bluuebunny/crossref_metadata_2025 huggingface dataset:
High mRNA expression of LMO4, a BRCA1 downregulator, correlates with better prognosis in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations.
Authors: Viteri Ramirez Santiago , Costa Carlota , Gimenez Capitan Ana , Benlloch Susana , Taron Miquel , Sanchez Jose Javier , Gasco Amaya , Martinez-Bueno Alejandro , Karachaliou Niki , Camps Carlos , Moran Teresa , Carcereny Costa Enric , Massuti Bartomeu , Cardenal Felipe , Porta Rut , Bosch Joaquim , Palmero Ramon , Buges Cristina , Rosell Rafael
Published: March 2020

e18137

Background: Advanced NSCLC p with EGFR activating mutations show an impressive progression-free survival (PFS) to erlotinib. The co-existence of the EGFR T790M mutation, in conjunction with high BRCA1 mRNA levels, affected PFS to erlotinib (Rosell et al. CCR 2011). LMO4 is a negative regulator of BRCA1 function in sporadic breast cancers, and CtIP can bind to BRCA1 and LMO4. We have assessed the expression of CtIP, LMO4 and BRCA1 and examined the impact of CtIP and LMO4 levels on outcome. Methods: mRNA expression of LMO4 and CtIP was examined by RT-PCR in the original pretreatment tumor biopsies of 81 NSCLC p with sensitive EGFR mutations. Results: Expression of BRCA1 and LMO4 was successfully assessed in 55 p: median age, 68; 61.8% female; 98.2% Caucasian; 63.6% never-smokers; 81.8% ECOG PS <2; 80% adenocarcinoma; 14.5% BAC; 4.5% LCC; 94.5% stage IV; 63.6% exon 19 deletion; 36.4% L858R mutation; 36.4% T790M; 83.1% showed clinical benefit to erlotinib (CR/PR/SD). BRCA1 expression was correlated with that of CtIP (r=0.31; P=0.01) and LMO4 (r=0.32; P=0.02). There was no correlation between CtIP and LMO4 (r=0.09; P=0.49). PFS for p with high LMO4 levels was not reached while it was 13 months (m) for p with low levels (P=0.006). Overall survival (OS) was not reached for p with high levels of LMO4 and was 31 m for p with low levels (P=0.17). No differences in PFS or OS were observed according to CtIP levels. When BRCA1 and LMO4 expression was analyzed together, PFS was not reached for p with low BRCA1 and high LMO4 levels and was 19 m for p with low levels of both genes (P=0.04). PFS was 8 m for p with high BRCA1 and low LMO4 levels and 18 m for p with high levels of both genes (P=0.03). In the multivariate analysis, BRCA1 and LMO4 expression emerged as markers of PFS (Table). Conclusions: BRCA1 and LMO4 mRNA expression can predict PFS to erlotinib in p with EGFR mutations and could be useful in the development of new therapeutic strategies. [Table: see text]
Should crizotinib be dosed to sinus bradycardia (SB) (HR < 55)? A single institution, retrospective analysis of heart rate (HR) changes and tumor response in crizotinib treated NSCLC patients.
Authors: Tong Wilson P. , Azada Michele , Ou Sai-Hong Ignatius
Published: March 2020

e18140

Background: Crizotinib can result in SB as a part of its dose-dependent pharmacodynamic property. We analyzed the correlation between SB and tumor response in ALK or MET+ NSCLC patients (pts). Methods: Single institution retrospectively analysis of SB incidence (HR < 55) of ALK or MET+ NSCLC patients enrolled in 2 phase II crizotinib trials. Comparison performed between pt characteristics, HR changes, treatment duration, tumor response and shrinkage according to SB status. Results: 42 ALK or MET+ NSCLC pts (30 from A8081001, 12 from PROFILE1005) rx’d with crizotinib 250 mg po bid were analyzed. 90% of pts had a HR decrease of > 10 beats per minutes (bpm). 19 (45%) patients developed at least 1 SB episode at anytime during crizotinib treatment including 8 (19%) pts with profound SB (HR =< 45). All pts with SB were asymptomatic. There was no difference in the median age of diagnosis between pts (57.6 yrs [SB] vs. 49.7 yrs [no SB]; p = 0.073) by SB status. Median time to SB was 3 wks (mean: 7.2 wks, range 2-32 wks). There was significant difference in the mean pre-Rx baseline HR by SB status (74.5 bpm [SB] vs. 92.6 bpm [no SB]; p = 0.005), Rx duration (57.3 wks [SB] vs. 33.3 wks [no SB]; p = 0.021). The average maximum HR decrease (MHRD) from baseline for all pts were 26.3 bpm. There was no significant difference in the mean MHRD from baseline according to SB status (28.2 bpm [SB] vs. 24.7 bpm [no SB]; p = 0.598). 68% (13/19) of SB pts compared to 35% (8/23) of pts without SB achieved a CR/PR (p = 0.030). The mean maximum decrease in tumor measurements (MDTM) (RECIST) was 46.2% for pts with SB compared to 32.0% for pts without SB (p = 0.095). There was no difference in the mean MDTM in pts who achieved CR/PR without SB (62.5%) and with SB (63.5%) (p = 0.913) nor the mean response duration (RD) in CR/PR pts by SB status (43.3 wks [SB] vs. 51.5 wks [no SB]; p = 0.426). Conclusions: HR decrease is common in pts treated with crizotinib. Pts who developed asymptomatic SB had significantly lower pre-Rx baseline HR, longer Rx duration, higher response rates. However there was no difference in the mean MDTM or RD between pts who achieved CR/PR by SB status.
Phase II tailored S-1 regimen study of first-line chemotherapy in elderly patients with advanced and recurrent non-small cell lung cancer.
Authors: Shiroyama Takayuki , Kijima Takashi , Komuta Kiyoshi , Yamamoto Suguru , Minami Seigo , Ogata Yoshitaka , Okafuji Kouhei , Imamura Fumio , Hirashima Tomonori , Tachibana Isao , Kawase Ichiro , Kumanogoh Atsushi
Published: March 2020

