bluuebunny/crossref_metadata_2025 huggingface dataset:
Wood-smoke exposure (WSE) as a predictor of response and survival in erlotinib-treated advanced lung adenocarcinoma (ALA) patients (pts) (ONCOLGroup study)
Authors: Castro C. , Cardona A. F. , Reguart N. , Carrasco-Chaumel E. , Otero J. M. , Carranza H. , Vargas C. , Reveiz L. , Torres D. , Blumenschein G.
Published: August 2020

e19052

Background: There is consistent information suggesting that long-term WSE constitutes a risk factor for lung cancer. More than 50 years of WSE was associated with non-small cell lung cancer (NSCLC). In Colombia the prevalence of WSE in areas having less economic development is approximately 24%. The aim of the study was to evaluate WSE as a predictor of response and survival in ALA pts. Methods: This study included 168 pts with ALA treated between 2002 and 2007 in four referring hospitals of Bogotá. Retrospectively, we estimated overall response rates (ORR), time to progression (TTP) and overall survival (OS) in a subgroup of pts with significant WSE (exposure >5 years for at least 4 hours/day) treated with erlotinib, and compared them with the non-WSE population treated with the same compound. Results: Median age was 66 years (range, 29–96), 53% were female, 39% had never been smokers, 24% of all cohort pts had been considerably exposed to WS and 45 pts had received erlotinib during disease treatment (as 2nd or 3rd line). Sixteen of these pts (F11/M5, PS ≥70% 9 pts) had been exposed to WS and 29 not so (F17/M12, PS ≥70% 22 pts); 10 pts having WSE had been smoking for a mean of 14pk/yr history. ORR to erlotinib was 7% and 32% in pts with and without WSE respectively (p = 0.02). TTP was significantly higher in pts treated with erlotinib with no history of WSE (4.9 mo. vs 1.7 mo., p = 0.034). and in those who had received this compound as second-line (vs erlotinib used as third line, p = 0.044). Among pts with WSE history, OS was 6.6 mo. (range, 5.8–7.3) for those treated with Erlotinib and 12.7 mo. (range, 10.2–17) for those not treated with this compound (p = 0.04). Multivariate analysis was carried out for determining the factors influencing mortality between pts with WSE; only PS (HR: 4.6, 95%CI: 1.2–29, p = 0.050) and gender (HR: 3.6, 95%CI: 2.7–18, p = 0.036) were significant. Conclusions: WSE was associated with a poorer response and survival in ALA pts treated with erlotinib in Colombia.

No significant financial relationships to disclose.
Subanalyses of the outcome of two carboplatin-based regimens in the treatment of advanced NSCLC
Authors: Hansen O. , Schytte T. K. , Hansen K. H. , Sørensen P.
Published: August 2020

e19067

Background: Recent data suggest that various chemotherapy regimen may have different efficacy in subsets of patients (pts.) with advanced NSCLC. For that reason we studied if it was also the case for two Carboplatin regimens, Carboplatin-Vinorelbine (CV) and Carboplatin-Gemcitabine (CG), which were used as standard treatments in our centre for two periods Methods: From 1998–2007, 800 consecutive pts. were treated with a 3-weekly schedule of C, AUC=5, plus either V (30 mg/m2 d.1+8), or G (1000 mg/m2 d.1+8) for 4–6 cycles. CV was used as the standard regimen 1998 - 2003, and CG, 2004 - 2007. All pts. were followed to death, and most data have been prospectively recorded, but supplemented with retrospectively collected data from pts. files. The endpoint of this study was crude survival. The data was analysed according to performance status (PS), gender, age, and histology (adenoca., squamous, other NSCLC) Results: 313 pts. were treated with CV, 487 with CG. Median, 1 yr and 2 yr survival was for CV: 8.6 m, 34% and 15%, and for CG: 8.6 m, 37% and 12%, p=0.32. Analysed by histology, adenoca.'s had better median survival, 9.7 m., than non-adenoca., 8.1 m, p= .002, females better than males 10.0 m. vs. 7.9 m., p=.008, and PS 0–1 better than PS=2, 10.0 m. vs. 4.7 m. (p=.000). Age was of no importance. Cox-analyses was performed separately in the two genders. In females, PS 0–1, adenoca. and CG regimen were statistically significant favourable prognostic factors while in males only PS 0–1 were of significance. In the 379 pts. with adenoca., PS and gender were of significance while the chemotherapy was of borderline significance (p=.06). In non- adenoca.'s, only PS was of significance Conclusions: While CV and CG were overall equal effective in the treatment of NSCLC, CG may be the superior regimen in females, and in adenoca.'s. No trends for differential efficacy was found in any other subset of patients

[Table: see text]
Current trend in incidence of severe interstitial lung disease (ILD) due to gefitinib in Japan
Authors: Goto K. , Kenmotsu H. , Nishiwaki Y. , Kubota K. , Ohmatsu H. , Niho S. , Yoh K. , Nagai K. , Saijo N.
Published: August 2020

e19075

Background: Although gefitinib is a promising agent for the treatment of advanced non-small cell lung cancer, ILD occurs in Japanese patients and sever ILD sometimes becomes fatal toxicity. ILD has been reported to be associated with preexisting ILD, smoking, and poor performance status. On the other hand, it has been reported that female gender, adenocarcinoma, non-smoker, and EGFR mutation are associated with sensitivity to gefitinib. Methods: To investigate the trend in incidence of severe ILD and patient characteristics receiving gefitinib, a total of 751 patients who were administered gefitinib in National Cancer Center Hospital East between 2002 and 2008 were retrospectively reviewed. To investigate how oncologists avoid administering gefitinib to patients with preexisting ILD, pretreatment chest CT films of all patients were also reviewed by two thoracic radiologists. Results: The patient number who received gefitinib in 2002/2003/2004/2005/2006/2007/2008 were 134/141/88/93/125/98/72, respectively. In these patients, percentages of female were 36/43/42/55/59/52/54%, adenocarcinoma 76/78/93/88/95/93/92%, non-smoker 35/30/40/53/49/48/46%, respectively. Almost all of the patient receiving gefitinib was recently restricted to adenocarcinoma. Grade 3–5 severe ILD was observed in 1.9% of all patients. However, the incidence rate of sever ILD were decreased as 3.0/2.8/2.3/1.1/0.8/1.0/1.4%, respectively. The rates of patients with preexisting ILD were also decreased as 22/14/15/5/2/3/6%, respectively. Conclusions: The correct information about efficacy and severe ILD about gefitinib influenced patient selection by oncologists, and it is reasonable to select more effective and safe patients in Japan. It is estimated that the incidence rate of severe ILD should be consequently controlled by the spread of these information.

