought to determine if ephrinB2 is expressed in the microenvironment of human lymphomas and thereby represents a novel therapeutic target. Methods: We evaluated by immunohistochemistry on paraffin tissue sections expression of ephrinB2, CD34 (endothelial cells) and CD163 (macrophages) in LN biopsies from 12 cases of FL and 11 cases of DLBCL retrieved from the archives of the Department of Pathology at the University of Chicago (2000-2011). Eleven cases of follicular hyperplasia or quiescent LNs were used as controls (Cs). Slides were digitally scanned and examined both semi-quantitatively and by digital image analysis. Stained cells were quantified both in internal areas and at lymphoma-fat interfaces. Results: CD34+ microvessel densities were comparable between DLBCL and C groups but showed a significantly higher trend of interface angiogenic sprouts in FLs. Interface recruited CD163+ cell numbers were significantly higher in DLBCLs than in both FLs and Cs (p<0.0001). EphrinB2-expressing blood vessels were significantly increased in FLs but not in DLBCL. Conclusions: FLs demonstrate an increase in ephrinB2+/CD34+ vessels at the lymphoma-fat interface. In contrast, DLBCLs demonstrate no increase in ephrinB2+ vessels versus controls. However, DLBCLs were notable for increased recruitment of CD163+ macrophages at the tumor/host interface. These data represent the first analysis of ephrinB2 expression in human lymphomas and demonstrate heterogeneity between locations within a lymphoma and between histologic subtypes. Analysis of ephrinB2 in human lymphomas reveals marked heterogeneity in lymphoma microenvironmental domains.