e18141

Background: The aim of this study was to evaluate the efficacy and toxicity of a novel oral 5-fluorouracil (5-FU) formulation (S-1), administered according to a tailored dose regimen based on body surface area (BSA) and creatinine clearance (Ccr), in patients with advanced non-small-cell lung cancer who were 75 years or older. Pharmacokinetic analysis was also performed to evaluate the adequacy of the tailored S-1 dose. Methods: S-1 was administered orally for 28 days, followed by 14 days, in 23 patients who received a tailored dose of S-1, adjusted on the basis of individual creatinine clearance (Ccr) and body surface area (BSA). In 8 of the patients pharmacokinetic study were performed on the 5 times points on seventh day after S-1 administration. Results: Of the 23 patients enrolled in this study, 2 (8.7%) had a partial response and 14 (60.9%) had stable disease. The disease control rate was 69.6% (16/23) (95% confidence interval, 50.8-88.4%). Grade 3/4 hematologic and non-hematologic toxicities were minor. In the pharmacokinetic study group the maximum plasma concentration (Cmax) and the area under the plasma concentration curve (AUC) of 5-FU at all 5 times points after administration of the tailored S-1 dose regimen were similar to the values reported in a previous study describing cancer patients with normal renal function who received a standard dose of S-1 (80 mg/m2/day). Conclusions: Our results suggest that tailored S-1 monotherapy is safe and therapeutically useful as first-line treatment for elderly patients with advanced and recurrent non-small-cell lung cancer.
Survival among advanced non-small cell lung cancer patients with poor performance status after first-line chemotherapy.
Authors: Salloum Ramzi George , Smith Thomas J , Jensen Gail , Elston-Lafata Jennifer
Published: March 2020

e18144

Background: Evidence-based guidelines recommend chemotherapy for medically fit patients with advanced stage non-small cell lung cancer (NSCLC). Performance status (PS) is a commonly used factor in determining the appropriateness for chemotherapy for this group of patients.The prevalence of poor PS and impact of chemotherapy on survival among NSCLC patients has not been studied in community populations. Methods: Insured patients, aged 50+ years, diagnosed with advanced stage NSCLC between 2000 and 2007 were identified via tumor registry (n=292) and linked to medical record abstracted PS, automated medical claims, and Census tract information. A multivariate Cox proportional hazards model was used to determine the factors associated with survival. Tests of statistical significance were two sided. We defined PS 3 or 4 as “poor” since the NCCN and ASCO guidelines agree that those patients should not routinely receive chemotherapy. Results: Of 292 stage IIIB-IV patients, 82 (28%) had PS 3 or 4, and 39% of PS 3-4 patients received first line chemotherapy. Those who received chemotherapy lived 4.8 months compared to 2.4 months for those who did not. Factors associated with a reduced likelihood of death included receipt of chemotherapy (hazard ratio [HR], 0.67) and surgery (HR, 0.27), and female gender (HR, 0.69). Conclusions: In advanced stage NSCLC, poor PS is common, and oncologists are treating about 40% of those patients with the same drugs as for PS 0-2. Modern chemotherapy is associated with positive effects on survival for poor PS patients, as for good PS patients, but we cannot tell if this is due to chemotherapy or some other factor. Further trials, especially randomized trials, in this common but neglected subgroup are indicated.
Treatment for frail elderly patients with diffuse large B-cell lymphoma (DLBCL): A single center experience.
Authors: Chaïbi Pascal , Chebib Amale , Baudry Elodie , Cotto Elise , Piette Francois , Berigaud Sylvie , Siriwardana Melany , Mitha Nathalie , Koenig Nelly , Spano Jean-Philippe
Published: March 2020

e18505

Background: DLBCL occurs frequently in elderly pts and recent studies demonstrated that immunochemotherapy with R-mini-CHOP could be a safe and effective treatment for selected pts over 80 years Methods: Since 2008, R-mini-CHOP has been the treatment proposed for elderly pts with DLBCL referred to our oncogeriatric unit, irrespectively of their performance status (PS). We reviewed data of elderly pts treated for DLBCL at our institution from January 2008 to June 2011. Results: 74 pts (50 women, 24 men) were treated for DLBCL. Median age was 85 years (range 71–97), 84 % of pts ≥ 80 years and 16 % of pts ≥ 90 years. 68 pts (92%) had at least one comorbidity. Median number of daily medicines was 4 (range 0 – 12), irrespectively of treatments for DLBCL. Malnutrition was diagnosed in 49 pts. 50 pts (67,5 %) had a poor PS (> 2). Age-adjusted International Pronostic Index (aaIPI) was 0-1 in 9 pts, 2 in 28 pts and 3 in 35 pts. 61 pts were treated with mini-CHOP (cyclophosphamide: 400 mg/m2 D1; doxorubicine: 25 mg/m2 D1; vincristine: 1 mg total dose D1 and prednisolone 40 mg/m2 by oral route from D1 to D5) plus rituximab (375 mg/m2 D1) every 21 days for 6 cycles. Doxorubicine was replaced by etoposide (150 mg/m2 D1) for 5 pts because of cardiac dysfunction. 8 pts received reduced dose intensity chemotherapy ( without doxorubicine) for the 2 first cycles because of high risk toxicity. Prophylaxis of neutropenia with GCSF was systematic. Median survival was 11 months. 21 pts died during treatment, because of progressive disease (13) or treatment toxicity (6). Complete response (CR) was observed in 44 pts (59,5 %). With a median follow-up of 18 months, 11 relapses were observed. In our population study, aaIPI appears highly predictive of CR, with a CR Rate of 87,5 %, 75 % and 43% respectively for pts with aaIPI 0 - 1, 2 and 3.Hematological toxicity was the most common side effect. Grade 3–4 neutropenia was observed in 28% of the pts and grade 3–4 thrombocytopenia in 12%. 14 pts (19%) experienced at least one episode of febrile neutropenia. Conclusions: In unselected elderly pts with DLBCL, immunochemotherapy with R-mini-CHOP can be effective, but with significant toxicity, even using systematic G-CSF prophylaxis. Prognosis remains poor for pts with aaIPI 3
Long-term follow-up and secondary malignancy in mycosis fungoides patients treated by electron beam irradiation.
Authors: Lutsyk Miroslav , Kaidar-Person Orit , Bar-Hanna Micha , Cohen Yoram , Kuten Abraham
Published: March 2020