No significant financial relationships to disclose.
Functional profiling in stage IV NSCLC: A phase II trial of individualized therapy
Authors: Nagourney R. A. , Blitzer J. , Deo E. , Nandan R. , Schuman R. , Asciuto T. , Mc Connell D. , Paulsen M. , Evans S.
Published: August 2020

e19079

Background: The introduction of new classes of agents has improved survival in NSCLC yet the accurate selection of candidates for these often costly & toxic drugs remains a challenge. Genomic platforms have identified several prognostic & predictive factors e.g. ERCC1, RRM1/2, EGFr mutations but the comparatively small number of known cellular analytes has limited their broad application. Methods: To address the complexity and redundancy of cell-death signaling pathways, we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, R. Curr Treat Options in Oncol. 2006) to select therapies for chemo- naïve pts with metastatic NSCLC. This functional platform uses morphologic and metabolic endpoints to gauge cellular response to drugs & signal transduction inhibitors in human tumor microspheroids isolated from surgical biopsies. Modified Z-scores & synergy analyses (median-effect) were used to identify the ex vivo best regimen (EVBR) for each pt. from FDA-approved NSCLC drugs. All pts signed informed consent. Results: 22/25 (88%) pts are evaluable with 3/25 (12%) excluded, 1 for CVA & 2 inadequate PFS at time of treatment. There were CR = 2/22 (9%); PR = 10/22 (45%); SD = 9/22 (41%) & PD = 1/22 (5%) for an ORR = 12/22 (54%) & CBR = 21/22 (95%). 1st line EVBR were CDDP/Gemcitabine 10/25 (40%); CDDP/Taxane 7/25(28%); Erlotinib 5/25(20%); CDDP/Vinorelbine 1/25 (4%); CDDP/Irinotecan1/25(4%) & Ifex/Gemcitabine1/25(4%). Six of 22 (27%) stage IV pts were converted to surgical and/or radiation candidates by therapy. Accrual continues with current TTP ranges from 1.2–35+ months and OS from 1.7 to 46+ months. Conclusions: EVA/PCD ORR in Stage IV NSCLC of 54%, many durable, compares very favorably with reports in this population. By examining drug-induced cell death events in native-state microspheroids, this platform has the unique capacity to capture stromal, vascular and inflammatory cell interactions with tumor cells, now known to be crucial for clinical response prediction. EVA/PCD analysis in NSCLC warrants further evaluation. Supported by the Memorial Medical Center Foundation of Long Beach.

[Table: see text]
Trends in chemotherapy for elderly patients with non-small cell lung cancer: The experience of one institution
Authors: Kim Y. , Nishiwaki Y. , Yoh K. , Niho S. , Goto K. , Ohmatsu H. , Kubota K. , Saijo N.
Published: August 2020

e19081

Background: In approximately the year 2000, the results of a number of important studies of non-small-cell lung cancer (NSCLC) were published. These included the first elderly-specific phase III trial and phase III trials showing a survival benefit for docetaxel when used as second-line chemotherapy. These results had a significant impact on clinical practice relating to advanced NSCLC in elderly patients. Methods: Between July 1992 and December 2003, 223 patients with NSCLC aged ≥70 years received chemotherapy alone as their initial treatment at the National Cancer Center Hospital East. These patients were divided into 2 groups: those that began treatment between 1992 and 1999 (group A) and between 2000 and 2003 (group B). The details of chemotherapy regimens and outcomes were compared. Results: In group A, 83% of patients received platinum-based chemotherapy, two-thirds of these regimens comprised platinum[[Unsupported Character -  ]]plus second-generation combination chemotherapy. In contrast, although 55% of patients received platinum-based chemotherapy in group B, 41% of patients received non-platinum-based chemotherapy. Among patients in group B, performance status was significantly associated with the selection of platinum-based or non- platinum-based chemotherapy; age was marginally associated with this selection. In group A, second-line chemotherapy was administered to only 4 patients (5%) and no patients received third-line chemotherapy. In group B, second-line and third-line chemotherapy was administered to 62 (42%) and 22 (15%) patients, respectively. Median survival time (MST), 1-year survival rate, and 2 year-survival rate were 6.7 months, 14%, and 7%, respectively, in group A, and 8.1 months, 35%, and 20% in group B (p = 0.0109). However, these differences disappeared when patients treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) were removed from the analysis (6.7 months in group A vs. 6.9 months in group B, p = 0.3684). Conclusions: In and after the year 2000, chemotherapy regimens changed greatly and survival of elderly patients significantly improved. However, the improvement in survival seems to be due mostly to the use of EGFR-TKI treatment.

