bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.