e18511

Background: Mycosis fungoides (MF) and Sezary's syndrome are the most common subgroup of cutaneous T-cell lymphoma. Total or partial skin electron beam irradiation (TSEI, PSEI) is an accepted treatment option in cases of disease that is limited to the skin and as palliative treatment in advanced disease. Consequently, long term follow-up of these patients and detection of secondary malignancies after TSEI/PSEI is crucial. The aim of this study was to summarize long term follow-up of MF patients treated by TSEI or PSEI and to evaluate the rates of secondary malignancies. Methods: A retrospective review of the medical charts of all consecutive patients diagnosed with MF who was treated from January 1960 to June 2010 at our hospital was conducted. Data collected included demographics, date of diagnosis, staging, treatment, and secondary malignancies. Results: One hundred ninety six patients were included (132 M, 64 F). The median age at diagnosis was 67.3 years. The mean follow-up was 109.4±89.4 months (range 1-566). One hundred patients received TSEI, 45 patients received PSEI, and one patient was treated by low dose total body photon irradiation combined with TSEI. Fifty patients (50/196, 25.5%) developed a second malignancy, 16 patients (16/196, 8%) had a third malignancy, and 4 (2%) patients developed a fourth malignancy. Conclusions: MF is associated with development of sequential malignancies. The contribution of TSEI or PSEI to the development of secondary malignancies is yet to be determined. Long term follow-up in this group of patients is essential.
Pharmacokinetics (PK) of bendamustine when administered in combination with rituximab in patients with non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).
Authors: Bond Mary , Burke John M. , Hellriegel Edward , Robertson Philmore , Phillips Luann , Ludwig Elizabeth , Darwish Mona
Published: March 2020

e18522

Background: The PK profile of bendamustine as a monotherapy in adult patients is well described. Because pathways of small molecules and monoclonal antibodies are distinct, a direct drug interaction between bendamustine and rituximab was not expected. Methods: In order to confirm the lack of a PK interaction, the population PK model that was developed based on the bendamustine monotherapy (120 mg/m2) was evaluated to determine its applicability to combination therapy (rituximab 375 mg/m2 on day 1, bendamustine 90 mg/m2 on days 1 and 2) in patients with NHL and MCL. Once the applicability was confirmed, model-predicted Bayesian bendamustine clearance (CL) values for monotherapy and combination therapy were generated and compared using the Wilcoxon signed rank test on the log-transformed CL values (alpha=0.05). Results: The previously developed population PK model in patients receiving bendamustine monotherapy was used to generate 500 sets of single-agent bendamustine concentrations at the same sampling times and bendamustine dosing regimens as those observed in the combination-with-rituximab study. Median, 10th, and 90th percentiles of observed bendamustine concentrations following combination therapy and modeled bendamustine concentrations following monotherapy exhibited similar patterns. Although slightly greater than 10% of the observed data fall above (13%) or below (15%) the specific percentiles, the previously developed monotherapy population PK model was considered applicable to the data following combination therapy. The 25th to 75th percentiles of the bendamustine CL estimates were similar for combination and monotherapy with median values within 8% of each other. The 2-sided Wilcoxon signed rank test of the log-transformed CL values did not show a statistical difference between the 2 groups (p >0.61). Conclusions: Comparison of bendamustine plasma concentrations and CL estimates in patients receiving bendamustine in combination with rituximab to those in patients receiving bendamustine alone indicate that rituximab does not affect systemic exposure to bendamustine. Support: Teva Pharmaceutical Industries Ltd.
Survival comparison between malignant lymphoma HIV+ versus HIV- in the post HAART era: INEN 2005-2011.
Authors: Cuéllar Ponce de león Luis Ernesto , Miranda Rosales Luis Miguel , Samanez Figari César , Vallejos Sologuren Carlos
Published: March 2020

e18524

Background: The incidence of non-Hodgkin lymphoma in HIV patients (ARLs) is higher than in general population. In the HAART era AIDS-related lymphoma (ARL) are more frequent in patients with advanced age, delayed diagnosis, non adherent HAART, multiresistant strains of HIV. The aim of this study is to compare the clinical characteristic, prognosis factors and survival of malignant lymphomas HIV( +) vs HIV(-) at the Instituto Nacional de Enfermedades Neoplásicas. Methods: Study retrospective, individually matched, case-controlled study according to HIV serologic status (positive vs negative) for patiens newly diagnosed of non-Hodgkin lymphoma between 2005 and 2011. Results: We included 51 cases HIV (+) and 102 controls HIV (-) (Table). On diagnosis, anemia (Hemoglobin < 110 g/L) and opportunistic infections (OI) were statiscal more frequent (p<0.05) in ARL. The overall response to chemotherapy (ORC) was 76.4% (cases) and 89.2% (controls) (p<0.05). In multivariate analysis ECOG ≥ 2, OI and no response to chemotherapy increase mortality risk in ARL (p<0.05). ARL had lower 6-year Disease Free Survival (DFS) (16.0 vs 25 months) (p>0.05) and lower 6- year Overall survival (OS) (37.9 vs 49.7 months (controls) (p<0.001) than HIV (-) patients. Conclusions: In multivariate analysis ECOG ≥ 2, OI and no response to chemotherapy were adverse prognostic factors for OS in ARL. ORC is lower in ARL, though similar DFS of patients with malignant lymphoma HIV(+) vs HIV(-). [Table: see text]
Marked efficacy of rituximab in two patients with Waldenstrom macroglobulinemia-like multiple myeloma.
Authors: Heuck Christoph J. , Usmani Saad Zafar , Tian Erming , Zhang Qing , Van Rhee Frits , Waheed Sarah , Nair Bijay P. , Petty Nathan , Papanikolaou Xenofon , Shaughnessy John D. , Barlogie Bart
Published: March 2020