No significant financial relationships to disclose.
Erlotinib and bevacizumab in chemotherapy-naive performance status 2 patients with advanced non-small cell lung cancer
Authors: Al Baghdadi T. , Hanna N. , Bhatia S. , McClean J. , Johnson C. , Yu M. , Taber D. , Harb W.
Published: August 2020

e19082

Background: Poor performance status is a negative prognostic variable for survival and a risk for increased toxicities with standard chemotherapy. A phase 2 study combining erlotinib (E) and bevacizumab (B) demonstrated encouraging efficacy in the treatment of recurrent NSCLC with acceptable toxicity. We, therefore, tested this regimen in untreated PS 2 patients with advanced NSCLC. Methods: Single-arm phase 2 trial in treatment-naïve patients with advanced non-squamous NSCLC and either a PS of 2 or age >75. Only patients eligible for bevacizumab per label were allowed onto study. Patients received E 150 mg orally daily and B 15 mg/kg IV on day 1 every 21 days for up to 6 cycles. The primary end-point was the rate of non progressive disease at 4 months (alternative hypothesis P>60%). Other end-points included overall survival, progression free survival (PFS), toxicity evaluations and patient-reported PS (PRPS) measures. Results: 25 patients were enrolled. Patient characteristics: 56% female, median age 77 years (range: 52–90); 88% stage IV; 92% were PS 2; 20% were never or remote smokers (> 30 years) The PRPS was 1, 2, 3 in 32%, 52%, 8% respectively with data on 2 patients missing. The rate of non-progression at 4 months was 40%; overall best response: 5% PR, 40% SD, 50% PD and 5% unevaluable; median PFS 2.6 months, 95% CI (1.3–5.1); MST 5.8 months, 95% CI (3.8- 8.7). 2 patients had G3 rash. G3 diarrhea, G3 hemorrhage, G3 proteinuria, G3 duodenal ulcer and G3 pneumonitis each developed in one patient. Conclusions: E + B is an active regimen with an acceptable toxicity profile; however, this study did not meet its’ primary endpoint. Further study of this combination will not be pursued in the Hoosier Oncology Group for this patient population.

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Carboplatin dosing by predictive formulae and factors related to its myelosuppressive toxicity
Authors: Ayirookuzhi S. J. , McLarty J. , Mansour R. , Mills G. M.
Published: August 2020

e19101

Background: Carboplatin is a commonly used drug in stage III/IV non-small cell lung cancer (NSCLC). Its dose in typically calculated with the Calvert equation that uses the glomerular filtration rate (GFR) from various predictive formulae such as MDRD, Cockroft-Gault, Jeliffe and Wright as well as the targeted area under the curve (AUC) for carboplatin. Myelosuppression is a common toxicity of carboplatin and this study aimed to assess the relationship between dosing and toxicity as well as if there would be any significant difference in dosing based on calculation of GFR from the above formulae in our patient population. Methods: Data from patients with Stage III and IV NSCLC seen between 1/1/99 to 12/31/2007 were analyzed. Patients who received concurrent radiation, who died before the first cycle was completed, as well as patients with missing lab values were excluded. Only the first cycle of the carboplatin based regime was used for analysis with nadir platelets, hemoglobin and wbc's used as endpoints. SPSS software was used for statistical analysis including Pearson correlation, ANCOVA, independent t-tests as well as multivariate linear regression models. Results: Of the 216 patients initially abstracted for analysis only 132 patients were analyzable. Demographically 71 were Caucasian and rest were African-American while 92 were male. The carboplatin dose calculated from all four formulae were highly correlated (p < 0.0001). The drop in the three cell counts were correlated to each other (p< 0.05), particularly the drop in platelet count with other two cell counts. The correlation between the drop in wbc and drop in hemoglobin approached significance (p=0.075). The nadir wbc was significantly associated with BSA (p=0.004), wbc level at baseline (p< 0.000) and approached significance for carboplatin dose (p=0.059) by ANCOVA analysis, while significance was not reached for nadir platelets or nadir hemoglobin. Conclusions: The different predictive equations resulted in similar doses of carboplatin that were statistically significant. BSA correlated significantly with myelosuppression while carboplatin dose only approached significance.

No significant financial relationships to disclose.
Phase II study of cladribine with rituximab (R-2-CdA) therapy in patients with relapsed indolent B-cell non-Hodgkin's lymphoma
Authors: Nagai H. , Kusumoto S. , Sawada K. , Yamaguchi M. , Takayama N. , Kinoshita T. , Motoji T. , Omachi K. , Ogura M. , Hotta T.
Published: August 2020

e19501

Background: Although cladribine has been reported to be one of active purine analogs against indolent B-cell non-Hodgkin's lymphoma (B-NHL), there are few reports of combination usage of cladribine and rituximab. We conducted a multicenter phase II study to investigate efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy for relapsed indolent B-NHL. Methods: Eligibility criteria were as follows: relapsed pts with indolent B-NHL from systemic chemotherapy, ages less than 75 years; PS 0–2 by ECOG's scale. Patients received 0.09mg/kg of cladribine intravenously (2 hrs infusion) on days 1 to 5 and 375mg/m2 of rituximab intravenously on days 1 and 15, every 4 weeks, for a total of 4 cycles. Primary endpoint was overall response rate (ORR). Secondary endpoints were % complete response (%CR), 2 years progression free survival (2-y PFS), and 2 years overall survival (2-y OS). Results: A total of 20 out of 45 planned patients were enrolled and received R-2-CdA therapy from Apr 2005 to Jul 2007. Their median age was 58.5 (42–72), and the median number of prior regimens was 2 (1–3). Histologies included 16 follicular lymphomas, 2 MALT lymphomas, 1 nodal marginal B cell lymphoma, and 1 lymphoplasmacytic lymphoma. Fifteen pts (75%) were previously treated with rituximab. The ORR was 90% with 70% of % CR. Median PFS was 20.1 months (5.6–32.9 months) at a median follow-up time of 27 months. 2-y PFS and 2-y OS were 63.2% (95%CI, 28.1–67.8%), and 89.5% (95%CI, 69.8–97.2%), respectively. Severe neutropenia and thrombocytopenia of grade 3 or 4 were observed in 15% and 10% respectively. Conclusions: R-2CdA therapy was demonstrated to have high activity with durable PFS and acceptable toxicity in relapsed indolent B-NHL, even if patients were previously treated with rituximab. Although a large-scaled further trial remains to be needed, R-2-CdA therapy could be a good option of salvage therapy in relapsed indolent B-NHL.

No significant financial relationships to disclose.
A phase II study of a 1-hour infusion of romidepsin combined with bortezomib for multiple myeloma (MM) patients with relapsed or refractory disease
Authors: Berenson J. R. , Yellin O. , Mapes R. , Eades B. , Abaya C. D. , Strayer A. , Nix D. , Swift R. A.
Published: August 2020

e19508

Background: Nonclinical studies have demonstrated that histone deacetylase inhibitors (HDACi) significantly reduce the growth of MM cells and enhance cytotoxicity of the proteasome inhibitor bortezomib (Velcade). Romidepsin, a pan-HDACi, has previously shown activity for patients (pts) with relapsed or refractory MM when administered as a 4-hr infusion in combination with dexamethasone and bortezomib. Methods: This open-label, multi-center, phase II study (GPI-08–0006) was initiated to evaluate the activity and safety of a 1-hr infusion of romidepsin in combination with bortezomib for MM pts with relapsed or refractory disease and to evaluate the safety and single dose pharmacokinetics (PK)/pharmacodynamics of romidepsin in the first 5 pts. Pts received 10 mg/m2 romidepsin on days 1, 8 and 15 and 1.0 mg/m2 bortezomib on days 1, 4, 8 and 11 of a 28-day cycle. PK sampling and triplicate ECGs were performed at 0, 0.25, 0.5, 1, 2, 3, 4, 6 and 24 hrs after initiation of the first 1-hr infusion of romidepsin. Results: To date, 5 pts have been enrolled (median age 68 [range, 65–72]) 2 pts who relapsed from recent bortezomib-containing regimens experienced minimal responses after 2 cycles. 2 pts have experienced grade 3 thrombocytopenia. No pt had a QTcF value of >480 ms the mean change in QTcF from baseline to Cmax was 4.2 ms (-10 to 13). Values for PK parameters are included in the table . When compared with data from pts who were treated with a 4-hr infusion of 14 mg/m2, the Cmax of the 1-hr infusion of romidepsin 10 mg/m2 was ∼ 20% higher and exposure (AUC0–24hr) was reduced by 70%. Conclusions: Preliminary data suggest that the 1-hr infusion of romidepsin combined with bortezomib is active for pts with MM relapsed or refractory to bortezomib. Based on the initial incidence of grade 3 thrombocytopenia and PK data, additional pts are being treated on the same schedule but with a reduced dose of romidepsin (8 mg/m2). This study continues to enroll pts.

[Table: see text]

[Table: see text]
CD3 immunotoxin therapy of cutaneous T cell lymphoma
Authors: Frankel A. E. , Woo J. , Zuckero S. L. , Mankin A. A. , Grable M. , Mitchell K. , Lee Y. , Neville D. M.
Published: August 2020

e19511

Background: T cell lymphomas represent 12% of lymphoma cases in the U.S. Cytotoxic chemotherapies, radiation therapies, monoclonal antibodies, transcription modulators and topical therapies yield remissions, but over half of patients relapse and die with progressive disease. Patients ineligible for allogeneic transplant need additional therapeutic options. One class of T cell directed agents are immunotoxins composed of protein synthesis inactivating peptide toxins covalently linked to antibodies or hormone ligands. We prepared a new immunotoxin, A-dmDT390-bisFv(UCHT1) composed of the catalytic and translocation domains of diphtheria toxin fused to two single chain antibody fragments reactive with an acidic loop on the extracellular domain of CD3epsilon. We prepared a clinical batch of drug and obtained FDA approval for a phase I trial (IND#100712). Methods: Cohort of three-six CTCL patients were treated with immunotoxin via 15min IV infusion twice daily for four days at 2.5–5ug/kg. CTCAEv3.0 toxicity grading, blood samples counts, chemistries, CMV/EBV PCR, PK, immune response and flow cytometry, and disease assessments by CT scans, skin mapping and bone marrow biopsies were done. Results: Six patients received all eight 2.5ug/kg doses. Toxicities were mild- moderate with fever, chills, nausea, transaminasemia, hypoalbuminemia, lymphopenia and reactivation of EBV and CMV. Side effects responded to antipyretics, anti-emetics, albumin infusions, rituximab and valgancyclovir. Lymphopenia was marked at the end of treatment (99.9% reduction) and was followed by partial recovery at two weeks. Circulating T regulatory cells doubled. Cmax occured 5 min post-infusion and was 18ng/mL. Half-life was 49 min. All patient had anti-immunotoxin antibodies at a median of 1.3ug/mL which increased after 30 days to 9–1700ug/mL. Two of five evaluable patients had PRs lasting one and 6+ months. Conclusions: This novel immunotoxin has dramatic clinical activity even at the lowest dose in CTCL patients and merits applications at higher doses in CTCL and other CD3+ T cell leukemia/lymphoma patients. The lymphodepletion with recovery of T regulatory cells suggests the drug may be beneficial for immunosuppression of T cell autoimmune disorders.