e18548

Background: Rituximab (R) has been deemed to be ineffective in multiple myeloma (MM), despite CD20 expression in 10-15% of MM. Here we report two cases, selected by a genomic approach, with an excellent response to single agent R. Methods: as below Results: Patient 1: A 49 yr old male with IgG lambda MM with 80% bone marrow (BM) plasma cells (PC) and IgG level of 23 g/L had been treated elsewhere with one cycle of CRD. Here, we noted CD-2 subclass by gene expression profilin (GEP), however without spiked expression of CCND1 and CCND3 genes as manifestation of a t[11:14] or a t[6:14]. GEP further revealed a del 6q and overexpression of EBI2, both commonly seen in Waldenstrom Macroglobulinemia (WM). All findings were confirmed by FISH. Unsupervised clustering in the context of MGUS, untreated MM and WM-PC, confirmed WM-like MM in this patient. Sole therapy with R (750 mg/m2/d x 5d, weekly x 4, bi-weekly x 4 and then monthly) resulted in a reduction of IgG from 1850 mg/dL to 950 mg/dl and BM PC from 60% to 10% at 9 months and a decrease in sLFLC from 68 mg/dL to 10 mg/dL at 12 months follow up. Patient 2: Based on the above observation, we identified a second patient. This 37-yr old male had been diagnosed with lambda light chain MM 42 months earlier with a BM PC of 15%, lambda light-chain proteinuria of 1.9 g/d and sLFLC in the 200mg/dL range. Because of absence of CRAB criteria, he was followed expectantly. Rising BM PC to 50% and concern for end-organ damage motivated a detailed examination of GEP data. GEP showed high expression of CD20 and EBI2 and absence of CCND1 and CCND3 spikes. This was confirmed by FISH, which also revealed a del 6q. As in the first case, this patient co-segregated with WM. R treatment on the same schedule resulted in a reduction of sLFLC levels from 249 mg/dL to 29.9 mg/dl and of Bence Jones proteinuria from 1766 mg/d to 242 mg/d. Conclusions: The presumed lack of activity of R in MM needs to be revisited in light of the marked response noted in these 2 patients. Studies are in progress (a) to extend R therapy to similar cases, and (b) to more fully characterize the prevalence of genetic/phenotypic characteristics, as seen in these 2 cases, among several thousand MM patients. This updated information will be presented at the meeting.
Feasibility of risk stratified allocation to single versus tandem autologous SCT in multiple myeloma.
Authors: Risendal Matthew , Hazlett Allison , Sabo Roy T. , Mpasi Priscilla , Bolling Joan , Clark William B. , McCarty John , Chung Harold M. , Roberts Catherine H. , Toor Amir A.
Published: March 2020

e18550

Background: Multiple myeloma (MM) is a plasma cell malignancy with variable prognosis depending on disease features such as β2m and cytogenetics. High dose therapy and stem cell transplantation (SCT) remains the current standard of care for MM, however the role of tandem SCT is controversial, particularly in the era of novel induction therapy. Methods: Our program has a practice of risk-stratified transplant allocation in MM patients referred for SCT, those with high-risk (HR) disease (β2m >5.5, adverse cytogenetics, >1st remission) are preferentially assigned tandem SCT, and those with standard risk (SR), a single SCT. Between 2008 and 2011, 129 MM patients underwent SCT, 43% SR patients received a single SCT (SRS), 22% HR received tandem SCT (HRT) & 36% HR a single SCT (HRS). Median age at SCT was 57 years. Maintenance therapy was administered in 51% SRS, 57% HRT & 67% HRS patients. Results: Complete response (CR) or very good partial response was achieved in 0.68, 0.72 and 0.80 for the HRT, HRS, and SRS groups. The HRT group (0.39) was more likely to achieve CR than HRS (0.20) (P=0.02). At a median follow up of 23.4 months, the overall survival for HRS was inferior to SRS (P=0.01) but there was no difference in the overall survival between HRT and SRS cohorts. Two-year survival rates were 0.81, 0.91 and 0.97 in the HRS, HRT and SRS cohorts (HRS vs. SRS P=0.02). This was attributable to a higher 1-year relapse rate in HRS (0.29) compared to HRT (0.07) and SRS (0.07) (P<0.01). Conclusions: Using a risk-stratified allocation system, we report that HR MM patients undergoing tandem SCT have outcomes comparable to SR patients. However, HR MM patients receiving a single SCT have inferior outcomes compared to those with SR. Notably, higher rate of CR and a lower relapse rate were observed in the HRT cohort when compared to HRS. This suggests that greater depth of remission achieved in HR patients undergoing tandem SCT may result in longer time to relapse and survival advantage compared to HR patients receiving a single SCT. In contrast, a single SCT may suffice for SR MM patients. These results demonstrate that risk-stratification based on disease prognostic features is an important treatment consideration when planning high dose therapy in MM patients.
Total costs of therapy with lenalidomide or bortezomib in relapsed/refractory multiple myeloma (rrMM).
Authors: Borrello Ivan , Binder Gary , Khan Zeba M. , Pashos Chris L , Durie Brian G.
Published: March 2020

e18561

Background: Advances in survival are increasing payers’ focus on the cost of care in rrMM. An economic assessment was conducted from the perspective of a US payer to compare the total costs of treatment with two NCCN guideline-listed therapies frequently used in rrMM: lenalidomide plus dexamethasone (LEN/DEX) and bortezomib (BORT). Methods: Costs of drug treatment, medical resource utilization, and adverse event (AE) management were determined for each regimen over a common 12-month time-period. Utilization rates and costs of specific medical procedures (e.g., lab tests, hydration, AE prophylaxis, and physician administration) as well as incidence and costs of grade 3/4 AEs, were calculated based on published literature, 3Q2011 fee schedules, and respective package inserts. Median time to progression (TTP) was obtained from the respective pivotal clinical trials (BORT, 6.2 months [APEX] and LEN/DEX, 13.4 months [MM-009/MM-010]). Univariate sensitivity analyses and alternative scenarios were conducted to confirm robustness. Relative cost per outcome (i.e., treatment cost per month during which disease control had been maintained) was also analyzed for the treatment regimens. Results: Although drug acquisition costs for the two regimens were similar (difference of <$10/day), total rrMM treatment cost per day was $58 higher with BORT ($356/day) vs. LEN/DEX ($298/day) due to higher physician administration, lab tests, and other medical and AE management costs for BORT. Annual total cost for BORT treatment was more than $20,000 higher than for LEN/DEX. A cost advantage for LEN/DEX was maintained across a variety of sensitivity analyses and alternative scenarios, including alternate therapy after relapse, changes to patient cost-sharing, and shorter time periods. Total cost per month without progression was 14% lower for treatment with LEN/DEX vs BORT. Conclusions: In rrMM, LEN/DEX and BORT had comparable drug acquisition costs, yet BORT had higher total costs due to physician administration and other medical resource and AE costs. Total cost per outcome (defined as month without progression) was lower with LEN/DEX.
Number needed to treat (NNT) as a measure of drug benefit: Lenalidomide versus bortezomib for treatment of relapsed/refractory multiple myeloma (MM).
Authors: Kaura Satyin , Dranitsaris George
Published: March 2020

e18562

Background: Lenalidomide(LEN) and bortezomib(BORT) are active agents in the treatment of refractory MM. The former is administered 25 mg/day orally on days 1-21 of repeated 28-day cycles. The latter as a 1.3 mg/m^2 intravenous dose on days 1, 4, 8 and 11 for eight, three week cycles. Both agents have demonstrated an improvement in disease response, progression free (PFS) and overall survival (OS) in the refractory MM setting. NNT represents the number of patients that need to be treated with a new intervention in order to have one additional patient deriving benefit, and is a powerful approach that can be used to make sense of numerical results from clinical trials. In this analysis, the NNT approach was used to compare LEN and BORT in patients with relapsed MM. Methods: The pivotal randomized trials for LEN (Weber, Dimopoulos, 2007) and BORT (Richardson, 2005) were reviewed. A key requirement for a NNT comparative analysis is that all outcomes be measured against a comparable control. The NNT was then calculated for both agents with respect to disease response and PFS at 12 months by taking the reciprocal of the absolute differences in treatment effect between the experimental therapies and the control group. Results: For a disease response, the NNT for LEN and BORT was 3 and 5 patients respectively; to have one additional patient achieving a disease response. A difference in the NNT was also noted for PFS at 12 months; only 3 patients would need to be treated with LEN for an additional patient remaining progression free compared to 9 with BORT. This is a relevant finding because it suggests a 3 fold relative increase in clinical benefit in patients treat with LEN compared to BORT. Conclusions: In situations of multiple numerical outcomes from randomized trials, NNT approach is a simple and effective method to express the findings in a clinically meaningful way. In this analysis, it appears that more patients treated with LEN are likely to respond and to achieve a 12 month PFS than comparable patients treated with BORT. Possible reasons for this effect include differences in the trial population, extent of disease, and/or true differences in efficacy.
Long-term results in multiple myeloma treated with high-dose melphalan and autologous peripheral stem cell transplantation and achieving complete remission.
Authors: Martino Massimo Vincenzo , Postorino Maurizio , Gallo Giuseppe Alberto , Irrera Giuseppe , Piro Eugenio , Messina Giuseppe , Neri Santo , Al Sayyad Said , Fedele Roberta , Musolino Caterina , Molica Stefano , Brugiatelli Maura , Nobile Francesco , Morabito Fortunato
Published: March 2020

e18564

Background: Major progress has been made in the treatment of multiple myeloma (MM) in recent years, including the introduction of novel agents and transplant strategy. High-dose melphalan (HDM) followed by autologous haematopoietic stell cell transplantation (AHSCT) remains an integral component of upfront treatment strategy. Many studies stress the importance of achieving a deeper response as a surrogate for improved survival but, despite the improvements, MM remains incurable and long-term survival appears elusive. The aim of study is to establish the actual prognosis for the different response categories in the same original cohort of patients with MM treated with HDM and AHSCT after long-term follow-up. Methods: We evaluated a cohort of MM patients treated up-front in the Bone Marrow Transplant Unit of Reggio Calabria between 1994 and 2006. Disease response was assessed with the use of criteria from the European Group for Blood and Marrow Transplantation modified to include Complete Remission (CR) and near Complete Remission (nCR). Results: The study group was composed by 150 patients (age at 1st AHSCT M±SD 55±9 years, male 64%); 94 (63%) of them had 2 AHSCT. After treatments 22 (15%) patients have a CR, 32 (21%) a nCR and 90(64.0%) a PR. After a mean follow up of 50 months the cumulative probability of survival was 69% for patients with CR, 43% for those in nCR and 0% for patients in PR (log-rank test P PR vs nCR=0.006; CR vs nCR and nCR vs PR<0.001 ). The estimate mean survival for patients with CR, nCR and PR was respectively 166, 81 and 46 months. For patients with CR the survival curves showed a plateau of cumulative probability of survival after 134 months. Conclusions: In MM achieving a CR after HDM and AHSCT is a central prognostic factor. The relapse rate is low in patients with >11 years of follow-up, possibly signifying durable remission in patients in CR.
Phase III study of panobinostat with bortezomib and dexamethasone in patients with relapsed multiple myeloma (PANORAMA 1).
Authors: San-Miguel Jesùs F. , Moreau Philippe , Yoon Sung-Soo , Dimopoulos Meletios A. , Hungria Vânia Tietsche de Moraes , Jedrzejczak Wieslaw W. , el Ghandour Ashraf , Corradini Paolo , Günther Andreas , Beksac Meral , Yong Kwee , Lee Jae Hoon , Lonial Sagar , Hou Jian , Einsele Hermann , Wroclawska-Swacha Monika M , Weber Hans-Jochen , Bourquelot Priscille M. , Richardson Paul Gerard Guy
Published: March 2020