No significant financial relationships to disclose.
Prognostic value of quantitative image analysis (QIA) for determination of proliferative index in mantle cell lymphoma (MCL) treated with sequential chemotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR)
Authors: Schaffel R. , Hedvat C. , Teruya-Feldstein J. , Portlock C. S. , Moskowitz C. H. , Zelenetz A. D.
Published: August 2020

e19522

Background: Gene expression studies have demonstrated that the proliferation signature is the most important factor in determination of outcome in MCL. However, visual assessment of immunohistochemical staining is not standardized. QIA of MIB-1/Ki67 staining may have a greater reliability for determination of the PI. We tested the agreement between manual counting (MC) and QIA and its prognostic value in patients with MCL. Methods: 105 patients with MCL underwent therapy for de novo MCL, of these, 66 had slides stained with MIB-1 for the analysis. The PI was determined in three ways: 1) estimation by a hematopathologist using a microscope (manual count, MC); 2) visual estimation by an independent hematopathologist after whole slide digitization; and 3) QIA software (color deconvolution algorithm). The survival analysis was restricted to 47 patients that were treated with sequential therapy followed by upfront consolidation with HDT/ASCR. Results: A median of 612,394 cells per slide were analyzed by QIA. There was a good correlation between the QIA and both the MC under the microscope and digital image (0.9061, P<0.001 and 0.9336, P<0.001; Spearman test) as well as between the pathologists (0.897, P<0.001). Based on a 30% cutoff, the agreements (kappa test) were: interobserver, 0.6 (80% of slides); between QIA and MC of visual image, 0.86 (94% of slides); and between the QIA and MC using standard microscopy, 0.72 (86% of slides). In the survival analysis, the median PI was 25% (0.7% to 74%). By QIA, 27 patients had a low PI (<30%) and 20 patients had a high PI. At a median follow-up of 4.4 years, the 5 year overall survival (OS) and event free survival (EFS) were inferior in the high PI cohort (66% v 93%, P=0.003 and 0 v 71%, P<0.001, respectively). In a Cox regression analysis, both OS and EFS were significantly associated with PI and not associated with either MIPI or inclusion of rituximab during therapy. No event was reported after 4.7 years of follow-up in the low-PI group. Conclusions: Digital image analysis of MIB-1/Ki67 staining is highly reproducible and further validates the prognostic significance of a high PI in MCL using a threshold of 30%.

No significant financial relationships to disclose.
A retrospective review of pegylated liposomal doxorubicin (PLD), bortezomib, and dexamethasone (DVD) for relapsed or refractory (R/R) multiple myeloma (MM)
Authors: Waterman G. N. , Yellin O. , Swift R. A. , Hilger J. , Berenson J. R.
Published: August 2020

e19523

Background: Preclinical data show that PLD and bortezomib demonstrate synergistic anti-MM effects. Clinical trials have demonstrated the efficacy of this combination for MM patients (pts) as well as its superiority to bortezomib alone. In vivo studies have shown that more frequent administration of low-dose PLD produces enhanced anti-MM effects with better tolerability compared to weekly standard doses of PLD. Thus, a low dose PLD dosing schedule was evaluated in combination with bortezomib and dexamethasone for pts with R/R MM. Methods: This retrospective analysis sought to evaluate the DVD regimen for pts with R/R MM. Twenty pts who had received and failed at least one prior treatment for MM were studied. Treatment consisted of intravenous administration of 40 mg dexamethasone, 1.0 mg/m2 bortezomib and 5.0 mg/m2 PLD on days 1, 4, 8 and 11 of a 28-day cycle. Pts ranged in age from 43–81 years (median 65), and had received between 1–14 prior therapies (median 5). Baseline disease stage was: 6 (I), 7 (II), and 7 (III). Elevated serum creatinine levels at baseline were found in 30% of patients. Results: The objective response rate (ORR) was 50%, which included 1 complete response (5%), 1 very good partial response (5%), 4 partial responses (20%), and 4 minimal responses (20%). Sixteen pts had previously received bortezomib-containing regimens and 6 (38%) responded. Among the entire cohort, the duration of response was 2+-19+ months (mo) (median 7 mo). Six pts had stable disease (30%) lasting between 5–9 mo (median 9 mo). Progression-free survival was 1+-19+ mo (median 8 mo). The regimen was well tolerated with a single mild case of transient hand and foot syndrome and 10 pts developed grade 1 or 2 peripheral neuropathy. One pt discontinued the regimen due to an adverse event (AE; 5%). The median overall survival was 17 mo (range 1+-33+ mo). Conclusions: Patients treated with the DVD regimen in this study who had failed many prior regimens (median 5) with progressive disease demonstrated a high response rate (50%). In addition, there were few significant or drug-related AEs. Because of these encouraging results, we are now evaluating this regimen in a phase 2 clinical trial in the frontline setting.

[Table: see text]
Elevated troponin and abnormalities of cardiac structure and function in AL cardiac amyloidosis
Authors: Apridonidze T. , Steingart R. , Comenzo R. L. , Hoffman J. E. , Goldsmith Y. , Liu J.
Published: August 2020

e19524

Background: Patients with systemic amyloidosis involving the heart have generally a poor prognosis. Elevated cardiac troponin (cTn) has been shown to predict poor survival in patients with AL cardiac amyloidosis (CA). However, cardiac structure and function associated with an elevated cTn in patients with CA remains uncertain. Methods: Eighty patients with CA who had an echocardiogram and cTnI measured at the time of diagnosis between March 1997 May 2008 were included in the study. The patients were divided into 2 groups: normal cTnI ( <0.06 ng/ml, n = 28) or elevated cTnI (≥0.06 ng/ml; n = 52). Results: The elevated cTnI group was slightly older with higher brain natriuretic peptide (BNP) level and creatinine clearance than the normal cTnI group. There was a trend towards higher prevalence of congestive heart failure (CHF) in the elevated cTnI group than the normal group at time of diagnosis. The elevated cTnIgroup had thicker interventricular septum and higher left atrial (LA) volume than the normal group. LV ejection fraction, left atrial systolic force (LASF) and stroke volume were lower in the elevated cTnI group than the normal group. Mean survival was significantly shorter in the elevated cTnI group than the normal group (10 vs. 47 months). Conclusions: Elevated troponin in patients with AL cardiac amyloidosis is associated with worse left atrial and ventricular structure and function. The raised troponin level reflects myocardial injury due to the amyloid deposition and correlates with more abnormal alteration of cardiac structure and function. Routine measurement of troponin is useful in identifying high risk patients with CA.

[Table: see text]

No significant financial relationships to disclose.
SEER analysis of subcutaneous panniculitis-like T-cell lymphoma (SPTL)
Authors: Martin M. G. , Cashen A. F.
Published: August 2020

e19527

Background: The uncommon nature of SPTL has hampered its clinical characterization. The EORTC described 83 cases of SPTL across 8 centers and suggested a difference in prognosis between patients with alpha/beta (AB) SPTL, who were predominantly younger (median age 36 y) and those with gamma/delta (GD) SPTL, who had a median age of 59 years (1–Blood 2008; 111: 838–45). But regional differences in the frequency of SPLT have also been suggested, with its frequency >2x higher in North America than Europe (2–J Clin Oncol 2008 26: 4121–30). We hypothesized that there may be differences in the presentation between SPTL in Europe and North America. Methods: Analysis of the SEER 17 Nov 2007 (1973–2005) database was conducted with SEER Stat version 6.4.4 and GraphPad Prism 5. Cases of SPTL were defined by the ICD-O-3 code 9708. We also analyzed outcomes for patients < and ≥ 50y at diagnosis. Results: 64 patients were identified with SPTL. The median age was 53y (range 2–83); 28 were <50y and 36 were ≥50y. 19 (30%) patients were male, 45 were female; 44 (69%) patients were white, 13 were black and 7 were Asian. Stage was available on 27 patients: 16 (59%) were Stage I/II and 11 were stage III/IV. There was no difference in gender, ethnicity or stage distribution between those < 50 and ≥ 50. Information on B symptoms was available on 20 patients, 11 (55%) of whom had B symptoms. 5-year lymphoma specific survival was 51%; 5-year OS was 41%. Median OS for patients < 50 was 60 months compared to 12 months for patients ≥50 (G-B-W p=0.0183). Lymphoma specific survival was also significantly longer in the younger patients (G-B-W p=0.0015). Conclusions: In the SEER database, outcome of SPTL is strongly correlated with age. This result suggests a different biology between younger and older patients with SPTCL, possibly because the AB- subtype is more prevalent in younger patients, as reported by the EORTC. As well as differences in the overall frequency of SPTL (2), there may be geographic differences in the distribution of subtypes.

[Table: see text]

No significant financial relationships to disclose.
Systematic assessment of potential cardiac effects of the novel histone deacetylase (HDAC) inhibitor romidepsin
Authors: Cabell C. , Bates S. , Piekarz R. , Whittaker S. , Kim Y. , Godfrey C. , Schoonmaker C. , McCulloch W. , Nichols J. , Burris H. A.
Published: August 2020

e19533

Background: Romidepsin is a novel pan-HDAC inhibitor with single-agent activity in T-cell lymphoma. HDAC inhibitors reportedly have cardiovascular effects, in particular, QTc prolongation. To systematically and rigorously evaluate the potential cardiac effects of romidepsin, a cardiac safety monitoring plan was developed after discussions with the FDA. Methods: The effect of romidepsin on the change from baseline QTcF (Fridericia's correction) at key pharmacokinetic and pharmacodynamic (PD) time points was investigated. ECGs from 110 pts with advanced malignancies in 3 open-label, clinical studies of romidepsin 14 mg/m2 administered on days 1, 8 and 15 of a 28 day cycle were evaluated by blinded, independent assessors. Results: A mean 2.7 msec increase (90% confidence interval [CI]: 0.2, 5.3) in QTcF interval from a baseline post-antiemetic administration to after infusion of romidepsin was measured. A subanalysis of 74 patients (pts) evaluated QTcF from pre-antiemetic to post-romidepsin showed a mean change in QTcF of 5.0 msec (90% CI: 2.3, 7.7). Thus, antiemetic comedications likely accounts for a portion of the clinically apparent QTc effect. The QTc returned to baseline within 48 hrs. No absolute QTc values >480 msec and no QTc changes >60 msec were observed. No relationship was observed in an analysis of romidepsin plasma concentration versus QT changes. Mean heart rate (HR) increased 10.1±9.0 bpm after romidepsin administration, with a return to baseline by 24 hrs. Several treatment-emergent morphological changes in ECGs (including T wave and ST-segment) were reported. Many of the ECG morphologic abnormalities (determined by automated machine reading) were also observed at baseline. These ECG changes were transient and were not associated with functional cardiovascular changes or with symptoms. Conclusions: Romidepsin has a slight effect on the QT interval but rigorous ECG evaluation found this effect to be mild, below the threshold of regulatory and clinical concern, and not associated with any observed clinical cardiovascular events. Concentration response modeling found no PD relationship between romidepsin concentration and changes in QTcF, but did suggest a relationship between romidepsin concentration and HR.

[Table: see text]
Relationship between efficacy of denileukin diftitox (Dd) and antibody development in cutaneous T-cell lymphoma (CTCL): An analysis of two phase III studies
Authors: Acosta M. , Duvic M. , Lopez-Anaya A.
Published: August 2020