e18572^

Background: Multiple myeloma (MM) is an incurable disease, and significant unmet need remains in the relapsed (Rel) and refractory (Ref) settings. Thus, effective agents and combination strategies are of continued interest. Clinical activity was observed in a phase Ib study of the novel pan-deacetylase inhibitor panobinostat (PAN) and the proteasome inhibitor bortezomib (BTZ) in patients (pts) with Rel or Rel/Ref MM. We report the results of a blinded safety analysis from PANORAMA 1, an international, randomized, double-blind, phase III study of PAN (or placebo) + BTZ + dexamethasone (Dex). Methods: Pts with Rel or Rel/Ref MM (1-3 prior lines of therapy) were enrolled. Pts with BTZ-ref MM were not eligible. The study was comprised of 2 treatment phases, and follow up was to be continued during and after treatment until progressive disease or relapse. Treatment phase 1 consisted of eight 3-week cycles of PAN or placebo administered thrice weekly and BTZ administered twice weekly for 2 weeks. Dex was administered on days of and after BTZ. Pts who achieved clinical benefit proceeded to treatment phase 2, which consisted of four 6-week cycles with BTZ and Dex administered at a reduced frequency. Results: Preliminary demographic and blinded safety data from 536 randomized pts were available with treatment ongoing in 257 pts (47.9%). Median age was 63 years (32-84 y). Approximately half of pts (51.7%) received 2-3 prior lines of therapy and 57.3% received prior stem cell transplant. Any-grade adverse events (AEs) included thrombocytopenia (47.6%), diarrhea (45.7%), fatigue (32.6%), anemia (30.5%), constipation (24.8%), and nausea (24.4%). Common grade 3/4 AEs were thrombocytopenia (36.2%), diarrhea (14.5%), anemia (13.0%), fatigue (12.2%), neutropenia (11.4%), and hypokalemia (11.0%). Of interest, peripheral neuropathy was observed in 24.6% at any grade and 5.3% at grade 3/4. Conclusions: Preliminary analysis in 525 pts treated in PANORAMA 1 demonstrated a comparable safety profile to clinical experience with BTZ + Dex. The data monitoring committee recommended the study continue as planned. Enrollment completion is anticipated for Feb 2012 (N = 762). Updated blinded safety data will be presented.
Correlates of fever in patients (pts) receiving combined dabrafenib (GSK2118436) plus trametinib (GSK1120212) for V600 BRAF-mutant metastatic melanoma (MM).
Authors: Lee Clara Inkyung , Menzies Alexander M. , Haydu Lauren , Clements Arthur , Kefford Richard , Long Georgina V.
Published: March 2020

e19011

Background: Dabrafenib is an effective targeted treatment of oncogenic BRAF-mutant MM. 20-30% of pts experienced drug-related fever in phase I and II trials of dabrafenib, but not trametinib. The combination of dabrafenib and trametinib reduces skin AEs seen with either drug alone, but dabrafenib-related fever persists as a common AE. We investigated correlates of fever in pts from a single institution enrolled in the BRF113220 phase I/II study of combined dabrafenib and trametinib. Methods: Demographics, BRAF genotype, extent and burden of disease, RECIST response, PFS and OS were collected on all pts enrolled into BRF113220 at Westmead Hospital between Nov 2010 and Nov 2011. Data were collected, including the number and severity of febrile episodes, associated symptoms, haematologic and biochemical alterations, the treatment and prophylaxis of fever, and the efficacy of these measures. Results: 23 pts were enrolled. 9 pts (39%) developed fever defined as ≥38.5°C, 5 had associated rash and 6 had rigors. Fever was not associated with pt age, sex, BRAF genotype (V600E vs V600K), M-stage, sites of distant metastases, baseline LDH and baseline tumor volume (RECIST target lesions). Fever did not predict RECIST response, PFS or OS. Fever recurred in 6 pts, and was repetitive (>2 episodes) in 2 (6 and 7 episodes). Neither dose reduction of either drug, nor anti-pyretic therapy (acetaminophen, NSAIDs) were effective in fever prophylaxis, but corticosteroids were effective in all cases. 8 of 9 pts had biochemical assessment at first fever, and all had a rise in AST (median 100%), ALT (79%), ALP (40%) and LDH (40%) compared to those without fever (p<0.05). At time of first fever, there was no significant change in neutrophil or lymphocyte counts, GGT or CRP, yet lymphopaenia had developed in the 4 pts subsequently requiring corticosteroid prophylaxis. Conclusions: Fever is not predictive of response or clinical outcome, and there are no clinical characteristics which predict fever. Febrile episodes are associated with transient elevation of ALT, ALP, LDH and especially AST. Corticosteroids are the only effective fever prophylaxis.
Correlation of caveolin 1 expression with disease-free survival in skin melanoma.
Authors: Sbenghe Maria Magdalena , Witkiewicz Agnieszka , Sato Takami , Queenan Maria B , Valsecchi Matias Emanuel , Feeney Kendra J. , Mastrangelo Michael J.
Published: March 2020

e19016

Background: As clinical and histological parameters are unable to precisely predict the behavior of skin melanoma, new criteria are required to improve risk assessment. Caveolin 1 (CAV1), a scaffolding membrane protein, has been implicated in cell proliferation, death and transformation. In melanoma cell lines, CAV1 was found to have an antimetastatic role and loss of stromal CAV1 expression in lymph nodes metastases was associated with poor survival. The objectives of this analysis were to correlate CAV1 expression in primary skin melanoma cells with tumor thickness and disease free survival (DFS). Methods: CAV1 immunostaining was performed on the primary skin melanomas of 40 patients. CAV1 expression was scored semi-quantitatively using a 3-point scale: 0 (no staining), 1 (diffuse weak staining or strong staining in less then 30% of the cells) and 2 (strong staining of 30% or more of the cells). For analysis purposes, CAV1 was dichotomized as present (score 1 or 2) or absent (score 0). Primary melanoma was classified based on 2009 AJCC T-stage. DFS was measured from removal of primary skin melanoma to development of loco-regional or systemic recurrence. Pearson Chi-Square, Kaplan Meier, and Cox-Proportional Hazard Ratio were used for data analyses. Results: T-stage distribution was: Cis 12.5%, T1 32.5%, T2 22.5%, T3 17.5%, T4 15.0%. There was a clear inverse relationship between T stage and Cav 1 expression in tumor cells, with higher CAV1 expression in less invasive melanomas (P= 0.01). Fifteen patients experienced either locoregional or distant recurrence (median time to recurrence 14 months; range <1 month -105 months). Twenty-five patients remained disease free for minimum of 3 years (median 77 months; range 36 – 111 months). Presence of CAV1 in primary melanoma tumor cells was correlated with increased DFS (P = 0.05) but this association was not significant when adjusting for T stage (P=0.59). Conclusions: CAV1 expression in melanoma tumor cells correlates with clinical behavior of skin melanoma as its loss is associated with invasiveness and distant recurrence. Whether the loss of CAV1 in primary melanoma tumor cells is just an epiphenomenon or a causal event is to be decided by further work on a larger population sample.
Cutaneous side effects (cAE) of vemurafenib (V): Single-center cohort study of 28 metastatic melanoma (mM) patients (pts).
Authors: Goldinger Simone M. , Rinderknecht Jeannine Desiree , Belloni Benedetta , Eggmann Nina , Dummer Reinhard
Published: March 2020

e19017

Background: V is a potent BRAF inhibitor with significant impact on progression-free and overall survival in mM pts. cAE are very common. This single-center observation analyses the clinical and histological spectrum of this new class-specific cAE in 28 pts treated with V in different clinical trials. Methods: 28 mM pts stage IV were treated with V 960mg b.i.d. in local ethic committees approved clinical trials. Occurring side effects were collected and documented prospectively. 65 biopsies were analysed. cAE were classified by reaction pattern as inflammatory diseases, hair and nail changes, keratinocytic proliferations, melanocytic disorders and proliferations. Results: V was well tolerated; in 2 pts dose reduction was necessary due to arthragia. 26/28 pts (93%) experienced cAE. UVA dependent photosensitivity and maculopapular exanthema were observed in 16 and 14 pts respectively. The histology of the rash demonstrated alteration of eccrine and follicular structures with mild inflammation and no increased keratinocytic apoptosis, thus differing from the rash of MEK inhibitors. Pruritus was observed in 8, folliculitis in 5, and burning feet in 3 pts. Hair thinning and alopecia occurred in 8 pts, 2 pts presented with curly hair. Follicular hyperkeratosis and acanthopapilloma were common skin reactions (n=12/n=13), as well as plantar hyperkeratosis (n=4), keratoacanthoma (n=5) and invasive squamous cell carcinoma (n=4). Histology of the acanthopapilloma (n=39) showed marked hyperkeratosis and acanthosis with koilocytes and mitosis, suggesting viral association. Single observations of morbus Bowen, Bowen carcinoma, basal cell carcinoma and a warty dyskeratoma were documented. 1 pt developed after more than 4 months of therapy a secondary primary melanoma on the capillitium (BRAF and RAS wildtype). Conclusions: V has a broad and particular cAE profile involving epidermis and adnexals. Regular skin examination by experienced dermatologists is crucial under V to detect and treat the possible side effects promptly. The treatment is very well tolerated but can have an impact in quality of life; ergo the pts have to be well informed. UVA optimized photoprotection is essential.
Ipilimumab use in a named-patient program in metastatic melanoma: Experiences in 185 German patients.
Authors: Eichhorn Christoph , Schlaak Max , Hassel Jessica C. , Loquai Carmen , Stoffels Ingo , Gutzmer Ralf , Paetzold Sylvie , Keller Ulrich , Ulrich Jens , Tsianakas Athanasios , Egberts Friederike , Janssen Eva , Garbe Claus , Eigentler Thomas K.
Published: March 2020

e19031

Background: The monoclonal antibody ipilimumab (ipi) showed a survival benefit in patients (pts) with unrespectable metastatic melanoma leading to its approval in 2011. Methods: Ipi was available in Germany before its approval in a Named-Patient Program for pts with unrespectable stage IV/IIIC melanoma. Pts were eligible if they failed at least one prior systemic treatment or were intolerant and did not suffer from auto-immune diseases. Ipi was administered at a dosage of 3mg/kg iv (4 cycles, q21). A re-induction was possible in case of progressive disease after initial clinical benefit. Results: Data from 185 pts (114 male; 71 female, median age: 60 [18-88Y]) of 12 German centers was evaluable. 175 pts actually received ipilimumab (100 pts received all 4 cycles). Reasons for early termination were: Reduced general condition (44%), tumor progression (28%), toxicity or wish of pts (11% each), and incompliance (6%). Response was evaluable in 161 pts. Objective response was observed in 17 pts (1 CR+16 PR), SD in 19 pts (disease control rate 22%). PD was diagnosed in 125 pts. Responding pts were characterized by less organs involved (p=0.028). Median survival for all pts was 8.1 months, 1-year overall survival was 36.4%. Median survival is not yet reached for pts with disease control (94% alive at last observation), whereas it was 5.5 for pts with PD (40% alive at last observation). Treatment was generally well tolerated. Severe (Grade 3+4) auto-immune related toxicities were diarrhea (15 pts), skin rash (1 pt) and hepatitis (1 pt). Aseptic meningitis was observed in 1 pt; and hypophysitis (Grade 2) likewise in 1 pt. Conclusions: Data coming from these 161 patients appear to be consistent with safety and efficacy profiles determined in large clinical trials. Tumor responses were induced in a subset of pts and associated with prolonged survival.
Surgery in stage IV melanoma patients: Results from a single institution.
Authors: Pennacchioli Elisabetta , Gandini Sara , Verrecchia Francesco , Tosti Giulio , Baldini Federica , Mosconi Massimo , Spadola Giuseppe , Ferrucci Pier Francesco , Latiano Tiziana , Testori Alessandro
Published: March 2020