e19534

Background: Dd is a novel IL-2 receptor-targeted recombinant fusion protein approved for persistent/recurrent CTCL expressing CD25. The effect of antibody titers on efficacy in CTCL was assessed in 2 phase III studies (11 & 14). Methods: Dd doses were 9 or 18 mcg/kg daily for 5 days, repeating every 21 days, up to 8 courses. Serum samples were collected prior to Dd infusion on day 1 of courses 1, 3, 5, and 7. Immune response to Dd was assessed using 2 enzyme-linked immunoassays: 1 for anti-IL-2 antibody (Ab) and the other for anti-Dd Ab. Immunogenicity data reflect percentage of subjects whose test results were considered positive for antibody to the intact Dd fusion protein. Results: In Study 11, 66% of subjects tested positive for anti-Dd Ab at baseline, possibly due to prior exposure to diphtheria toxin or its vaccine. In both studies, and for both doses, rapid increases in Ab titers were observed in nearly 100% of subjects from courses 1 to 3 (∼650-fold, 11; >=625-fold, 14). After 3 treatment courses, mean Ab levels stabilized and did not change appreciably with time. Pharmacokinetic (PK) parameters (Cmax and AUC) decreased substantially during the same period, but no relationship between Ab formation and clearance was identified. Low Spearman Correlation coefficient values indicated lack of a significant association (i) between the pre-treatment or treatment-related Ab levels and (ii) between PK changes for subjects who responded and subjects who did not respond. Of subjects positive for Ab at baseline, 43% (27/63) and 38% (13/34) responded to treatment, as compared to 50% (16/32) and 54% (7/13) for subjects who had no detectable Ab at baseline in Studies 11 and 14 respectively. There appeared to be higher incidences of response in subjects with lower initial Ab titers. Conclusions: In the studies analyzed, antibody formation in response to Dd exposure did not appear to compromise efficacy for treatment of CTCL.

[Table: see text]
Unexpected toxicity (UT) and opportunistic infections (OI) after rituximab-containing therapy for non-Hodgkin's lymphoma (NHL)
Authors: Hentrich M. , Gerl A. , Lutz L. , Karthaus M. , Schiel X.
Published: August 2020

e19546

Background: Rituximab (R) is increasingly used for the treatment of B-NHL. Most adverse events are mild to moderate. In rare cases, however, R may be associated with severe UT and OI. Methods: The records of consecutive pts treated at 2 institutions from 01/06 to 12/08 with R-containing chemotherapy or R-maintenance therapy (R-M) for NHL were analyzed for severe UT and OI. UT was considered as related to R if it could not be explained otherwise. Results: 99 pts were included in the cohort study. Pts received a median of 6 cycles (range 1 - 18) of R. A total of 517 cycles of R were evaluable for OI or UT. 7 of 99 pts (7%) (2 females, 5 males) with a median age of 69.5 yrs (range 41–76) experienced UT (n=4) or OI (n=3). UT consisted of interstitial pneumonitis (IP) in 2 pts after 8 and 6 cycles of R-CHOP for diffuse large cell lymphoma (DLCL), a case of congestive heart failure (NYHA III°) after 6x R-CHOP + 2x R-M for follicular lymphoma (FL) and a case of grade 4 pancytopenia lasting for 22 days following 2x R-FC for chronic lymphocytic leukemia. IP completely resolved after initiation of prednisone (n=1) or under empiric antimicrobial therapy (n=1). Congestive heart failure improved under appropriate therapy and the pt received 2 more cycles of R-M. Pancytopenia slowly recovered under therapy with G-CSF, R was terminated. OI consisted of pneumocystis jirovecii pneumonia after 5x R-CHOP-14 for DLCL, Epstein-Barr-virus (EBV)-associated hepatitis after 5x R-CHOP-21 for relapsed FL and generalized herpes zoster following 6x R-bendamustine (RB) + 1x R-M for recurrent BALT-lymphoma. R was restarted in the latter 2 pts. Infections resolved under antimicrobial therapy. EBV-hepatitis improved spontaneously. Moreover, 2 pts were transferred to us for therapy of enterovirus-induced encephalitis after 6x R-CHOP-21 + 2x R-M for FL (n=1) and cerebral toxoplasmosis in a pt heavily pretreated with R-containing therapy for relapsed mantle cell lymphoma (n=1). Conclusions: Severe UT and OI are rare but potentially fatal complications. Awareness of UT/OI, rapid diagnostic proceedings and, whenever possible, initiation of therapy are essential. In selected cases reexposure of R may be feasible.

No significant financial relationships to disclose.
The usefulness of interphase fluorescence in situ hybridization at diagnosis of myeloma in addition to metaphase cytogenetics
Authors: Park S. , Kim C. , Kim H. , Hong D. , Lee S. , Won J. , Park H. , Bae S. , Lee Y. , Kim E. , Jung Y.
Published: August 2020

e19558

Background: Multiple myeloma is characterized by the accumulation of malignant plasma cells within the bone marrow and regarded as incurable, but remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants. The clinical heterogeneity of myeloma is dictated by the cytogenetic aberrations present in the clonal plasma cells. Fluorescence in situ hybridization (FISH) overcomes the limitations of standard cytogenetics and allows for the detection of numerical and structural chromosomal abnormalities in both metaphase spreads and interphase nuclei. Methods: We evaluated the chromosome abnormalities in 34 MM patients using conventional cytogenetics and interphase FISH with 6 probes such as IGH/CCND1, IGH/FGFR3, IGH/MAF, DS13S319/LAMP1, IGH/BAP, and p53/CEP17. Results: Cytogenetic abnormalities were found in 24 (70.6%) of the 28 MM patients. 10 (35.7%) patients had abnormal metaphases by conventional cytogenetics. Interphase FISH results were abnormal in 21 (61.8%) patients and 11 (52.3%) patients had abnormal interphase FISH but normal metaphases. The evidence of the loss of D13S319 with or without loss of LAMP1 was found in 6 (21.4%) patients, and loss of p53±CEP17 for 2 patients, IGH-BAP for 9 (26.5%) patients, IGH/FGFR3 for 2 patients, and IGH/CCND1 for 7 (20.6%) patients, respectively. However, there were none positive for IGH/MAF. Chromosome 13 abnormalities and IGH rearrangement is correlated with poor clinical outcome. Conclusions: Interphase FISH can provide useful information to evaluate the presence of prognostic chromosome abnormalities in addition to metaphase cytogenetics. And it should be used in the routine evaluation of multiple myeloma.