e19035

Background: There is no consensus regarding the appropriate management of melanoma patients at stage IV and resectable metastases. Methods: We conducted a systematic review and meta-analysis to examine the effect of surgery on overall survival (OS) in patients with resectable metastases. The systematic review was performed by searching MEDLINE, EMBASE, Cochrane and ISI Web of Science. The meta-analysis was performed using time-to-event data from which hazard ratios (HRs) and 95% confidence intervals (CIs) of OS were estimated and summary estimates were obtain through random effects model. Heterogeneity and publication bias were investigated by sensitivity analyses and funnel plot regression Results: Thirty-three retrospective studies evaluating survival from resected and unresected metastases were found from 1978 until 2010. In resected patients median follow-up is 1.5 years and 2-year OS is 27% whereas in unresected the median follow-up is 6 months and 2-year OS is 12%. Meta-analysis was carried out on the seven studies reporting information on visceral metastases and including 1,165 patients. We included also 93 patients at stage IV treated at the European Institute of Oncology, Milan, Italy. Surgery has shown an improvement in survival of patients managed with palliative resection of their visceral metastases: the summary estimate suggests a significant decrease in the risk of mortality of 40% for patients who undergo surgery, with no indication of heterogeneity (HR=0.6 (0.45-0.78); I2=0). However we found indication for publication bias (P=0.03) suggesting that small studies published only mainly if they found significant results. Conclusions: Our results suggest the benefit of surgical resection for advanced-stage melanoma. Patients with limited sites and numbers of metastases should be considered for curative resection regardless of the location of the disease.
Identification of novel melanoma gene expression signatures using a Bayesian approach to filter out gene expression noise from normal tissues.
Authors: Liebner David A. , Parvin Jeffrey , Huang Kun
Published: March 2020

e19053

Background: Identification of pertinent gene expression signatures may be confounded by failure to account for admixture of tumor specimens with normal tissue. We propose a novel method for filtering out gene expression “noise” from normal tissues in a set of melanoma samples derived from the NCBI Gene Expression Omnibus (GEO) public database. Methods: Using customized software implemented in MATLAB, we performed a preliminary search of GEO using the query term “melanoma”. We manually identified 695 clinical samples within 19 different gene expression studies (median 43 samples per series). Gene expression results were merged across different platforms using rank normalization for the target gene of the respective probes. Standardized gene expression signatures for 36 normal tissues were identified in GEO (GSE2361). We performed a modified sparse Bayesian factor regression analysis that incorporated signatures of normal tissues. Additional regression allowed for discovery of latent factors characteristic of melanoma subtypes. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA) on characteristic genes for inferred melanoma-specific latent factors. Results: Normal tissue contributed significantly to the reported gene expression profiles, explaining a median of 11.5% of specimen variability (range 1.3-55.0%). In a subset analysis of 40 primary or in situ melanoma lesions versus 16 metastatic lesions (GSE7553), primary lesions were more likely contaminated with genes characteristic of normal skin (p<0.001). The top 5 latent factors explained a median of 17.0% of residual sample variance (range 0.6-64%). On IPA analysis, latent factor 1 was strongly associated with dermatologic disease (p = 7.46 e-36), latent factor 2 was associated with inflammatory response (p = 9.71e-25), and latent factor 3 was associated with upregulation of the MITF transcription factor regulation (p = 4.16e-19). Conclusions: Appropriate methods that filter out normal tissue contamination of melanoma specimens can improve our understanding of gene expression patterns in melanoma subtypes, and potentially improve future translational studies.
Survival for melanoma patients with pre-existing chronic lymphocytic leukemia.
Authors: Whitman Eric D. , Bustami Rami
Published: March 2020

e19057

Background: Recent successes in melanoma drug development have rekindled interest in immunotherapy for melanoma (MM). Patients (pts) with chronic lymphocytic leukemia (CLL), a malignant expansion of B-lymphocytes, have an impaired immune system and not uncommonly develop secondary MM. We hypothesized that MM pts with pre-existing CLL are more likely to die than MM pts without a second malignancy. Methods: Pts were identified in the updated Surveillance Epidemiology and End Results (SEER) (1973-2008) database with MM only (MEL) or with primary CLL and secondary MM (MELpCLL). Time between diagnosis and death or last follow up and other demographic SEER data were recorded. The Chi-Square Test was used to make unadjusted comparisons between group death rates. A Cox proportional hazards regression model, adjusted for patient characteristics, predicted the risk of death by group. Results: 8,294 SEER pts were included (8,115 in MEL, 179 in MELpCLL). With a median follow-up time of 7 years, 2,454 pts (30%) died. There was a significant difference in mortality rates between the groups: MEL 29% / MELpCLL 71%; p<0.001 by Chi-Square. In the multivariate Cox model (Table), MELpCLL pts were significantly more likely to die than MEL pts (HR = 1.22, 95% CI = 1.02-1.46, p = 0.034). Higher risk of death was also significantly associated with older age and male gender (p<0.001) but not MM location (data not shown). MM data like thickness and ulceration were only available in more recent SEER records, precluding survival analysis. Conclusions: MELpCLL pts had a 22% increased risk of death compared to MEL pts in multivariate analysis, consistent with the hypothesis. [Table: see text]