No significant financial relationships to disclose.
Regression of follicular lymphoma with alternative therapy using Devil's Claw (DC); Coincidence or causation?
Authors: Wilson K. S.
Published: August 2020

e19560

Background: Alternative therapies are used by c 30% of cancer pts (Ernst and Cassileth, Cancer 2000). Two follicular lymphoma (FL) pts who had objective tumor regression after taking the herb DC without cytotoxic therapy are reported here. Methods: This was a retrospective chart review. In January 2000, pt #1 presented with co-existent IgG plasma cell dyscrasia and stage 3A grade 2 FL with 5 cm cervical and R/P nodes. CT scan 10 months later showing partial regression of adenopathy. On enquiry, he was taking DC and Essiac. He developed overt myeloma in Aug 2001, when he stopped DC/Essiac and received HDCT/ASCT following which there has been no clinical progression of lymphoma. In November 2003, pt #2 presented with stage 3A grade 1 FL. CT scan showed widespread adenopathy (2.5 cm max.). He learned of pt #1 through the local Lymphoma Patient Support Group and started DC alone. CT scan 11 months later showed decreased adenopathy and splenomegaly which has been sustained. Results: CT images at baseline and follow-up confirm objective regression. Conclusions: DC (Harpagophytum procumbens) tuberous root contains Harpagoside and Beta sitosterol and has anti-inflammatory properties probably by suppressing COX-2 and iNOS expression (Jang et al, J Pharmacol Sci, 2003). There is good evidence for its use in osteoarthritis ( http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-devilsclaw.html ) but it has not been reported to have anticancer activity. COX-2 inhibition has an accepted role in cancer prevention (Steinbach et al, NEJM 2000), has been implicated in lymphomagenesis (Wun et al, Leuk Res 2004) and associated with both stage of lymphoma and response to standard treatment (Hazar et al, Leuk Lymphoma 2004). However, spontaneous regression in low grade lymphoma has been reported in 7 of 44 pts on observation only (Krikorian et al, 1980); none were on herbal medications or COX-2 inhibitors. The key issue in both these patients is whether or not the disease regression was “spontaneous” or causally related to DC therapy, but the timing of response suggests a potential therapeutic benefit. Considering the role of COX-2 inhibitors and the relation between components of DC and COX-2, further investigation is warranted, preferably with a COX-2 inhibitor of known purity.

No significant financial relationships to disclose.
The signet ring cell melanoma-rare morphologic variant of melanoma: Case report
Authors: Maksimovic S. , Jakovljevic B.
Published: August 2020

e20020

Background: Melanoma is a malignant tumor of melanocytes of skin. The histopathological variants of malignant melanoma include the common type (lentigo maligna (5%), superficial spreading melanoma (65%), nodular melanoma (15%), acrolentiginous melanoma (5%). The signet ring cell melanoma is a rare form melanoma, being seen in some 0.5% of melanomas. Aim of work: That showed young women with signet ring cell melanoma is a rare form melanoma. Methods: We describe a 39-year-old patient with a primary signet-ring cell melanoma of the skin located on the left upper quadrant of abdominal wall. Results: Diagnosis the tumour of skin was in department of surgery and histhopatology in General hospital in Bijeljini in December of the 2007. We performed clinical and histhopatologic examination. Physical examination revealed a well circumscribed and firm mass measuring 150x 100x 80 mm of the skin located on the upper quadrant of abdominal wall and solid mass in pelvis. Because of high suspect melanoma in patient performed surgical excision of skin tumor. Pathohysthology diagnosis was: Melanoma nodularis achromaticum. Immunohistochemistry showed positive reaction of the tumor cells for S-100, HMB-45 protein and vimentin, confirming their melanocytic differentiation. Tumor cells were negative for cytokeratins, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). After immunohistochemistry analysis definitive pathohystology was: Signet ring cell melanoma. The signet-ring cell melanoma disclosed an invasion to Clark Level V and tumor thickness Breslow level III. Tumor from pelvis was appertain uterus and histopathologic diagnosis is a leomyoma. Conclusions: Signet-ring cell melanoma is a rare morphologic variant of melanoma. Its recognition is important for differentiation from other tumors featuring signet ring cells.

No significant financial relationships to disclose.
The impact of telemedicine in cancer care
Authors: Yunus F. , Gray S. , Fox K. C. , Allen J. W. , Sachdev J. , Merkel M. , Chambley B. , Yunus R. , Waters T. M.
Published: August 2020

e20508

Background: The Technology Exchange for Cancer Health Network is a collaborative, multi-state effort using Telemedicine and integrated electronic health records to provide rural cancer care management. Methods: The purpose of the study was to compare quality, safety, and cost outcomes for patients receiving rural Telehealth care versus “routine” urban care. Patients with a cancer diagnosis requiring treatment for at least 1 year were eligible for the study. Telehealth patients saw their oncologist in person at rural sites for initial care and via telemedicine for about half of subsequent visits, allowing clinicians in-person clinical assessments while still taking advantage of time savings associated with telemedicine. Results: 217 patients (134 rural, 83 urban) were enrolled from 05/25/05 to 09/30/08. Patient satisfaction was high; 95 % of patients indicated their telemedicine visit was as good as or better than an in-person visit. Telemedicine patients also reported significant time and travel cost savings. Cost analysis comparing cost savings (physician travel time) with telemedicine costs (equipment, high speed lines) indicated that cost-benefit is driven by distance to rural facility and number of physician trips avoided. Telemedicine must save at least 5 hours of physician travel time per month to break even. Telemedicine was also associated with improvements in access to care. Using patient self-reported health care visit data (verified with local providers), we identified a significant decline in disparities between urban and rural patients (see Table ). Conclusions: Telemedicine offers a promising method for increasing access to oncology care that is convenient for and well-accepted by patients at reasonable costs. Our results also suggest that telemedicine facilitates access to more than just oncology care. The regular follow-up care provided through telemedicine visits may identify unmet need that might otherwise go untreated, yielding improvements in patient outcomes.

[Table: see text]

No significant financial relationships to disclose.